IE40532L - Tetrazolyyl penam derivatives - Google Patents

Abstract

1481600 Penicillin derivatives PFIZER Inc 8 Oct 1974 [17 Oct 1973 12 March 1974] 43620/74 Heading C2C [Also in Division C3] The invention comprises compounds of the formula and salts thereof, where R x is an amino or substituted amino group, which substituted amino group is R<SP>1</SP>-NH-, (R<SP>5</SP>)<SP>1</SP>-NH-, or Ry is a tetrazolyl group of the formula or a precursor for a tetrazolyl group of the formula and R<SP>2</SP> or R<SP>3</SP> is hydrogen trialkylsilyl having 1-4 carbon atoms in each of said alkyl groups, alkanoyloxymethyl having from three to eight carbon atoms, 1 - (alkanoyl oxy)ethyl having from four to nine carbon atoms, phthalidyl or a tetrazolylpenam nitrogen protecting group removable from specific compound of said formula; Hal is Cl or Br, R<SP>1</SP> is an acyl group of an organic carboxylic acid; (R<SP>5</SP>)<SP>1</SP> is an amino protecting group other than an acyl group, R<SP>8</SP> is phenyl, 1,4-cyclohexadienyl, 3-sydnonyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, tetrazolyl, triazolyl, imidazolyl, pyrazolyl, substituted phenyl, substituted thienyl, substituted furyl, substituted pyridyl, substituted thiazolyl, substituted isothiazolyl, substituted triazolyl, substituted imidazolyl or substituted pyrazolyl, each substituted moiety being substituted by up to two of fluoro, chloro, bromo, hydroxy, alkyl having from one to six carbon atoms, alkoxy having from one to six carbon atoms or alkylthio having from one to six carbon atoms; R<SP>9</SP> and R<SP>10</SP> are hydrogen, methyl or ethyl; R<SP>12</SP> and R<SP>13</SP> are each alkyl having from one to six carbon atoms, or taken together with the nitrogen atom to which they are attached form a pyrrolidino, morpholino, piperidino or azacyloheptan-l-yl group, and G<SP>1</SP> is a tetrazolyl penam nitrogen protecting group or a group readily convertible to a tetrazolyl penam protecting group and providing that when Ry is a precursor for a tetrazolyl group R x must be (R<SP>5</SP>)<SP>1</SP>-NH. The compounds may be prepared by (a) converting a -COOH group at 3-position of a precursor into a group Ry by known methods, (b) acylating an amino group at a 6- position of the penam structure with an acylating agent by known methods to form a grouping for R x of R<SP>1</SP>NH-. [GB1481600A]

Description

40532 ■» This Invention relates to penam derivatives and preparation thereof.

The Invention particularly relates to novel antibacterial penam agents which are of value as animal feed 5 supplements, as therapeutic agents for the control of Infectious diseases caused by graa-posltlve and gram-negative bacteria, and for the sterilization of hospital surfaces and the like; and to novel Intermediates for their production. More specifically, the antibacterial compounds of the 10 Instant Invention are derivatives of 6-amlno-2,2-dlmethyl-penam, which also bear a 5-tetrazolyl group or certain 1-or 2-substltuted 5-tetrazolyl groups at the 3-posltlon of the penam nucleus.

In spite of the large number of penam derivatives 15 which have been proposed for use as antibacterial agents, there still exists a need for new agents.

United States Patents 3,l'27,302 and 3,468,87^ disclose penam derivatives which incorporate a tetrazolyl group as part of the 6-acylamlno substltuent; however, the 20 compounds of the Instant Invention are unique In having a tetrazolyl group bonded directly to the penam nucleus.

The vast majority of penam compounds disclosed In the prior art have a carboxyllc acid group (or a salt thereof) attached to the 3-posltlon. However, penam compounds with 25 other carboxyllc acid derivatives at the C-3 locus are also -2- 40532 known. Pcnam-3-carboxylIc acid esters have been disclosed, for example, by Kirchner et aK , Journal of Organic Chemistry. 14. 388 (1949); Carpenter, Journal of the American Chemical Society. 70, 2964 (1948); 5 Johnson, Journal of the American Chemical Society, 75, k 3636 (1953); Barnden et al., Journal of the Chemical Society (London), 3733 (1953) and Jansen and Russell, Journal of the Chemical Society (London), 2127 (1965); and penam-3-carboxamides have been reported, for example, lO by Holysz and Stavely, Journal of the American Chemical Society, 72. 4760 (1950) and Huang et al., Antimicrobial Agents and Chemotherapy. 493 (1963). Peron et al., (Journal of Medicinal Chemistry. 7, 483 ^1964/) prepared several 6-(substituted amino)-2,2-dimethyl-penam-3-1^> carboxyllc acid azides, which were subsequently converted into the corresponding 3-isocyanates and 3-benzylcarb-amates. Peron et al., (loc. clt) also reported certain 3-(hydroxymethyl)-penam derivatives. Dehydration of the simple amide of benzylpenicillin yields the correspond-20 ing nitrile (Kho^khlcv et al., Doklady Akad. Sci. Nauk S.S.S.R., 135, 875 ^19607). Generally, opinion in the art has been that modification of the 3-position woul-J be unlikely to give improved result:;.

The invention provides a novel 6- amino or 6-25 substituted amino-2,2-dimethylpenam derivative having a 5-tetrazolyl or substituted tetrazolyl group in the 3-position of the penam structure. - 3 - 40532 10 15 Thus the invciiLlon provider: a dcriwtiv. of formula: or the salts thereof} wherein Rg is an amino or substituted amino group, which substituted amino group is R^-NH-, or >8 12 V or w-CH-N- or (R5)'-NH- pl^ /v Ry is a tetrazolyl group which is Y) - R or is a precursor for a tetrazolyl group which is -C - NH - G' -C - N - G* t Hal or 2 3 and R or R is hydrogen, triallcylsilyl having from one to four carbon atoms in each of said alkyl groups. alkanoyloxymethyl having from three to eight carbon ator>Si 1-(alkanoyloxy)ethyl having from four to nine carbon aton.3, phthalidyl or a tetrazolylpenam nitrogen protecting croup removable from specific compound of said formula; -4- 40532 Hal is CJ or Br R* is an acyl group of an organic carboxylic acid- (R5)' is an amino protecting group; R® is phenyl, 1,4-cyclohexadienyl, J-sydncnyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyi, tetrazolyl triay.olyl, imidazolyl, pyrazolyl, substituted phenyl, substituted thienyl, substituted furyl, substituted pyridyl, substituted thiazolyl, substituted isothiazolyi, substituted triazolyl, substituted imidazolyl or substituted pyrazolyl. each substituted moiety being substituted by up to two of fluoro, chloro, bromo, alkyl having from one to six carbon atoms, alkoxy having from one to six carbon atoms and alkylthio having from one to six carbon atoms; q 10 R and R are hydrogen, methyl or etnyl; 12 13 R and R are each alkyl having from one to six carbon atoms, or taken together with the nitrogen atom to which they are attached form a pyrrolidino, mor-pholinc, piperidino or azacycloheptan-l-yl group, and G' is a tetrazolyl penam nitrogen protecting group or a group readily convertible to a tetrazolyl penam protecting group and providing that when Ry is a precursor for a tetrazolyl group R^ must be (R^)'-NH-.

The invention will be particularly illustrated in relation to certain preferred compounds where R^ is an acylated amino group and these compounds are those of formulae 40532 nnd the salts thereof; wherein R* is .in acyl moiety of an organic carb-oxylir .icitl; 2 R is hydrogen, triallcylsilyl having from one to 5 four carbon atoms in each of said alkyl groups, alkanoyloxymethyl having from three to eight carbon atoms, 1-(alkanoyloxy)ethyl having from four to nine carbon atoms, phthalidyl or a tetrazolylpenam nitrogen protecting group, the nature of which is to be defined hereinafter; lo and R^ is hydrogen, trialkylsilyl having from one to four carbon atoms in each of the said alkyl groups and alkanoyloxymethyl having from three to eight carbon atoms, 1-(alkanoyloxy)ethyl having from four to nine carbon atoms or phthalidyl. 15 Other structures on the amino group arc available.

In choosing the appropriate substituted amino structure, structures which are found to be of use in other forms of penicillin would appc-ar to b° also active with the tetrazolyl substituent at the 3-position. Thus, although the 2() present invention is particularly illustrated by the acyl substituent, other substituents can be used as will be illustrated later.

As intermediates there are particularly valuabLe the structures in which R is amino or amino substituted n 25 with an amino protecting group as hereinafter defined and alternatively or in addition R2 or is trialkylsilyl having from 1 to 4 carbon atoms in each alkyl group or R2 is a tetrazolyl penam nitrogen protecting group.

Particularly desirable penam compounds of the 30 present invention, by virtue of their high activity against 40 S 32 a wide raru'.e of |>uthog<*nli: twicterlu, are tlione compi.uii'ln of I • yormiiJ.i.. I unci J I, wherein l<" :mtl M ui'c c;u.*h hyUroi»,uii mid R* Is a mono- or di-substituted acetyl group, such as, for example. 2-arylacetyl, 2-amlno-2-arylacetyl and 2-(substi-5 tuted amino)-2-arylacetyl.

Particularly Indicated as intermediates are those 10 and the salts thereof; wherein R-* is hydrogen, trialkylsilyl having from one to four carbon atoms in each of the said alkyl groups or an amino protecting group, the nature of which is to be defined later; 2 o 15 and R and R3 are as previously defined. p The compounds of Formulae III and IV, wherein R , R^ and R** are each hydrogen or trialkylsilyl having front cne to four carbon atoms in each of said alkyl groups are especially valuable 20 for the preparation of the novel penam compounds of Fornuil&c I and II. - 8 - 40532 The term "amino protectiny group* encompasses those groups which protect- the amino group on the 6-position of the penam ring system during synthesis of the basic structure, and particularly during the synthesis of the tetrazole r> ring; and it Is a necessary requirement of such groups that they can be removed easily before or after acylation of the nitrogen atom to which they are attached. Although acyl groups are sometimes considered to be amino protecting groups, such groups do not constitute amino protecting groups IO according to the present invention. In the specific embodiment of the invention the term is intended to contemplate all protecting groups known, or obvious, to one with ordinary skill in the art, which will (a) permit synthesis of the compounds of Formula III, wherein R~* is protected 2 amino and R is a tetrazolylpenam nitrogen protecting group; and (b) can be removed from a compound of formula III, 2 wherein R is hydrogen or a tetrazolylpenam nitrogen protecting group, using conditions wherein the penam ring system remains substantially intact. Thus, when R5 is an amino protecting 20 group, it can represent any group which will effectively protcct the 6-nmino moiety of 6-amino-penicillanic acid, during the process to be described in detail later in this specification for the conversion of 6-(protected amino) penicillanic acid into the said compounds of Formula III, and is removable under 2^ conditions which do not destroy the penam ring system. There are situat ions, however, wherein a group o.in Le re«j; r-'t.-o attaciiod to l.liu amino group at the C-6 position of the tetrazolylpenam ring system; (b) will then permit acylation of the C-6 amino group; jo .uui (».*) can then be removed from the nitrogen atom to which it is attacucu. Specific examples of amino protecting groups of each type are triphenylmethyl and trialkylsilyl, rcspec- - 9 - 40532 tlvely. However, all such groups of both types are to be considered wlth*»the scope of this invention. The exact chemical structure of the amino protecting group is not critical to the invention, since Its importance resides In 5 its ability to perform In the above-described aanner. Identification and selection.of individual groups which can be used will be readily accomplished by one skilled in the art, and the nature of the group chosen does not affect the novelty of the antibacterial agents of this invention in 10 any way. Additional examples of groups which can be used as amino protecting groups for the purposes of this invention are enumerated hereinafter.

In like manner, the term "tetrazolylpenam nitrogen protecting group" is Intended In the most general sense to 15 cover those groups which protect the tetrazole ring during or after formation thereof, and can encompass a group such as trialkylsilyl or trlphenylmethyl which can be attached to the tetrazole ring during for example acylatlon of the amino substituent at the 6-posltlon. In the specific and preferred 20 embodiment of the Invention, however, this term Is Intended to connote all groups known, or obvious, to one skilled In the art, which can be used (a) to permit the synthesis of 5 the compounds of Formula III, wherein R Is an amino protec-2 ting group and R is the said tetrazolylpenam nitrogen pro-25 tecting group, by the process starting with 6-(protected amlno)penlclllanic acid described hereinafter; and (b) can be removed from a compound of Formula I, wherein R* is an 2 acyl group and R is the said tetrazolylpenam nitrogen pre • tecting or from a ?ompour.fl of Formula III, v/herc-1n P.' 30 is hydrogen or an amino - 10 - 40839 protecting group, and R" la the said tetrazolylpenam nitrogen protecting group, u:-.Ing a method wherein the penam ring system remains substantially Intact. The tetrazolylpenam nitrogen protecting group is required in order to protect 5 the nitrogen atom which ultimately becomes N-l of the tetrazole ring In the said compounds of Formulae I and III, during the conversion of a 6-(protected amlno)penlclllanlc acid Into a compound of Formula III. It is likewise the ability of the tetrazolylpenam protecting group to perform 10 a specific function, to be discussed In more detail hereinafter, rather than Its precise chemical structure, which is Important; and the novelty of the antibacterial agents of the invention does not depend upon the structure of the protecting group. Selection and Identification of appropriate pro-15 tecting groups can be made readily and easily by one skll^-'d in the art, and examples of several applicable groups are given hereinafter.

The Invention also Includes the production of penam derivatives wherein a carboxyl group at the 3-position is 20 converted Into the tetrazolyl ring. Where the structure of the substituted amino group permits such conversion could directly prepare an active compound but in the most usual Instance, particularly for acyl structures, the conversion from the carboxyl ring to the tetrazolyl ring will be effect-25 ed prior to attaching an active group to the nitrogen on the 6-position. Thus, for Instance, a tetrazolyl group can be formed then a free amino group at the 6-position which can then be acylated. The particular choice of sequence is of course dependent on the groups involved but would offer no 30 problem to one skilled in the art from a knowledge of the - 11 - 40532 stability of the groups In question and the prooeotes to be applied.

Thus, there Is particularly provided a process for the production of a compound of Pormula I or II, which 5 comprises acylating a compound of Pormula III or IV, wherein 5 R Is hydrogen or trialkylsilyl having from one to four carbon atoms In each of said alkyl groups, and R2 and R^ are as previously defined. 10 A particular process is for the Intermediates of 5 9 Pormula III, wherein R is a protected amino group and R is a tetrazolylpenam nitrogen protecting group, which comprises the novel sequence of: (a) converting a 6-(protected amino)penlclllanlc acid Into an amide of formula: 15 (R5) '-NH^ ^Sv CH- WrJ -NH-0 N 0 ; (b) contacting the said amide with an lmldoyl hallde forming agent, in the presence of a tertiary amine; and (c) contacting the so-produced lmldoyl hallde with a source of aside ion; wherein (R^)1 is an amino protecting group and 0 20 Is a tetrazolylpenam nitrogen protecting group or a group which Is readily convertible to a tetrazolylpenam nitrogen protecting group during or after the instant process.

The novel Intermediates so produced are used to prepare the penam compounds of Formulae I and II by methods 25 to be discussed in detail hereinafter.

Alternative techniques for conversion of a carb= oocy group to a tetrazolyl group are visuallzable. - 12 . 40538 Prom another point of view In the preferred embodiments of the Invention the Invention may be regarded as lyin& in taking the tetrazolyl derivative with an amino or protected amino group on the 6-posltlon and converting to the acyl 5 group. Before or after acylatlon the tetrazolyl penam protective group can be removed and correspondingly the alkanoyl-oxyalkyl group substituent for R1 or R2 can be attached before or after acylatlon.

A further additional object of this Invention is 10 to provide a method for the treatment and prevention of infectious diseases caused by gram-positive and gram-negative bacteria; for the topical control of bacteria on human tissue, hospital surfaces and the like; and for the supplementation of animal feeds; which comprises utilizing an 15 effective amount of compound of Pormula I or II, or a salt 1 2 ^ thereof, wherein R is an acyl group and R and RJ are each hydrogen, alkanoyloxy methyl having from three to eight carbon atoms, l-(alkanoyl~ oxy)ethyl having from four to nine carbon atoms or phthalidyl. 20 For the 3ake of convenience the compounds of the invention are identified as derivatives of "penam", which has been defined by Sheehan et iQ., in the Journal of the American Chemical Society, 75, 3293 (1953). as rsferrlng to the structure: 1 S. 6. 3^ N2 25 7 , N 1 3 Although tin tons pen-uu -iot a normally carry any •■'-.oreo-chsmtcul Implications, '.hi siort 1t r.7 -»r tht* po:i.;in com pounds of the instant lor. ~• .-re.-;.oi;'.K- to that found i-i - 13 - 4#53* ,2 r2 and ^N-v. the naturally-occurring penicillins. Using this terminology, the well-known antibiotic penicillin 0 (benzylpenlclllln) Is designated as 6-(2-phenylacetamido)-2,2-dlmethylpenam-3-carb-oxylle acid. 5 Many of the compounds of this Invention are also 5-substltuted tetrazoles, and 5-substituted tetrazoles can •xlst In two Isomeric forms, viz: ... . -c/ V-" As will be appreciated by one skilled In the art, when the 10 substituent R Is hydrogen, the two forms co-exist In a dynamic, tautomeric, equilibrium mixture. However, In the J case where R Is a substituent other than hydrogen, the two forms represent different chemical entitles, which do not « spontaneously lnterconvert. 15 The preferred antibacterial agents of this inven tion are the compounds of Formulae I and II, and the salts thereof, wherein R* is an acyl moiety of an organic carb-oxylle acid, and R and RJ are each hydrogen* alkanoyloxynethyl having from three 20 to eight carbon atoms, l-(alkanoyloxy)ethyl having from four to nine carbon atoms or phthalidyl. The possession of antibacterial properties by the said compounds of Formulae I and II is not predicated upon the selection of the acyl substituent R*. Indeed, any acyl moiety of any carboxyllc acid 25 can serve as R*", and all the compounds of Formulae I ar.-3 II, wherein R2 and R^ are each hydrogen, aikanoyloxymetiiyl having from three to eJcht - 14 - 40832 carbon atoms, l-(alkanoyloxy)ethy1 having from four to nine carbon atoms or phthulldyl, which bear an acyl group at R*, have useful antibacterial properties. The carboxyllc acid from which the acyl group Is derived can be a mono- or poly-5 carboxyllc acid. Included within the scope of "acyl" are the aeyl moieties of carboxyllc acids which themselves cannot be isolated, but which nonetheless exist in the form of their esters, amides,aoid chlorides, etc.

However, a particularly favorable configuration of 10 the acyl moiety Is: R7- H C 0 It ■ C- ...V wherein n is 0 or 1; 7 R is hydrogen, alkyl having from one to twelve carbon atoms, alkenyl 15 having from two to twelve carbon atoms, cycloalkyl having from three to seven carbon atoms, cycloalkenyl having from five to eight carbon atoms, cycloheptatrlenyl, 1,4-cyclo-hexadlenyl, 1-amlno-cycloalkyl having from four to seven carbon atoms, cyanomethyl, 5-methyl-3-phenyl-'l-lsoxazolyl, 20 5-methyl-3-(o-chlorophenyl)-1i-lsoxazolyl, 5-methyl-3-(2,6- dlchlorophenyl)-1»-isoxazolyl, 5-methyl-3-(2-chloro-6-fluoro-phenyU-1-isoxazolyl, 2-alkoxy-l-naphthyl having from one to four carbon atoms in said alkoxy, phenyl, phenoxy, phenyl-thlo, pyridylthio, benzyl, sydnonyl, thienyl, furyl, pyridyl, 25 thiazolyl, isothiazolyi, pyrir.-dir.yl, tetrazolyl, trlazolyl, imidazolyl, pyrazolyl, substituted phenyl, substituted phenoxy, substituted ph»nylthi , substituted pyridylth-to, - 15 - 40533 I substituted benzyl, substituted thlenyl, substituted furyl, substituted pyridyl, substituted tetrazolyl, substituted thiazolyl, substituted Isothiazolyi, substituted pyrlmldlnyl, substituted trlazolyl, substituted imidazolyl or substituted 5 pyrazolyl, each substituted moiety being substituted by up to two members selected from the group consisting of fluoro, chloro, bromo, hydroxy, hydroxymethyl, amino* N,N-dialkyl-aalno having from one to four carbon atoms In each of said alkyl groups, alkyl having from one to four carbon atoms, 10 amlnomethyl, amlnoethyl, alkoxy having from one to four oarbon atoms, alkylthlo having from one to four carbon atoms, 2-amlnoethoxy and N-alkylamlno having from one to four carbon atoms; and Q Is 15 hydrogen, alkyl having from one to six carbon atoms, hydroxy, azldo, carboxy, sulfo, carbamoyl, phenoxycarbonyl, indanyl-oxycarbonyl, sulfoamlno, amlnomethyl, amino or HH-(C0-CH2-NH)b-C0-Z; wherein Z Is 20 alkyl having from one co six carbon atoms, phenyl, substituted phenyl, furyl, thlenyl, pyridyl, pyrrolyl, amino, N-alkylamlno having from one to six carbon atoms, anilino, substituted anilino, guanldino, acylamlno having from two to seven carbon atoms, benzamldo, substituted benzamldo, thlophene-25 carboxamido, furancarboxamido, pyridinecarboxamido, amlnomethyl, guanidlnomethyl, alkanecarboxamidinomethyl having from three to eight carbon atoms, benzamldlnomethyl, (substituted benzamidino)methyl, thiophenecarboxamidinoraethyl, f-yrancarbcxanidinomethyl, pyridinecarboxaraidinonethyl, 30 pyrrolecarbox^midinomethyl or 2-benzlaidazolecarbox&nidino- - 16 - Itlll methyl, each substituted moiety being substituted by up to two mombers oolected from thr group consisting of i'luoro, chloro, bromo, lodo, alkyl having from on* to four carbon atoms, alkoxy having from one to four carbon atoms, sulfamyl, 5 carbamoyl and cyano; ' • * \ and m It 0 or 1; provided that when R? is 1-aminocyoloalkyl, n Is 0; 7 and provided that when R la phenoxy, phenylthlo, pyrldylthlo, substituted 10 phenoxy, substituted phenylthlo and substituted pyrldylthlo and n Is 1, Q Is selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, carboxy, sulfo, carbamoyl, phenoxycarbonyl, substituted phenoxycarbonyl, lndanyloxycarbonyl or amlnomethyl. 15 Particularly useful antibacterial agents of the Instant Invention are the compounds of Formulae Z and TZ, 2 3 1 wherein R* and R are each hydrogen and R is of Pormula V, 7 wherein n is 1 and R is phenyl, phenoxy, substituted phony1 or substituted phenyl. 20 Especially valuable members of this series of compounds are the compounds of Formulae Z and ZZ, wherein R2 and R^ are each hydrogen and R* Is of Formula 7, wherein n is 1, R^ is phenyl, phenoxy, substituted phenyl or substituted phenoxy and Q Is 25 hydrogen.

Purther especially valuable members of this series 2 i are the compounds of Formulae Z and II, wherein R and RJ are each hydrogen and R* is of Formula V, wherein n is 1, 7 R Is phenyl or sub-30 stituted phenyl and Q is amino. - 17 - 40833 Still further especially valuable members of this series are the cumpuuiul:i <>f KutiuIuo I uiui fi, wherein l(' and are each hydrogen and R1 is of Pormula V, wherein n 7 is 1, R' Is phenyl 5 or substituted phenyl and Q is NH-(C0-CH2-NH)n-C0-Z. The preferred value for m is 0, and preferred values for Z are benzamldo* substituted benzamldo, thiophenecarboxamldo, furancarboxamldo, pyridinecarboxamldo, amlnomethyl* beni-amldlnomethyl, (substituted benzamldlno)methyl( thiophene-10 carboxamldlnomethy1, pyrldlnecarboxamldlnomethyl and 2-benzlmldazolecarboxamidlnomethyl.

In like manner, there is a second series of particularly useful antibacterial agents of this Invention, which Is the compounds of Pormulae I and II, wherein R2 and r3 are 15 each hydrogen and R* is of Formula V, wherein n is 1 and R^ is sydnonyl, thlenyl, furyl, pyridyl, thiazolyl, isothiazolyi, pyrimldlnyl, teira-zolyl, trlazolyl, imidazolyl and pyrazolyl, each of which can be substituted as indicated hereinbefore. Preferred 20 heteroaryl groups are thlenyl, furyl or isothiazolyi.

Within this second series of compounds of Pormulao I and II, especially valuable sub-series are those In which Q is hydrogen, those in which Q is amino and those in which Q is NH-(C0-CH2NH)m-C0-Z. The preferred value for ra is 0, 25 and preferred values for Z are those listed above.

Compounds of the Instant invention which are extremely valuable are: 6-(2-phenylacetami do)-2,2-4imethy1-3-(5-tetrazoly1)pernn, 6-(2-phcnoxyacetamido>-2,^-dimethy1-3-(5-tetrazolyl)-3p pen^m, - 18 - 40532 6~( D-2-amino-2-phenylacetamldo)-?,2-dimethy1-3-(5-tetra-zolyl)penam, 6-(D-2-amino-2-[£-hydroxyphenylJacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, 5 6- (D-2-amino-2- [ 3-chloro-l|-hydroxyphenyl ]acetamldo)-2,2- dimethy1-3-(5-tetrazolyl)penam, 6-(D-2-amlno-2-[2-thlenyl]acetamldo)-2,2-dlmethyl-3-(5- tetrazolyl)penam, 6-(D-2-amlno-2-[3-thlenyl]acetanido)-2,2-dimethyl-3-(5- 10 tetrazolyl)penam, 6-(D-2-[2-aminoacetamido]-2-phenylacetamido)-2,2-dimeth-y1-3-(5-tetrazolyl)penam, 5-(D-2-[2-aminoacetaraido]-2-['i-hydroxyphenyl]acetsunldo)-2,2-dimethy1-3-(5-tetrazolyl)penam, 15 6-(|>-2-[2-ainlnoacetamido]-2-[2-thienyl]acetamido)-2,2- dimethy1-3-(5-tetrazolyl)penam, 6-(D-2-[2-aainoacetamido]-2-[3-thienyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-[o-(amlnomethyl)phenyl]acetamido)-2,2-dimethy1-3-20 (5-tetrazolyl)penam, 6-(D-2-[2-(1-pyrldinecarboxamidlno)acetamido]-2-phenyl-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, and 6-(D-2-[2-(3-[Kuanyl]"reido)acetamido]-2-['»-hydroxy-phenyl3acetamido)-2,2-dlmethy1-3-(5-tetrazolyl) 25 penam.

As will be recoRnized by one skilled in the art, the acyl group R* can contain one or more asymmetric centers, and asymmetric centers can exist in one or two forms, the 30-called D- and L-forms. Both forms of each asymmetric 30 center, and all combinations of each of the forms, are to be - 19 - 40533 considered within the scope and purview of this Invention. 3CHBMB I t«2 .3 1 J CH^ <*3 J, °°^ MX m (R2)* XI, \"> i—r t-*®3 n - ^r-o y «. \ a1-*. .P ^ - « WJ3 ■MX (R2) tr ■®3 ° ~X> ""V/t J—1^-t\ I R* Is an acyl group.

(R2)1 Is a tetrazolylpenam nitrogen protecting grcap. (R^)* Is an amino protecting group. - 20 - 40532 SCHFME II (HP)'-nh ""td5 R1- in "CH3 O HN—W ^S-™3 ^-V > ^M—1 I ®3 'S-rS^ .A-"— R^-*W S al3 Sj " Ni4* R26 V-/ R Is an acyl groug.

(H?)* is an amino protecting group.

R2^ is alkanoyloxymethyl, l-(alkanoyloxy)ethyl or phthalidyl. - 21 - 40532 When contemplating methods to be used for the synthesis of the preferred antibacterial agents of this invention of Formulae I and II, wherein R1 Is an acyl group 2 3 and R and RJ are each hydrogen, they can be prepared start-5 ing from the well-known Intermediate 6-amlnopenlclllanle aoid (6-APA), and several of the ways In which this can be accomplished are outlined diagrammatlcally in Scheme I.

Ways In which the antibacterial agents of Formulae I and II wherein R* Is an acyl group and R2 and R^ are each 10 alkanoyloxymethyl# 1-(alkanoyl oxy)ethyl or phthalidyl, are prepared, are outlined In Scheme II. However, In Scheme II, for the sake of simplicity, the substituent R2® has been shown only at N-l of the tetrazole ring. However, as explained hereinafter* alkylation of 15 a 5-monosubstltuted tetrazole results in mixture of mono-alky lated products, In which the newly-Introduced group Is located at either N-l or N-2 of the tetrazole ring.

From a consideration of Scheme I, the manner In which the compounds of Foraulae I and III, wherein R2 Is a 20 tetrazolylpenam nitrogen protecting group, are useful as Intermediates for antibacterial agents of the invention will be apparent. When considering the nature of the said tetrazolylpenam nitrogen protecting group, the group must fulfill two functions. First, it must permit the synthesis of com-25 pounds of Formula III, wherein is an amino protecting 2 group and R 13 the said tetrazolylpenam nitrogen protecting group. Second it must be removable from a compound of 1 2 Formula I, wherein R Is an acyl croup and R is the tetrazolylpenam nitrogen protecting .^roup; or from a compound of 30 Formula III, wherein Is hydrogen and R2 is the tetrazoDyl- - 22 - 40538 ponam nitrogen protecting Rroup; or from a compound of Formula '» ** III* wliPivlli l< la an nnilno |«i*»»1-0011fiK tV'Mlp and H' In Mio tetrazolylpenam protecting group, In each case without decomposing the penam ring system. As will be apparent from 5 the discussion which follows, not all the tetrazolylpenam nitrogen protecting groups useful In this Invention need be removable from each of the said compounds of Formulae I and III. In order to be useful in this invention, the tetrazolylpenam nitrogen protecting'group needs to be removable 10 from at least one of the following three types of compound*: (a) compounds of Formula I, wherein R1 is acyl and R2 is the said tetrazolylpenam nitrogen protecting group; (b) compounds c 2 of Formula III, wherein is hydrogen and R is the tetrazolylpenam nitrogen protecting group; and (c) compounds of 15 Formula III, wherein R^ is an amino protecting group and R2 is the tetrazolylpenam nitrogen protecting group. The conditions which it will be necessary to use for removal of a given tetrazolylpenam nitrogen protecting group will be known or obvious to one skilled In the art. Moreover, the reaction 20 conditions which can be used without causing decomposition of the penam ring system are also well-known, and obvious, by reference to the prior art on penam compounds.

A specific group of tetrazolyl protective groups are -CH2CH2Y, -C^O-O-R1*, SO^R1* or (R6)*; 25 wherein Y is cyano, alkoxycarbonyl having from two to seven carbon atoms, phenoxycarbonyl, alkylsulfonyl having from one to six carbon atoms, phenylsulfonyl or -SOj-NR^R*®, where R*5 16 and R arc each hydrogen, alkyl 30 -having from on- to four 0Tb'>n ?tomr., Irr/.yl or phenyl; - 23 - r 40832 R1*1 is alkyl having from ono to six carbon atoms, benzyl, phenyl or phenyl substituted by up to two of nitro, fluoro, chloro, bromo, alkyl having from one to four carbon atoms and alkoxy having from one to four carbon atoms; and (R^)' is selected from the group consisting of -CH 10 15 20 25- wherein R* and R1? are each hydrogen, hydroxy, nitro, fluoro, chloro, brnmo, iodo alkyl having from one to six* carbon atoms, alkoxy having fro: one to six carbon atoms, alkanoyloxy having from two to sever carbon atoms, formyloxy, alkoxymethoxy having from two to seven carbon atoms, phenyl or benzyloxy; R18 is hydrogen, alkyl having from one to four carbon atoms or phenyl; R19 and R20 are hydrogen or methyl; and X is oxygen or sulfur.

An example of a typical tetrazolylpenam nitrogen protecting group is - ~wi»2 .y •Y' wherein Y is an electron-withdrawing group, and Y' Js either - 24 - 40833 hydrogen or a further elestron-wlthdrawing group, which can be the same as or different from Y. The function of the electron-withdrawing group Is to render a hydrogen atom, on the carbon atoms to which Y and Y' are attached, suffi-5 olently acidic that the group is removable in a retrograde Michael reaction. Such a reaction Is well-known In the art. Por example consult House, "Modern Synthetic Reactions", W.A. Benjamin, Inc., New York/Amsterdam, 1965* page 207. Typical electronwlthdrawing groups are cyano, alkoxycarbonyl 10 having from two to seven carbon atoms, phenoxycarbonyl, alkylsulfonyl having from one to six carbon atoms, phenyl-sulfonyl and SOg-NR^R*®, wherein R*® and R*® are each hydrogen, alkyl having from one to four carbon atoms, phenyl or benzyl. A particularly 15 convenient configuration for this protecting group is that wherein Y* is hydrogen; and preferred values for Y are alkoxycarbonyl having from two to seven carbon atoms and phenylsulfonyl.

A further tetrazolylpenam nitrogen protecting 20 group which can be used is a grouping of formula -C(«0)-0-P.^i'. Such a grouping can be removed by mild hydrolysis, such as mild alkaline hydrolysis, or by treatment with a nucleophlle, such as an amine, or a thiol or thiolate anion. Although ft wide variety of groups can serve as R^, particularly con-25 venient values are alkyl having from one to six carbon atoms, benzyl, phenyl and substituted phenyl, for example, phenyl substituted by up to two of nitro, fluoro, chloro, bromo, alkyl having from 0(ne. to four carbon atoms and alkoxy having from one to four 30 carbon ato^.3. 40532 A still further tetrazolylpenam nitrogen protecting group which can be use] h a grouping of formula 14 -S02-R . Such a group Is also removed by hydrolysis, or by treatment with a nueleophlllc agent, as indicated for 5 the group-c(-0)-0-R11', and convenient values for are also alkyl having from one to six carbon atoms, benzyl, phenyl and substituted phenyl, for example, phenyl substituted by up to two . of nitro, fluoro, chloro, bromo, alkyl having 10 from one to four oarbon atoms and alkoxy having from one to four carbon atoms.

A yet further tetrazolylpenam nitrogen protecting group which can be used Is ^.V -CH \w. 15 wherein W Is phenyl, substituted phenyl, furyli substituted furyl, thlenyl or substituted thlenyl and W' is hydrogen, alkyl, phenyl, substituted phenyl, furyl, substituted furyl, thlenyl or substituted thlenyl. When W is phenyl or substituted phenyl, and W' is hydrogen, alkyl, phenyl or sub-20 stltuted phenyl, this group can be removed by hydrogenol^sis. Thi3 group can also be removed by solvolysls in trifluoro-acetlc acid, when the combined effect of W and. W' Is sufficient to offer the requisite degree of stability to the incipient carbonium ion + W CH 25 \W» Particularly convenient configurations for this protecting strouD are - 26 - % 40892 wherein r" and are each b hydrogen, livdroxy, nitro, fluoro, chloro, bromo, iodo alkyl having from one to 3lx carbon atoms, alkoxy having from one to six carbon atoms, alkanoyloxy having from two to seven carbon atoms, formyloxy, alkoxymethoxy having from two to seven carbon atoms, phenyl or benzyloxy; 10 R*® is hydrogen, alkyl having from one to four carbon atoms or phenyl; R*9 and R2® are each hydrogen or methyl; and X is *5 oxyaon or sulfur.

As will be recognised by one skilled In the art, other groups which will al:;o stabilize the carboniun ior. (W-CH-W,)+ can replace those cited above for W and V.

Still another tetrazolylpenam nitrogen protecting 20 group which can be used is phenacyl or substituted phenacyl. Such a group is removed by reaction with a nucleophilic reagent, such a: ihiophenoxide. Typical phenacyl groups which can be used are those of formula: --KT' 40532 * wherein R21 la hydrogen, nitro, fluoro, chloro, bromo or phenyl.

Several Individual methods for the preparation of the antibacterial agents of this Invention are now to be 5 discussed and described in detail. For convenience, they t will be designated as Methods A, B, C, D, E and P.

Methods A, B and P relate to removal of penam tetrazolyl protective groups, method C Is acylatlon to form R*, method D relates to alkylatlon of the tetrazolyl ring, 10 method B Is related to method C In providing modification of the acylatlon reaction product to form other acyl derivatives. It will be appreciated that to form a particular product two or more of these methods can b6 employed. Por Instance method A may be used to remove a protective group from an 15 Intermediate followed by an acylatlon under method C with or without modification by method E and then acylatlon by method D. Clearly choice of a particular method or sequence of steps is not determined by other than the known characteristics of the compound? and chemical processes involved. 20 Method A is useful for the synthesis of compounds 1 J of Formulae I and II, wherein R is an acyl group, and Rc and R^ are each hydrogen. The method comprises c^taly&c hydrogejnolysi3 of a compound of Formula I, wherein R1 is an racyljproup and R2 is , ?5' ; ; ' t h 17 wherein P R ' are each hydrogen, hydroxy, nitro, fluoro, chloro, bromo, iodo - 28 - 4053a alkyl having from one to six carbon atoms, alkoxy having from one to six carbon atomu, alkanoyloxy having front two to five carbon atoms, formyloxy, alkoxymethoxy having from two to seven carbon atoms, phenyl or benzyloxy. _ I The starting ruterial can be prepared by acylatlon of an appropriate corresponding compound of Pormula III or salt thereof wherein R^ is selected from hydrogen and trialkylsilyl of 1 to 4 carbon atoms in the alkyl groups with R substituted as indicated above. Acylatlon can be as described subsequently under method C.

The reaction can be carried out by a variety of procedures well known in the art for this type of transformation, such as, for example, those discussed by Augustine in "Catalytic Hydrogenation", Marcel Dekker, Inc., New York 1965, pp. 139-142. As will be appreciated by one sklllca in the art, however, conditions must be chosen-which are compatible with the ^-lactam moiety of the moiety of the penam nucleus. A particularly convenient procedure comprises shaking or stirring a solution of the reactant in a reaction-inert solvent, such as methanol, ethanol, ethyl acetate or water, or mixtures of these solvents, In the presence of a catalyst, such as 102 palladium-on-carbon, under an atmosphere of hydrogen. The catalyst is normally present In an amount from about 102 to about 100 t by weight based on the penam starting material, and the hydrogen pressure can wiry from about one to about one hundred atmospheres. At or around ambient temperature the reaction take3 a few hours to reach completion.

Method B is useful for preparing compounds oi' Formulae 1 ar.d II", wherein R1 is -?.n acyl sroup, and R2 and - 29 - 40532 ll3 are each hydrogen. The method comprise* treating * eam-pound of Pormula I, wherein R* ia an acyl group, and R* 1* wherein at least one of R* and R17. is a hydroxy group at th* 5 2- or the 4-position, with base. The starting mateiral can be prepared by hydrogenolysis of the corresponding compound wherein any hydroxy group at R* or is protected a* it* benzyl ether. Th* procedures discussed under method A are conveniently used. Indeed one can go directly from method 10 A to method B without separation or where a hydrogenolysi* i* *ff*ct*d in th* presence of a basio agent method B may occur concomitantly with hydrogenolysis. Under certain hydrogenolysis conditions formation of the penam compound * where R is a hydroxy benzyl group is immediately followed 15 by hydrogenolitia removal of the hydroxy benzyl group to produce the compound of Pormula I or IX wherein R2 and R3 are each hydrogen. The reaction of Method B is carried out by dissolving starting material in an appropriate solvent, and then adding about one molar equivalent of a base, at 20 around ambient temperature or slightly below. The reaction is usually complete within a few minutes. Appropriate solvents for this process are those which will serve to dissolve the starting material but are otherwise inert. Examples of solvents which find utility are esters, such as ethyl acetate 25 and butyl acetate; lower-aliphatic ketones, such as acetone and mathyl ethyl ketone; chlorinated hydrocarbons, such a* chloroform, methylene chloride and 1,2-dichloroethane; and - 30 - lower-alkanol;i, such aa methanol and ethanol; and tetrahydro-furan. A wide variety of basic ayents are operative in this process, since it appears that the primary purpose of the basic agent is to remove the hydrogen from the phenolic 5 hydroxyl group of the hydroxybenzyl protecting group. Basic agents which can be used include alkali metal salts of alkanoic acids, such as sodium acetate and sodium 2-ethyl-hexanoate; organic amines, such as tributylamina, triethyl-amine, N,N-dimethylaniline, N-ethylpiperidine, pyridine and 10 N-rae thy lino rpholine; alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; and alkali and alkaline earth metal hydrides, such as sodium hydride, potassium hydride and calcium hydride. Although it 15 is usual to employ about one molar equivalent of base in this process, an excess of base can be used under certain circumstances. In fact in those cases where there is another acidic function in the starting material, it becomes necessary to add two molar equivalents of the basic agent. It will La 20 appreciated by one skilled in the art, however, that conditions for this reaction must be chosen with due regard for the sensitivity of the ^-lactam moiety of the penam nucleus, and the presence in the reaction medium of an excess of a basic agent which will adversely react with the said p~ 25 lactam is to be avoided. A particularly convenient method of carrying out this process is to expose the starting material to an aqueous solvent system, at a pH in the range from about 7.5 to about 9.5 Method C is useful for the preparation of compounds 3D of Formulae I and II, wherein R^- is an acyl group and and - 31 - 40632 R3 aro each hydrogen, alkanoyloxymnthyl h->vin An activated derivative commonly used is an acid hallde, such as an acid chloride. Xn a typical acylatlon procedure, approximately one molar equivalent of an acid chloride is added to c. solution of the said compound of 20 Formula XXX or IV, or a salt thereof, dissolved in a solvent such as a chlorinated hydrocarbon, for example, chloroform or methylene chloride; an ether, for example, tetrahydro-furane or 1,2-dimethoxyethane; an ester, for example, ethyl acetate or butyl acetate; a lower aliphatic ketone, for ex-25 ample, acetone or methyl ethyl ketone; or a tertiary amide, for example, H,N-dimethylformanide or N-methylpyrrolidone; at a temperature in the rang* from about -40°C. to about 30°C., and preferably from about -10°C. to about 10°C., optionally in tho prcsonco o' about one inolar Rquivalorifc of 30 an acid-binder, fi.y.# trict.Viy limine, pyridine or sodium bi- - 32 - 40132 carbonate. The reaction is complete within a short period, i.e., approximately one hour. When R2 and R* are hydrojon, «. it is convenient to employ a tertiary amine salt# for example, the triethylamine salt, of the compound of Formula III ro IV.

S An alternative proceduro useful for the acylatlon of a compound of Formula III or IV# wherein R2# R^ and R® are each hydrogen, with acid halides involves the use of an aqueous solvent system. In this procedure, which approximates the Schotten-Baumann procedure# the acid halide is added to a solution of 10 the starting material in water, or a mixture of water and another inert solvent, at, or slightly below, ambient temperature, with the pH of the solvent being maintained within the range from about 6.0 to about 9.0 before, during, and after the addition. 15 Another activated derivative of the carboxylic acid which finds use in Method C is a mixed anhydride. Tn this case, a carboxylate salt of the appropriate carboxylic acid is treated with about one molar equivalent of a lower-alkyl chloroformate in a reaction-inert, aprotic organic 20 solvent, at a temperature in the range from about -20°C. to about 20°C. and preferably at about 0°C. Appropriate salts for this process are alkali metal salts, such as sodium and potassium salts, and tertiary amine salts, such as triethylamine# ktributylamine, N-ethylpiperidine, N,N-dimethylaniline, 25 N-methylmorpholine and pyridine salts; and appropriate solvents are, for example chloroform, methylene chloride, acoto-nitrile, tetrahydrofuran, dioxane and N,N-dimethylforman>idc. The mixed carboxylic-carbonia anhydride thus formed is usually used in situ to acylnre the sail?. compound of Forn.'l?? 30 III or IV. This is normally carried out by mixing saJ.utirns - 33 - 40532 of the preformed mixed anhydride and the compound of Formulae III or IV. When R and R are hydrogen, it is particularly convenient to employ a tertiary amine salt, for example the triethylamine salt* of the compound of Formula III or IV. 5 Tho acylatlon is normally conductcd at a temperature in the range from about -30°C. to about 20°C., and preferably at about -10°C., and it usually takes a few hours to reach completion . In most instances the mixed anhydride and the compound of Formulae III or IV are contacted substantially in a 10 1:1 molar ratio.

Another variation of Method C, comprises conversion of the carboxylic acid to an active ester, followed by treat-metn with a compound pf Formula ill or IV or a salt thereof. Active esters which can be used in this regard are, for ex-15 ample, phenyl esters, such as g-nitrophenyl and 2,4,5-tri*-chlorophenyl esters, thio esters, such as thiol phenyl and thiol methyl esters; and N-hydroxy esters, such as N-hydroxy-succinimide and N-hydroxyphthalimide esters. The esters are prepared by methods well established in tho art, and the 20 acylatlon is conveniently conducted by dissolving the active ester and the said compound of Formula III or IV, or a salt thereof, in a dipolar aprotic solvent such as N,N-dimethyl-formamide, N,N-dimethylacetamide or N-methylpyrrolidone. The solution is stored at auout ambient temperature for several 25 hours, for example overnight, and then the product is isolated by standard methods. In many cases the active ester used in this process can be replaced by the corresponding acid azide.

A still further variation of Method C which is use-30 ful for the acylation of compounds of Formulae III and IV - 34 - comprises contacting the said compound of Formulae III or IV with a carboxylic acid in the presence of certain agents in the art for forming peptide bonds. Such agents include carbo diimides, for example, dicyclohexylcarbodiimide and l-ethyl-3 S (3-dimethylaminopropyl)carbodilmide, alkoxyacetylenes, for example methoxyacetylene and ethoxyacetylene, and N-ethoxy-carbonyl-2-ethoxy-l,2-dihydroquinoline. The reaction is carried out in on appropriate solvent, i.e., one which will serve to dissolve the reactants, and does not adversely 10 interact with the starting materials or the product, for examplo acetonitrile, N,N-dimethylformamide and N-methyl-pyrrolidonc.

Implicit in the above description of Method C, is the observation that in a process for the acylation of a 15 compound of Formula III or IV, hydrogen substituents located 2 3 5 at R , R or R can successfully be replaced by trialkylsilyl substituents. Said trialkylsilyl substituents are then removed, and replaced by hydrogen, at the end of the acylation, simply by brief exposure of the product to a protic 20 solvent system, such as water or a loweralkanol, for example, methanol or ethanol. By virtue of the ready availability of the starting materials, the trimethylsilyl group is a preferred member. It can be introduced into the starting penara of Formula III or IV by methods well known in the art, such 25 as, for example, using trimethylchlorosilane or N-trimethyl-silylacetamide, as discussed by Birkofer and Ritter in Angewandte Chemie (International Edition in English), 417-418 and 426 (1965). Conditions must be chosen, however, ./hich are compatible with the -lactam group of the penam 30 nucleus. Also, operative in Method C are the silylated - 35 - 40332 derivatives formed by interaction of the said compounds of Formulae III and IV with dichlorodi(lower-alkyl)silanes. The silylation step is carried out by methods known in the art (for example, German Patent No. 1,933,187). After the acyla-5 tion reaction, the silyl group is removed by treatment with a protic solvent, such as water or a lower-alkanol, for example, methanol or ethanol.

Additionally, if desired, the tetrazole ring of a compound of Formula III or IV, wherein R2, R"* and R® are 10 each hydrogen, can be protected by various other groups, prior to acylation by Method C. The protecting group is then removed, after acylation, to liberate the desired antibacterial agent of Formula I or II, wherein R* is acyl and 2 3 R and R are each hydrogen. A wide variety of protecting 15 groups can be used for this purpose, such as, for example, triphenylmethyl, substituted triphenylmethyl, alkoxymethyl, benzyloxymethyl, substituted benzyloxymethyl and cyanomethyl. A particularly convenient group, however, is the triphenylmethyl group. 20 It will be appreciated by one skilled in the art that not all the variations discussed under Method C are equally effective or convenient in all cases, for the acylation of a compound of Formula III or IV. The relative effectiveness of a particular variation will differ according 25 to a number of factors, such as, for example, the precise structure of the said compound of Formula III or IV, the availability of starting materials, the scale of the reaction and, in particular, the structure and reactivity of the acyl group being introduced. In practice, one skilled in the 30 art will select the most appropriate variation in each case, - 36 - 40532 having full regard for the relevant factors. Moreover, in some instancos ccrtain further precautions and modifications become neccnsary or desirable, especially in the cases wherein I R* has the Formula V and n is 1. For example, in the case 5 wherein R* is of Formula V, wherein.n is 1 and*0 is phonoxy-carbonyl, substituted phenoxycarbonyl or indanyloxycarbony1, t use can be made of tho acylation technique taught in United States Patent No. 3,679,801. Further, in the preparation of the compounds of Formulae X and XX, wherein R* is of Formula 10 V, wherein n is 1, Q is carboxy and R7 is phenyl, substituted phenyl, heterocycZyl or substituted heterocyclyl, the mono-acid chloride of the 2-substituted malonic acid precursor is an effective and useful acylating agent in Method C. Preparation and use of IS the said mono-acid chlorides is taught in Belgian Patent No. 1 788,928. In the case wherein R is of the Formula V, wherein n is 1 and Q is or contains a basic, primary or secondary, amino group, it is necessary to protect the amino group in the starting carboxylic acid, prior to•activation of the 20 carboxy group of the said acid. After the amino group has been protected, the carboxy group is activated, the acylation is carried out by one of the methods described under Method C, and then the antibacterial penam compound of Formula I or II is obtained by removal of the protecting 25 group. A wide variety of protecting groups known in the art for protecting amino groups during peptide synthesis can be used for this purpose. Groups which have been found to be particularly sui table are the ber.zyloxycarbonyl group vino of which is taught by Doyle, et al. , in the Journal of ths - 37 - 40332 formed by interaction of the starting amino-acid with a dicarbonyl compound, as taught by Dane and Dockner in the Angewandte Chemie (International Edition in English) 3, 439 (1964), and in Chemische Berichte der Doutschen Chemlschen 5 Cesellschaft, 98. 789 (1965). Por the use of other protecting groups, consult Greenstein and Winitz, "Chemistry of the Amino Acids", John Wiley & Sons, Inc., New York/London, 1961, pp. 882-922. In certain instances where n is 1 and Q is or contains a basic amino group, a particularly valuable acyl-10 ation procedure comprises use of the acid chloride hydrochloride of the precursor acid. The acid chloride hydrochlorides are prepared, and the acylation is conducted, by the methods described for the preparation of 2-amino-2-phenylacetyl chloride hydrochloride and the subsequent acyl-15 ation of 6-aminopenicillanic acid, respectively, (United States Patent No. 3,140,282).

Method D is useful for the preparation of compounds of Pormulae I and II, wherein R* is an acyl group and R^ and R^ are each alkanoyloxymethyl, 1-(alkanoyloxy)ethyl or 20 phthalidyl. This Method comprises alkylation of the corresponding compound of Formula I or II, wherein R* is an acyl 2 3 group and R and R are each hydrogen, with an alkanoyloxymethyl, 1-(alkanoyloxy)ethyl or phthalidyl halide. In this context, the term "halide" is intended to contemplate iodide, 25 bromide, and chloride. The reaction is conveniently carried out by dissolving a tetrazolate salt of the said compound of Formula I or II, wherein R^ and R^ are each hydrogen, in a suitable, polar, organic solvent, such as N,N-dimethylform-amide, and then adding about one molar equivalent of the 30 alkanoyloxymethyl halide. Salts of the starting material - 38 - which are commonly used are alkali metal salts, such as sodium and potassium salts, and tertiary amine salts, such as triethylamina, N-ethylpiperidine, N,N-dimethylaniline and N-methylmorpholine salts. The reaction is usually run 5 at about ambient temperature, and the length of time needed to reach completion varies according to a variety of factors, such as the concentration of the reactants and the reactivity of the reagents. Thus, when considering the halo compound, the iodide reacts faster than the bromide, which in turn re- 10 acts faster than the chloride. In fact, it is customary, when utilizing a chloro compound, to add up to one molar equivalent of an alkali metal iodide. This has the effect of speeding up the reaction, and it is postulated that this technique brings about a halogen exchange, thereby generating 15 in situ some of the more reactive iodo compound. With full regard for the foregoing factors, reaction times of several hours, e.g., overnight, are quite commonly used.

As discussed earlier, for any given substituent R*, the com- 5 3 pounds of Formulae I and II, wherein R and R are each 20 hydrogen, co-exist in an equilibrium mixture, and it is found that the crude product obtained from alkylation of this mixture also comprises a mixture. The mixture consists of mono-alkylated products, in which the newly-introduced alkanoyloxymethyl group is located at either the N-l or N-2 25 position of the tetrazole moiety. The ratio of products varies according to a variety of factors, such as the structure of the penam, the structure of the alkylating agent, and the conditions under which the reaction is run. In some instances one isomer may be produced almost exclusively. 30 Mthough this mixture of products can be separated by con- 39 - 40938 ventional means, for example by chromatography, both isomers have antUMcturi.il properties, and tho mixture of isoators can bo used for tho further synthetic transformations to be described hereinafter, if desired. 5 The alkanoyloxyalkyl halides are either known com pounds, or they are prepared by known procedures (Ulich and Adams, Journal of the American Chemical Society, 43, 662 ^T92l7; Daehne et al., Journal of Medicinal Chemistry, 13, 607 ^19707). 10 Method E is valuable for the preparation of compounds of Formulae I and II, wherein R and R are each hydrogen, alkanoyloxymethyl, 1-(alkanoyloxy)ethyl or phthalidyl, and R* is of Formula V, wherein R7 is as previously defined, n is 1 and Q is 15 carboxy, sulfoamino, carbamoyl, amino or NH-(CO-CH2-NH)m-CO-Z. This Method comprises carry-ing out further transformations on certain of the compounds of Formulae I and II which are prepared by Method C.

Thus, the compounds of Formulae I and II, wherein 20 n is 1 and Q is carboxy, can be obtained from the corresponding compound of Formula I cr II, wherein Q is phenoxycarbonyl, substituted phenoxycarbonyl or indanyloxycarbonyl, by mild hydrolysis of the phenoxycarbonyl, substituted phenoxycarbonyl or indanyloxycarbonyl group to liberate a carboxy group. The 25 reaction is carricd out by exposing the starting material to a mildly-alkaline aqueous solvent system until hydrolysis is substantially complete, for example, according to the procedure- aC ^ j a. \ ■ - ^ TCi n a •. ui uiu twu .jgir.cs .• :\u, / 7f Thq compounds wht-rnin n is 1 and 0 is suitcoir.vr.o, 30 can lx.- ol>!:Jinod from Lh< cji ri -.spond inq cc The compounds wherein n is 1 and Q is carbamoyl, 5 can be obtained from the corresponding compound wherein Q is phenoxycarbonyl or preferably, phenoxycarbonyl substituted by one or more'electron-withdrawing groups, by treatment with ammonia. Particularly convenient substituted phenoxycarbonyl groups are nitro- and'dinitro-substituted phenoxy-10 carbonyl groups, and the reaction is carried out using woll-known methods (Consult Johnson, Journal of the American Chemical Society, 75, 3636, £19537).

The compounds wherein n is 1 and Q is NH-(CO-CH^-NH)m-C0-Z, wherein m is 0 and 2 is 15 alkyl having from one to six carbon atoms, phenyl, substituted phenyl, furyl, thienyl, pyridyl or pyrrolyl, are prepared from the corresponding compound of Formula I or II, wherein q is amino by reaction with an activated derivative of the appropriate carboxylic acid. 20 The techniques for activation of a carboxylic acid, and for acylation, discussed above under Method C can be used in the instant process. In many instances, use of the acid chloride of the carboxylic acid is a particularly convenient technique. 25 The compounds wherein n is 1 and Q is NH-tCO-CHj- NH)m-C0-Z, wherein m is 0 and 2 is arainomethyl, are prepared from the corresponding compound of Formula I or II, wherein Q is amino, via coupling with glycixie. The coupling vrocadure comprises taevstfps of: (1) protecting the amino function of 30 ^Kq nlycine; (2) activatiri^* tho carboxyl group of the M-oro- - 41 - 40532 tected glycine; (3) reacting the so-produced intermediate with the said compound of Formula I or H, or a salt thereof; and (4) removing the N-protecting group. Convenient techniques for achieving these steps are taught in Belgian Patent 5 No. 681,660.

The compounds wherein n is 1 and Q is NH-(CO-CHj-NlI)a-CO-Z# wherein m is 0 and Z is anilino or substituted anilino, are prepared from the corresponding compound of Formula I or II, wherein Q is amino, by reaction with phenyl 10 isocyanate or a substituted phenyl isocyanate. The reaction is carried out by contacting substantially equimolar proportions of the isocyanate and the penam compound, or a salt thereof (e.g., the triethylamine salt), in a reaction-inert organic solvent (e.g., N,N-dimethylformamide) at about 15 ambient temperature. The reaction requires a few hours (e.g., about three hours), and the product can be isolated simply by evaporation of the solvent.

The compounds wherein n is 1 and Q is NH-tCO-CHj-NH)n-C0-Z, whereir. m is 0 and Z is guanidino, are prepared 20 from the corresponding compound of Formula I or II, wherein Q is amino, via reaction with a guanylcarbamoylating agent. The guanylcarbamoylating agents obtained by treatment of 4-guanylsemicarbazide either with a source of nitrous acid, or with certain oxidizing agents, are particularly valuable 25 in this process. Preparation and use of these carbamoylating agents are described in United States Patents Nos. 3,579,501 and 3,579,514. The term "amidino" is an accepted synonym for guanyl.

The compounds wherein n is 1 and Q is NH-tCO-CHj-30 NH)m-CO-Z, wherein m is 0 and Z is guanidinomethyl, are pre- - 42 - 40533 pared from tho "correspond inq compound of Formula 1 or II, wherein Q is amino via reaction with the acid chloridc hydrochloride of guanidinoacetic acid. Tho reaction is normally carricd out by treating a solution of the start-5 inq penam compound, or a salt thereof* in a po-lar, organic solvent such as N,N-dime thy1£orraamida or N,N-dimethylacot-amide, at about 0°C., with guanidinoacetyl chloride hydrochloride. The reaction commonly takes around two hours to reach completion. A salt of the starting material is used 2 ^ 10 in those cases wherein R or RJ is hydrogen, and appropriate salts are, for example, alkali metal salts and tertiary amine salts. In order to achieve a good yield of product, it is usually necessary to utilize at least one molar equivalent, and preferably up to about four molar equivalents, of the 15 acylating agent.

The compounds wherein, n is 1 and Q is NH-(CO-C!^-NH)ra-CO-Z, and wherein m is O and z is acylamino, benzamldo, substituted benzamido, thiophenecarboxamido, furancarboxamido or pyridinecarbox-20 amido, are prepared from the corresponding compound of Formula I or II, wherein Q is amino, by reaction with the appropriate acylisocyanate. The acylisocyanates are prepared and the reaction is carried out, according to the procedures described in United States Patent No. 3,479,339. 25 The compounds wherein n is 1 and Q is NH-(CO-CK^- NH)ra-CO-Z, wherein m is 1 and Z is alkyl having from one to six carbon atoms, phenyl, substituted phenyl, furyl, thienvl, pyridyl, nyrrolvl, aminomothy.l, anilino, substituted anilino, guanidino, guan-30 idinomethyl, acylamino, benzamido, substituted benzawido, - 43 - 40892 thiophenecarboxamido, furancarboxamido or' pyridinecarbox-amido. are prepared in a manner analogous to that described for tho corresponding compounds wherein m is 0, except that the corresponding compound of Formula I or IX, wherein Q is 5 NH-CO-CHj-NH^ replaces tho compound wherein Q is amino.

The compounds wherein n is 1 and Q is NH-(CO-CHj-NH)n-CO-Z, wherein m is 0 and Z is alkanecarboxamidinomethyl having from three to eight carbon atoms, benzamidinomethyl, (substituted benz-10 amidinomethyl), thiophenecarboxamidinomethyl, furancarbox-amidlnomethyl, pyridinecarboxamidinomethyl, pyrrolecarbox-aaidinomethyl or 2-benzimidazolcarboxamidinoraethyl are prepared from the corresponding compound of Formula X or II, wherein Q is NH-CO-CHj-NHj by a reaction with the appropriate 15 imidate ester (e.g., ethyl benzimidate). The reaction is normally carried out by contacting substantially equimoiar quantities of the imidate ester and the penam compound, or a salt thereof (e.g., the triethylamine salt), in a reaction-inert organic solvent (e.g., chloroform, N,N-dimethylform-20 amide or N,N-dimethylacetamide) at about ambient temperature. The reaction usually takes several hours (e.g., about six hours), and the product is isolated. The imidate esters used in the instant process are either known compounds or they are prepared by known methods. For example, they can 25 be prepared by the acid-catalyzed addition of an alkanol to the appropriate nitrile (the Pinner reaction), by reaction of the corresponding carboxamide with the trialkyloxonium fluoborate (e.g., triethylcxonium fluoborate) , or in sotip .esses, t-y tlie base-catalyzed addition of an alkanol to a 30 nitrile. The bano-ccttulyzr-fl reaction is particularly co.n- - 44 - 40838 vrniont when t.ho cyano moiety i*: bonded to an eloctron-wi Ihdmwiruj Method P is valuable for the preparation of compounds of Formulae 1 and XI, wherein R* is an acyl group and 2 3 R and R arc each hydrogen. The Method comprises hydrolysis 10 of the corresponding compound of Formula X, wherein R* is an acyl group and R* is a group of Formula -C("O)-O-R^* or SOj-R** wherein R*-* is alkyl having from one to six carbon atoms, benzyl, phenyl or phenyl substituted by up to two 15 of nitro, fluoro, chloro, bromo, alkyl having from one to four carbon atoms and alkoxy having from one to four carbon atoms. The hydrolysis is normally carried out by contacting t-he starting material with an aqueous or partially aqueous solvent system, at a.temperature normally 20 in the range from about -5°C. to about 30°C., and preferably from about 10°C. to 25°C., at a pH in the range from about 7.5 to 9.5, and usually at about 8.5, until hydrolysis is substantially complete. The reaction usually takes about 1 hour to reach completion. It is usual, although not essential, 25 to use a co-solvent in this process. Co-solvents which can be used are those which are miscible with water, and will serve to dissolve the starting penam compound. Typical examples of co-solvents which can be used are acetont:; lower alkancfts, such as methanol and cthanol; ethylene glycol; ir.c>-30 and d.i (lower-»aifcyl) ethers of ethylene glycol, such as - 45 - • 4 0 532 2-m«!thoxyc:Lhano I and 1 ,2-diinethoxyethane; totrahydrofuran; iliox.me and .M-i-11ii»11 r i I<•. Tin' product, i.-; i -.ul.it ivi by met InmI:; wi-I I-known in I.lie .ul .

' The starting penam compounds of l-'ormulae 111 and 2 3 5 r> XV, wherein R , R and R are cach hydrogen, used in Method C, can be obtained from the appropriate compound of Formula 5 III, or an acid addition salt thereof, wherein R is hydrogen 2 and R is selected from the group consisting of lo -CU > .ind Alternatively, particularly when operating on a small scale, it is sometimes convenient to arrest the reac- I tion by rapid evaporation of the trifluoroacetic acid, at or around ambient temperature, in vacuo. The amount of 15 trifluoroacetic acid used in this process is not critical, provided that enough is present to efficiently dissolve the starting material, and from about ten molar equivalents to about one hundred molar equivalents based on the penam compound is commonly used. About one molar equivalent of anisole 2u is normally used, buc larger amounts, even as large as ten molar equivalents, may be added, if desired. A starting material which operates particularly efficiently in this process is a sulfonate salt, for example, the methanesulfon-ate or g>-toluenesulfonate salt, of the said compound of 25 Formula III. The time course of the instant reaction varies according to a variety of factors, such as the reaction temperature, the structure of the starting material, the concentration of the solution. However, a convenient mode of operation involves monitoring pilot reactions using 30 nuclear magnetic resonance spectroscopy, so that the time 4 0 532 period which leads to the optimum conversion to product for a given set of reaction conditions can be determined. When working at about 35°C., reaction times in the range from about 0.1 to about 1.5 hours are commonly employed. 5 The starting penam compounds of Formula III and IV, wherein R2, R3 and R® are each hydrogen, used in Method C, can also be obtained by hydrogenolysis of the appropriate compound of Formula 111, or an acid-addition salt thereof, 5 1 wherein R is hydrogen and R is in wherein R4 and R^ are hydrogen, hydroxy, nitro, fluoro, chloro, bromo, iodo, alkyl having from one to six carbon atoms, alkoxy having from one to six carbon atoms, alkanoyloxy having from two 1 "> to seven carbon atoms, phenyl or ben2yloxy. The same techniques and conditions discussed earlier under Method A are useful in the instant process.

A still further method for obtaining the starting materials of formula III and IV, wherein R2, R"* and R5 are 2o each hydrogen comprises removal of the triphenylmethyl protecting group from a compound of Formula III, wherein R^ is triphenylmethyl and R is hydrogen. The triphenylmethyl protecting group is removed by treatment of the said compound of Formula III with acid, and a wide variety of acidic re-25 agents and condition?; known in the art. for removal of the triphenylr.ethyl group a»;r* operable in thi*: process. For example, it is possible to use a .sulfonic :;cid, such as nether.;-. - 48 - 40833 sulfonic acid, benzenesulfonic acid or £-toluenesulfonic acii an anhydrous hydrohalic acid, such as hydrogen chlorido or hydrogen bromide; or an alkanoic acid, such as hydrogen chlorido or hydrogen bromide; or an alkanoic acid, such as S acetic acid, propionic acid, chloroacetic acid and trifluoroacetic acid . The reaction is normally carried out by dissolving the starting material in an appropriate solvent and adding about two molar equivalents of the acid reagent, at or about ambient temperature. Reaotion is cora-10 pleto within about one hour, and the product ia present in the reaction medium in the fora of the acid-addition salt corresponding to the acid reagent used. A solvent should be chosen which will dissolve the starting penam, and examples of solvents which find use are: ethers, such as di-15 ethyl ether, tetrahydrofuran, dioxane and 1,2-dimethoxy- ethane; chlorinated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethane} lower aliphatic ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, such as ethyl acetate and butyl acetate; 20 hydrocarbons, such as hexane, cyclohexane and benzene; and lower alkanols, such as methanol, ethanol and butanol. Although it is common to use about two molar equivalents of acid in this process, only one molar equivalent is necessary when either the reaction is carried out in the presence of 25 one molar equivalent of water, or the acid is introduced as a monohydrate. However, as will be realized by one skilled in the art, the product from this reaction should not be exposed to an excess of acid Cor prolonged periods, sinco in this case thore is a danger of destroying th& ^ff-lactam sys-30 torn. A particularly convenient mode of operation for this - 49 - 40832 10 IS proccss, is to choose an acid-solvent system such that tho starting material is soluble, but the acid-addition salt generated during the reaction precipitates as it is formed. Zt can then be recovered by filtration at the end of the reaction. When using the combination of £-toluenesulfonic acid in acctono, the £-toluenesulfonate salt of the product: often precipitates.

In like manner, the starting materials of Formula 5 2 III, wherein R is hydrogen and R is -C(=0)-R14, -S02-R14 or ii, .1 Iky I li.ivinij from one to four carbon atoms or phenyl; R*® and R2® are each or methyl, and X is oxy-5 gen °r sulfur, are prepared from the corresponding compound wherein R5 is triphenylmethyl. The triphenylmethyl group is removed by treatment with acid, exactly as described hereinbefore.

The starting materials of Pormula III, wherein R® 10 is triphenylmethyl and R2 is hydrogen are prepared by a retrograde Michael reaction, on a corresponding compound wherein R2 is -CH2CH2Y, wherein ¥ is (,*yuno, alkoxycarbonyl having from two to seven carbon atoms, phenoxycarbonyl, alkylsulfonyl having from one to four 15 carbon atoms, phenylsulfonyl or SOj-NR^R*-®, wherein R15 and are each hydrogen alkyl having from one to four carbon atoms, phenyl or benzyl. The retrograde Michael reaction comprises treating the said compound with about ce equivalent of base, using conditions 20 known in the art for retrograde Michael reactions, but which are compatible with the penam ring system. Typically, the said compound of Formula IV is treated with about one equivalent of a relatively non-nucleophilic base, in a non-hydroxylic solvent, at a temperature in the range from about 0°C. to 25 about 25°C., for a period of from about ten minutes to about two houcr.. (Consult further Journal of the Chemical Society /London/, Part B, 5867 /T9707).

Preparation of those starting materials for Method C which nro compounds of Formulae III and IV, wherein R^ is 2 ** 30 hydrogorv, R*" and RJ are each - 51 - 40532 ulkanoyloxymcthy I h.iviny from three to oicjht carbon Atom.*:, 1-(alk.moyloxy)«'tliyl h.ivln«j from fun; to nino i*nibon atoms or phthalidyl, is achieved by alkyl.iLlon of a fcetr-azolatc salt, such as the triethylamine salt of the corre-5 spondincj compound of Pormula III or IV, wherein R2 and R^ are hydrogen, using the appropriate alkanoyloxyalkyl or phthalidyl halide. The procedure of Method D is used in this process, exccpt that it is common to utilise at least two molar equivalents, and preferably about three molar 10 equivalents, of the alkylating agent.

Tho ultimate starting materials for production of the antibacterial compounds of this invention are the novel penam compounds of Formula 111, wherein R* is an amino protecting group for example triphenylmethyl and R2 is a 15 tetrazolyl penam protective group for example -CI!2C!12Y, -C (-O) -O-R14 or (R®)', wherein Y, R**.and (R®)• are as previously defined. The compounds can be prepared by a novel three step series of reactions, which forms an important embodiment of this 20 invention, and which is now to be described and discussed in detail.

The said novel penam derivatives of Formula III can be prepared starting from the well-known intermediate, 6-triphenylmethylaminopenicillanic acid, via certain trans-25 formations of the C-3 carboxyl function. Preparation of 6-triphenylmethylaminopcnicillanic acid is taught by Sheehan and Henery-Logan in the Journal of the American Chemical Society, 81, 5838 (1959).

In St«ip 1, 6-(trit:henyln:ethylai»>jno) ponicillanic 30 acid is converted into an o.-::ide of Koimul.; VI - 52 - 40832 CH: (c6»5> j-e-mi o / N ~i N —XI11 ^>C-NH-G II 0 ...VI wherein G is -C(»0)-=0-R14, -SOj-R14, CH2CH2Y or R6; wherein Rl* is as previously defined and R® is or 18 iq 20 wherein R , R , R , X and.Y are as previously defined, and (R4}" and (R4)" and (R*^)" are each hydrogen, hydroxy, nitro, fluoro, chloride bromo, iodo, alkyl having from one to 9ix carbon atoms, alkoxy having from one to six carbon atoms, phenyl or benzyloxy.

In the case wherein G is -CH2CH2Y or R® the araide of Formula VI is prepared by activation of the 3-carboxy group of 6-(triphenylmethylamino)penicillanic acid, e.g., by mixed anhydride formation, followed by reaction with an amine of Formula NII2CH2CH2V or R6-NH2. Thus, formation of the mixed anhydride involves suspending or dissolvinq an appropriate carboxy) ato sail', of the G-1-iph^nylmethyl.jnino-penicillanic ae.id in a roaotiion-inort oro<>n>c solvent, and - 53 - 40332 then adding to this suspension or solution a reagent selected from pivaloyl chloride and lowor-alkyl chloroformates. Appropriate salts are, for example, alkali metal salts, such as sodium or potassium salts, and amine salts, such as triethyl-5 ammonium, pyridinium, N-ethylpiperidinium or N,N-dimethyl- anilinium salts. Appropriate solvents are those which serve to dissolve at least one of the reactants, and the mixed anhydride product, and do not adversely interact with the reactants or product. Examples of such solvents are chlorinated 10 hydrocarbons, such as chloroform, methylene chloride; aromatic hydrocarbons, such as benzene, toluene and xylene; and ethers, such as diethyl ether, tetrahydrofuran and 1,2-dimethoxy-ethane. The reaction is usually carried out at a temperature in the range from about -50°C. to about 30°C., and preferably 15 at about 0°C. At about 0°C., the reaction commonly requires about one hour. The triphenylmethylaminopenicillanic acid salt and the pivaloyl chloride or lower-alkyl chloroformate are normally present in roughly equimolar proportions, although in some instances a small excess of the acid chloride 20 component is used. The product can be isolated simply by filtering off the insoluble materials, and then evaporating the solvent in vacuo to give the crude product. The latter can be used directly, or purified further by methods known in the art. If desired, however, the mixed anhydride product 25 need not be isolated. It can be used in situ for reaction with the amine of Formula or R^-NI^. Reaction of the mixed anhydride with the amine of formula R®-NH2 or NH2CH2CH2Y is usually carried out simply by contacting the reactants in an inert solvent, for about 0.5 to about 2.0 30 hours, at a temperature in the range from about -30°C. to - 54 - 40532 about 30°C. and preferably at around 0°C. The same solvents identified above for mixed anhydride formation are useful for the instant reaction, and the reagents are usually used in approximately equimolar proportions. As will be realized by 5 one skilled in the art. the product should not be exposed to an excess of the starting amine, since this runs the risk of causing extensive decomposition of the penam ^-lactam. In the cases wherein this reaction is conducted in a water-immiscible solvent, the product is usually isolated by wash-10 ing the reaction mixture with water and then concentrating the organic solvent to dryness in vacuo, to give the crude product. The latter product can be used immediately for Step 2, or, if desired, it can be purified further by well-known methods. However, it is sometimes convenient simply 15 to wash the reaction mixture with water, and then use the ao-produccd solution of amide directly in Step 2. In the cases wherein the reaction is conducted in a water-miscible solvent, the product is usually isolated by first removing the water-miscible solvent by evaporation in vacuo, replacing it 20 by a water-immiscible solvent, and then proceeding as described above.

When the amine R®-NH2 is of formula: NH,-CH 4 17 ' wherein either (R ) " or {R )" is a hydroxy group, it is 25 convenient to protect the phenolic hydroxy group of the hydroxybenzylamide produced, before proceeding to Step 2. A wide Variety of protecting groups known in the art for ■ protecting hydroxy groups are operative for this purpose. - 55 - 40332 For example, the hydroxy group can be protected as an alkoxy-methyl or tetrahydropyranyl ether, or it can be silylated. The types of silyl derivatives, and the methods of preparation, referred to hereinbefore under "Method C" are useful 5 in the instant process. Also, the hydroxy group can be converted to an alkanoyloxy group, by reaction with an alkanoyl halide, e.g., an alkanoyl chloride; or to a formyloxy group, by reaction with formic acetic anhydride. Techniques for the acylation of phenolic hydroxyl groups are discussed by 10 Sandler and Karo in "Organic Functional Group Preparations". Academic Press, New York & London, 1968, p 250. Conditions compatible with the penam ring system must be chosen, however. This, of course, then provides intermediates which are precursors of compounds of Formula 111, wherein R5 is methoxy.

In the case wherein G is -C(=0)-0-R*4 or -SOj-R*4, 20 the amide of Formula vr is prepared by reaction of 6-(triphenyl-methylamino) penicillanic acid with the appropriate isocyanate of Formula R14-0-C(=0)-N=C=0 or R14-S02-N=»C=0. The reaction is usually carried out by contacting substantially equimolar quantities of the reactants, in a reaction inert organic solv-25 ent, at a temperature in the range from about 0°C to about 30°C., for a period of from about one hour to about twenty hours. The product can be isolated simply by removal of the solvent in vacuo or the solution of the amide of Fornula VI - 56 - 40532 can bo used ill situ for Stfej> 2. The irocyanates of formula R*4-0-(00)-N=C=0 are prepared by reaction of a carbamate of 14 formula R -0-C(=0)-NH2 with oxalyl chloride, and the iso-cyanatcs of formula R^-SC^-N^OO are prepared by reaction 5 of a sulfonamide of formula R^-SOj-NI^ with oxalyl chloride. (See J. Hetero. Chem., 6, 261 (1969).

In Step 2 of the said novel three-step series of reactions, the product from Step 1, or a simple transformation product thereof in which any phenolic hydroxy groups 10 have been converted into an alkanoyloxy. formyloxy or alkoxy-methoxy group, as discussed above, is converted into an intidoyl chloride of formula: (C6H5)3-C-NH wherein G* is selected from the group consisting of -CHjCl^-Y, 15 -C(=0)-0-R14, -S02R14 and (R6)•, wherein Y, R14 and (R6)• are as previously defined. For imidoyl chloride formation, a convenient method comprises dissolving the said amide in a reaction-inert organic solvent and then treating the solution with phosgene and a tertiary amine. About one molar equival-20 ent of phosgene is usually used, but amounts up to *bout two or three molar equivalents are sometimes employed. The tertiary amine is preferably present in an amount equal to or greater than the amount of phosgene. The reaction is carried out at a temperature in the range from about -20°C. to about 25 30°C., and preferably at about 25°C., and it usually requires a few hours to reach completion. It is sometimes advantageous, - 57 - 40832 from o standpoint of hastening tromplote conversion to imino chlorido# to add further 'juanti tion of l.rrllary amine and phosgeno as the reaction proceeds. A variety of tertiary amine8 can be used in this process, for example tximethyl-amine, trlethylaraine, N,N-dimethylaniline, N-mathylmorpholine and pyridine, and typical solvents which can * be used are chlorinated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethano, and ethers such as tetrahydrofuran and 1,2-dimethoxyethane. If desired, the lmldoyl chloride can be isolated by evaporation of the filtered reaction mixture, but in many instances it is convenient to use the imino chloride in situ. chloride or a phosphorus halide such as phosphorus penta-chloride are operative in the imidoyl chloride forming reaction. Moreover, if desired, use can be made'of the corresponding imidoyl bromiue. reactions, the above imidoyl chloride is converted into a tetrazolylpenam compound of formula wherein G* is as previously defined. This transformation comprises treating the said imidoyl chloride with a source of a/.idn ion oml a convenient way of carrying out this transformation involves.dissolving the imidoyl halide in an appropriate solvent, an-i then adding about one molar orjuiv- Several other reagents, for example, thionyl Xn Step 3 of the said novel three-step series of - 58 - 40832 alent, or sometimes a small excess, of the azide ion source. Tho rc.K'iion mixt..uio is tl»*n stored .iL or about ambient temperaturos for itcverai hours, for example, overnight, until conversion into tetrazole is substantially complete. A wide 5 variety of azide ion sources are operative in this process, and examples of those which are particularly valuable are trialkyluilyl azides having from one to four carbon atoms in each of said alkyl groups, such as trimethylsilyl azide and triethylsilyl azide; metal.salts of hydrazoic acid, such 10 as potassium azide and sodium azide, tributylanmonium aside, N,N-dimethylanilinium azide, N-methylisorpholinium azide and pyridiniura azide; tetramethylguanidinium azide. Appropriate solvents are those which will serve to dissolve both the imidoyl halide and the azide ion source, but do not adversely 15 react with either the reactants or the products of the process. In the eases where the azide ion source-is a trialkylsilyl azide or a trisubstituted ammonium azide, chlorinated hydrocarbon solvents, such as chloroform, methylene chloride and 1,2-dichloroethane, are commonly used. However, dipolar 20 aprotic solvents such as N-methylpyrrolidine, can also be used; and in the cases where a metal salt of hydrazoic acid constitutes the azide ion source, these dipolar aprotic solvents become the solvent-typ"- of choice. As regards ease of operation, and availability of reagents, the use of trimothyl 25 silyl azide in chloroform is particularly convenient. As indicated earlier, the reaction takes several hours to reach completion. However, the conversion to tetrazole can often l>e hasten*.-'"; bv ad-ling further ijuanti ;..io3 of azide i.on dv.riii*, the coriiT.o of the reaction. Prsciuct violation is achieved 30 usimj r l. MidarcJ Kcli.ods. V.'.hc.:-: u low boi.liny chior ir.ated h.'d'.v - 59 - 40532 carbon is tho solvent, the reaction solution is washed with dilute alkali and then tho orqanic solvent is evanorated off. When a dipolar aprotic solvent is the solvent, the reaction mixture is usually first diluted with a large excess of 5 dilute alkali, and then, after appropriate adjustment of the pH, the product is isolated by solvent extraction.

As indicated hereinbefore, synthesis of the antibacterial agents of this invention involves the use of two kinds of protecting groups, and these groups have been 10 identified in terms of their ability to function in a particular fashion.

The tetrazolylpenam nitrogen protecting group has been identified in terms of its ability to fulfill two functions. The first of these, its capacity to be removed under 15 certain specified conditions, has already been discussed.

The second of these is its ability to permit the synthesis of a compound of Formula III, wherein R~* is an amino protecting group and R* is the said tetrazolylpenam nitrogen protecting group. 20 From the foregoing discussion it will be apparent that the tetrazolylpenam nitrogen protecting group must be a group which will permit operation of the above-described three-step series of reactions. That is, it must be of such a nature that the amide of Formula VI can be prepared, that 25 the amide cm be converted to an imidoyl halide, and that the imidoyl halide can be converted to the said l-protected 5-tetrazolylpenam compound of Formula IV, substantially as described.

In like manner, the sriino protecting group oust 30 fulfill two functions. Tho first of thi is that, aftev - 60 - 40532 attachment to the 6-amino function of 6-aminoponicillanJc acid, it must permit operation of the alwjve-doscribed thr<»e-step series of reactions. That is, it must orotect the per.an ring system during formation of the amide of Pormula VI, 5 during conversion into an imidoyl halide# and during conversion into the 1-protected 5-tetrazolylpenam compounds of Pormula III. The second function of an amino protecting group for use in this invention, is that it must be removable under conditions which do not decompose the penam ring system 10 from either: (a) a compound of Pormula III, wherein R5 is the said amino protecting group and R2 is a tetrazolylpenam nitrogen protecting group; (b) a compound of Pormula III, wherein R^ is the said amino protecting group and R2 is hydrogen; or (c) a compound of Formula III wherein R® is 15 alkanoyloxymethyl, 1-(alkanoyloxy) ethyl or phthalidyl.

Selection of appropriate amino protecting groups will be achieved readily and easily by one skilled in the art. In particular all such groups known in the art for 20 peptide synthesis are operative. However, particularly convenient protecting groups are triphenylmethyl, substituted triphenylmethyl and -tribromocthoxycarbonyl and carbonyl. Examples of substituted triphenylmethyl groupr 25 which arc especially valuable are those of formula: 61 40532 ,22 10 15 wherein R*^» and are each hydrogen, fluoro, chloro, bromo, alkyl having fron one to four carbon atoms, alkoxy having from one to four carbon atoms or phenyl. Because of Its readily availability, the triphenylmethyl group is especially valuable.

The amines of formulae OT^CHjCHjY and NHj-R®, used in Step 2 above, are either known compounds or-they are prepared by known methods from commercially-available starting aaterials. For example, "nines of formula NH, - CH (R17)1 ...VII can conveniently be prepared rrom the corresponding aldehyde or ketone of formula (R17)■ via conversion to the oxime followed by reduction, or, in cases where, the (R4)" and/or (R^4)" groups would be unaffected, by thfr. reductive alkvlation of ammonia. (Consult Harbison and garrison, "Ccnpendiura of Organic Synthetic - 62 - 40532 Muthoda", Wi ley-InterBcifni*', 1971, pages 233-235 nnd 2'^fl-261 A furUivr nub-ol«>C novrl 3-(5-tetrazolyl) >r» conpounds which are valuable antibacterial agents, and which fall within the scope and purview of the instant invention are those compounds.* of formulae: >V \io ...VII \_«{ . ..iy .11 g wherein R is phenyl 1,4-cyclohoxadienyl, 3-sydnonyl, thienyl, furyl, pyridyl, 10 thiazolyl, isothiazolyi, tetrazolyl, triazolyl, inidazoiyl, pyrazolyl, substituted phenyl, substituted thienyl, substituted furyl, substituted pyridyl, substituted thiazolyl, substituted isothiazolyi, substituted triazolyl, substitute.: imidazolyl or. substituted pyrazolyl, each substituted -.ciet; 15 being substituted by up to two of fluoro, chloro, bromo, hydroxy, alkyl having £*'>!* one to six carbon atoms, alkoxy having rrc:.. - 03 - 40533 to six carbon atore.i and alkylthio havin-j from one to six carbon atomu; R® and R*® ar-: cach hydrogon, methyl, or ethyl) and R11 is hydrogen, alkanoyloxymethyl 5 having from three to eight carbon atoms, 1-(alkanoyloxy)-ethyl having from four to nine carbon atoms or phthalidyl. The compounds of Pormula Vlll and XX are prepared from tho corresponding compound of Pormula X or XX, wherein R* is of Pormula V wherein n is 1, Q is amino and r' is as defined 10 above for R® and R^ and R"* are as defined above for R**, by condensation of the said compound of Pormula X or XX with the appropriate aldehyde or ketone of Formula R9-CO-R10. The condensation reaction is usually carried out by contacting the starting penam compound with a large excess of the 15 aldehyde or ketone in the presence of at least one molar equivalent of a tertiary amine, at or slightly, below room temperature. A sufficient afoount of the aldehyde or ketone is normally used so that a further solvent is not necessary. However, a further diluent which does not adversely react 20 with either the starting materials or the product can be used if desired. Examples of tertiary amines which are operative in the process arc triethylamine, tributylanir.e, pyridine, N,N-dimethylaniline, N-methylmorpholine and quinoline. Although at least one equivalent of tertiary 25 amino is required, it is common to use a fairly large excess, up to about ten molar equivalents. The instant process normally requires a reaction time of several hours, for ox-ample overnight. In those eases v;herein the product is out of solution at thf> end of reaction is filtered c.-Zt. 30 Alternatively, when t.he product is in solution at the end ot - 64 - * 40832 tli« reaction, it is recovered by evaporation of tho Holvont In y.iw>.

A nt.ill farther sub-class of novel 3- (5-tntrasolyi; • penam compound* which are valuablo antibacterial agents, and which fall within the scope and purview of this invention, are those compounls of Formulao: r" .7 N-CH-N rU^ .X N-CH=W.

.. .XI wherein R** and RAJ arc each alkyl having from one to six 10 carbon atoms, or, when taken together with the nitrogen to which they are attached, they represent pyrrolidino, morpholino, piper- idino or azacycloheptan-l-yl; and R** is as defined above. The compounds of Formula X and XI, are prepared from the 15 appropriate corresponding compound of Formula III or IV, wherein R^ and R^ are as defined above for R-* and R5 is hydrogen, by introducing the formomidine moiety, using the methods taught by Lund ond Tybring (Nature, Mew Biology, 23jc, 135 /t?'/?/). 20 A «:!>.-.raotfiii.«tic feature of th?.' •:o»r.oour..*Jr; r-T. - 65 - 4 0332 .Pormulao I, II, III,. IV, VIII, IX, X and XI, wherein R2, I3 and R^ are hydrogen, is their ability to form salts. By virtue of the acidic nature of a 5-monosubstituted tetrazole# the said compounds have the ability to form salts with basic 5 agents, and these salts, referred to generically as "tetrazolate" salts in this specification, are to be considered within the scope of this invention. The salts can be prepared by standard techniques, such as contacting the acidic and basic components, usually in a 1:1 molar ratio, 10 in an aqueous, non-aqueous or partially aqueous medium, as appropriate. They are then recovered by filtration, by precipitation with a non-solvent followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate. Basic agents 15 which are suitably employed in salt formation belong to both the organic and inorganic types, and they include ammonia, organic amines, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkaline earth metal hydroxides, carbonates, hydrides and alkoxide9. 20 Representative examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexyl-amine, benzylamine, j>-toluidine and octylamine; secondary amines, such as diethylamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethyl-25 amine, N,N-dimethylaniline, N-ethylpiperidlne, N-methyl- morpholine and 1,5-diazabicyclo/4.3.07non-5-ene; hydroxides, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and barium hydroxide; alkoxides, such as sodium ethoxide and potassium ethoxide; hydrides, such as calcium 30 hydride and sodium hydride; carbonatcs, such as potassium - 66 - v 4., i 40538 carbonate and sodium oarbonato; and bicarbonatas# such as sodium bicarbonate and potJnnium bicarbonato.

Further, the compounds of Formulae""Tand XX, wherein R* contains one or more acidic functions (e.g., 5 carboxy, sulfa etc.), have the ability to fori® other salts (e.g., salts of the carboxylate and sulfonate type). These salts, which can bo prepared in exactly the sane manner and using the same basic agents, as described above for the tetrazolate salts, are also within the purview of this in-10 vention. Clearly, certain of the compounds of Formulae Z and XX can form both mono- and poly-salts. Whan considering poly-salts, the various cationic moieties can be the same or different.

The compounds of Formulae X, II, III and IV which 15 contain a basic group, have the ability to form acid-addition salts. Said acid-addition salts are also- to be considered as being within the scope of this invention. Examples of acid-addition salts which are particularly valuable are: hydrochloride, hydrobromide, phosphate, perchloratc, 20 citrate, tartrate, pamoate, glutarate, benzoate, sulfate, lactate, and arylsulfonate salts.

When therapeutic use in mammals is being contemplated for a salt of a compound of the instant invention, It is of course essential to use a pharmaceutically-acceptahlc 25 salt. However, other salts are useful for a variety of ether purposes; such as, for example, isolating and purifying individual compounds, changing the solubility characteristics of an individual compound, and for intcrconvorting pharr<-»-..ceutically-acccptciblc salty vith thoi r non-salt counterparts. 30 The antibacterial penan compounds of the inst'.nt - 67 - 40832 invention show activity against a wide v.iriety of gram-positive arul qr.un-ncyutivi- txictcria. Tho in vitro Activity can bo demonstrated by tho conventional two-fold serial dilution tedmlque in Drain-Heart Infusicn bzoth (Difco Registered Trade Mark) .The 5 broth is inoculated with tho bactorial culture# and with the test antibiotic# and then it is incubated overnight.

On the next day, the test is read visually. The minimum inhibitory concentration (MIC) is the lowest concentration of antibiotic which prevents turbidity, i.e.# which prevents 10 growth of the microorganism. In vitro activities of several of the penam compounds of the invention are presented later In this specification.

The in vitro activity of the antibacterial compounds of the instant invention makes them particularly suitable 15 for topical application# for example# in the form of creams and ointments, and for the sterilization of sickroom and hospital surfaces, equipment*, and the like.

The antibacterial penam compounds of the instant invention are also active in vivo. In determining such 20 activity, the test antibiotic is administered to infected mice, using a multiple dosing regimen. The severity of the infection varies from about one to about ten times that needed to kill 100% of the mice under the conditions of the test. At the end of the test, the activity of a compound is 25 assessed by counting the number of survivors among tha treated animals. Both the subcutaneous (SC) and the oral (PO) dosac* routes are used. Results are given in Table I for two of the compounds of the invention. The ability of the to protect mice against sybteaivc infections caused by a leti ~I 30 intraperitoneal inoculum of Staphylococcus aureus or of - 68 - Escherichia coll is presented.

TABLE I 40832 10 15 20 25 30 COMPOUND 6-(D-2-amino-2-£T-thienyl7-acet-amido)-2,2-di-me thy1-3-(5-tetr-asolyl)-penam DOSAGE (mg./kq.) 50 25 12 6 200 DOSAGE SC SC SC SC po 6-(D-2-amino-2-/p-Kydroxyphenyl7-acetamido)-2,2-di-ma thy1-3-(5-tetrazolyl)-penam 50 25 12 6 200 SC SC SC SC PO PER CENT PROTECTION s. aureus a. coll 40 60 50 50 20 20 80 70 50 50 100 80 100 The In vivo activity of the antibacterial compounds of this invention makes them suitable for the control of bacterial infections in mammals, including man, by both the oral and parenteral modes of administration. The compounds will find wide use in the control of infections caused by susceptible gram-positive and gram-negative bacteria in human subjects.

When considering therapeutic use of a compound of this invention, or a salt thereof, in a mammal, particularly man, the compound can be administered alone, or it can be mixed with other antibiotic substances and/or pharmaceutic-ally-acceptabla carriers or diluents. Said carrier or diluent is chosen on the basis of the intended mode of ad- - 69 - 40532 ministration. For example, when considering the oral mode of administration, an antibacterial pen.im compound of this Invention can bo used in the form of tablets, capsules, lozenges, troches, powders, syrups, elixirs, aqueous solu-5 tions and suspensions, 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 10 of tablets for oral use, carriers which are coamonly 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 coamonly used in tablets. For oral administration in IS capsule fora, useful diluents are lactose and high molecular weight polyethylene glycols. When aqueous suspensions are required for oral use, the active ingredient is combined with, emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents can be added. For paren-20 teral 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 25 be controlled to render the preparation isotonic.

As indicated earlier, the antibacterial penam compounds of this invention are of use in human subjects and the daily dosages to be used will not differ significantly from other, clinically-used, penam antibiotics. The pro-30 . scribing physician will ultimately determine the appropriate - 70 - 40839 dose for a given human subject, and this can be expected to vary according to tho ayc»# w*J«jht# nnd ros^nso of the Individual patient# as veil as the nature and the severity of the patient's symptoms. The compounds of this invention 5 will normally be used orally at dosages in the range from about 10 to about 200 mg. per kilogram of body weight per day# and parenterially at dosages from about 5 to about 100 mg. per kilogram of body weight per day. These figures are illustrative only# however# and in some cases it may be 10 necessary to use dosages outside these limits.

Certain of the compounds of this invention have the ability to form solvates (e.g.# hydrates)# and all such hydrates are to be considered within the scope and purview of the invention. 15 The following examples are provided solely for the purpose of further illustration. Infrared.(IR) spectra are measured as potassium bromide discs (KBr discs) or as Nujol (Registered Trade Karkjoulls# and diagnostic absorptl.cn bands are reported In wave numbers (cm""*). Nuclear magnetic resonance spectra 20 (NMR) are measured at 60 MHz for solutions in deuterochloro-form (CDCI3)# perdeutero dimethyl sulfoxide (DMSO-dg) or deuterium oxide (O2O)# and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane or sodium 2,2-dimethyl-2-silapentane-5-sulfonate. The follow-25 ing abbreviations for peak shapes are used: s, singlet; d# doublet; t, triplet; q, quartet; m, multiplet. 40532 EXAMPLE I 6-(Triphenylroethylami.no) -2,2-dimethyl-3- (l-£T-methoxybenzyl7-totrazol-5-yl)penam 6- (Triphenylmethylamino)-2,2-dimethy1-3-(N-^T-meth-5 oxybenzyl7carbanoyl)penam — To a stirred slurry of 216 g. of 6-aminopenicillanic acid in 1,500 ml. of anhydrous chloroform is added 278 ml. of triethylamine, and the mixture is then stirred at ambient temperature until a clear solution is obtained. This requires about IS minutes. The solution 10 is cooled to about 0°C., and then 306 g. of triphenylmethyl chloride is added. The stirring is continued at about 0°C. for 30 minutes, and then at ambient temperature for a further 24 hours. The mixture is cooled to about 0°C. again, and 14 ml. of trie thy lamine, followed by 95 ml. of ethyl chloro-15 formate, is added. During this process the temperature rises to about 15°C., and a precipitate forms. To facilitate stirring a further 200 ml. of chloroform is added. The stirring is continued Tor 30 minutes. Then, at about 0°C., 50 ml. of 4-methoxybenzylamine (available from the Aldrich 20 Chemical Company, Inc.) is injected into the reaction medium, below the surface of the solvent. At 10 minute intervals, three further aliquots of 4-methoxybenzylamine (35 ml., 25 ml. and 21 ml.) are injected in the reaction in similar fashion. The total volume of 4-methoxybenzylamine added is 25 131 ml. The cooling bath is then removed, and the reaction is stirred for a further 1 hour. The chloroform solution is washed successively with five 2,000 ml. portions of water and one 2,000 ml. portion of saturated brine. The chloroform is finally dried using anhydrous sodium sulfate. 30 Examination of the reaction mixture at this point - 72 - 40532 by NMR spectroscopy, reveals that the conversion into amide / is approximately 85% complete. Accordingly, the chloroform solution is cooled in an ice-bath and 21 al. of triethy1-amine, followed in about 5 minutes by 14.2 al. of ethyl chloro-5 foraate, is added. After a further 15 minutes, 9.8 al. of 4-methoxybenzylamine is added, and then in another 5 ainutes a further 9.8 al. of 4-methoxybenzylaaine is added. The reaction is concentrated in vacuo giving 6-(triphenylmethylamino) -2,2-dimethy 1-3- (N-£T-methoxybensyl7carbaaoyl) penaa, 10 as an amorphous solid. 6-(Triphenylmethylamino)-2,2-dimethy1-3-(chloro-^N- (4-methoxybenzyl)imino/penam — The amide described above is dissolved in 480 ml. of pyridine, and then the solution is cooled to about -5°C. To this solution is added dropwise, 15 with stirring during 10 minutes, 108 ml. of thionyl chloride. The reaction mixture is then allowed to warm slowly to ambient temperature for a further 21 hours. All the volatile components are removed in vacuo leaving the crude imino chloride as an amorphous solM. The NMR spectrum (in CHCI3) of this 20 product shows absorption bands at 4.70 ppm (singlet, C-3 hydrogen), 4.65 ppm (singlet, benzyl hydrogens), 4.30-4.60 ppm (multiplet, C-5 and C-6 hydrogens), 3.75 ppm (singlet, methoxy » hydrogens), 1.57 ppm {singlet, C-2 methyl hydrogens) and 1.38 ppm (singlet, C-2 methyl hydrogens). 25 6-(Triphenylmethylamino)-2,2-dimethy1-3-(1-^T-meth- oxybenzyl7tetrazol-5-yl)penam — The imino chloride described above is re-dissolved in 500 ml. of chloroform and then the solution is cooled to about -5°C. in an ice-salt bath. To the solution is then added, with stirring, 160 ml. of tri-30 methylsilyl azide (available from the Aldrich Chemical Com- 73 - * 40332 pany, Inc.). After being allowed to warm to ambient temperature, the reaction mixture is stirred for a further 22 hours. It is then cooled to about 0°C. and 2,000 ml. of 1.5N sodium hydroxide solution is added, followed by sufficient additional 5 1.5N 8odium hydroxide to bring the pH of the aqueous to 6.0. The aqueous phase is separated off, and the chloroform phase is washed successively with five 2,000 ml. portions of water and one 500 ml. portion of saturated brine. The chloroform is then dried by filtration through anhydrous sodium sulfate* 10 and finally concentrated to dryness. The residue is triturated with 1,000 ml. of ether, and then filtered off. This affords 150 g. of crude product, m.p. 174-178*C. The crude product is purified by re-dissolving it in chloroform and filtering the solution through chromatographic grade silica 15 gel. The chloroform is removed by evaporation in vacuo, and the residue is again triturated with ether. This affords 128 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1—14— methoxybenzyl)tetrazol-5-yl)penam as a light tan solid, m.p. 193-195*C. The infrared spectrum (KBr disc) of the pro-20 duct shows an absorption band at 1790 cra"^ (B-lactam carbonyl). The NMR spectrum (in CDCl^) shows absorption bands at 7.25 ppm (multiplet, aromatic hydrogens), 5.50 ppm (broad singlet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 4.40 ppm (broad singlet, C-5 and C-6 hydrogens), 3.80 ppm (singlet, 25 methoxy hydrogens), 1.45 ppm (singlet, C-2 methyl hydrogens) and 0.70 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE II The following compounds are prepared by repeating the procedure of Example I, except that where necessary the 30 triphenylmethyl chloride is replaced by an equimolar amount - 74 - 40532 of the appropriately-substituted triphenylmethyl chloride* and where necessary the 4-methoxybenzylamine is replaced by an equimolar amount of the requisite amine. 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-benzyltetr-5 azol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-I2-methoxy-benzylJ tetrazol-5-yl)penam, 6-! triphenylmethylamino) -2,2-dimethy 1-3- (1- [4-isopro-poxybenzyl)tetrazol-5-yl)penam, 10 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro- benzyl J tetrazol-5-yl) penam, 6-(triphenylmethylamino)-2,2-dimethy1-2-(1-I3-methyl-benzyl]tetrazol-3-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-[3-chloro-15 4-methoxybenzyl)tetrazol75-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[1-phenyl-ethyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetr-azol-5-yl)penam, 20 6-(diphenyl-4-fluorophenylmethylamino)-2,2-dimethy1-3- (1-14-nitrobenzyl)tetrazol-5-yl)penam, 6-(diphenyl-3-tolylmethylamino)-2,2-dimethyl-3-(fc-[4- ethoxybenzyl] tetrazol-5-yl)pen£tm, 6-(diphenyl-2-methoxyphenylmethylamino)-2,2-dimethy1-3-\ 25 (1-[4-phenylbenzylJtetrazol-5-yl)penam, 6-(diphenyl-4-chlorophenylmethylamino)-2,2-dimethy1-3-(1-[diphenylmethyl]tetrazol-5-yl)penam, 6-(diphenyl-4-bromophenylmethylamino-2,2-dimethyl-3-(1- [ 2—thieny lir.e thyl ] tetrazol-5-yl) penam, 30 6-(di[4-methoxyphenyl]phenylmethylamino)-2,2-dimethyl- - 75 - 40532 3-(l-benzyltetrazol-5-yl)penam, 6-(di[3-chlorophenylJ phenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam, 6-(diI2-tolyl1phenylmethylamino)-2,2-dimethy1-3-(1-5 [2,4-dimethoxybenzyl]tetrazol-5-yl)penam, 6-([4-chlorophenyl][4-methoxyphenyl)phenylmethylamino)-2,2-dimethy1-3-(1-l4-methoxyphenyl)ethylltetrazol-5-yl)penam# 6-(di[4-fluorophenyl)(biphenylyl]methylamino)-2,2-dimethy 1-3- (1- [1-(4-chlorophenyl)butylltetrazol-5-yl)penam, 10 6-(tril4-tolyl]methylamino)-2,2-dimethyl-3-(l-[(4- methoxyphenyl)phenylmethyl)tetrazol-5-yl)penam, 6-(tri[3-ethoxyphenyl]methylamino)-2,2-dimethy1-3-(1-[4-ethylbenzylJ tetrazol-5-yl)penam, 6-(diphenyl-I3-bromopheny1]methylamino)-2,2-dimethyl-15 3-(l-l3-furylmethyl)tetrazol-5-yl)penam, and- * 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methyl-furfuryl]tetrazol-5-yl)penam, respectively. example iii 20 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-benzyloxy-benzyl)tetrazol-5-y1)penam 6-(Triphenylmethylamino)-2,2-dimethy1-3-(N-4-benzyl-oxybenzyljcarbamoyl)penam — To a stirred solution of 20.0 g. of 6-triphenylmethylamino-penicillanic acid (Sheehan and 25 Henery-Logan, Journal of the American Chemical Society, 81, 5836

[1959]) in 140 ml. of acetone, at 0-5°C., is added 6.08 ml. of triethylamine followed by 5.78 ml. of isobutyl chloroformate. After a further 10 minutes, the mixture is filtered directly into a stirred solution of 9.28 g = of 30 4-benzyloxybenzylamine in 1,000 ml. of water and 300 ml. of - 7 fi - 40532 acetone at ambient temperature. The mixture so obtained is stirred £or 4 minutes, and then an additional 500 ml. of water is added. Stirring is continued for a further 7 minutes, and then the reaction mixture is extracted with 5 ether. The ether is dried using anhydrous magnesium sulfate* and then evaporated to dryness in vacuo. The crude product so obtained is redissolved in 200 ml. of ether, which is then added dropwise over 10 minutes to 2*500 ml. of hexane. The solid which precipitates is filtered off* giving 21.5 10 g. of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-ben*y1-oxybenzyl]carbamoyl)penam. 6-(Triphenylmethylamino)-2,2-dimethy1-3-(chloro-lN-(4-benzyloxybenzyl)imino)methyl)penam — To a stirred solution of 2.0 g. of the above-described amide in 10 ml. 15 of dry chloroform, at 0-5°C., is added 0.99 ml. of pyridine, followed by 5.42 ml. of a 2.26 M solution of phosgene in chloroform. The reaction mixture is then stirred at ambient temperature overnight. At this point, it is evaporated to dryness in vacuo, yielding a viscous gum, which is extracted 20 with 100 ml. of ether. The ether is filtered, and evaporation of the filtrate affords the imino chloride as a yellow foam. 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-14-benzyloxybenzyl)tetrazol-5-yl)penam — The above described 25 imino chloride is redissolved in 8 ml. of dry N,N-dimethyl-formamide. To this solution is added 249 mg. of potassium azide, and the turbid solution is stirred at ambient temperature for 2.25 hours. The solvent is evaporated at ambient temperature, under high vacuum leaving a brown gum. This 30 residue is partitioned between 60 ml. of water and 150 ml. • 4 0 5 3 2 of ether. The ether phase is separated off, washed with saturated brine, dried using anhydrous sodium sulfate, and finally evaporated to dryness in vacuo. The residue is 980 rag. of 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-14-5 benzyloxybcnzyl]tetrazol-5-yl)penam. Its NMR spectrum (in CDClj) shows absorption bands at 7.30 ppm (multiplet, aromatic hydrogens), 5.45 ppm (quartet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 5.00 ppm (singlet, benzyl hydrogens), 4.40 ppm (multiplet, C-5 and C-6 hydrogens), 10 1.40 ppm (singlet, C-2 hydrogen) and 0.70 ppm (singlet, C-2 hydrogen).

EXAMPLE IV The procedure of Example III, is repeated, except that the 4-benzyloxybenzylamine used therein is replaced by 15 an equimolar amount of the appropriate amine, to produce the following congeners: 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-(4-methoxy-benzylJ tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-I4-n-hexyl-20 oxybenzyl)tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[4-fluoro-benzyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-(4-isopropyl-benzyl]tetrazol-5-yl)penam-25 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3,4-di- methoxybenzyl1tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3,5-di-chlorobenzyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[3-chloro-30 4-ethoxybenzyl]tetrnzol-5-yl)penam. - 78 - 40832 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-[1-(4-chloropheny1)othy1)tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-[1-phenyl-propyl]tetrazol-5-yl)penam, 5 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-II-(4-tolyl)- butyl)tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-[phenyl(4-tolyl)methyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfury1-10 tetrazol-5-yl)penam and 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-I(5-methyl-2-thienyl)methyl1tetrazol-5-yl)penam, respectively.

EXAMPLE V 15 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl]-tetrazol-5-yl)penam (A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-[4-methoxy-benzyl] carbamoyl) penan; To a stirred slurry of 86.4 g. (0.8 mole) of 6-amino-20 penicillanic acid in 600 ml. of anhydrous chloroform is added 11.2 ml. (0.4 mole) of triethylamine, and the mixture is stirred at ambient temperature until a clear solution is obtained (ca. 15 minutes). To this solution is then added, portionwise over about 25 minutes, 134.9 g. (0.44 mole) of 25 90% pure triphenylmethyl chloride, at ambient temperature.

Stirring is continued for a further 64 hours, and then 5.6 ml. of triethylamine is added. The solution is cooled to 0-5#C. and then an ice-cold solution of 38 ml. (0.4 mole) of ethyl chloroforrnate in 80 ml. of chloroform is added dropwise during 30 30 minutes with the reaction temperature being maintained - 79 - between 4 and 9"C. After a further 15 minutes of stirring 52.4 ml. (0.4 mole) of 4-methoxybenzylamine is injected into tho reaction medium, below the surface of the solvent, at 4 to 9°C., and over a period of 30 minutes. Stirring is con-5 tinucd for a further 30 minutes at 3 to 6°C., for 20 minutes while the reaction medium warms to 20®C. The reaction mixture is then washed with water, followed by brine. Finally, it is dried using magnesium sulfate to give a chloroform solution of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-10 raethylbenzyl] carbamoyl) penam.

(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-g-methoxy-benzyl]tetrazol-5-yl)penam To a chloroform solution containing 69.4 g. (0.120 mole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(H-[4-15 methoxybenzyl]carbamoyl)penam, and having a volume of 133.3 ml., prepared by the method described in (A) above, is added a further 132.7 ml. of chloroform, followed by 29.1 ml. (0.360 mole) of pyridine. This solution is cooled to 10°C. and then 26.22 g. (0.12o mole) of phosphorus pentachloride 20 is added during 15 minutes, with stirring. Stirring is continued at ca. 10°C. for 10 minutes, and then at ambient temperature for a further 1.5 hours, giving a solution of the imino chloride. To a one-sixth aliquot of this imino chloride solution is added 4.85 ml. (0.060 mole) of pyridine, 25 followed by 2.42 ml. (0.060 mole) of methanol at ca. 25°C., with stirring. After a further 15 minutes of stirring 2.03 g. (0.038 mole) of ammonium chloride, followed by 2.59 g. (0.039 mole) of 95% pure sodium azide, is added. The reaction mixture is then stirred at ambient temperature for a 30 further 4 hours. At this point, 400 ml. of water and 200 ml. - 80 - 40832 of chloroform are added, and then the layers are separated. The organic phase is washed with water, dried using magnesium sulfate, and then concentrated to a small volume in vacuo.

This final chloroform solution is added dropwise with stir-5 ring to a large volume of diisopropylether, and, after 30 minutes, the precipitate which has formed is filtered off.

This affords 6.1 g. of 6-(triphenylmethylamino)-2,2-dimethy1-3-(l-[4-methoxybenzyl)tetrazol-5-yl)penam. The infrared spectrum of the product (KBr disc) shows an absorption band 10 at 1790 cm-*- (p-lactam); and the NMR spectrum (in COCI3) shows absorptions at 7.25 ppm (multiplet, aromatic hydrogens), 5.40 ppm (broad singlet, benzyl hydrogens), 5.05 ppm (singlet, C-3 hydrogen), 4.50-4.30 ppm (multiplet, C-5 and C-6 hydrogens), 3.70 ppm (singlet, methoxy hydrogens), 3.50-3.10 ppm 15 (broad peak, NH), 1.50 ppm (singlet, C-2 methyl hydrogens) and 0.75 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE VI When the procedure of Example V is repeated, and the 4-methoxybenzylrmine used therein is replaced by an 20 equimolar amount of the appropriate amine, the following compounds arc obtained: 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-[4-ethoxy-benzylltetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-[3-chloro-25 4-methoxy]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-ll-phenyl-ethyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[diphenyl-methyl]tetrazol-5-yl)penam, and 30 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryl- tetrazol-5-yl)penam, respectively.

EXAMPLE VII 6-(Triphenylmethylamino)-2,2-dimethy1-3-(1-furfuryltetrazol-5-yl)penam 5 (A) 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-furfuryl-carbamoy1)penam To a stirred slurry of 216 g. (1 mole) of 6-amincr penicillanic acid in 1500 ml. of chloroform, is added, at 25-30*C., 278 ml. (2 mole) of triethylomine. To the solu-10 tion thus obtained is added, portionwise during 25 minutes, 306 g. (1.1 mole) of triphenylmethyl chloride, at 25-30*C. Stirring is then continued for 44 hours at ambient temperature.

A 522 ml. portion (0.25 mole) of the above 6-(tri-15 phenylmethylamino)penicillanic acid solution is cooled to 4°C., and then 3.5 ml. of triethylamine is added. With vigorous stirring is then added 23.75 ml. of ethyl chloro-formate at 5-10°C. Stirring is continued for a further 30 minutes at ca. 6°C. at the end of the addition, and then 20 8.43 ml. of furfurylamine is injected into the reaction medium below the surface of the solvent. At 10 minute intervals, three further portions of furfurylamine (5.90 ml., 4.22 ml. and 3.54 ml.) are then injected into the reaction medium in similar fashion. The total volume of furfurylamine 25 added is 22.09 ml. (0.25 mole), and the temperature is maintained at ca. 6°C. throughout the addition of the amine.

When the addition of the amine is complete, the cooling bath is removed and the reaction medium is stirred at ca. 25°C. for 45 minutes. It is then washed successively with three 30 portions of water, and one portion of brine. Finally, it is - 82 - dried using anhydrous magnesium sulfate. This affords 610 ml. of a chloroform solution of 6-(triphenylmethylamino)-2,2-dimethyl-3- (N-furfurylcarbamoyl)penam. Tho NMR spectrum of this solution showed absorptions at 7.3 ppm (17H, ra) , (.2 S ppm (1H, m), 4.35 ppm (3H, m), 4.05 ppm (2H, s), 1.6 ppm (3B# s) and 1.35 (3H, s).

(B) 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-furfuryl-tetrazol-5-y1)penam To a stirred solution of 3.05 g. (5.7 mmole) of 10 6-triphenylmethylamino) -2,2-dimethyl-3- (N-furfurylcarbamoyl), penam, in 8 ml. of chloroform, at 0*C., is added 1.35 ml. (17 nmole) of pyridine, followed by 2.64 ml. of a 4.33 M solution of phosgene in chloroform. Stirring is then continued for 1 hour at 25*C. The chloroform, and excess phosgene and 15 pyridine, are then removed by evaporation in vacuo, and the residue is redissolved in 5 ml. of chloroform. The solution is cooled to 0*C., and then 2.25 g. (14.4 mmole) of tetra-methylguanidinium azide is added in several small portions. Stirring is continued for 15 minutes at ambient temperature 20 and then 20 ml. of chloroform, followed ny 30 ml. of water, are added and the pH is adjusted to 6.5. The chloroform layer is separated off, washed with water, followed by brine, and then dried (MgSO^) ; Removal of the solvent by evaporation in vacuo leaves 3.37 g. of a dark red foam. The foam 25 is redissolved in a small volume of chloroform and absorbed onto a column of chromatographic 3ilica gel. Elution of the column with chloroform, followed by evaporation of the appropriate fractions in vacuo, affords 6-(triphenylmethylamino) -2,2-dimethyl-3- (l-furfuryltetrazol-5-yl)penam. The 30 NMR spectrum of tne product (CDCl^) shows absorptions at - 83 - . 4 0 5 3 2 7.40 ppm (m, 16 H), 6.40 ppm (m, 2H), 5.50 ppm (s, 2H), 5.20 ppm (s, 1H), 4.90 ppm (m, 2H), 1.60 ppm (s, 3H), and 0.80 ppm (a, 3H).

EXAMPLE VIII 5 The procedure of Example VII is repeated, except that where necessary the triphenylmethyl chloride used therein is replaced by an equimolar amount of the appropriately-substituted triphenylmethyl chloride* and where necessary the furfuryl amine is replaced by the requisite 10 amine, to produce the following congeners: 6- (triphenylmethylamino) -2,2-dimethy 1-3- (1-bensyltetr-azol-5-yl)penam, 6- (triphenylmethylamino)-2,2-dimethyl-3-(l- (4-methoxy-benzyl1tetrazol-5-yl)penam, 15 6- (triphenylmethylamino)-2,2-dimethyl-3- (1-15-roe thy 1- furfuryl]tetrazol-5-y1)penam, 6- (diphenyl-3-chloropheny lmethylami.no)-2,2-dime thyl-3-(l-J4-iodobenzyl] tetrazol-5-yl)penam, 6- (diphenyl-2-fluorophenylmethylamino)-2,2-dime thyl-3-20 (1-[4-tolylmethyl]tetrazol-5-yl)penam, 6- {diphenyl-2-rnethoxyphenylmethylami.no) -2,2-diraethyl-3-(1-14-biphenyly lmethy11tetrazol-5-yl)penam, 6-(diphenyl-4-tolylmethylamino)-2,2-dimethyl-3-(1-[1-(4-benzyloxybenzy1]tetrazol-5-yl)penam, 25 6-(diphenyl-4-chlorophenylmethylamino)-2,2-dimethyl-3- (1-(3,4-diethoxybenzyl]tetrazol-5-yl)penam, 6-(diphenyl-4-isopropylphenylmethylamino)-2,2-dimethyl-3- (1-[2-methoxybenzyl]tetrazol-5-yl)penam, 6- (diphenyl-4-n-butylphenylmethylamino) -2,2-dimethyl-3-30 (H4-isopentylbenzyl] tetrazol-5-yl) penam. - 84 - 40832 6-(diphenyl-J-iaopropoxyphenylBWthylamino)-2,2-dimethyl-3-(1-[3-chloro-4-ethoxybenzyl]tetrazol-5-yl)penam, 6-(diphenyl-3-n-butoxyphenylmethylamino)-2,2-dimethy1-3-{1-[3-n-pentyloxy-4-benzyloxybenzyl]tetrazol-5-yl)penam, 5 6-(di13-methoxyphenyl)phenylmethylamino)-2 , 2-dime thyl- 3-(1-[1-phenylethyl]tetrazol-5-yl) penam, 6-(di[2-tolyl)phenylmethylamino)-2,2-dimethyl-3-(1-[1-(4-methoxyphenyl)ethyl]tetraxol-5-yl) penam, 6-(triI4-tolyl]methylamino)-2,2-dimethyl-3-(1-[1-phenyl-10 pentyl)tetrazol-5-yl)penam, 6-(tri[3-methoxyphenyl]methylamino)-2,2-dimethyl-3-(1-[4-n-hexylbenzyl]tetrazol-5-yl)penam and 6-(tri[4-biphenylyl]methylamino)-2,2-dimethyl-3-(1-[4-methoxybenzyl)tetrazol-5-yl)penam, respectively. 15 EXAMPLE IX 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[4-hydroxybenzyl]-tetrazol-5-yl)penam (A) 6- (Triphenylmethylamino)-2,2-dimethyl-3-(N-14-hydroxybenzyl) carbamoyl) penam 20 To a stirred slurry of 43.2 g. (0.20 mole) of 6-aminopenicillanic acid in 300 ml. of chloroform is added 55.6 ml. (0.40 mole) of *riethylamine, followed by 61.2 g. (0.22 mole) of triphenylmethyl chloride, at ambient temperature. Stirring is then continued for a further 48 hours at 25 ambient temperature.

A 120 ml. portion (containing 0.060 mole of tri-ethylammoniu" 6-[triphenylmethylaminoJpenicillanate) of the above chloroform solution is withdrawn. It is diluted with a further 40 ml. of chloroform, and then 1.67 ml. (0.012 mole) 30 of triethylamine is added. The mixture is cooled to ca. 4°C., - 85 - 4 0 5 3 2 in an ice-bath, and then 6.84 ml. of ethyl chloroformate is added all at once, with stirring. Stirring is continued for 30 minutes with ice-bath cooling, and then 7.5 g. (0.060 mole) of 4-hydroxybenzylamine is added. Stirring is contin-5 ued for 10 minutes with ice-bath cooling, and then for a further 1 hour without cooling. At this point, the chloroform solution is washed with water, followed by brine, and then dried using anhydrous sodium sulfate. Removal of the solvent by evaporation in vacuo affords the crude amide. 10 The crude amide is re-dissolved in 50 ml. of chloroform and absorbed on a column of chromatographic grade silica gel. The column is eluted with chloroform, taking 400 ml. fractions. Fractions 9 to 15 are combined and concentrated to an oil. which solidifies on trituration with methylene 15 chloride. After further trituration with ether; there is obtained 12.63 g. of 6-(triphenylmethylamino)-2.2-dimethy1-3-(N-l4-hydroxybenzyl)carbamoyl)penam, m.p. 166-168*C. (dec.). The infrared spectrum of the product (CHCl^ solution) shows absorptions at 1785 cm"1 (p-lactam) and 1675 cm"1 20 (amide I). The NMR spectrum of the product (CDCl^) shows absorptions at 7.60-6.40 ppm (multiplet, 20H, aromatic hydrogens and amide hydrogen), 4.70-4.10 ppm (multiplet, 5H, C-5 and C-6 hydrogens, benzyl methylene hydrogens and C-3 hydrogen), 2.98 ppm (doublet, 1H, amine nitrogen), 1.64 ppm 25 (singlet. 3H, C-2 methylhydrogens) and 1.31 ppm (singlet, 3H, C-2 methyl hydrogens).

(B) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-{4-hydroxybenzyl ]tetrazol-5-yl)penam To a stirred solution of 1.69 g. (3 mmole) of 30 6- (triphenylmethylamino) -2 ,2-dimethyl-3- (N- [4-hydroxybenzylJ- - 86 - 40532 carbamoyl)penam (prepared as described in A) in 9 ml. of chloroform is added 1 ml. (12 mmole) of pyridine. The solution is cooled to ca. 4*C. in an ice-bath and 0.80 ml. of chlorotrimethylsilane is added. The solution is stirred for 5 40 minutes at ambient temperature, and then it is again cooled to ca. 4*C. Phosgene (1.5 ml. of a 4.3M solution in chloroform (6.45 mmole) is added and the cooling bath is removed. Stirring is continued for a further 1.5 hours, and then all the volatile components are removed by evapora-10 tion in vacuo.

The oily residue is redissolved in 6 ml. of chloroform and the solution is cooled to ca. 4°C. in an ice-bath. To the stirred solution is added 0.95 g. (6 mmole) of tetra-methylguanidinium aside, and then stirring is continued for 15 a further 1 hour at ambient temperature. At this point# 25 ml. of water is added, followed by sufficient IN sodium hydroxide to bring the pH of the aqueous phase to 10. The chloroform layer is separated off, washed with water, dried using sodium sulfate and evaporated to dryness in vacuo. The 20 oily residue (2.3 g.) is dissolved in a small volume of chloroform and absorbed on a column of 30 g. of chromatographic silica gel. The column is eluted with chloroform, taking 50 ml. fractions. Fractions 13 to 19 are combined and concentrated in vacuo to give 0.71 g. of 6-(triphenyl-25 methylamino)-2,2-dimethy1-3-(1-t4-hydroxybenzyl]tetrazol-5-yl)penam. The infrared spectrum of the product (in CHCI3) shows an absorption at 1780 cm-1 (^-lactam). The NMR spectrum (CDCI3) shows absorptions at 7.80-6.67 ppm (multiplet, 20H, aromatic hydrogens and phenolic hydrogen), 5.66-5.10 ppm 30 (quartet, 2H, benzyl methylene hydrogens), 5.02 ppm (singlet. - 87 - 40532 1H, C-3 hydrohen), 4.60-4.20 ppm (multiplet, 2H, C-5 and C-6 hydrogen), 3.10 ppm (doublet, 1H, amine hydrogen), 1.44 ppm (singlet, 3H, C-2 methyl hydrogens) and 0.71 ppm (singlet, 3H C-2 methyl hydrogens). 5 EXAMPLE X The procedure of Example IX is repeated, except that where necessary the triphenylmethyl chloride is replaced by the appropriately-substituted triphenylmethyl chloride, and where necessary the 4-hydroxybenzyl amine is replaced by the 10 requisite hydroxybenzylamine, to produce the following congeners: 6-(triphenylmethylamino)-2,2-dimethy1-3-(1- 12-hydroxy-benzyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethy1-3-(1-(3-hydroxy-15 benzyl)tetrazol-5-yl)penam, 6-(dipheny1-[3-methoxyphenyl}methylamino)-2,2-dimethy1-3-(1-(4-hydroxybenzyl]tetrazol-5-yl)penam, 6-(di(4-chlorophenyl)phenylmethylamino)-2,2-dimethyl-3-(1-(4-hydroxybenzyl]tetrazol-5-yl)penam, and 20 6-(tri(4-tolylJmethylamino)-2,2-dimethyl-3-(1-(4-hydr oxybenzyl) tetrazol-5-yl)penam, respectively.

EXAMPLE XI 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-(4-acetoxybenzyl]-tetrazol-5-y1)penam 25 To a stirred solution of 1.69 g. (3 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[4-hydroxybenzyl]-carbamoyl)penam in 9 ml. of chloroform is added 1 ml. (12 mmole) of pyridine. The solution is cooled to ca. 4°C. in an ice-bath and 235 mg. of acetyl chloride is added slowly. 30 The solution is stirred for 2 hours at ambient temperature, - 88 - 40532 and than it is again cooled-try ca. 4*C. Phosgene (l.S ml. of a 4.3M solution in chloroforo [6.45 mmole]) is added and the cooling bath is removed. Stirring is continued for a further 1.5 hours, and then all the volatile components are removed 5 by evaporation in vacuo. The residue is redissolved in 6 ol. of chloroform and the solution is cooled to ea. 4*C. in an ica-bath. To the stirred solution is added 0.95 g. (6 nsaole) of tetramethylguanidinium azide, and then stirring is continued for a further l hour at ambient temperature. At this 10 point, 25 ml. of water is added, followed by sufficient IN sodium hydroxide to bring the pB of the aqueous phase to 10. The chloroform layer is separated off, washed with water, dried using sodium sulfate, and evaporated to dryness In vacuo. This affords crude 6-(triphenylmethylamino)-2,2-di-15 methyl-3-(1-[4-acetoxybenzyl]tetrazol-5-yl)penam, which is purified further by chromatography. example xii Starting with the appropriate 6-(triphenylmethylamino) -2, 2-dimethyl-3- (N-(hydroxybenzyl]carbamoyl)penam or 20 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(N- [hydroxybenzyl]carbamoyl)penam, and where necessary replacing the acetyl chloride by the requisite acid chloride, and following the procedure of Example XI, the following compounds are prepared: 25 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-(2-acetoxy- benzyl]tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-(4-iso-butyryloxybenzyl]tetrazol-5-yl)penam, 6-(diphenyl- [4-methoxyphenyl]methylamino)-2,2-dimethvl-30 3-(1-[4-heptanoyloxybenzyl]tetrazol-5-yl)penam. -89 - 40532 6-(diphenyl-[2-fluorophenyl)methyl amino)-2,2-dimethy1-3-(1-[3-propionyloxybenzyl]tetrazol-5-yl)penam, 6-(diI3-methoxypheny1)phenylmethylamino)-2,2-dimethyl-3-(1-(2-acetoxybenzylJtetrazyl-5-yl)penam, and 5 6-(tri(4-tolyl)methylamino)-2,2-dimethy1-3-(1-[2-acet oxybenzyl] tetrazol-5-yl)penam, respectively.

The starting penam compounds used in this Example arc prepared according to the procedure of Example XX, Part A, by utilizing triphenylmethyl chloride, or the appro-10 priately substituted triphenylmethyl chloride, and the appropriate hydroxybenzylamine.

EXAMPLE XIII Starting with the appropriate 6-(triphenylmethylamino) -2,2-dimethyl-3-(N-(hydroxybenzyl)carbamoyl)penam or 15 6-(substituted triphenvlemthylamino)-2,2-dimethyl-3-(N-hydroxybenzyl)carbamoyl)penam, and replacing the acetyl chloride by formic-acetic anhydride, and following the procedure of Example XI, the following compounds are obtained: 6-(triphenylmechylamino)-2,2-dimethyl-3-(1-{4-formyl-20 oxybenzylj tetrazol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-(2-formyl-oxybenzylJ tetrazol-5-yl)penam, 6-(diphenyl-I2-ethoxyphenyl]methylamino)-2,2-dimethyl-3-(1-[4-formyloxybenzyl]tetrazol-5-yl)penam, 25 6-(di14-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3- (1-(3-formyloxybenzyl)tetrazol-5-yl)penam and 6-(tri[3-tolyl]methylamino)-2,2-dimethy1-3-(1-[4-form-yloxybenzyl)tetrazol-5-yl)penam, respectively.

The starting penam compounds used in this Example 30 are prepared by the procedure of Example IX, Part A, by - 90 - 40532 utilising triphenylmethyl chloride* or the appropriately substituted triphenylnethyl chloride, and the appropriate hydroxybensylanine.

EXAMPLE XIV 5 By following the procedure of Example XI, but starting with the appropriate 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-lhydroxybenzyl)carbamoyl)penam or 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(N-(hydroxy-bensyl]carbamoyl)penam, and replacing the acetyl chloride 10 by the requisite alkoxyalkyl chloride, the•following compounds are prepared:. 6- (triphenylmethylamino)-2,2-dimethyl-3-(1-(4-methoxy-methoxybenzyl]tetrasol-5-yl)penam, 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-(2-ethoxy-15 methoxybenzylltetrasol-5-yl)penam, 6- (diphenyl-[3-tolyl]methylamino)-2,2-dimethyl-3-(1-[4-n-butoxymethoxybenzyl]tetrazol-S-yl)penam, and 6- (tri 13-chlorophenyl] me thylamino)-2,2-dime thyl-3- (1-(4-n-hexyloxymethoxybenzyl]tetrazol-5-yl)penam, 20 respectively.

The starting penam compounds used in this Example are prepared by the procedure of Example IX, Part A, by utilizing triphenylmethyl chloride, or the appropriately-substituted triphenylmethyl chloride, and the appropriate hydroxy-25 benzylamine.

EXAMPLE XV 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-[5-methylfurfuryl]-tetrazol-5-yl)penam The title compound is prepared according to the pro-30 cedure of Example VII, but using 5-methylfurfurylamine in - 91 - 40532 place of furfurylamine. The NMR spectrum (CDCl^J of the product shows absorptions at 7.36 ppm (m, 1511), 6.33 ppm (ra, 1H) , 5.93 ppm (m. 111), 5.50 ppm (s, 211), 5.20 ppm (s, ID), 4.50 ppm (m, 211), 3.23 ppm (d, 1H), 2.26 ppm (s, 3H), 1.63 ppm (s, 3H) 5 and 0.90 ppm (m, 3H).

EXAMPLE XVI 6- (Triphenylmethylamino) -2,2-dimethyl-3- (1- [2,4-dimethoxy-benzyl)tetrazol-5-yl)penam The title compound is prepared in 46% overall 10 yield from 6-(triphenylmethylamino)penicillanic, by replacing the furfurylamine of Example VII by 2,4-dimethoxybenzylamine. The crude product is purified by recrystallization from a mixture of methylene chloride and methanol. The NMR spectrum of the product (CDCI3) shows absorptions at 7.40 ppm (m, 16H), 15 6.45 ppm (m, 2H), 5.40 ppm (s, 2H), 4.50 ppm (m, 2H), 3.75 ppm (s, 3H), 3.70 ppm (s, 3H), 1.55 ppm (s, 3H) and 0.90 (s, 3H).

EXAMPLE XVII 6-Amino-2,2-dimethyl-3- (1- [4-methoxybenzyl1tetra20l-S-yl) -20 penam £-toluenesulfonate To a stirred slurry of 143 g. of 6-(triphenylmethylamino) -2,2-dimethyl-3-(1-[4-methoxybenzyl]tetrazol-5-yl)penam in 1,000 ml. of dry acetone is added 45.0 g. of £-toluenesulfonic acid monohydrate, at ambient temperature. 25 The solids slowly dissolve, giving a clear solution. After about 15 minutes, the product starts to precipitate. Stirring is continued for a further 45 minutes after the product starts to appear, and then a first crop of product is filtered off and washed with chloroform. The acetone is evaporat-30 ed to dryness, and the solid residue is slurried for 45 - 92 - 40532 minutes in 300 ml. of chloroform. This affords a second crop of product. The two crdps are combined, slurried for 1 hour in 1,000 ml. of chloroform, filtered off, and dried in vacuo giving 123 g. of 6-amino-2,2-dimethy1-3-(1-[4-5 methoxybenzyl]tetrazol-5-yl)penam g-toluenesulfonate, m.p. 174-175.5*C. The infrared spectrum (KBr disc) of the product shows an absorption band at 1795 cm-1. The NMR spectrum (in DMSO-dg) shows absorption bands at 7.20 ppm (multiplet, aromatic hydrogens), 5.80 ppm (multiplet, benzyl 10 hydrogens, C-5 hydrogen and C-3 hydrogens), 5.20 ppm (doublet, C-6 hydrogen), 3.75 ppm (singlet, methoxy hydrogens), 2.35 ppm (singlet, sulfonate methyl hydrogens), 1.70 ppm (singlet, C-2 methyl hydrogens) and 0.85 ppm (singlet, C-2 methyl hydrogens). 15 EXAMPLE XVIII By reacting the appropriate 6-(triphenylmethylamino) -2, 2-dimethyl-3- (1-substituted tetrazol-5-yl)penam or 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam, chosen from those in 20 Examples II, III, IV, and VI to XVI, with £-toluenesulfonic acid, according to the procedure of Example XVII, the follow ing compounds are obtained as their £-toluenesulfonate salts 6-amino-2,2-dimethyl-3-(l-benzyltetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[2-methoxybenzylJ tetrazol-25 5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[4-isopropoxybenzylJ tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[3-chlorobenzyl)tetrazol-5-yl)penam, 30 6-amino-2,2-dimethyl-3-(1-[3-chloro-4-methoxybenzyl]- - 93 - 40532 tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-tl-phenylethyl]tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(l-furfuryltetrazol-5-yl)penam, 5 6-amino-2,2-dimethyl-3-(1-(4-nitrobenzyl]tetrazol-5- yl)penam, 6-amino-2,2-dimethyl-3-(1-[4-ethoxybenzyl]tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(l-l4-phenylbenzyl]tetrazol-5-10 yl) penam, 6-amino-2,2-dimethy 1-3- (1- [dipheny line thy 1] tetrazol-5-yl)penam, 6-amino-2,2-dimethy1-3-(1-12-thienylmethylJtetrazol-5-yl)penam, 15 6-amino-2,2-dimethy1-3-(1-f2,4-dimethoxybenzyl)tetr azol- 5-yl)penam, 6-amino-2,2-dimethy1-3-(1-[1-(4-me thoxyphenyl)ethyl)-tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[1-(4-chlorophenyl)butyl]-20 tetrazol-5-yl)penam, 6-amino-2,2-dimethy1-3-(1-((4-methoxyphenyl)phenyl--methyl]tetrazol-5-yl)penam, 6-amino-2,2-dimethy1-3-(1-[3-furylmethylJ tetrazol-5-yl) -penam, 25 6-amino-2,2-dimethyl-3-(1-(4-n-hexyloxybenzyl)tetrazol- 5-yl)penam, 5-»amino-2,2-dimethy 1-3- (1- [ 4-f luorobenzyll tetrazol-5-yl') penam, 6-amino-2,2-dimethyl-3- (1- [ 3,4-dirr.ethoxyben3yii tetrazol-30 5-yl)penam, 40532 6-amino-2,2-dimethyl-3-(1-f4-isopropylbenzyl)tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[(5-methyl-2-thienyl)nethylJ-tetrazol-5-yl)penam, 5 ' 6-amino-2,2-dimethyl-3-(1-[5-methyIfurfuryl]tetrazol- 5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[4-iodobenzyl]tetrazol-5-yl)-penam, 6-amino-2,2-dimethy1-3-(1-[4-biphenylylmethyl]tetrazol-10 5-yl)penam, 6-amino-2,2-dimethy1-3-(1-[4-n-hexylbenzyl]tetrazol-5-yl)penam, 6-amino-2,2-dime thyl-3-(1-(4-hydroxybenzyl]tetrazol-5-yl)penam, 15 6-amino-2,2-dimethy1-3-(1-[2-hydroxybenzyl]tetrazol-5- yl)penam, 6-amino-2,2-dimethyl-3-(1-[2-acetoxybenzyl]tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[4-acetoxybenzyl]tetrazol-5-20 yl) penam, 6-cimino-2,2-dimethyl-3-(1-[4-isobutyryloxybenzyl]tetr-azole-5-yl) pen£un, 6-amino-2,2-dimethyl-3-(1-[4-formyloxybenzyl]tetrazol- 5-yl)penam, and 25 6-amino-2,2-dimethyl-3-(1-[2-ethoxymethoxybenzyl]tetr- azol-5-yl)penam, respectively.

EXAMPLE XIX 6-Amino-2,2-dimethyl-3-(1-[4-benzvloxybenzyl]tetrazol-5-yl)-penam 30 A solution consisting of 558 mg. of 6-(triphenyl- - 95 - 40532 methylamino)-2,2-dimethy1-3-(1-I4-benzyloxybenzyl)tetrazol- 5-yl)penam, 156 mg. of £-toluenesulfonic acid monohydrate and 1 ml. of acetone is stored at ambient temperature for 2.5 hours. It is then added with stirring to 50 ml. of 5 ether. After stirring for a further 10 minutes, the solid which has precipitated is filtered off. This affords 394 mg. of the £-toluenesulfonate of the product. A 304 mg. aliquot of this £-toluenesulfonate salt is dissolved in 10 ml. of methylene chloride, and to the solution is added 10 69.7 ^il. of triethylamine. After 3 minutes, 5 ml. of water are added and the mixture is stirred vigorously. The organic phase is then separated off, diluted with ether, dried using anhydrous magnesium sulfate, and evaporated to dryness in vacuo. The residue is 189 mg. (69% yield) of 15 2-amino-2,2-dimethyl-3- (1- (4-benzyloxybenzylJ tetrazol-5- yl)penam. The NMR spectrum (in CDCl^) of the product shows absorption bands at 7.40 ppm (singlet, phenyl hydrogens), 7.15 ppm (quartet, phenylene hydrogens), 5.55 ppm (broad singlet, C-5 and benzyl hydrogens), 5.20 ppm (singlet, C-3 20 hydrogens), 5.10 ppm (singlet, benzyl hydrogens), 4.60 onm (doublet, C-6 hydrogen), 1.50 ppm (singlet, C-2 methyl hydrogens) and 0.90 ppm (singlet, C-2 hydrogens).

EXAMPLE XX 6-Amino-2,2-dimethyl-3- (l-furfuryltetrazol-5-yl)penam 25 To a stirred solution of 0.422 g. (0.75 mmole) of 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-furfuryltetrazol-5-yl)penam in 1 ml. of acetone at ambient temperature, is added 0.142 g. (0.75 mmole) of £-toluenesulfonic acid mono-hydrate. Stirring is continued for 30 minutes, and then the 30 solvent is removed by evaporation in vacuo. This affords - 96 - 40532 the title compound as its £-toluenesulfonate salt. XR (Nujol mull)s 1780 cm"1 (3-lactam). NMR (DMSO-dg): 7.20 ppm (q, 4H), 6.40 ppm (n, 2H), S.90 ppm (s, 2H), 5.60 ppm (a, 2H), 5.00 ppm (d, 1H), 2.20 ppm (s, 3H), 1.60 ppm (s, 5 3H), 0.80 ppm (s, 3H).

EXAMPLE XXI 6-Ami no-2,2-dime thy 1-3- (1- [ 5-methvlfur furyl] tetrazol-5-yl) -penam To a stirred solution of 1.827 g. of 6-(triphenyl-10 methylamino) -2,2-dime thy 1-3- (1- [ 5-sae thy 1 fur furyl] tetrasol- 5-yl)penam in 3 ml. of acetone is added a solution of 0.59 g. of £-toluenesulfonic acid monohydrate in 2 ml. of acetone. The mixture is stirred at ambient temperature for 30 minutes, and then the precipitate which has formed is filtered off. 15 This affords 0.87 g. (54% yield) of the title compound as its £-toluenesulfonate salt. The NMR spectrum of the product (CDC13) shows absorptions at 7.28 ppm (q, 4H), 6.50 ppm (d, 1H), 6.01 ppm (s, 1H) , 5.86 ppm (s, 2H), 5.71 ppm (s, 1H), 5.68 ppm (d, 1H). 5.09 ppm (d, 1H), 2.00 ppm (2s, 6H), 20 1.66 ppm (s, 3H) and 0.88 ppm (s, 3H).

EXAMPLE XXII 6-Amino-2.2-dimethyl-3-(1-[2,4-dimethoxybenzyl)tetrazol-5-yl)penam To a stirred solution of 2.0 g. of 6-(triphenyl-25 methylamino)-2,2-dimethyl-3-(1- [2,4-dimethoxybenzyl]tetrazol-5-yl) penam in 40 ml. of methylene chloride, is added a solution of 0.600 g. of [>-toluenesulfonic acid mono-hydrate in 4 ml. of acetonc. The resulting clear solution is stirred at ambient temperature for 18 hours, and then 30 the solvent is removed by evaporation in vacuo. The - 97 - v 4 0 5 3 2 residue is triturated with other, to «jivo 1.76 «j. (99% yiold) of a white solid, which is the title compound as its £-toluenesulfonate salt. The NMR spectrum (DMSO-dg) shows absorptions at 7.65 ppm (m,' 511), 6.90 ppm (m, 2H), 5 5.95 ppm (m, 311), 5.40 ppm (d, 1H) , 3.95 ppm (a, 3H), 2.45 ppm (s, 3H), 1.95 ppm (s, 311) and 1.15 ppm (s, 3H).

EXAMPLE XXII1 6-Amlno-2,2-dimethyl-3-(5-tetra2olyl)penaia A stirred solution of 32.0 g. of 6-amino-2,2-10 dimethyl-3-(1-[4-methoxybenzylltetrazol-5-yl)penam £-tolu-enesulfonate, and 24 ml. of anisole, in 96 ml. of trifluoroacetic acid is maintained at 40 t 1*C. for 35 minutes. The trifluoroacetic acid is then removed rapidly by vacuum distillation. A 120 ml. portion of ether is added to the 15 residue, which produces a white flocculent suspension. The suspension and solvent is cooled to about 0°C., and to it is then added, portionwise, 80 ml. of 2N sodium hydroxide, giving two clear phases. The pH of the aqueous phase at this point is about 2.7. The layers are separated, and the 20 ether phase is discarded. The pH of the aqueous phase is raised to 4.1 with 2N sodium hydroxide. This aqueous phase is then washed with 100 ml. of ether and filtered. It is combined with the corresponding aqueous phases from four other identical experiments, and the total aqueous solution 25 i3 lyophilized to give crude 6-amino-2,2-dimethyl-3-(5- tetrazolyl)penam. This crude product is slurried in a small amount of water and filtered off. It is; then re-suspended in water and brought into solution by raising the pH to 7.4 by the addition of sodium hydroxide solution. The clear 30 solution is extracted with ether and tho extracts are dis- 98 - 40832 carded. The pH of the aqueous phase is adjusted to 4.1 using dilute hydrochloric acid, and the product which precipitates is filtered off. The infrared spectrum of the product 8hows an absorption at 1795 cm**1. Its NMR spectrum i 5 (in DMSO-dg) shows absorptions ac 5.65 ppm (doublet C-5 hydrogen), 5.20 ppm (singlet, C-3 hydrogen), 4.70 ppm (doublet, C-6 hydrogen), 1.65 ppm (single*.. C-2 methyl hydrogens) and 1.10 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE XXIV 10 Reaction of the £-toluenesulfonate salt of a 6-amino-2,2-dimethyl<-3-(1-substituted tetrazol-5-yl)penam, selected from: 6-amino-2,2-dimethyl-3- (1- [2-methoxybenzyl]tetrazol-5-yl)penam, 15 6-amino-2,2-dimethyl-3- (1- [4-isopropoxybenzyl] tetrazol- 5-yl)penam, 6-amino-2,2-dimethy 1-3- (1- [ 3-chloro-4-methoxybenzyl ] -tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1-[1-phenylethyl] tetrazol-5- 20 yl)penam, 6-amino-2,2-dimethy1-3- (l-furfuryltetrazol-5-yl)penam, 6-amino-2,2-dimetvenam, 6-amino-:*, 2- EXAMPLE XXVI 10 When the procedure of Example XXV is repeated, but using as starting material 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[2-hydroxybenzyl]carbamoyl)penam, there is produced 6-(triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam. 15 The 6-(triphenylmethylamino)-2,2-dimethyl-3-(N- [2-hydroxybenzyl]carbamoyl)penam is prepared according to the procedure of Example IX, Part A, but using 2-hydroxy-benzylamine in place of 4-hydroxybenzylamine.

EXAMPLE XXVII 20 Starting with the appropriate 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(N-I4-hydroxybenzyl]-carbamoyl)|>cnam, and following the procedure of Example XXV, there is obtained the following congeners: 6-(diphenyl-[3-methoxyphenyl]methylamino)-2,2-dimethyl- 25 3-(5-tetrazol-5-yl)penam, 6-(diphenyl- [2-fluorophenyl]methylamino)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam, 6-(di[4-chlorophenyl]phenylmethylamino)-2,2-dimethyl-3-(5-tetrazol-5-yl)penam, and 30 6-(tri[4-tolyl]methylamino)-2,2-dimethyl-3-(5-tetr- - 102 - 40532 azolyl)penam, respectively.

The starting materials used in this Example are prepared by the method of Example IX, Part A, but using the appropriately-substituted triphenylmethyl chloride. 5 EXAMPLE XXVIII 6-(Triphenylmethylamino)-2,2-dimethyl-3-(1-tethoxycarbonyll-carbamoyl)penam (A) 6-(Triphenylmethylamino)-2,2-dimethyl-3-(N-ethoxycarbon-yl-carbamoyl)penam 10 To a stirred solution of 4.58 g. (10 mmole) 6-(triphenylmethylamino)penicillanic acid and 1.45 ml. (10 mmole) of triethylamine, in 75 ml. of acetonitrile, is added 1.15 g. (10 mmole) of ethoxycarbonyl isocyanate dissolved in 5 ml. of acetonitrile. The resulting solution is stirred 15 at ca.25®C. for 16 hours, and then the solvent is removed by evaporation in vacuo. The residue is redissolved in chloroform and the chloroform solution is washed successively with water, sodium bicarbonate solution and sodium chloride solution. The chloroform solution is then dried using an-20 hydrous magensium sulfate, and evaporated in vacuo. The residue is again redissolved in chloroform, and the chloroform solution is washed with dilute hydrochloric acid, dried using magnesium sulfate, and again evaporated in vacuo. This affords the crude product, which is purified by chroma-25 tography using silica gel as the adsorbent and eluting the column with chloroform containing 4% by volume of ethanol. The final yield of 6-(triphenylmethylamino)-2,2-dimethyl-3-(N-[ethoxycarbony1carbamoy1)penam is 2.54 g. (48% yield). - 103 - 4 0532 (B) 6-(Triphunylmnthy1 amino)-2,2-dimethy1-3-(1-(ethoxycarbonyl] tetr-T7.ol-5-yi) [tunam To a stirred solution of 529 mg. (1 mmole) of 6-(triphenylmethylamino)-2,2-dimethy1-3-(N-[ethoxycarbonyl] 5 carbamoyl)penam and 240 mg. (3 mmole) of pyridine, in 25 ml. of methylene chloride, is added 208 mg. (1 mmole) of phosphorus pentachloride, at 0°C. The reaction mixture is stirred at 0*C. for 0.5 hour and then at ca. 25*C. for 2 hours. The solvents and the excess pyridine are then 10 removed by evaporation in vacuo, and the residue is redissolved in 15 ml. of chloroform. The latter chloroform solution is cooled to 0"C., and 0.47 g. (3 mmole) of tetra-methylguanidinium azide is added in several small portions with stirring. Stirring is continued for 2 hours at 15 ambient tem|>eraturo, and then to the reaction mixture is added a further 15 ml. of chloroform followed by 30 ml. of water. The pH is adjusted to 6.5, and then the chloroform layer is removed. The chloroform solution is washed with water followed by brine, and then it in dried using 20 anhydrous sodium sulfate. Removal of the solvent by evaporation in vacuo affords crude 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam. The crude product is purified further by chromatography using silica gel. 25 EXAMPLE XXIX Starting with 6-(triphenylmethylamino)penicillanic acid, or the appropriately-substituted 6-(triphenylmethylamino) penicillanic acid, and the requisite isocyanate of formula R^O-C (=0) -N=C=0, and following the procedure of 30 Example XXVIII, the following compounds are prepared: - 104 - 40532 \ R22 o»c k" R22 R23 R2* R14 h H H ch3 H H h ch3ch2ch2 5 H H H (ch3)2chch2 H H H ch3(ch2)4ch2 H H H c6h5ch2 H H H 4-02NC6h4 H H H 2-FC6H4 10 H H H 3-BrCgH4 H H H C6H5 H H H 4-(ch3[ch2j2ch2)c6h4 H H H 3-ch3ocgh4 H H H 4-([ch3]2cho)c6h4 15 H H h 2,4-Cl2C6H3 H H H 3,4-{ch3ch20)2c6h3 H H h 3,5-(ch3)2c6h3 H H H 4-Cl-3-CH3CgH3 3-ch3 H H 4-(ch3ch2ch20)-2-02nc6h3 20 4-ch3ch2ch2 h H 4-(ch3[ch212ch20)cgh4 4-Br H H ch3ch2 - 105 - 40532 in 20 r22 r« r24 r" 2-f h h c6h5ch2 3-c6h5 h h c6»5 3-ch3ch20 h h 4-02nc6h4 4-c1 4-c1 h 2,4-(02n)2c6h3 4-CH3 3-CH3O 3-CH30 ch3ch2 4-CH3 4-CH3 4-CH3 c6h5 EXAMPLE XXX Starting with 6-(triphenylmethylamino)penicillanic acid, or the appropriately-substituted 6-(triphenylmethylamino) penicillanic acid, and the requisite isocyanate of formula R14-S02-N=C=0, and following the procedure of Example XXVIII, the following compounds are prepared: r" r23 r' h h h h h h h h h h h h h h h h h h 24 ,14 ch, ch3ch2 (ch3)2chch2 c6h5ch2 c6h5 4-02nc6h4 - 106 - 40832 r23 R24 R14 H H H 3-fc6b4 H H H ' 2-ClCfiH4 H b b 4-brc6b4 H b b 2-(CH3CH2)C6h4 h b b 3-(cb3cb2ch2cb2)c6b4 H b b 4-cb3oc6b4 b b b 3-([cb3]2cbcb20)c6b4 b b b 2,4-Cl2C6b3 b b b 3-cb3-4-cb3oc6b3 H b b 2,4-(02n)2c6b3 b b b 2-cb30-5-02ncfiH3 2-cb3 b H cb3 3-ch3cb2 h H C6h5ch2 3-c) H H 4-02nc6h4 4-CH3O h H c6»5 4-c6h5 b h ch3ch2 3-c1 3-c1 h 4-C1CsH4 3-ch30 3-CB3O 3-CB3O 2,4-(02n)2c6h3 EXAMPLE XXXI 6- (Triphenylmethylamino) -2,2-dimethyl-3- (5-tetrazolyl) penam To a stirred mixture of 2 ml. of tetrahydrofuran and 4 ml. of water is added 150 mg. of 6-(triphenylmethylamino) -2,2-dimethy1-3-(1- lethoxycarbonyl]-tetrazol-5-yl)-25 penam. The pH of the mixture is adjusted to 9.5, and stirring is continued at that pH for a further 30 minutes, at ambient temperature. The bulk of the tetrahydrofuran is removed by evaporation in vacuo, and the residue is portioned between water and ethyl acetate at pH 9. The 30 ethyl acetate is removed and discarded. Fresh ethyl - 107 - 10 40532 acetate is added and the pH is adjusted to 2.0. The ethyl acetate layer is removed, washed with water* dried using anhydrous sodium sulfate, and evaporated in vacuo to give tbe crude title compound.

EXAMPLE XXXII Reaction of any of the 6-(triphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam or 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(1-substituted tetrasol-5-yl)penam compounds* listed in Bxaaples XXIX and XXX, with water at pH 9.5* according to the procedure of Bxaxnple XXXI, results in removal of the C(-0)-0-R14 or SOj-R14 group and its replacement by hydrogen. In this way* the following compounds are obtained! -R22 15 ,22 ,23 ,24 20 h 3-CB3 4-CB3CB2CB2 4-Br 2-F 3-C6H5 3-CH3CB20 4-C1 B H B B H H H 4-C1 B B B B B H H H - 108 - 40833 R22 R« R24 4-ch3 3-ch3o 3-ch3o 4-CH3 4-ch3 4-CHj 2-ch3 H b 3-CH3CH2 H b 3-C1 H b 4-ch3o H b «-C6«5 b b 3-C1 3-C1 b 3-ch3o 3-ch3o 3-cb3o EXAMPLE XXXIII 6-Amino-2,2-dimethy1-3-(5-tetrazolyl)penam To a stirred solution of 2.0 g. of 6-(triphenylmethylamino) -2, 2-dimethy 1-3- (5- tetrazolyl) penam in 35 ml. of IS acetone* is added 788 mg. of £-toluenesulfonic acid mono- hydrate , at ambient temperature. Stirring is continued tor 45 minutes and then the solvent is removed by evaporation in vacuo. To the residue is added 30 ml. of water and 30 ml. of ether, and the pH is adjusted to 7.0. The ether 20 layer is separated and discharged. The pH of the aqueous phase is adjusted to 4.1, and then the aqueous phase is ^qnc^entrated to small volume. The solid which has precipitated ip removed by filtration and dried. This affords i tjje. *4tie pompound.

; EXAMPLE XXXIV When each of the 6-(substituted triphenylmethyl-aminp)-3jj2-dimethyl-3-(5-tetrazolyl)penam compounds describ- ^yf^$le XXXII is reacted with £-toluenesulfonic acid* according to the procedure of Example XXXIII, the product in ^jJ f® 6~amino-2,2-dimethyl-3-(5-tetrazolyl)penajn. 1 ^ 1 « / - 109 - -0532 EXAMPLE XXXV 6-Ami no-2.2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)-penam To a stirred solution of 554 mg. of 6-(triphenyl-5 methylamino)-2,2-dimethyl-3-(1-[ethoxycarbonyl]tetrazol-5-yl)penam in 2 ml. of acetone is added a solution of 190 ag. of £-toluenesulfonic acid of 1 ml. of acetone. Stirring is continued for a further 3 hours, and then the acetone is removed by evaporation in vacuo. The residue is slurried 10 in ether, filtered and dried, to give the title compound as its £-toluenesulfonate salt.

The above £-toluenesulfonate salt is added to a mixture of 15 ml. of water and 15 ml. of chloroform. The pH of the aqueous phase is adjusted to 7.0, and the chloro-15 form layer is removed. The chloroform is dried using sodium sulfate, and then it is evaporated in vacuo to give the title compound as its free base.

EXAMPLE XXXVI Reaction of the appropriate 6-(triphenylmethyl-20 amino)-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam or 6-(substituted triphenylmethylamino)»2,2-dimethyl-3-(l-substituted tetrazol-5-yl)penam, chosen from those in Examples XXIX and XXX, with £-toluenesulfonic acid, according to the procedure of Example XXXV, provides the follow-25 ing compounds as their £-toluenesulfonate salts. nh2 ,sx ch3 - no - 40532 r2 co2ch3 c02 (cii2ch2ch3 c02(ch2chich3)2) 5 C°2CB2C6U5 C02(4-C6H4N02 co2(2-csH4r) C02(3-C6H4Br) co2c6h5 10 c02(4-c6h4CH2CH2cb2CH3) °°2<3"C6H4CH3> c02(4-c6b4och[ch3 j 2) C02(2,4-C6H3C12) c02(3,4-c6h3[0ch2ch3]2) 15 coj(3,5-cgh3(ch3)2) c02(cgh3-4-Cl-3-ch3) c°2(c6h3-4-10ch2ch2ch3)-2-n02> co2(4-c6h4och2ch2ch2ch3) c02(2.4-c6h3[n02]2) 20 s02ch3 so2ch2ch3 s02(ch2ch(ch3j2) so2ch2c6h« s02c6h5 25 s02(4-c6h4n02) s02(3-c6h4p) S02(2-CgH4Cl) S02(4"C6H4Br) s02(2-c6h4ch2ch3) 30 s02{3-cgh4ch2ch2ch2ch3) - Ill - 40932 s02(4-c6h4°ch3) S<>2(3-C6H4OCH2CH(CHj]2) S02(2,4-C6H3C12) 5 S02(C6H3-3-CH3-4-OCH3) s02(2,4-c6h3[n02j2) s°2(C6H3-2-0CH3-2-N02 EXAMPLE XXXVII 6- (Triphenvlme thylamino) -2.2-dimethyl-3- (1-12-methoxycarbon-10 ylethylltetrazole-5-yl)penam (A) 6- (Triphenylmethylamino) -2,2-dimethy 1-3- (N- [2-methoxy-carbonylethy1Jcarbamoyl)penam To a stirred solution of 35 g. of 6-(triphenylmethylamino) penicillanic acid in 250 ml. of dry, ethanol-15 free chloroform, is added 11.7 ml. of triethylamine at 0-3*C. The solution thus obtained is then added dropwise, with stirring, at 0-6°c£, to a second solution, prepared from 7.3 ml. of ethyl chlorofornate in 155 ml. of dry, ethanol-free chloroform. Stirring is continued for a 20 further 10 minutes. This affords a chloroform solution of the mixed anhydride of 6-(triphenylmethylamino)penicillanic acid.

In a separate flask, a solution of y3-alanine methyl ester is prepared by adding 11.7 ml. of triethylamine to a 25 slurry of 10.73 g. of ^-alanine methyl ester hydrochloride and 2 g. of anhydrous sodium sulfate in 115 ml. of dry, ethanol-free chloroform, at ca. 10°C. Stirring is continued for a further 10 minutes.

The latter amino-ester solution is then added drop-30 wise, with stirring at 3-6sC., to the above-described mixed - 112 - 40832 anhydride solution. After the end of the addition* stirring is continued for a further 2 hours.

At this point, the reaction solution is washed successively with three portions of water and one portion 5 of brine. The solution is then dried using anhydrous sodium sulfate, and evaporated in vacuo to give 40.1 g. of crude 6- (triphenylmethylamino) -2,2-dime thyl-3- (N- [2-me thoxy car bony 1 ethyl]carbamoyl)penam as a glassy solid, m.p. 60-70*C. The crude product is purified by extracting it into refluxing 10 ether, treating the filtered solution with activated carbon, and then re-precipitating the product by the addition of petroleum ether.

(B) 6-(Triphenylmethylamino)-2,2-dimethy1-3-(1-[2-methoxy-carbonylethyl]tetrazol-5-yl)penam 15 To a stirred solution of 2 g. of the amide describ ed under (A) above, in 5 ml. of dry, ethanol-free chloroform, is added, at ca. 0*C., 1.36 ml. of pyridine, followed by a solution of 620 mg. of phosgene in 4 ml. of dry, ethanol-free chloroform. The solution is stirred for 2.5 hours, at 20 ambient temperature, and then the solvent is removed by evaporation in vacuo. The residue is re-dissolved in 9 ml. of dry, ethanol-free chloroform, and 580 mg. of tetramethyl-guanidinium azide is added. The reaction mixture is stirred for 45 minutes, at which point a further 200 mg. of tetra-25 methylguanidinium azide is added. The reaction mixture is then stirred 18 hours to complete the conversion to tetrazole To the reaction solution is then added saturated sodium bicarbonate solution, in sufficient quantity that the pH of the aqueous phase is 7.6. The chloroform layer is removed, 30 washed with water at pH 5, washed with water at pH 7, dried - 113 - 40532 10 15 20 using anhydrous sodium sulfate# and finally evaporated in vacuo. This affords 2.19 g. of crude product, which is re-crystallized from methanol giving 1.11 g. (48% yield) of product with m.p. 100-105°C. The NMR spectrum (cdci3) shows absorptions at 7.40 ppm (ra, 15H), 5.15 ppm (s, 1H), 3.80 (m, 4H), 3.70 ppm (s, 3H), 3.10 ppm (s, 3H) and 1.17 ppm (s, 3H), and further indicates that the product contains methanol of solvation.

EXAMPLE XXXVIII The procedure of Example XXXVII is repeated, except that where necessary the 6-(triphenylmethylamino)-penicillanic acid is replaced by the appropriately-substituted 6-(triphenylmethylamino)penicillanic acid, and where necessary the p-alanine methyl ester is replaced by the appropriate amine to produce the following compounds: .22 h H H H H h h h h h h h h h h c(=o)och2ch3 c(=0)0ch(ch3)2 c(=o)och2(ch2)4ch3 c(=o)oc6h5 s°2ch3 - 114 - 40532 r" R" r2« y h h h so2cb2(ch2)2cb3 h b b so2nbc6e5 a h b so2n(c6b5)2 a b b so2n(ch3)c6b5 a h b s020ch3 a b b so2ocb2cb3 a h b so2och2cb(cb3)2 B h b s02c6h5 h h b so2nb2 a h b so2nbch3 h h b s02n(ch2cb2ch3)2 h h h so2nbcb2c6h5 h h h cn 2-f h h c(=0)0ch3 3-ch30 h h so2ch2ch3 3-c6h5 h h s02mh(ch2(ch212ch3> 3-c1 3-c1 h c(=0)0ch3 4-ch3 4-chj 4-CH3 c(=0)0ch2ch3 20 EXAMPLE XXXIX 6- (Triphenylmethylamino) -2,2-dlroethyl-3- (1-12-methoxycarbonylethyl] tetrazol-S-yl) penam To a stirred solution of 8 g. of 6-(triphenylmethylamino) -2,2-dimethyl-3-(N-[2-methoxycarbonylethyl]carb-25 amoyDpenam (prepared as described in Example XXXVII, Part A) in 20 ml. of dry, ethanol-free chloroform, is added 5.4 ml. of pyridine. To this solution is then added a solution of 2.7 g. of phosgene in 16 ml. of dry, ethanol-free chloroform, at ca. 0°C. The reaction mixture is stirred at 30 ambient temperature for 1.5 hours, and then the solvent is - 115 - removed by evaporation in vacuo. The viscous residue is re-dissolved in 36 ml. of dry chloroform, the solution is cooled to ca. 0°C.* and 2.6 ml. of trimethylsilyl azide is added. Tho reaction mixture is stirred at ambient tempera-5 ture for 17 hours. At this point 1.26 9. of solid sodium bicarbonate is added to the chloroform solution* followed by sufficient aqueous saturated sodium bicarbonate to give a pH of 7.6. The chloroform is separated* washed with water* washed with brine* dried using anhydrous sodium 10 sulfate* treated with 200 mg. of activated carbon* and finally evaporated in vacuo. The residue is triturated with cyclohexane* and then recrystallized from methanol* giving 3.85 g. (46% yield) of the title compound* m.p. 94-98*C. After further recrystallization of the product 15 from methanol, the melting point is raised to 104-106*C. The NMR spectrum (COCI3) shows absorptions at 7.40 ppm (m* 15H), 5.15 ppm (s, 1H), 3.80 ppm (m, 4H), 3.70 ppm (s, 3H), 3.10 ppm (t, 2H), 1.70 ppm (s, 3H) and 1.17 ppm (s, 3H)* and further indicates that the product contains 20 ca. 3% of methanol of solvation. example xl 6-(Triphenylmethylamino)-2 * 2-dimethyl-3-(5-tetrazolyl)-penam To a stirred solution of 600 mg. of 6-(triphenyl-25 methylamino)-2,2-dimethyl-3-(1-[2-methoxycarbonylethyl]-tetrazol-5-yl)penam (containing ca. 4.5% of methanol) in 1 ml. of chloroform* is added a solution of 375.2 mg. of diazabicyclo[4.3.0]non-5-ene in 0.5 ml. of chloroform. Stirring is continued for a further 3 hours, and then the 30 solution is diluted with a further 2 ml. of chloroform. - 116 - 40532 The latter solution is washed quickly with 5 ml. of 2N hydrochloric acid, and then a further 5 ml. of 2H hydrochloric are added. The resulting mixture is cooled to ca. 0*C.« and the solid which precipitates is filtered off, 5 giving 323 mg. (71% yield) of the title compound. The NMR spectrum (DMSO-dg) of the product shows absorptions at 7.40 ppm (m, 15H), 5.30 ppm (s, 1H) , 4.60 ppm (m, 2H) , 1.58 ppm (s, 3H) and 0.78 ppm (s, 3H). 2,2-dimethy1-3-(1-substituted tetrazol-5-yl)penam or 6-(substituted triphenylau lamino)-2,2-dimethyl-3-(l-substituted tetrazol-5-yl)ptsnam compounds, listed in Example XXXVIII, with diazabicyclo[4.3.0]non-5-ene, accord- of the 2-substituted ethyl substituent from the tetrazole ring, and its replacement by hydrogen. In this way, the following compounds are obtained: 10 EXAMPLE XU Reaction of any of the 6-(triphenylmethylamino) 15 ing to the procedure of Example XL, results in removal - 117 - 40532 r22 R23 r2« H H H 2-F H H 3-ch3o H H 3-C6H5 H R 3-C1 3-C1 H 4-CHj 4-ch3 4-CH The above 6-(substituted triphenylmethylamino)-2,2-dimethyl-3-(5-tetrazolyl)penam compounds are converted 10 into 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam by reaction with £-toluenesulfonic acid, according to the procedure of Example XXXIII.

EXAMPLE XLII 6-(3-to-Chlorophenyl)-5-methyl-4-isoxazolecarboxamldo)-2,2-15 dimethyl-3-(5-tetra2olyl)penam A stirred slurry of 240 mg. of 6-amino-2,2-di-methy1-3-(5-tetrazolyl)penam in 10 ml. of water is cooled to 0®C., and then the pH is adjusted to 7.1 using IN sodium hydroxide. The resultant solution is diluted with 10 ml. 20 of acetone, and then a solution of 281 mg. of 3-(o-chloro- phenyl)-5-methylisoxazole-4-carbonyl chloride (Doyle, et al., Journal of the Chemical Society {London] 5838 {1963]) in 10 ml. of dry acetone is added portionwise during 3-4 minutes. During the addition the pH of the solution is 25 maintained in the range from 5.5 to 6.5 by adding 0.1N sodium hydroxide. At the end of the addition the reaction is stirred an additional 15 minutes at around 0°C. At this point, the acetone is removed by evaporation under reduced pressure at around 15°C., the resultant aqueous phase is 30 filtered and the pH is lowered to 2 with dilute hydrochloric - 118 - acid. The product is extracted into chloroform. The extract is dried using anhydrous sodium sulfate, and then it is evaporated in vacuo to give the crude product as a gun. The gum is re-dissolved in 3 ml. of tetrahydrofuran* 5 and then the solution is added to 15 ml. of vater at 10*C. The pH of the solution is raised to 7.0 by the addition of 0.1N sodium hydroxide* the solution is filtered, and then it is lyophilized. This affords 430 mg. of the sodium salt of 6- (3- [o-chlorophenyl] -5-methyl-4-isoxazole-10 carboxamido) -2,2-dimethyl-3-(5-tetrazolyl) penam as an amorphous solid. The infrared spectrum (KBr disc) of the product shows absorption bands at 1770 cm"*1 ({{-lactam carbonyl), 1650 cm-1 (amide I band) and 1520 cm-1 (amide XI band). The NMR spectrum (in CDCl^) shows absorption 15 bands at 7.40 ppm (multiplet, aromatic hydrogens), 5.90 and 5.60 (2 doublets, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 2.80 ppm (singlet, isoxazole methyl hydrogens), 1.50 ppm (singlet, C-2 methyl hydrogens) and 1.05 ppm (singlet, C-2 methyl hydrogens). 20 example xliii When the procedure of Example xlii is repeated, and the 3-(o-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride used therein is replaced by 3-phenyl-5-methylis-oxazole-4-carbonyl chloride, 3-(2,6-dichlorophenyl)-5-methyl-25 isoxazole-4-carbonyl chloride and 3-(2-chloro-6-fluoro- phenyl)-5-methylisoxazole-4-carbonyl chloride, respectively, there is produced: 6-(3-phenyl-5-methyl-4-isoxazolecarboxamido)-2,2-di-methyl-3-(5-tetrazolyl)penam; 30 6-(3-[2,6-dichlorophenyl]-5-methyl-4-isoxazolecarbox- - 119 - 4 0 5 3 2 amido)-2,2-dimethyl-3-(5-tetrazolyl)penam, and 6-(3-[2-chloro-6-fluorophenyl]-5-methyl-4-isoxazole-carboxamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, respectively. 5 The starting acid chlorides used in this experi ment are prepared by the action of thionyl chloride on the corresponding acids, which in turn are prepared by the published methods (Long, et al., Journal of the Chemical Society (London], 5838 (1963); United States Patent No. 10 2,996,501).

EXAMPLE XLIV 6-(2-Azido-2-phenylacetamldo)-2,2-dlmethyl-3-(5-tetrazolyl)-penam A solution of 1.61 grams (9.1 mmole) of 2-azido-15 2-phenylacetic acid [Forster and Mueller, J. Chem. Soc., 97, 138 (1910)] and 5 ml. of thionyl chloride is heated under reflux for hour. The reaction solution is evaporated under reduced pressure to furnish a residue of 2-azido-2-phenylacetyl chloride which is dissolved in 10 ml. of di-20 chloromethane and is added over 5 minutes to a stirred ice-bath cooled solution of 2.4 grams (10 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 2.02 grams (20 mmole) of triethylamine and 50 ml. of dichloromethane. After 30 minutes the reaction solution is allowed to warm to room 25 temperature. After a further 3 hours, the more volatile components of the solution are evaporated under reduced pressure and the residue is taken up in 50 ml. of water. The aqueous solution is washed twice with 25 ml. portions of ethyl acetate, and it is then adjusted to pH 2.5 by the 30 csrsful addition of 6N hydrochloric acids Th© rgsultin.9 - 120 - 40832 cloudy mixture is extracted twice with 30 ml. portions of ethyl acetate. After being dried using anhydrous sodium sulfate, the combined extracts are filtered and the solvent is evaporated in vacuo. The residue is dissolved in 10 ml. 5 of dichloromethane; 1.0 ml. of triethylamine is added, and the resulting solution is poured into 350 ml. of rapidly stirred diethyl ether. The solid which precipitates is filtered off giving 1.62 g. (38% yield) of the title compound as its triethylamine salt. IR (KBr disc): 1792 cm-1 10 ^-lactam) and 1693 cm'1 (amide X). NMR (in D2<>/NaHC03) : 7.40 ppm (s, 5H, aromatic hydrogens), 5.60 and 5.80 ppm (m and m, 2H, C-5 and C-6 hydrogens), 5.30 ppm (m, 2H, C-3 hydrogen and side-chain methine hydrogen), 3.20 (q, 6H, NCHjCHj), 1.60 ppm (s, 3H, C-2 methyl hydrogens), 1.30 ppm 15 (t, 9H, NCH2CH3), 1.10 ppm (s, 3H, C-2 methyl hydrogens).

EXAMPLE XLV 6-(2-Cyanoacetamido)-2,2-din»ethyl-3-(5-tetrazolyl)penam To a solution of 2.0 g. of 2-cyanoacetic acid and 2.7 g. of N-hydroxysuccinimide, in 50 ml. of tetrahydro-20 furan, is added 4.85 g. of dicyclohexylcarbodiimide. The mixture is stirred at ambient temperature overnight, and then the precipitate is filtered off and discarded. Evaporation of the solvent then affords the N-hydroxysuccinimide ester of cyanoacetic acid, which after recrystal.'.ization 25 from chloroform has m.p. 123-30°C. and is suitable for use as described below. (A more highly purified sample has m.p. 128-130°C.) To a stirred suspension of 177 mg. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 10 ml. of methylene 30 chloride, under nitrogen, is added 157 mg. of triethylamine. - 121 - 10532 Stirring is continued until a clear solution is obtained (ca. 35 miputes). To this solution is then added 135 mg. of the N-hydroxysuccinimide ester of cyanoacetic acid, all in one portion. After stirring for a further 2.5 hours, 5 the reaction mixture is poured into 15 ml. of water and the pH of the aqueous phase is adjusted to 8.0. The methylene chloride layer is separated off and discarded. The aqueous phase is acidified to pH 2, and then extracted with ethyl acetate. The ethyl acetate is dried using an-10 hydrous sodium sulfate, and then to it is added a solution of 110 mg. of sodium 2-ethylhexanoate in a small volume of ethyl acetate. The precipitate which forms is filtered off, to give 138 mg. (57% yield) of the sodium salt of 6-(2-cyanoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. 15 The infrared spectrum (KBr disc) of the product shows absorption bands at 2260 cm-1 (cyano), 1775 cm"1 (^-lactam carbony1), 168o cm-1 (amide I band) and 1550 cm"1 (amid* II band). The NMR spectrum (in D2O) shows absorptions at 5.90 and 5.40 ppm (2 doublets, C-5 and C-6 hydrogens), 20 5.30 ppm (singlet, C-3 hydrogen), 1.65 ppm (singlet, C-2 methyl hydrogens) and 1.00 ppm (singlet, C-2 methyl hydrogens).

EXAMPLE XLVI 6-(2-[1-Tetrazolyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-penam 25 To a stirred solution of 90 mg. of tetrazol-1- acetic acid and 71 mg. of triethylaraine, in 5 ml. of chloroform, cooled to 0°C., is added 85 mg. of pivaloyl chloride. Stirring is continued at 0°C. for a further 30 minutes, and then the resultant solution is added to an ice-cold 30 solution prepared from 169 mg. of 6-amino-2,2-dimethyl-3- - 122 - 4 0 532 (5-tetrazolyl)penam, 142 mg. of triethylamine and 5 ml. of chloroform. This combined solution is stirred at about 0°C. for 2.5 hours. It Is then warmed to ambient temperature and poured into 20 ml. of water. The pH of the aqueous phase is 5 raised to 7.0, the layers are separated, and the chloroform is discarded. The aqueous phase is acidified to pH 2, and then it is extracted with ethyl acetate. The ethyl acetate is dried, and then to it is added a solution of lOO mg. of sodium 2-ethylhexanoate in a small volume of ethyl acetate. The lO solid which precipitates is filtered off, giving 80 mg. (31% yield) of the sodium salt of 6-(2-/l-tetrazolyl7acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorption bands at 1785 cm * (({-lactam carbonyl) , 1695 cm 1 (amide I band) and 1575 cm 1 15 (amide II band). The NMR spectrum (in D2O) shows absorption bands at 5.90-5.40 ppm (multiplet, C-5 and C-6 hydrogens), 5.25 ppm (broad singlet, tetrazole hydrogen), 5.20 ppm (singlet, C-3 hydrogen), 1.70 ppm (singlet, C-2 methyl hydrogens) and l.OO ppm (singlet, C-2 methyl hydrogens). 20 The tetrazole-l-acetic acid used in this Example is obtained by the method described in United States patent no. 3,468,874. - 123 - 40532 KXAMl'LK XI.VII Using the procedure of Example XL.VI, and replacing the tetrazole-1- acetic acid by the appropriate acid, the following compounds arc prepared as their sodium salts. 6-(2-/^-tetrazolyl7acetamido)-2,2-dimethyl-3(5- tctrazolyl)penam, 6-(D-2-hydroxy-2-phenylacetamido)-2,2-dimethyl-3-(5-tctrazolyl)penam, 6-(D-2-hydroxy-2-/£-hydroxyphenyl7acetamido)-2,2-dim.-! thyl-3-(5-tetrazolyl) penam, 6- (D-2-hydroxy-2-/2-furyl7acetamido) -2,2-dime thyl-3 (5-tetrazolyl)penam, 6-(D-2-hydroxy-2-/2-thienyl7acctamido)-2,2-dimethyl 3-(5-tetrazolyl)penam, 6-(2-/2-(hydroxymethy1)phenyl7acetamido)-2,2-dimcthyl-3-(5-tetrazolyl)penam and 6- (2-/"4- (hydroxymethyl) pheny^7acetamido) -2,2-dimethy1-3-(5-tetrazol-5-yl)penam, respectively.

The tetrazoie-2-acetic acid is prepared by the method described in United States patent No. 3,468,874. D-2-llydroxy-2-phenylacetic acid is commercially available. D-2-Hydroxy-2-(£-hydroxyphenyl)acetic acid, D-2-hydroxy-2-(m-chlorophenyl)acetic acid, D-2-hydroxy-2-(2-furyl)acetic acid and D-2-hydroxy-2(2-thienyl)acetic acid are each prepared from the corresponding aldehyde, using the method of Corson et al^., Organic Synthesis, Collective Volume I, p. 336. - 124 - 40832 EXAMPLE XLVIII 6-(2rPhenoxyacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam A stirred slurry of 480 mg. of 6-amino-2,2-dimethy1-5 3-(5-tetrazolyl)penam in lO ml. of water is cooled to 0°C., and then the pH is adjusted to 8.0 using IN sodium hydroxide. To this solution is then added 0.25 ml. of phenoxyacetyl chloride, in portions, with the pH of the solution being maintained between 7 and 8 during the addition, using O.IN lO sodium hydroxide. The solution is stirred a further 30 minutes at 0°C. at pH 8. It is then extracted with chloroform, and the extracts are discarded. The aqueous phase is acidified to pH 2 with dilute hydrochloric acid, and then it is further extracted with chloroform. The latter extracts are 15 dried using calcium sulfate and then evaporated in vacuo to give the crude product as a gummy solid. This is purified by dissolving it in 20 ml. of chloroform, and adding the resultant solution dropwise to 250 ml. of hexane. The precipitate which forms Is filtered off, giving 385 mg. of 6-(2-phenoxy-20 acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as a white amorphous solid. The infrared spectrum (KBr disc) of the product shows absorption bands at 1785 cm * (B-lactam car-bony 1) , 1670 cm ^ (amide I band) and 1540 cm ^ (amide II band). The NMR spectrum (in DMSO-dg) shows absorption bands 25 at 7.50-6. 70 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6 hydrogens), 5.35 ppm (singlet, C-3 hydrogen), 4.60 ppm (singlet, methylene hydrogens), 1.60 ppm (singlet, C-2 methyl hydrogens), and 1.05 ppm (singlet, C-2 methyl hydrogens). - 125 - . 4 0 532 KXAMPLK XLIX The procedure of Example XLVIII is repeated, using the appropriate acid chloride, to provide the following compounds R' -Nil - 126 - Melting Yield Point (*) 2-(2-thienyl)acetyl 26 ( ° C.) 192-194 Infrared Spectrum ( cm"1) 1808, 1718, 1670 phenoxycarbonyl 43 102-118 1795, 1740 benzyloxycarbonyl 30 145-170 1800, 1725 ethoxycarbonyl 32 80-115 1800, 1725 NMR Spectrum (ppn) 7.10(n,1H), 7.00(m,2H), 5.70(m,2H), 5.30(s,lH), 3.90 (s,2H), 1.70(s,3H), 1.10(s,3H). DMS0-dg. 9.00(s,1H), 7.40-7.70(ro,5H), 6.20(d,lH), 5.70(ro,2H), 5.35(3,1H), 1.90(s,3H), 1.13(s,3H). CDClj. 11.30(s,1H), 7.40(8, 5H), 5.70(m,2H), 5.30 O 0* w (0 40532 EXAMPLE L 6-Acetamido-2.2-dime thyl-3-(5-tetrazolyl)penam The procedure of Example XLVIII is repeated, except that tho phcnoxyacetyl chloride used therein is replaced by acetic anhydride. This affords a 48% yield of the title compound. IR (KBr disc) i 1780 cm-1 (6-lactam) , 1645 cm"1 (amide I). NMR (in DMSO-dg): 5.65 ppm (m, 2H), 5.25 ppm (s. III), 1.95 ppm (s, 3H), 1.70 ppm (s, 3H), and 1.10 ppm (s, 311). - 128 - 40532 EXAMPLE LI Reaction of 6-amino-2,2-dimethy1-3-(5-tetrazolyl)-penam with the appropriate acid chloride, according to the procedure of Example XLVIII, provides the following com-5 pounds: 6-(2-/cyclopent-2-eny17acetamido)-2,2-dimethy1-3-(b-tctrazolyl)penam, 6-(2-/cyclohex-2-enyl7acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, lO 6-(2-/cyclohept-l-eny4/acetamido)-2,2-dimethy1- 3-(5-tetrazolyl)penam, 6-(2-/cyclooct-l-enyl7acetcunido)-2,2-dimethy1-3-(5-tetrazolyl)penam and, 6-(2-^cyclohept-2,4,6-trienyl7acetamido)-2,2-15 dimethyl-3-(5-tetrazolyl)penam, respectively. - 129 - . 4 0 5 3 2 KXAMI'l.i: I. II The [>riK:ixlurc of Kxamplc XLVIII i;; repeated, except that. Liu: |>licnoxyac<»ty I clilorldo uhc-chlorophenyi7acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam, 6- (2-/jn-methoxypheny\7acetainido) -2,2 -dime thy 1-3- (5-30 tetrazolyl)penam, and 6-(2-/£-tolyl7acetamido)-2,2-dimethyl-3-(5-tetrazolyl) penam. respectively. - 131 - 40532 Tho acid chlorides used in this Example are prepared from the corresponding acids, using methods well known in the art (Buehlcr and Pearson, "Survey of Organic Syntheses," Wiiey-Interscience, 1970, pp. 859-867). 2-(Cycloheptyl)ace-5 tic acid and 2-(cyclohex-l-enyl)acetic acid are prepared from their corresponding nitriles (which are items of com-erce) by hydrolysis, using methods discussed by Buehler and Pearson (loc. clt.. pp. 752-753). 2-(Cyclohex-3-enyl)acetic acid is prepared by the method of Boehne, Journal of Organic lO Chemistry, 26, 2107 (1961). The 2,6-dialkoxybenzoic acids arc prepared .»«*cording to Doyle, et al., Journ.iL of the Chemical Society (l prepared by adding 2.40 g. (lO m mole) of 6-amino-2,2-dim-ethyl-3-(5-tetrazolyl)penam to a mixture of 15 ml. of water and 15 ml. of tetrahydrofuran and adjusting the pH to 7.5. The resulting mixture is then stirred for a further 1 hour at 0° c. At this point, the tetrahydrofuran is removed by lr» evaporation vacuo, and the residue is diluted with more water. The pll is adjusted to 8.0 with 6 N sodium hydroxide, and then the mixture is extracted with ethyl acetate. The extracts are discarded The pll of the residual aqueous phase is adjusted to 2.0 with 4 N hydrochloric acid and then the 20 product is extracted into ethyl acetate. The organic layer is dried and concentrated in vacuo to give 6-(3-/carbamoyl/-acrylamido)-2,2-dimethy1-3-(5-tetrazolyl)penam (1.03 g., 33% yield). The infrared spectrum (KBr disc) of the product shows absorption bands at 1818 cm-1 (B-lactam) and 1692 2r» cm *. The NMR spectrum (DMSO-d^) shows bands at 7.00 and 6.25 (quartet, 211, J = 12 llz, olefinic hydrogens), 5.80-5.48 ppm (multiplet, 2H, C-5 and C-6 hydrogens), 5.26 ppm (singlet, 1H, C-3 hydrogen), 1.65 ppm (singlet, 3H, C-2 methyl hydrogens) and 1.06 ppm (singlet, 3H, C-2 methyl 3o hydrogens). 133 - 40532 EXAMPLE LIV b-Pormnmido-2,2-dimethyl-3-(5-tctrazolyDpenam To a stirred solution of 480 mg. of 6-amino-2,2-dim-ethyl-3-(5-tetrazolyl)penam and 0.56 ml. of triethylamine 5 in 5 ml. of methylene chloride, at 0°C., is added 0.3 ml. of formic acetic anhydride. Stirring is continued for a further 45 minutes, at 0°C., and then the solvent is removed by evaporation in vacuo. The residue is partitioned between water and ethyl acetate, and then the ethyl acetate is lO separated off and dried. Evaporation of the ethyl acetate in vacuo affords 0.216 g. of 6-formamido-2,2-dimethyl-3-(5-tetrazolyDpenam as a foam. The NMR spectrum (CDCl^) shows absorptions at 8.20 ppm (singlet, 1H, formamido hydrogen), 5.80 ppm (multiplet, 211 C-5 and C-6 hydrogen), 5.30 ppm I(singlet, 111, C-3 hydrogen), 1.7<) ppm (singlet., 311, C-2 mi-lhyl liyilriM|t'ii:() .mil l.lo |>|>m (:: I n<| I «*L, <11, V.-V. nirt.liyl hydrogen:;). Tli«» infrared spectrum of the sni (broad singlet, tetrazole hydrogen), 8.8 25 ppm (doublet, amide hydrogen), 5.8-5.4 ppm (multiplet, C-5 and C-6 hydrogens), 5.35 ppm (singlet, C-3 hydrogen), 4.0 ppm (singlet, methylene hydrogen), 1.90 ppm (singlet, C-2 methyl hydrogens) and 1.15 ppm (singlet, C-2 methyl hydrogens) . 30 The above product is dissolved in 15 ml of water con taining 1 equivalent of sodium bicarbonate. The resulting solution is then lyophilized leaving the sodium salt of the title compound (3.4 g, 72% yield). - 135 - 4 0 5 3 2 KXAM1M.K LV1 f>- (2-^-l'yr idy 1 thio7acctamido) -2,2-dimethy1-3-(5-tetra- zolyl)pcnam To a stirred suspension of l.O g (0.0028 mole) of 6-(2-bromoacctamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.28 g (0.0028 mole) * of triethylamine. The mixture is stirred at ambient temperature until a clear solution i3 obtained, and then Q.39 g of 4-mcrcaptopyridine is added. Stirring is continued for a further 4 hours at ambient temperature, and then the solid which has precipitated is filtered off. It is washed with methylene chloride, followed by ether, to give 0.68 g (78% yield) of l» (2-/4-pyridyIthiq/aeetamido)-2,2-dimethy1-3-(5-tetra/.olyl)penam, m.p. 12o°C (dec.). The infrared spectrum of the product (KBr disc) shows absorption bands at 1790 cm ' (I'.-lactain) , 1670 cm * (amide II) . The NMR spectrum (l)MSO-d^) shows absorption bands at 9.0-7.0 ppm (multiplet), pyridine hydrogens), 5.9-5,'j ppm (multiplet, C-5 and C-6 hydrogen), 4.1) ppm (singlet, methylene hydrogens), 1.7 ppm (singlet, C-2 methyl hydrogens) and 1.1 (singlet, C-2 methyl hydrogens). - 136 - EXAMPLE LVII 6--Diethylamidinothia7acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam To a stirred solution of 1.40 g (0.039 mole) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml of methylene chloride is added 0.54 ml (0.039 mole) of triethylamine, followed by 0.52 g (0.039 mole) of N,tf -diethyl thiourea. Stirring is continued for a further 45 minutes, and then the solvent is decanted from the oil which has separated. The oil is triturated with ether, giving a white solid, which is filtered off. The yield is 1.28 g (76% of theory) of 6-(2^6,N1 -diethylamidinothio/acetamldo) -2,2-di-mcthyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm~* (tf-lactam) and 1670 cm * (amide I). The NMR spectrum (DMSO-dg) shows absorption bands at 5.65 ppm (multiplet, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 4.10 ppm (singlet, methylene hydrogens), 3.45 ppm (quartet, ethyl hydrogens), l.GO ppm (singlet, C-2 methyl hydrogens), l.lO ppm (triplet, ethyl hydrogens) and l.OO ppm (singlet, C-2 methyl hydrogens). - 137 - 40532 EXAMPLE LVIIJ *>~ (2 ,f»-Dimc thoxy benzamldo) -2,2-dimethy 1-3 - (5-tetrazolyl) - penam To .i stirred solution of 1.2 g. (S mmole:) of 6-amino-5 2,2-dimethy1-3-(5-tetrazolyl)penam, l.Ol g. (lO mmole) of triethy lamine and 50 ml. of methylene chloride, is added 1.0 g. (5 mmole) of 2,6-dimethoxybenzoyl chloride (Norris and Ware, Amer. Chem. Soc.. 61, 1418 /1936/, at ca. 0°C. Stirring is then continued for three hours at ambient tem-lo pcrature. To the reaction mixture is added 50 ml. of water, and the pit of the aqueous phase is adjusted to 8.O. The organic phase is separated off and discarded. The pH of the residual aqueous phase is lowered to 2.5, and the precipitate which forms is filtered off. This affords 1.2 g. (59% 15 yield) of the title compound, m.p. 215°C. (dec.). IR (KBr disc): 1808, 1643 and 1605 cm"1. NMR (in DjO/HCOj): 7.50 ppm (t, 1H), 6.90 ppm (d, 2H), 5.90 and 6.0 ppm (q, 2H), 5.40 ppm (s, lH), 4.00 ppm (s, 6H), 1.80 ppm (s, 3H) and 1.20 ppm (s, 311) . - 138 - 40532 KXAM1'LK LIX 6-(2-Kthoxy-l-naphLhamido)-2,2-dlmethy1-3-(5-tetrazolyl)- penam Pollowlng the procedure of Example LVIII, the title 5 compound is prepared from 2.84 g. (0.012 mol) of 6-amino-2, 2-dimethyl-3-(5-tetrazolyl)penam and 1.39 (0.006 mol) of 2-ethoxy-l-naphthoyl chloride and is isolated as the sodium salt by standard procedures: yield 1.5 (54%); IR (KBr); 1780, 1715, 1667 cm"1; NMR (D20) 8.0-6.8 ppm (mf 6H), 5.85 lO (s, 1H), 5.40 (s, 1H), 5.2* (s, 1H), 3.90 (q, 2H), 1.45 (s, 311), 1.25 (t, 311), l.OO (s, 3H). - 139 - 40532 KXAMPLK LX (»- (l)-2-Amino-2-phonylacetamiclo) -2,2-dimethy 1 - 3- (5-tetrazolyl) - penam A stirred suspension of 200 mg. of 6-amino-2,2-dimethyl-5 3-(5-tetrazolyl)penam in 5 ml. of water is cooled to 0-5°C. in an ice-bath. The pll is then adjusted to 7.0 using dilute sodium hydroxide solution. At this point, 274 mg. of D-2-amlno-2-phenylacetyl chloride hydrochloride (Hardcastle et al., Journal of Orqanic Chemistry, 31, 897 £1966^ is added portionwise lO during 15 minutes at 0-5°C., and with the pH maintained between 6 and 7 by the addition of dilute sodium hydroxide. At the end of the addition, the reaction mixture is stirred for a further 15 minutes and then filtered. The pit of the mother liquors is adjusted to 4.4 with dilute hydrochloric acid, and then the 15 solution is stored overnight in the refrigerator. The solution is then filtered, and the mother liquors are placed on a column of 25 g. of Sephadex LH-20 (Pharmacia Fine Chemicals, Inc. (^Sephadex" is a Registered Trade Mark) made up in water. The column is elutcd with water, taking fractions, and the composit-20 ion of the fractions is assayed by thin-layer chromatography. The fractions containing the pure product are combined, and evaporated under high vacuum to a volume of approximately 1 ml. After this solution has been set aside for a short period, the product crystallizes out. It is filtered off, washed briefly 25 with water and dried. The yield is 55 mg. of pure 6-(D-2- amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, m.p. 192-196°C. The infrared spectrum (KBr disc) shows absorptions at 1770 cm 1 (fl-lactam carbonyl), 1680 cm 1 (amide I band) and 1520 cm 1 (amide II band). - 140 - 40832 EXAMPLE LXI When the procedure of Example LX is repeated, and the 0-2 amino-2-phenylacetyl chloride hydrochloride used there is replaced by an equivalent amount of the appropriate acid chlor-5 ide hydrochloride, the following compounds are produced. 6-(DL-2-amino-2-phenylacetamido)-2,2-dimethy1-3-(5-tetrazoly1)penam, 6-(DL-3-amino-2-phenyIproplonamldo)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2-/2-pyridyl/acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-penam, 6-(2-/5-pyridyl7acetamido)-2,2-dimethyl-3-(b-tetrazolyl)-penam, 6-(2-/3-pyridyl/acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-penam, 6-(2-/3-pyridylthio7acetamido)-2,2-dimethyl-3-(5-tetra-zolyl/penam, 6-(2-/£-aminopheny\/acetamido)-2,2-dimethyl-3-(5-tetra-zolyl)penam, 6-(1-aminocyclobutanecarboxamldo)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(1-aminocyclopentanecarboxamido)-2,2-dimethyl-3-(5-tetrazoly Dpenam, 6-(1-aminocyclohexanecarboxamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(1-aminocycloheptanecarboxamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-/m-(N-methylamino)phenyl7acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, and 6-(2—/g—(N-n-butylamino)pheny1/acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam. respectively.

DL-2-Amino-2-phenylacetic acid, 2-pyridylacetic acid, 4-pyridylacetic and £-aminophenylacotic acid are items V, of commerce. PL-3-amino-2-pheny1-propionic acid is prepared - 141 - 15 20 25 40532 by the method of Testa et al^, Anna 1 en der Chemle. 614. 167 (1958), and (4-pyrldylthio)acetic acid is prepared by the method described in Netherlands patent No. 6,912,855. The 1-aminocycloalkanccarboxyllc acids are prepared by the method 5 of Alburn et al., Antimicrobial Agents and Chemotherapy. 586 (1967). The amino-acids are converted into their acid chloride hydrochlorides by sequential treatment with hydrogen chloride gas and phosphorus pentachloride (Hardcastle et al., Journal of Orqanic Chemistry, 31 897 /1966 - 142 - 40532 EXAMPLE LXII Acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with the acid chloride hydrochloride of 2-(N-methylaroino)-2-phenylacetic acid, 2-(N-ethylamino)-2-phenylacetic acid, 2-(N-isobutylamino)-2-phenylacetic acid, 2- (N-n-hexylamino)-2-phenylacetic acid, 2-(N-methylamino)-2-(2-thienyl)acetic acid and 2-(N-methylamino)-2-(£-chlorophenyl)acetic acid, respectively, according to the procedure of Example LX, produces the following congeners: 6- (2-/ft-me thy 1 amin<27~2-pheny lace tamido) -2,2-dime thy 1-3-(5-tetrazolyl)penam, 6-(2-/R-ethylaminq7-2-phenylacetamldo)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2-/R-isobutylaminq7-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-/?l-n-hexylaminq7-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-/T<-methylaminq7-2-/2-thienyl7acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam and 6-(2^fi-methylaminQ/-2-/g-chlorophenyL7acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, respectively. 2-(N-Methylamino)-2-phenylacetic acid is prepared by the met hot! of Ar.ig.i et a 1. (Nippon Kagaku Za^shi, 86, 111 /19657; Chemical Abstracts, 62 16365 /1965/) The other amino-acids are prepared in analogous fashion, using the appropriate aldehyde and amine. Acid chloride hydrochlorides are prepared by the method of Hardcastle et al. (Journal of Organic Chemistry, 31, 897 /1966/). - 143 - 40532 EXAMPLE LXIII (»- (D-2-Amlno-2-phenylacetamido) -2, 2-dimethy1-3- (5-tetrazolyl) - penam hydrochloride A slurry of SO mg. of 6-(D-2-amino-2-phenylacetamido)-5 2,2-dimethy1-3-(5-tetrazolyl)penam in 2 ml. of de-ionized water is stirred for 5 minutes at ambient temperature. The pll is then adjusted to 2.45 using dilute hydrochloric acid, and the solution thus obtained is immediately lyophilized. This affords 52 mg. of 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-Ki tetrazolyl)penam hydrochloride as a fluffy white solid. - 144 - 40532 EXAMPLE LXIV 6- (D-2-Amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)- penam To a stirred solution of 23.8 ml. of ethyl chloroformate 5 in 600 ml. of acetone, is added 25 ml. of a 3% solution of N-methylmorpholine in acetone. The resulting solution is cooled to -40°C., and then 75.2 g. of sodium N-(2-methoxycarbonyl-l-methylvinyl)-D-2-amino-2-phenylacetate is added. Tho temperature is adjusted to -20°C. and stirring is continued for 28 minu-lO tes. The solution is re-cooled to -40°C., and an ice-cold solution, prepared by suspending 60.0 g. of 6-amino-2,2-diinethyl-3-(5-tetrazolyl)penam in 250 ml. of water and then adjusting the pll to 7.0, is added. The resulting solution is stirred for 30 minutes without further cooling, and then the acetone is remo-15 ved by evaporation in vacuo. To the aqueous residue is added an equal volume of tetrahydrofuran, and then, at 5°C. the pH is adjusted to 1.5 with dilute hydrochloric acid. The mixture is held at this temperature and pH for 30 minutes, and then the tetrahydrofuran is removed by evaporation in vacuo. The aqueous 20 residue is extracted with ethyl acetate, followed by ether, and the extracts are discarded. The pll of the remaining aqueous phase is raised to 5.4, and the product begins to crystallize out. After 1 hour it is filtered off and dried. The crude yield Is 68.8 g. 2r> The product is suspended in water at 25°C., and the pll is lowered to 1.5. After stirring for a short period, the insoluble materials are filtered off, and the filtrate is extracted with ether. The aqueous solution is then cooled to 5°C., and the pll is adjusted to 5.2. The solid which precipitates is 30 filtered off, giving 62.7 g. (58.7% yield) of 6-(D-2-amino-2- - 145 - 40532 phenylacetamido)-2,2-dimethy1-3-{5-tetrazoly1)penam trihydrate, m.p. 20l-202°C., f'\7^ + 228.2 (1% in CH-jOH) . IR (KBr. disc) : 1780 cm-1 (fl-lactom). NMR (in DMS0-dg/D20): 7.60 ppm (s^ 511), 5.70 ppm (d, 111), 5.55 ppm (d, 111), 5.20 ppm (s, 1H) , 5115 ppm 5 (d. 111), 1.50 ppm (s, 311), 0.90 ppm (s, 311).

Analysis - Calcd. for CjgH^^OjN^S. 3H20 (percent): C, 44. 95; II, 5.89; N, 22.94; S, 7.50. Found (percent): C, 45.Ol; H, 5.84; N, 22.81; S, 7.34.

The sodium N-(2-methoxycarbonyl-l-methyl-lO vinyl)-D-2-amino-2-phenylacetate is prepared from methyl aceto-acetatc and D-2-amino-2-phenylacetic acid by the procedure used by Long et al. (J. Chem. Soc., London, Part C, 1920 ^l97\7) f°r the corresponding £-liydroxy compound. - 146 - 40532 EXAMPLE LXV The procedure of Example LXIV is repeated, except that the sodium N-(2-methoxycarbonyl-l-methylvinyl)-2-amino-2-phenylacetate is replaced by the appropriate a-amino acid, pro's tcctcd as its acetoacetic ester enamine derivative. This affords the following compounds. In some instances, the products are purified by Sephadex chromatography of their sodium salts.

S CU, fY 3 I CH, N I J \ // UN N R -CII-C-NIl Nil.

/ O - 147 - m-hydroxypheny1 Infrared Side-chain Yield Spectrum Configuration (%) (cr"1) 1776, 1686 3,4-dihydroxyphenyl DL 3 1770/ 1684 ■ 'i £-methoxyphenyl 30 1775 15 £-hydroxyphenyl 2-thienyl a CO £- (N,N-dimethyl-aminoTphenyl 2 rs 3-chloro-4-hydroxy-phenyl (*J £-chlorophenyl viz (2/ 25 m-chlorophenyl © © D DL D DL DL 28 1770 27 1775, 1690 44 1783 7 1785, 1695 14 1780, 1700 XXR Spectrum (ppm) © o? 7.55-6.73(m,4H), 5.72(d,lH), 5.44(d,lH), 5.24 U (S,1H), 5.12(S,1H), 1.37(s,3H), 0.90(s,3H). K (D20). 6.97(s,lH)/ 6.80(S,2H), 5.75-5.34(m,2H), 5.03 (s,lH), 4.93 and 4.86(2s,lH), 1.56 and 1.50(2s,3H), 0.96 and 0.92(2a,3H). (DMSO-dg) 7.56-6.90(q,4H), 5.60(m,2H), 5.16(s,lH), 5.10 (s,lH), 4.77(n,2H), 3.84(»,3H), 1.56(s,3H), 1.00 (8,3H). (DMSO-dg). 7.35(d,2H), 6.85(d,2H), 5.68(d,lH), 5.50(d,lH), 5.08 (s,lH) , 4.98(8,1.1), 1.58(s,3H), 1.00(s,3H). (DMSO-dg). 7.74-7.10(m,3H), 5.75-5.54(m,2H), 5.44(s,lH), 5.12 (8,1H), 1.52(s,3H), 0.96(8,3H). (DMSO-dg). 7.44-6.79(q,4K), 5.84-5.46(m,2H), 5.23-4.99(m,2H), 2.94(s,6H), 1.59 and 1.50(2s,3H), 1.00 and 0.93 (2s,3H). (DMSO-dg). 7.63-6.88(m,3H), 5.60(d,lH), 5.43(d,lH), 5.06(s,lH), 5.03(S,1H), 1.42(S,3H), 0.90(s,3H). (DMSO-dg). 7.53(s,4H), 5.63(d,lH), 5.53(d,lH), 5.30(s,lH), 3.20(q,6H), 1.63(s,3H),1.26(t,9H), 1.06(s,3H).

(DjO). 7.43(m,4H), 5.76(n,lH), 5.50(m,lH), 5.28(d,lH), 5.16(s,lH), 3.16(q,6H), 1.36(s,3H), 1.26(t,9H), 0.96(d,3H). (D20).

Infrared Side-chain Yield Spectrum Configuration (I) (cm'l) NMR Spectrum(ppm) m-nitrophenyl ©® £-sulfamoylphenyl £-fluorophenyl 2-furyl 2-tetrahydrofuryl 3-pyridyl DL DL D D D DL 22 1785, 1666 7.8-8.6(m,4H), 5.9(m,lH), 5.5(d,lH), 5.15(s,lH), 5.10(8,1H), 3.10(q,6H), 1.7(S,3H), 1.3(t,3H), 1.0(s,3H) (DMS0-d6/D20) 1775, 1650 8.2-7.2(m,4H), 5.8-5.3(m,2H), 5.2(s,lH), 5.10 (s,lH), 1.5 and 1.3(d,3H), 1.0 and 0.7(d,3H), (DMSO-dg/DjO). 1775, 1650 3.0-7.0(m,4H), 6.7(d,lH), 6.5(d,lH), 5.2(s,lH), 5.1(s,1H), 1.4(8,3H) 0.9(s,3H) (DMS0-dfi/D20) 18 1780, 1695 7.5(m,1H), 6.5(m,2H), 5.8(s,lH), 5.5(m,2H), 5.3 (S,1H), 1.6(s,3H), 1.0(s,3H) (D20). 50 1780, 1690 5.6(ra,2H), 5.2(s,lH), 4.1(m,lH), 3.7(m,3H), 1.8 (m,4H), 1.6(s,3H), 1.0(s,3H) DMSO-dg/DjO) 1775 9.0-8.6(m,2H), 8.1-7.7(m,lH), 7.7-7.4(m,lH), 5.8-5.5(m,2H), 5.2-5.0(m,2H), 1.5(d,3H), 0.9(d,2H) (DMSO-dg). e w u M t Infrared Side-chain Yield Spectrun Configuration (I) (cm~l) NMR Spectrum (ppm) 10 15 2-bromo-5-hydroxy-phenyl ^ m-fluorophenyl © hydrogen isopropyl benzyl 3-indolylmethyl DL D D G^Isobutyl chloroformate is 20^Dpivaloyl chloride is used © 28 30 41 58 1780, 1690 17 1780, 1670 1785 1775, 1680 1775, 1680 1775, 1680 5.76(m,lH),5.56(-,lH), 1.46(S,3H), 0.96(s,3K) 7.56(m,2H), 7.03(m,lH), 5.30(s,lH), 5.15(s,lH), (DMS0-d6/D20). 7.58-7.23(m,4H), 5.33(d,lH), 5.26(d,lH), 5.16(s,lH) 5.10(s,lH), 1.43(S,3H), 6.35(m), 5.76-5.46(n,2H) 1.62(s,3H), 1.00(8,3H).

(DMS0-d6/D20) 5.85(d,lH), 2.08(m,lH), (D20). 7.36(s,5H), 3.10(m,3H) , 7.30(m,5H), 3.80(m,lH), (D20). 5.55(d,lH), 1.67(8,3H), 5.73(d,lH), 1.53(8,3H), 5.42(d,lH), 3.20(m,2H), used for mixed-anhydride formation, for mixed-anhydride formation. 0.90(s,3H), , 5.12(8/lH), 3.71(s,2H), (DMS0-d6). 5.35(s,lH), 3.9(m,lH), 1.07(s,3H), 1.00(d,6H). 5.53(d,lH), 5.35(8,1H), 1.00(8,3H).

(D20). 5.30(d,lH), 5.23(s,lH), 1.33(s,3H), 0.94(s,3H).

The product is isolated as its triethylamine salt. 40532 The starting enamines arq. obtained by condensation of tho appropriate glycine with methyl acetoacetate, according to the procedure of Long, et al^ (Journal of the Chemical Society /tondoo7» Part C, 1920 /19717). Those a-amino acids 5 which are described in the literature are prepared by the published procedures. The new a-amino acids are prepared from the corresponding aldehydes via a Strecker synthesis, techniques for which are discussed by Greenstein and Hinitz in "Chemistry of the Amino Acids," John Wiley and Sons, Inc., lO New York/London, 1961, pp. 698-700, and references cited therein. The Strecker synthesis produces DL amino acids, which are resolved into their optical isomers by conventional means (consult Greenstein and Winitz, loc. cit., pp. 715-755; Nishimura, et al., Nippon Kagaku Zasshi. 82, 1688 ^19617 IS /fchcmical Abstracts. 5P, 11464 (1963)^); and Belgian patent No. 795,874. See also British Patent No. 1,221,227. 5-(3-Pyridyl)hydantoin is prepared by the method of ltenze and Knowles, J. Org. Chem., 19, 1127 (1954), and it is hydrolysed to 2-amino-2-(3-pyridyl)acetic acid by the method 20 described by Davis et al^ (Archives Blochem and Biophys., 87 88 /lOho/) for tho correspondiny 4-isomer. - 151 - 40532 Example l.XVt Jlt.irtiinj with tho appropriate 2-subr.tltuted sodium N- (2-iw»l.hoxycnrl>onyI-1 -methylviny 1) -2-aminoacetat.e, and fol 1- owlng the procedure of Example LXIV, the following compounds 5 are prepared: 6-(D-2-amlno-2-/^-fluorophenyl7acetamido)-2,2-dimethyl-3-(5-tctrazoly1)penam, 6-(L-2-;unlno-2-/g-fluorophenyl7acetomido)-2,2-dlmethyl-3- (5-tetr.v/olyl) penam, I«> 6- (D-2-.»mino-2-/o-chlorophenyl^acet.unido) -2,2-dimethyl- 3-(5-tetrazolyl)penam, 6-(L-2-amino-2-/o-chlorophenyl/acetamido)-2,2-dimethy1-3- (5-tetrazolyl) penam,. 6-(D-2-amino-2-/m-bromophenyl7acetamido-2,2-dimethy1-15 3-(5-tetrazolyl)penam, 6-(L-2-amino-2-/m-bromopheny lyacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penara, 6-(D-2-amino-2-/ra-chloropheny1/acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, 20 6-(L-2-amino-2-^n»-chlorophenyl/acetamido)-2,2-dimethvl- 3-(5-tetrazolyl)penam, 6- (D-2-amino-2-/£--rhlorophenyl7acetamido) -2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(L-2-amino-2-/£-chlorophenyl7acetamido)-2,2-dimethyl-25 3-(5-tetrazolyl)penam, 6-(DL-2-araino-2-/2.4-dichlorophenvl7acetamldo)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(DL-2-amino-2-/3.4-dichlorophenyl7acetainldo)-2,2-dimethyl-3-(5-tetrazolyl)penam, JO 6-(D-2-amino-2-/S-fluorophenyl/acetamido)-2,2-dimethy1- 3-(5-tetrazolyl)penam, 6-(DL-2-amino-2-/b-fluorophenyl7acetnmido)-2,2-dimethyl-3-(5-tetrazolyl)penam. - 152 - 40832 6-(D-2-amino-2-/m-fluorophenyl7acetamido) -2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(L-2-amino-2-/m-£luorophenyl7acetamido)-2,2-dlmethy1-3-(5-tetrazolyl)penam, 5 6-(D-2- The starting 2-substituted sodium N-(2-methoxycarbonyl)- 1-mcthylvlnyl)-2-amino-acetates are obtained by condensation of the appropriate 2-substituted glycines with methyl aceto- 5 acetate, according to the procedure of Long, et al. (Journal of the Chemical Society ^london7, Part C, 1920 /l97\7)• Those 2-substituted glycines which are described in the literature are prepared by the published procedures. The new 2-substituted glycines are prepared from the corresponding lo aldehydes via a Strecker synthesis, techniques for which are discusscd by Greenstein and Winitz in "Chemistry of the Amino Acids," John Wiley and Sons, Inc., New York/London, 1961, pp. 698-700, and references cited therein. The Strecker synthesis produces DL amino acids, which are resolved into their opti-15 cal isomers by conventional means (consult Greenstein and Winitz, loc. cit., pp. 7l!>-755; Nishimura, et al., Nippon Kagaku Zasshi, 82, 1688 /I9617 ^Chemical Abstracts, 58, 11464 (1963)7) • - 155 - 40532 EXAMPLE LXVII 6-(D-2-Amino-2-/4-hydroxyphenyI/acetamldo)-2,2-dimethy1- 3-(5-tetrazolyl)penam To a stirred solution of 0.19 ml. of ethyl chloro-5 formate in 15 ml. of dry acetone, cooled to 0°C., is added 1 drop of N-methylmorpholine, followed by 576 mg. of sodium N-(2-methoxycarbonyl-l-methylvinyl) -D-2-amino-2- (4-hydroxy-phenyl) acetate (Long et al^, Journal of the Chemical Society /London/, Part C, 1920 /1971/) . The mixture is stirred for a lO further 30 minutes, and then it is cooled to about -35°C. To it is then added an ice-cold solution of the sodium salt of 6-amino-2,2-dimethy1-3-(5-tetrazolyl)penam, prepared by adding 10% sodium hydroxide to a suspension of 436 mg. of 6-amlno-2,2-dimethyl-3-(5-tetrazolyl)penam in 5 ml. of water 15 (to give a pll of 7.8), followed by dilution with 25 ml. of acctone. The cooling bath is removed, and tho reaction mixture is stirred for a further 30 minutes. At this point, the acetone is removed by evaporation under reduced pressure, and then 20 ml. of methyl isobutyl ketone is added to the aqueous 20 residue. The two-phase system is cooled to 10°C., acidified to pll = 0.9 with dilute hydrochloric acid, and then it is stirred at 10°C. for 1 hour. The methyl isobutyl ketone is removed and discarded. The pll of the aqueous phase is raised to 6.6 and then it is stored in the refrigerator for 3 hours. 25 The precipitate which forms is filtered off, giving 320 mg. of 6-(D-2-amino-2-/5-hydroxyphenyl7acetamido-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorptions at 1775 cm 1 (fl-lactam carbonyi) and 1680 cm x (amide I band). The NMR spectrum (in DMSO-d,/ 6 30 D20) shows absorptions at 7.35 and 6.85 ppm (2 doublets. - 156 - 40532 .iromntlc hydrogens) , 5.60 ppm (quartet, C-5 and C-6 hydrogens), 5.LO ppm (multiplet, benzyl hydrogen and C-3 hydrogen), 1.45 ppm (singlet, C-2 methyl hydrogens) and 0.95 ppm (singlet, C-2 methyl hydrogens). - 157 - 40532 EXAMPLE LXVIII 6- (D-2-Amino-2-/3-thlenyl/acetamldo) -2,2-dimethyl-3- (5-tetrazolyl)penam The procedure of Example LXVII is repeated, except that 5 the sodium N-(2-methoxy-carbonyl-l-methylvinyl)-D-2-amino-2- (4-hydroxyphenyl)acetate used therein is replaced by an equi- roolar amount of N-(2-methoxy-carbonyl-l-nwthylviny1)—D—2— amino-2-(3-thienyl)acetate. There is obtained a 38% yield of 6-(D-2-amino-2-/3-thienyl/acetamido)-2,2-dimethyl-3-(5-tetra-lO zolyDpenam. The infrared spectrum of the product (KBr disc) shows absorptions at 1770 cm-1 (B-lactam carbonyl), 1680 cm"1 (amide I band) and 1505 cm 1 (amide II band). The NMR spectrum (in DMSO-Dg/D20) shows absorptions at 7.60-7.05 ppm (multiplet, aromatic), 5.70-5.35 (multiplet, C-5 and C-6 15 hydrogens), 5.30 and 5.lO ppm (2 singlets, methine hydrogen and C-3 hydrogen), 1.50 ppm (singlet C-2 methyl hydrogens) and 0.95 ppm (singlet, C-2 methyl hydrogens).

The sodium N-(2-methoxycarbonyl-l-methyl-vinyl) -D-2-amino-2- (3-thienyl) acetate used in this Exaunple is 20 prepared from D-2-(3-thienyl)glycine and methyl acetoacetate using the method described by Long, et al. (Journal of the Chemical Society /Eondon7» Part C, 1920 /1971/) for the condensation of D-2-(4-hydroxyphenyl)glycine with methyl acetoacetate. The D-2-(3-thienyl)glycine is prepared from thio-25 phene-3-aldehyde by a Strecker reaction, followed by resolution of the DL-2-(3-thienyl)glycine so produced into its optical antipodes (Nishimura et al., Nippon Kagaku Zasshi, 82 1688 /19617) (Chemical Abstracts. 58, 11464 /19637). - 158 - EXAMPLE LXIX 4 0 53? 6-(D-2-Ajnino-2-/4-£uninophenyl/acetamido) -2 ,2-dimethy1-3- (5-tetrazolyl)penam A mixture of 23.9 g. of D-2-amino-2-(4-aminophenyl)-5 acctic acid dihydrochloride (United States-^patent No. 3,6347 405), 45.4 ml. of triethylamine and 90 ml. of methanol is stirred at 25°C. for lO minutes, and then it is heated under reflux for 30 minutes. It is cooled to 25°C. again, and 31.5 ml. of methyl acetoacetate is added. This new reaction raix-10 ture is stirred at ambient temperature for 20 minutes, and then it is heated under reflux for 40 minutes. The cooled reaction mixture is then poured, with stirring into 3,000 ml of ether. The solid which precipitates is filtered off and discarded. Removal of the solvent by evaporation in vacuo 15 leaves 42. 3 g (93% yield) of the required trIcthy1ammonium N,N,-bls(2-methoxycarbonyl-l-methylvlnyl)-D-2-amino-2-(4-aminopheny1)acctate.

To 19.O g. of the above bis-enamine in 200 ml. of tetrahydrofuran is added with vigorous stirring 8 drops of N-methyl-2() morpholine, followed by 5.38 ml. of isobutyl chloroformate, at o-5°C. Stirring is continued for 1 hour at 0-5°C. at the end of the addition. A solution is then prepared by suspending 9.85 g. of 6-amino-2,2-dlmethyl-3-(5-tetrazoiyl)penam in 80 ml of water, cooling to 0-5°C., adding 6N sodium hydroxide to 25 give a pll of 7.5, and finally diluting with 200 ml. of tetrahydrofuran. This latter solution in then added to the above mixed anhydride solution at ca. -40°C. The resulting mixture is stirred at 0-5°C. for 1 hour. The pH is then lowered to 2.0, and the stirring is continued for a further 30 minutes 30 at 0.5°C. At this point, the bulk of the tetrahydrofuran - 159 - 40532 is removed by evaporation in vacuo, and then the residual aqueous phase is washed twice with ethyl acetate. The aqueous phase is then cooled to 5°C., adjusted to pll 6.0, filtered, and lyophilized. This affords the title compound in a crude 5 state. It is purified by chromatography on Sephadex LH-20.

The final yield is 591 mg. (3.7%). IR (KBr disc): 1770 cm""1. NMR (DMSO-dg): 7.18 and 6.60 ppm (q, J=8Hz, 4H), 5.61 and 5.50 ppm (q, J=4Hz, 2H), 5.03 ppm fs, 1H), 4.91 ppm (s, 1H), 1.51 ppm (s, 3H) and 0.95 ppm (s, 311). - 160 - EXAMPLE LXX 40532 6- (D-2-Amino-2-/3-aminophenyl7acetamido) -2,2-dime thyl-3- (5-tetrazolyl)penam To a stirred solution of 5.0 g. of D-2-amino-2-(3-5 nitrophenyl)acetic acid in 26 ml. of 1.0N sodium hydroxide, at 5°C., is added 4.4 g. of benzyl chloroformate. Stirring is continued for 1 hour with the pH being maintained between 9 and 11. The reaction mixture is washed with ethyl acetate^ and then the pH is lowered to 2.O. The aqueous residue is then lO extracted with ethyl acetate. The extract is dried using anhydrous sodium sulfate, and then it is evaporated in vacuo to give 5.3 g. of N-(benzyloxycarbonyl)-D-2-amino-2-(3-nitro-phenyl)acetic acid, = -108° (C=l, CHjOH).

To a stirred suspension of 5.0 g. (15 nonole) of the 15 above benzyioxy carbonyl derivative, and 3.6 g. of 6-amino-2, 2-dimethyl-3-(5-tetrazolyl)penam in 70 ml. of water is added sufficient 20% sodium hydroxide to adjust to pH 6.O. The resulting solution is cooled to 5°C, and to this is added a solution of 2.8 g. (15 mmole) o:. l-ethyl-3,3'dimethylamino-20 propyicarbodiimida hydrochloride in lO ml. of water. The pH of the solution is maintained between 6.0-6.2 for 2 hours. The reaction is then warmed to room temperature and the pH adjusted to 7.O. The solution is washed with SO ml. of ethyl acetate and the pll is then readjusted to 2.0 (6N hydrochloric 25 acid). The solution is extracted with 300 mi. ethyl acetate, and the ethyl acetate layer dried and evaporated, to yield 3.5 grams of 6-(2-/N-benzyloxycarbonylaminq7-2-phenylacetamido) -2,2-dimethyl-3-(5-tetrazolyl)penam. - 161 - 40932 A suspension of 3.4 g. of the above penam compound in GO ml. of water is adjusted to pll 7.0 using 1.0N sodium hydroxide. To the resultant solution is added 3.4 g. of 10% patladium-on-carbon, and the mixture is shaken for 2 hours under an atmosphere of hydrogen at 50 psi. The reaction mixture is then filtered, acidified to pll 2.0, and extracted with ethyl acetate. The extracts are discarded, and the pH of the aqueous phase is adjusted to 5.5. The solution is th*n lyophilized. The residue is stirred with 30 ml. of N,N-dimethylformamide for 20 minutes, and then the insoluble material is removed by filtration and discarded. The filtrate is added dropwise to 800 ml. of hexane. The resulting precipitate is collected by filtration to give 0.78 g. of 6-(D-2-amino-2-/3-aminophenyl7acetamido)-2,2-dimethy1-3-(5-tetra-zolyDpenam. 1R (KBr disc): 1775 and 1650 cm NMR (DMSO-dg/ D20) : 6.7-7.4 ppm (m, 411), 6.4-6.8 ppm (m, 211), 5.lO ppm (s. 111), S.OO ppm (s, 1H) 1.50 ppm (s, 3H) 0.90 ppm (s, 311). /u7^4=196 (C=.l IN HC1). - 162 - 40532 KXAMPLB LXXI / (2-/4-Am Lnome tliy ipliony l/acc tamldo) -2,2 -d imethy 1- 3- (5- tetrazolvl)penam Sodium 4-/"(l-methoxycarbonyl-2-propenyl)aminomethyl7~ 5 phenylacetate is prepared from 4-aminomethylphenylacetic acid /7augg and Horrom, J. Am. Chem. Soc.. 80, 4317 (1958)^ and methyl acetoacetate by the method described by Dane and Dock-ner /them. Ber.. 98. 789 (1965^7.A suspension of this salt (2.15 g, 7.5 mmole), 7 drops of N-methylmorpholine and lOO ml. lO of tetrahydrofuran is stirred at -20°C; ethyl chloroformate (0.81 g. 7.5 mmole) is added and the mixture is stirred for 60 minutes. 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam (1.80 g., 7.5 mmoles) is suspended in a 50:50 mixture of tetrahydrofuran and water (40 ml), and the pH is adjusted to 7.5 with 15 IN sodium hydroxide solution whereby a homogeneous solution is obtained. This is added to the above suspension, in one portion, the new mixture is stirred at -20°C for 1 hour and then it is allowed to warm to room temperature over 1 hour. Most of the tetrahydrofuran is removed in vacuo, the resultant aqueous 20 solution is cooled in an ice bath, and the pH is adjusted to 1.5 3N hydrochloric acid. After 30 minutes the pH is adjusted to 2.5, and the solution is extracted with ethyl acetate. The aqueous phase is adjusted to pH 6.0 and freeze-dried. The resultant lyophylate is combined with that from another pre-25 paration (5 mmoles) and chromatographed on Sephadex LH-20 (ISO g) eluting with water. Like fractions (tic analysis) are combined and freeze-dried, yielding the title compound as a colorless amorphous solid (570 mg., 11% yield), m.p. 190-200°C. - 163 - • • 40532 IK (KBr) : 177(>, K>r>0 and 1510 cm"1. NMR (DMS0-d6-D20) : 7.4 ppm (:i, 411), 5.05 pjnn (d, J=4llz, 111), 5.45 ppm (d, J=4llz, 1H) , 5.2 ppm (s, 111), 4.1 ppm (s, 211), 3.6 ppm (s, 211), 1.6 ppm (s, 311) and l.O ppm (s, 3H). 5 When tho above procedure is repeated, and the 4-amino- mcthyIphcnylacetic acid is replaced by an equimolar amount of 3-(2-aminoethyl)phenylacetic acid, 4-(2-aminoethyl)phenyl-acetic acid, 5-(2-aminoethyl)-1-tetrazolylacetic acid and 5-(2-aminoethyl)-2-tetrazolylacetic acid, respectively, there 10 is obtained: 6-(2-/3-(2-aminoethyl)phenyl^acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-/4- (2-aminoethyl) pheny l7acetamido) -2.. 2-dimethyl-3-(5-tetrazolyl)penam, 15 6-(2-/5-(2-aminoethyl)-l-tetrazolyl7acetamido)-2,2- dimethyl-J-(5-tetrazolyl)penam and 6-(2-/5-(2-aminoethyl)-2-tetrazoly l7acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, respectively. - 164 - EXAMPLE LXXII 40532 6- (2-/o- (amlnomethyl) pheny l7ace tamldo) -2,2-dimethyl-3- (5- tetrazolyl) penam To a stirred mixture of 2.25 g. of sodium N-(1-methyl-5 2-mcthoxycarbonylvinyl)-2-(o-/aminomethyl7phenyl) acetate and 2 drops of N-methylmorpholine in 20 ml. of tetrahydrofuran, at -10°C., is added 0.856 g. of ethyl chloroformate. Stirring is continued for a further 15 minutes at ca. -5°C., and then the mixture is cooled to -30°C. To this mixture is then added lO a solution prepared by adding 1.68 g. of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam to 20 ml. of 1:3 water-tetrahydrofuran and adjusting the pH to 7.O. After the addition, the cooling bath is removed, and the reaction mixture is allowed to warm to ambient temperature. The tetrahydrofuran is removed by 10 evaporation in vacuo, and 15 mi. of tetrahydrofuran are added to the aqueous residue. The pH is adjusted to 1.5, and then the mixture is stirred at this pH for 30 minutes. The pH is then raised to 3.0 and the tetrahydrofuran is removed by evaporation in vacuo. The aqueous residue is washed with ethyl 20 acetate, and then the aqueous solution is concentrated to small volume. The solid which precipitates is filtered off giving 0.52 g. of 6-(2-^o-(aminomethyl)phenyl/acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorptions at 1780 cm 1 (0-lactam) 25 and 1645 cm-1. The NMR spectrum (DMS0-dg/D20) shows absorptions at 7.45 ppm (singlet, 411), 5.60 ppm (quartet, 2U), 5.10 ppm (singlet, iH) , 4.10 ppm (singlet, 211), 3.80 ppm (singlet, 2H), 1.65 ppm (singlet, 3H), and 0.95 ppm (singlet, 3H).

The starting sodium N-(l-methyl-2-methoxycarbonylvinyl)-30 2-(o-£aminomethyi/phenyljacetate is prepared from 2-{o- - 165 - 40532 /niiiliimiM-l hy l_7i»li«'iiy | ).icoL ic .iclil United States patent No. 3,7M>, 17'») and methyl acetoacetate using the method of Long ot al. (Journal of the Chemical Society /Londoi£7, Part C, 1920 /19717 for the condensation of D-2-^-hydroxy's phenyl)glycine with methyl acetoacetate. - 166 - 40532 EXAMPLE LXXIII 6-(2-/7-(amlnomethyl)phenylthio/acetamido)-2,2-dimethyl- 3-(5-tetrazolyl)penam The title compound 1s prepared in 14% yield, as a color-5 less amorphous solid, by acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with 2-(2-/aminomethyl/phenylthio)acetic acid (United States patent No. 3,766,176), using the method of Example LXXIX. IR (KBr disc): 1780 and 1665 cm-1. NMR (DMS0-d6/D20): 7.50 ppm (m, 4H), 5.70 ppm (d, 1H), 5.43 lO ppm (d. 111), 5.19 ppm (s, 1H), 4.35 ppm (s, 2H), 3.94 ppm (s, 211), 1.60 ppm (s, 3H), and l.OO ppm (s, 3H). - 167 - 40532 EXAMPLE LXXIV 6-(i-Aminocyclohexanecarboxamido)-2,2-dimethy1-3-(5-tetra- zolyl)penam The pi! of a stirred suspension of 720 mg. (3.0 mmole) 5 of 6-amlno-2,2-dimethyl-3-(5-tetrazolyl)penam in 50 ml. of water, at o°C, is adjusted to 7 using l.o N sodium hydroxide.

When all the solid has dissolved, the pll is lowered to 6.0 (l.O N hydrochloric acid), and then 750 mg. (3.4 mmole) of 2,4-oxazaspiro/4.^decane-l,3-dlone (Alburn, et al., Antimi-lo crobial Agents and Chemotherapy, 506 /19677 is added. The reaction mixture is stirred at ca. 0°C, and at pll 6, for 1 hour. It is then filtered. The pi! is adjusted to 4.2, and the reaction is lyophilized. The residue is dissolved in 5 ml. of methylene chloride containing 606 mg of triethylamine. This new solution is 15 added dropwise with stirring to lOO ml of ether, and the solid which precipitates is tiltered off. This affords 1.3 g (93% yield) of a 2:1 complex of the title compound and triethylamine. IR (KBr disc): 1786, 1680 and 1640 cm NMR (in O2O): 5.90 ppm (d. 111), 5.40 ppm (d, 1H), 5.30 ppm (s, 1H) , 3.10 20 ppm (q, 3)1), 1.90-1.50 ppm (m, 10H), 1.60 ppm (s, 3H) , 1.20 ppm (t, 4.511), l.OO ppm (s, 3H). - 168 - 40532 EXAMPLE LXXV 6- (D-2-Amino-2-/I,4-cyclohexadienyl7acetamido) -2 , 2-dimethy 1-3- (5-tetrazolyl)penam Following the procedure used to prepare 6-(1-aminocyc-lohexanecarboxamido) -2 , 2-dime thy i-3-(5-tetrazolyl) penam (Example LXXIV, the title compound is prepared from 0.5 g (2.8 mmole) of D-4-(l,4-cyclohexadienyl)-l,3-oxazolidin-2,5-dione and 6-amino-2,2-dimethyi-3-( 5-tetrazolyl) penam; the product is isolated as a 1:2 complex with triethylamine: yield 520 mg (36%); IR (KBr) 1779, 1678 cm-1. NMR (in DjO): 6.10 ppm (s, ill), *>.80 (s, 211), 5.90 ppm (d. 111), 5.60 ppm (d, 211), 5.4<> ppm (s. III), 4.50 ppm (s. 111), 3.30 ppm (q, 1211), 2.80 ppm (broad s, 411), 1.70 ppm (s, 311), 1.40 ppm (5, 18H), 1.20 ppm (s, 311) .

D-4-(1,4-cyclohexadieny1)-1,3-oxazolidin-2,5-dione is prepared from 2.0 g (13.1 mmole) D-2-(l,4-cyclohexadienyl)-glycine (Dolfini et aJL., J. Med. Chem. 14, 117 £L9T\J and phosgene by the method described by Alburn, et al.(Antimicrobial Agents and Chemotherapy, 586 /196X7): yield 1.2 g (51%). - 169 - 40532 EXAMPLE LXXVI (»- (I),L-3-AmIno-2-phonyIproplonamldo) -2,2-dlmothyl-3- (5- Lctraxolyl )r>cnam Sodium 0,1,-3- (/l-methoxycarbonyl-2-propenyl7amino)-2-r> phcnylpropionate is prepared from DL-3-amino-2-pheny 1- propionic acid /Testa, Pava and Fontanella. Anna1en. 614, 167 (1958/ and methyl acctoacetate by the method described by Dane and Dockner /Chem. Ber.. 98, 789 (196S17. A suspension of 1.43 grams (5 mmole) of this salt, one drop of N-methyl-lo morpholinc, 5 ml of tetrahydrofuran and 30 ml. of dichloro-methane is stirred at 0°C.; 0.6 grams (5 mmole) of 2,2-dim-othylpropionyl chloride is then added, and the mixture is stirred for 30 minutes. A solution of 1.2 grams (5 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, 1.01 grams (10 15 mmole) of triethylamine, and 30 ml. of dichloromethane is added to the suspension, and the new mixture is cooled and stirred for two hours. The volatile components are evaporated under reduccd pressure, and the residue is dissolved in 60 ml. of water. This mixture is stirred and cooled in an ice bath 20 while it is adjusted to pll 2.7 by the addition of IN hydrochloric acid. After an hour some gummy material is filtered, and the filtrate is cooled and is adjusted to pH 4.5 by the addition of 2N sodium hydroxide. After stirring the new mixture for 30 minutes another small amount of solid matter is 25 filtered, and the filtrate is lyophilized. The lyophilate is slurried in 50 ml. of dichloromethane and this mixture is filtered. The insoluble portion is dissolved in 100 ml. of dichloromcthane and 4 ml. of triethylamine; a small amount of insoluble matter is filtered, and the filtrate is evaporated. 30 The residue from the filtrate is triturated under ether to furnish the title compound as an amorphous 1:3 - L70 - 40532 complex with triethylamine: yield 600 mg. (17%). IR (KBr \ disc): 1792, 1681 and 16i8 an"1. NMR (in D20): 7.50 ppm (s, 511), 5.80 ppm (d. 111), 5.60 ppm (d. 111), 5.30 ppm (s, 1H) , 4.20-3.50 ppn (m, 311), 3.30 ppm (q, 18H), 1.50 ppm (s, 3H), 1.30 ppm (t, 2711), l.OO ppm (s, 3H) : - 171 - 40532 EXAMPLE LXXVII 6-(2-/2-(2-Aminoethoxy)phenyl/acetamido)-2,2-dimethy1-3- (5-tetrazolyl)penam The title compound is prepared in 64* yield from 2-(2-5 /2-aminoethoxy7phenyl)acetic acid (United States patent No. 3,750,905) and 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, by a procedure analogous to that of Example LXXVI, IR (KBr disc): 1780 cm 1 (ft-lactam) and 1667 cm-1 (amide I). NMR (in D20) : 7.1 ppm (m,4ll), 5.7 ppm (d, 1H), 5.5 ppm (d,lll), 5.2 ppm l(> (s,lli), 3.7-3.3 ppm (m, 411), 3.1 ppm (q,12H)» 1*6 ppm (s, 3H) , 1.2 ppm (t, 1811), l.O ppm (s, 311). The product is a 1:2 complex of the title compound and triethylamine. - 172 - 40532 EXAMPLE LXXVIII ' 6-(2-/3-(2-Aminoethoxy)phenyl/acetamido)-2,2-dimethyl-3- (5-tetrazolyl)penam The title compound is prepared in a manner analogous 5 to that used to make its isomer 6-(2- -(2-aminoethoxyphenyl7~ acetamldo)-2,2-dimethyl-3-(5-tetrazolyl)penam (Example LXXVII), and consists of a 1:1 molar ratio of the tetrazole product to triethylamine. The starting materials, 2-/J-(2-aminoethoxy)-phenyl7acetic acid, is obtained by the procedure described in lO U.S. patent 3,579,905. On a 3.5 mmol scale the yield is 600 mg. (33*): IR (KBr) 1780 and 1660 cm"1; NMR (D20-NaHC03) 7.4-6.7 ppm (m, 311) , 5.70 (d,lH) , 5.40(d,lll), 5.2b (s,lH) , 4.35-4.00 (m,2H), 3.70-3.35 (m,4U), 3.15 (q,6ll) , 1.50 (s,3H), 1.25 (t ,911) , 0.95 (s,3ll) . - 173 - 40532 EXAMPLE LXXIX 6-(2-/9-(2-Aminoethoxy)phenyl7acetamido)-2, 2-dimethy1-3- (5-tetrazolyl)penam The title compound is prepared in a manner analogous to I that used to make its isomer 6-(2-/2-(2-aminoethoxy)pheny1/-acetamido)-2,2-dimethyl-3-(5-tetrpzolyl)penam (Example LXXVU), and consists of a 3:1 molar ratio of the tetrazole product to triethylamine. The starting material, 2-/3-(2-aminoethoxy)-phenyi7acetic acid is obtained by the procedure described in U.S. patent No. 3,759,905. On a 5.0 mmol scale the yield is 1.35 g. (60%): IR (KBr) 178b and 1667 cm"1; NMR ID20) 7.10 ppm <«I»4II), 5.75 (d, 1H), 5.40 (d,H), 5.30 (s, 1H) , 4.40-4.05 20) 7.4-6.8 ppm (m, 4H) , 5.80 (d. 111), 5.55 (d. 111), 5.40 (s, 1H) , 4.3-4.0 (m, 2H) , 3.9-3.4 (m, 411), 1.55 (s, 311), l.OO (s, 311). - 175 - 4 0 5 3 2 EXAMPLE LXXXI 6- (L-2-Amlno-3-/£-hydroxyphenyl/propionamido)-2,2-dimethyi- 3-(5-tetrazolyl)penam The title compound is prepared from 1.5 g. of sodium 5 N-(l-methoxycarbonyl-2-propenyl) -L-2-amino-3- (j>-hydroxy- phenyl)propionate and 1.2 g. of 6-amino-2,2-dimethy1-3-(5-tetrazoly)penam, by a procedure analogous to that of Example LXXVI. The crude product is purified by chromatography using 25 g. of Lll 20 grade dextran gel as the column packing, and lO cluting with water. The final yield is 90 mg. of the title compound as its sodium salt. IR (KBr disc): 1780, 1688 and 1620 cm"1. NMR (in D-jO) : 6.9 ppm (q,4H), 5.7 ppm (d,lli), 5.4 ppm (d,lll), 5.2 ppm (s,l!l), 3.1-2.7 ppm (m,3ll), 1.4 ppm (s,3ll), .ind l.o |>(hh (k,3II). - 176 - EXAMPLE LXXXII 40532 6- (2-^enzamido7ace tamldo) -2,2-dimethy1-3-(5-tetrazolyl)- penam To a stirred solution of 0.80 g. (2.7 mmole) of 6-(2-5 amlnoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 0.453 g. (5.4 mmole) of sodium bicarbonate in 21 ml. of water and 15 ml. of acetone at 0-5°C. is.added 0.32 ml. (2.8 mmole) of benzoyl chloride. Stirring is continued for a further 20 minutes at ca. 0°C., and then the acetone is removed in vacuo. The lO aqueous residue is extracted with ethyl acetate and the extracts are discarded. The pll of the aqueous phase is adjusted to 2.O, and the product is extracted into ethyl acetate. The solvent Is dried (Na2S04), and then concentrated in vacuo to give 150 mg. (37* yield) of tho title compound, m.p. 85-93°C. 10 IR (KBr disc): 1785 on"1 (p-lactam) and 1695 cm 1 (amide I). NMR (in D^O): 7.90 ppm (m,2H), 7.50 ppm (m,3H), 5.82 ppm (s,ll!) , 5.58 ppm (s,lH), 5.19 ppm (s,lH), 4.25 ppm (m,2H) , 1.67 ppm (s,3II), 1.67 ppm (s. 111). - 177 - 4 0532 KXAMI'I.K hXXXIU (>-(2-/2-Hromoacc;tamldq7-2-phenylacetamido) -2,2-dimethyl-3- (5-tetrazolyl)penam To a stirred slurry of 4.27 g. (lO mmole) of 6-(2-amino-5 2-phonylacctamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 25 ml. of water, at 0°C., is added 1.39 g. (lOmole) of bromacetic acid in 6 ml. of water. The pll is adjusted to 6.0, and then 1.9 g. (lO mmole) of l-ethyl-3-(dimethylaminopropyl)carbodimide hydrochloride In 9 ml. of water is added. The mixture is stirred lo for 3 hours at pll 6. At this point, the pll is raised to 7.0, and the reaction mixture is washed with ethyl acetate. The pH is then lowered to 2.0, and the product is extracted into ethyl acetatc. The dried extracts are concentrated to dryness in vacuo to give 2.0 g. (40% yield) of the title compound, m.p. lr> 128-135°C. IR (KUr disc): 1800 cm"1 (P-iactom) and 1653 cm-1 (amide I). NMR (in DMSO-d^/DjO) : 7.43 ppm (s,5ll), 5.73 ppm (s. 111) , r>.()3 ppm (m,2ll), 5.23 ppm (s,lll), 4.02 ppm (s,2ll) , 1.60 ppm (s, 3ll), l.(X> ppm (s, ill) . - 178 - HXAMI'I.K l.XXXIV 40532 6- (2-/2-(4-1'yr Idyl thio)acetainidq7-2-pheny lacetamldo)-2,2-dimethy1-3-(5-tetrazolyl)penam To a stirred solution of 644 mg. of 6-(2-/2-bromacet-5 amldo7~2-phonylacetamldo)-2,2-dimethyl-3-(5-tetrazolyl)penam in lb ml. of N,N-dimethylformamide is added 45 mg. of 4-mer-captopyridine followed by 0.19 ml. of triethylamine. Stirring is continued for 3 hours at 25° and then the reaction solution is added dropwise into 200 ml. of vigorously stirred chloroform lo The precipitate is removed by filtration, and the filtrate is added dropwise with stirring to 400 ml. of hexane. This causes the product to precipitate. After being slurried with methylene chloride, it weighs 228 mg. (33% yield), m.p. 182-198°C. (dec.) IR (KBr disc): 1780 cm-i (B-lactam) and 1667 cm"1 (amide I). 15 NMR (DMSO—d6/DzO): 8.33 ppm (d,4H), 7.33 (s,5H), 5.60 ppm (m,3ll), "j.Ib ppm (s,lH), 3.68 ppm (s,2ll), 1.47 ppm (s,3H), 1.OO ppm (s, 311) . - 179 - 40532 EXAMPLE f.XXXV 6-(2-/i-(A*-Imidazolin-2-ylthio)acetamidq/-2-phenylacetamido)-. 2,2-dimethyl-3-(5-tetrazolyl)penam ■The title compound is obtained in 73% yield by replace-ing the 4-mcrcaptopyridine of Exaunple LXXXIV with ethylene thiourea. Tho product has m.p. 166-175°C. (dec.). IR (KBr disc): 1785 cm 1 (B-lactam), 1667 cm 1 (amide 1). NMR (in D20) > 7.37 ppm (s,51I), 5.65 ppm (s,2H) 5.53 ppm (m,2H) , 5.23 ppm (s,l)l), 3.62 ppm (s,2II), 3.50 ppm (m,4H), 1.42 ppm (s,3H), 0.87 ppm (s,31l). - 180 - EXAMPLE LXXXVT 4 0 5 3 2 6-(D-2-/2-Chloroacctamido7-2-phenylacetamldo)-2,2-dimethyl- 3-(5-tetrazolyl)penam To a stirred solution of 2.02 g. of 6-(D-2-amino-2-phcnylacotamido)-2,2-dimethyl-3-(0-tetrazol-0-yl)penam and 1.5 ml. of fcricthylnmim*, in 20 ml. of dichloromothane, is added, dropwise, ().48 ml. of chloroacetyl chloride, at 0°C. Stirring Is continued for a further 2 hours at 0°C., and then the solvent is removed by evaporation J_n vacuo. The residue is stirred witn chloroform and recovered by filtration. This affords 1.16 g <48* yiela) of the title compound, m.p. 142-146°C. IR (KBr disc): 1780 ami Lf.OO cm-1. NMR(IJMS0-«lft/D20) : 7.4/ ppm (m,01l), 0.77 ppm (s,lll), 0 .(>/ ppm (m,2ll), 0.20 ppm (s,lll), 4.20 ppm (s,2H) , 1.6i ppm (s,3!l) and l.OZ ppm (s,31l). - 181 - 40532 EXAMPLE LXXXVII 6- (D-2-/5-Chloroacetamidq/-2-/2-furyl7ncctninido) -2,2-dimethyl 3-(5-tctrazolyl)penam To a solution of lO drops of N-mothylmorpholine in 40 5 ml. of acetone, cooled to -50°C., is added 030 ml. of ethyl chloroformate (3.2 mmole). After stirring 5 minutes at -50°C., a solution of 0.696 g. (3.2 mmole) of N-chloroacetyl-2-/3-furyl/glyclne /ap=-170° ethano\7 and 0.44 ml. of triethylamine (3.2 mmol), in lO ml. of acetone, is added. The resulting solu-lO tion is stirred lO minutes at -50°C. and then a solution prepared by suspending 0.72 g. (3 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in a mixture of 12 ml. of water and 8 ml. of acetone and adjusting the pll to 7.0, is added in one portion. The cooling bath is removed, and the solution is allo-15 wed to warm to room temperature over a 45 minute period with stirring. The acetone is removed using a rotary evaporator and an equal volume of ethyl acetatc is added to the aqueous layer. The pll is adjusted to 2.0, and the ethyl acetate is separated. The aqueous layer is extracted with ethyl acetate (2 x 50 ml). 20 and the combined organic layers are washed with water, brine, and dried (NajSO^). Concentration in vacuo gives an oily solid, which is washed with dichloromethane and dried to give 590 mg. (45% yield) of the title compound as a white solid, mp 149-151°C. IR (KBr disc): 1785 and 1667 cm"1. NMR (DMSO-dg): 7.57 25 ppm (m,lll), 6.35 ppm (m,2II), 5.77 ppm (d,lll), 5.60 ppm (m,2H), 5.17 ppm (s,111) , 4.13 ppm (m,2H), , 1.60 ppm (s,3H) and 1.03 ppm (s,3ll) . - 182 - EXAMPLE LXXXVIII 40532 6- (D-2-/Tl,N>-dlmethylainldlnothlo) acetamidq7-2-phenylacetamido) -2,2-dimethyl-3-(5-tetrazolyi)penam To a stirred solution of 300 mg. of sodium azide in 30 5 ml. of acetone, is added a solution of 900 mg. of 6-(D-2-£l- chloroacetyl7~2-pheny lacetamldo) -2,2-dimethy 1-3- (5-tetrazolyl) penam and 0.3 ml. of triethylamine in 20 ml. of acetone. A solution of 208 mg. of N,N'-dimethylthiourea in lO ml. of acetone is added, and then the resulting reaction mixture is lO heated at 55°C. for 8 hours. At this point, the mixture is coolcd to 25°C. and the precipitate is removed by filtration to give 390 mg. (37% yield) of the title compound, m.p. 240-25«°C. IK (KBr disc): 1775 and 1667 cm-1. NMR (DMSO-dg/C^O) : 7.4 ppm (m,51l), 5.8 ppm (s,l!l), 5.68 ppm (m,2ll), 5.16 ppm 10 (3,111), 4.2 ppm (s,21I), 2.97 ppm (s,6H), 1.50 ppm (s,3H) and 0.90 ppm (s,3!l) * - 183 - 40532 EXAMPLE LXXXIX Using tho procedure of Example LXXXVIII, but replacing the N,N'- dimethylthiourea with the appropriate reagent, the following compounds are prepared. - 184 - mp Yield IR (°C.) C%) Ccm-1) NMR (DMSO-dg) (ppm) pentamethylene-amidino 2-benzinidazol- yi N,N1-diethyl-amidino 10 N/N'-di-n-butyl-anTdino 2 4-oxo-:. -imidazo-lin-2-yl a yi 15 amidino imidazolyl 190-210 52 1770, 1667 7.4 (ra,5H), 5.8(s,lH>, 5.61-2-/3- (2-/TJ,N' --2-Meth.inesu I fonamido-2-pheny lacetamldo) -2,2-dimethy1- 3-(;>-tetrazolyl)penam The pll of a stirred solution of 1.42 g. of 6- (D-2-5 amino-2-phenyl-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in 6 ml. of water and 6 ml. of tetrahydrofuran is adjusted to 7.8 (6N sodium hydroxide). To this solution is then added 570 mg. of methancsulfonyl chloride, and stirring is continued for 1 hour with 6N sodium hydroxide being added as necessary to lO maintain the pll at 7.2. At this point, the tetrahydrofuran is removed by evaporation in vacuo, and the aqueous residue is washed with ethyl acetate. The pll is then lowered to 2.0, and the product is extracted into ethyl acetate. The ethyl acetate is washed successively with 6N hydrochloric acid and water, and 15 then dried using anhydrous sodium sulfate. Evaporation of the solvent in vacuo gives the crude product. This crude product is dissolved in the minimum amount of ethyl acetate, and then the solution is added dropwise with stirring to 200 ml. of hexane. The solid which precipitates is filtered off, giving 675 mg. 20 (4VA) of tho title compound, m.p. 117-48°C. IR (Nujol mull): 178r> cm"1 (I'.-lactam). NMR (in l)MSO-d6) : «).4r>-'».15 ppm (m,lll), 8.o5 ppm (d,ill), 7.60-7.10 ppm (m,5II), 5.60-5.15 ppm (m,4!I), 2.75 ppm (s,3ll), 1.60 ppm (s,3H), and l.OO ppm (s,3H). - 188 - 40832 EXAMPLE XCIII Reaction of citrier 6- (D-2-amino-2-phenylacetamldo)-2, 2-dimethyl-3-(5-tetrazolyl)penam or 6-(D-2-/2-aminoacetamidc^-2-phcnylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with the appropriate sulfonyl chloride, according to* the procedure of Example XCII provides the following congeners: - 189 - vD O 15 Yield (%) propanesulfonamido £-methoxybenzene-sulfonamido 10 2-naphthalene-sulfonamido 2-thiophensulfon-amido ethanesulfonamide £-chlorobenzene-sulfonamido £-nitrobenzenesulfon-amido 20 benzenesulfonamido a-toluenesulfon-amido 2-(methanesulfon-amido)acetamldo 25 *wlth decomposition 39 50 35 52 62 68 74 50 37 Melting Point* (°C) Infrared Spectrum (cm"1) 63 100-130 1780 130-155 1790 70-105 127-161 126-145 135-149 135-154 133-147 117-145 1780 1790 1785 1780 1790 1790 1780 93-125 1780 NMR Spectrum (DMSO-dgj ppm) MIC Streo. pyogenes ^ (•-g./ml.) ® u w 9.40-9.20(m,lH), 8.10(d,lH), 7.65-7.25(m,5H), 5.70-5.20(m,4H), 2.80(t,2H), 1.80-1.40 (m,5H), 1.05-0.70(m,6H). 9.25(d,lH), 8.45(d,lH), 7.70(d,2H), 7.50-7.10(m,5H), 0.2 7.00(d,2H), 5.60-5.l5(m,4H), 3.80(s,3H), 1.55(s,3H), 1.00(s,3H). 9.20(d,lH), 8.80(d,lH), 8.40-7.05(ra,7H), 5.55-5.50 (n.,4H), 1.50(s,3H) , 0.95(s,3H) . 9.30(d,1H), 3.95(d,lH), 7.90-7.00(ra,8H), 5.70-5.20 0.39 (rr.,4H), 1.60(s,3H), 1.00(m,6H). 9.40-9.10(m,1H), 8.lO(d,lH), 7.70-7.20(m,5H), 5.70- 0.39 5.20(n,4H), 2.90(q,2H), 1.60(s,3H), 1.10(s,3H). 9.30(d,1H), 8.90(d,lH), 7.85-7.10(o,9H), 5.60-5.15 (m,4H), 1.60(s,3H), 1.00(s,3H). 9.35-9.10(m,2H), 8.35(d,2H), 8.00(d,2H), 7.50-7.10 (m,5H), 5.60-5.20(m,4H), 1.60(s,3H), 1.00(s,3H). 9.30(d,lH), 6.75(d,lH), 7.90-7.05(ra,lOH), 5.60-5.20 (ro,4H), 1.60(s,3H), 1.00(s,3H). 9.ls-9.05(m,1H), 8.15(d,lH), 7.65-7.25(m,10H), 5.70-5.20(m,4H), 1.60(s,3H), 1.05(s,3H). 9.50-9.25(m,1H), 8.60(d,lH), 7.70-7.20{m,5H), 5,90- < 0.1 5.50(m,3H), 5.25(s,lH), 3.75(d,2H), 2.90(s,3H), 1.60 (s,3H), 1.00(s,3H).

.Melting Infrared Yield Point* Spectrum (%> (°C) (cm"1) 2- (berizenesulfon- 56 120-144 1790 araido)acetamido 2-(.\-toluenesulfon- 29 130-152 1780 amido)acetamido ln 2-(2-thiophenesul- 42 128-150 1780 fonamido) acetamido I £ *wi£h decomposition MIC Strep, pyogenes NMR Spectrum (DMSO-dg; ppn) e.g./ml. 9.60-9.30(m,lH), 8.60 (d,lH) , 8.20-7.20(m,10H), 5.80-5.50(m,3H), 5.25(s,lH), 3.60(d,2H), 1.60 (s,3H), 1.00(s,3H). 9.60-9.30(m,1H), 8.60(d,lH), 7.70-7.20(m,10H), < 3.1 5.90-5.50(m,2H), 5.25(s,lH), 5.00(s,lH), 4.40 (s,2H), 3.70(d,2H), 1.60(s,3H), 1.00(s,3H). 9.60-9.20(m,1H), 8.55(d,lH), 8.25(t,lH), 7.95(d,iH), 7.70-7.10(m,7H) , 5.90-5.50(m,3H), 5.25(s,lH), 3.70 (d,2H), 1.60(s/3H), 1.00(s,3H). lU o « u w 40532 EXAMPLE XCIV 6-(n-2-/T>ropanesulfonamido7-2-/£-hydroxyphenyl7acetamido)-2,2-dimethyl-3-(5-tetrazolyi)penam The title compound is prepared in 38% yield from 6-(D-5 2-aroino-2-/£-hydroxyphenyl7"acetamido)-2,2-dimethy 1-3- (5-tetrazolyDpenam and propancsulfonyl chloride, using the procedure of Example XCII. The product has m.p. 115-157°C. (dec.). IR (Nujol mull): 1780 cm"1 (fl-lactam). NMR (in DMSO-dj): 9.20-8.90 ppm (m,lll), 7.90 ppm (d,lil), 7.30 ppm (d,2h), lO 6.70 ppm (d,2ll) , 5.70-5.00 ppm (m,4ll), 2.80 ppm (t,21l), l.OO-1.30 ppm (ro,5ll)» 1.10-0.65 ppm (m,6U). - 192 - 40532 EXAMPLE XCV (>- (n-2-/ftenzcncsulfonamidq/-2-/£-hydroxyphenyi7acetamldo) -2,i-dimethyl-3-(5-tetrazolyl)penam Tho title compound is prepared in 53% yield from 6-(D-5 2-amino-2-/g-hydroxyphenyi/acetajnido) -2,2-dimethyl-3- (5-tetrazolyl)penam and benzenesulfonyl chloride, using the procedure of Example XCV. The product has m.p. 152-165°C. (dec.). IR (nujol mull): 1780 cm"1 (B-lactam). NMR (in DMSO-dg): 9.10 ppm (d,lH), 8.50 ppm (d,lH), 7.90-7.40 ppm (m,5H), lO 7.10 ppm (d,2H), 6.55 ppm (d,2H) , 5.60-5.10 ppm (m,4H) , 1.55 ppm (s,311), l.OO ppm (s,3H). - 193 - 40532 EXAMPLE XCVI 6-(2-D-/2-Benzamidoacetamido7-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam To a stirred solution of 1.29 g. of 6-(2-D-/2-amino-5 acct.-unids7~2-phcnylacetamldo) -2 , 2-dimethyl-3- (5-tetrazolyl) -penam and 1.3 ml. of triethylamine in 15 ml. of dimethyl* formamide, is added 0.4 ml. of benzoyl chloride. Stirring is continued for a further 30 minutes, and then the reaction mixture is filtered. The filtrate is added dropwise to 300 ml lO of ether, which causes a gummy solid to precipitate. The ether is removed by decantation, and the solid is partitioned between ethyl acetate and water. The pH of the aqueous phase is adjusted to 2.0 (dilute hydrochloric acid), and the ethyl acetate layer is removed and combined with a further ethyl 15 acetate cxtract of the acidified aqueous phase. The combined extracts are washed with water, followed by brine, and then dried using anhydrous sulfate. Evaporation of the solvent In vacuo gives a gum, which is redissolved in 30 ml. of ethyl acetate, and Lhc?n the solution is added dropwise to 200 ml. 20 of hcxane. The white solid which precipitates is filtered off giving 0.85 g. of the title compound, m.p. 150°C. (dec.). IR (KBr disc): 17BO cm"1 (8-lactam). NMR (DMSO-dfi): 9.40-9.20 ppm (in,111), 8.«>0-».40 ppm (m,2U) , 8.00-7.10 ppm (3,1211), 5.90 5.40 ppm (m,3ll), 5.25 ppm (s,l!l), 4.00 ppm (d,2H) , 1.60 ppm 25 (s,311) and l.oo ppm (s,3H). - 194 - 40532 KXAMPIJi XCV 11 Following the procedure of Example XCVI, and replacing the benzoyl chloride used therein by the appropriate acid chloride, the following congeners are produced: a CH-CO-NH NH I CO i CH2 Nil / f _N CHi ,CH.

\ N \ // ,N N CO - l')r> - Melting Infrared Yield Point* Spectrum (t) (°C.) (on"1) methyl 59 135-142 1780 5 ethyl 58 148-153 1790 £-chlorophenyl 67 180-185 1790 10 £-nitrophenyl 67 155-164 1780 £-r.ethoxyphenyl 54 151-158 1780 15 n-propyl 60 120-132 1785 ethoxy 40 131-138 1780 2o benzyloxy 65 123-128 1780 *with decomposition ». k NMR Spectrum DMSO-dg (p?r.) * o at to 9.3 (d,lH), 8.6 (d,lH), 8.1 (t,lH), 7.4 (s,5H), 6.4-5.4 (m,9H), - 5.2 (S,1H), 3.85 (d,2H), 1.85 (s,3H), 1.6 (s,3H), 1.0 (s,3H). • « 9.3 (d/lH)» 8.5 (d,lH), 8.0 (t,lH), 7.4 (s,5H), 5.9-5.4 (m,3H) 5.25 (s,1H), 3.8 (d,2H), 2.19 (q,2H), 1.0(s,3H), 1.18-0.8(m,6H). 9.4-9.2 (m,lH), 9.0-8.4 (m,2H), 8.0-7.2 (m,9H), 5.85-5.45 (m,3H), 5.2 (s,1H), 4.0 (d,2H), 1.6 (d,3H), 1.0 (s,3H). 9.6-8.0 (m,7i), 7.4 («,5H), 5.9-5.4 (m,3H), 5.2 (s,lH), 4.05 (d,2H), 1.6 (s,3H), 1.0 <8,3H), 9.55-9.2 (n,lH) , 8.7-8.4 (m,2H), 7.9 (d,2H), 7.6-7.2 (ia,5H) , 5.05 (d,2K), 5.9-5.4 (m,3H), 5.2 (s,lH), 4.0 (d,2H), 3.8 (s,3H), 1.6 (S,3H), 1.0 (s,3H). 9.5-9.2 (d,1H), 8.6-8.35 (d,lH), 8.2-7.9 (n,lH), 7.45 (s,5H), 5.9-5.9 (m,3H), 5.3 (S,1H), 3.85 RA-NII CI). /" (> \ N V ^ \ // ,.N N - V)1 - 2-(phenylthio)acetyl D-2- (2-/|jhenylthi<27ace-amido)-2-phenylacetyl 2-(ethylthio)acetyl D-2-(2-/ithylthi27acet-amido)-2-phenylacetyl 3-(methoxycarbonyl)-butryl D-2-(3-/methoxycarbonyl/-butyramldo)-2-phenylacetyl 2-(ethoxycarbonyl)acetyl D-2-(2-/ethoxycarbonyl/-acetamido)-2-phenyl acetyl Yield IR (%) (cm-1) 31 1780 22 1785 45 1785 59 1785 46 1785 68 1790 31 1785 31 1775 NMR (DMSO-dg) (ppm) 1.10 (s,3H), 1.70 (s,3H), 3.85 (s,2H), 5.25-5.80 (n,3H), 7.10- « 7.50 (m,6H), 9.10 (d,lH). " 1.05 (s,3H), 1.60 (s,3H), 3.80 (8,2H), 5.10-6.00 (m,5H), 7.10-7.60 (m,10H)/ 8.8-9.10 (m,lH), 9.30-9.60 (m,lH). 0.80-1.30 (m,6H), 1.60 (s,3H), 2.30-2.80 (m,2H + DMSO), 3.20 3.20 (s,2H), 5.10-6.10 (ra,4H), 8.8 (d,lH). 0.80-1.30 (m,6H), 1.55 (s,3H), 2.30-2.80 (m,2H + DMSO), 3.20 ls,2H), 5.10-5.80 (m,4H), 6.00-7.00 (ra,lH), 7.10-7.60 (m,5H), 8.60 (d,lH/, 9.10-9.50 (m,lH). 1.05 (s,3H), 1.50-2.05 (m,5H), 2.10-2.65 (m,4H + DMSO), 3.60 (s,3H), 5.20-6.00 (niy4H), 8.90 (d,lH) . 0.80-1.40 (m,5H), 1.50-2,10 (m,5H), 2.20-2.80 (m, 2H ♦ DMSO), 3.65 (s,3H), 5.20-5.80 (m,4H), 7.20-7.60 (ro,5H), 8.60 (d,lH), 9.20-9.50 (m,lH). 0.80-1.40 (m,6H), 1.65 (s,3H), 3.40 (s,2H), 4.10 (q,2H), 5.20-5.75 (m,4H), 9.10 (d,lH). 0.90-1.40 , 7.0-8.1 (m,10H), 8.35-8.8 (m,2H), 9.1-9.4 5 (broad hump 1H). 1.05 (s,3H), 1.6 (s,3H), 2.25-2.7 (m,2H), 3.2-3.7 (m,2H) 5.25 (s,1H), 5.45-5.9 (m,3H), 7.2-8.0 (n,9H), 8.45-8.8 (m,2H), 9.2 (d,1H). 1.05 (s,3H)/ 1.6 (s,3H), 2.2-2.7 (n,2H), 3.1-3.7 (abroad 2-H) 5.25 (s,lh), 5.4-5.95 (m,3H), 6.55-6.7 (m,lH), 7.0-7.75 (G,7H), 7.8 (s,1H), 8.1-8.4 (m,lH), 8.65 (d,lH), 9.05-9.35. (m,lH). 1.05 (s,3H), 1.65 (s,3H), 2.2-2.65 (m,3H), 3.1-3.6 (m,2H), 5.25 (s,lH), 5.4-6.0 (m,3H), 7.2-7.7 (n,5H), 7.7-8.0 (m,lH), 8.6 O methyl O phenyl O p-chlorophenyl O 2-thienyl O propyl O isobutyl O n-hexyl O m-tolyl O j>-me thoxyphenyl O £-bromophenyl O 2-furyl O 4-pyridyl O £-fluorophenyl - 200 - m Z ra-bromopheny1 2-thienyl 3-thienyl 2-furyl £- (hydroxymethyl)phenyl phenyl phenyl phenyl £-hydroxyphenyl £-hydroxyphenyl O 3,4-dichlorophenyl O £-n-hexyloxyphenyl O phenyl O 3-thienyl 0 2-furyl 1 n-butyl 1 2-pyridyl 1 m-bromophenyl 1 2-thienyl 1 methyl - 201 - , 40932 EXAMPLE C 6-(2-/5-PhGnylureidq7-2-/£-hydroxyphenyI7acetamido)-2,2-dlmethyl-3-(5-tetrazolyl)penam To a stirred solution of 0.78 g. (0.002 mole) of 6-5 (2-amino-2-/£-hydroxyphonyl/acetamido) -2,2-dimethy 1-3- (5-tetrazolyDpenam in 40 ml. of 1:1 acetone-water, the pH of which has been adjusted to 6.0 by the addition of sodium bicarbonate solution, is added 0.238 g. (0.002 mole) of phenyl isocycnate at ambient temperature. Stirring is continued at lO ambient temperature for a further 30 minutes, and then 50 ml. of ethyl acetate is added. The pH of the aqueous phase is lowered to 1.5 with 1 N hydrochloric acid, and then the organic layer is removed, dried and evaporated to dryness in vacuo. The residue is re-dissolved in a small volume of etna-15 nol, to which 0.2 ml. of triethylamine is then added. The resulting solution is added dropwise to 200 ml. of ether, with vigorous stirring, and then tho .solid which precipitates is filtered off. This affords o.B ij. (66% yield) of 6- (2-/3-phonylureido7-2-/£-hydroxyphcnyl/acetamido)-2,2-dimethy1-3-20 (5-tetrazolyl)penam as Its triethylamine salt, m.p. 165-170°C. (dec.). The infrared spectrum of the product (KBr disc) shows absorptions at 1790 cm"1 (fl-lactam) and 1670 cm"1 (amide I). The NMR spectrum (DMSO-dg/I^O) shows absorptions at 7.60-6.70 pjan (multiplet, 9H, aromatic hydrogens), 5.80-5.50 ppm 25 (multiplet, 311, C-5 and C-6 hydrogens, and side-chain methine hydrogen), 5.05 ppm (singlet, 1H, C-3 hydrogen), 3.05 ppm (quartet, 6H, N-CHjCH^), 1.5s ppm (singlet, 3H, C-2 methyl hydrogen), l.lO ppm (triplet, 911, N-CH2CH3) and 0.95 ppm (singlet, 3H C-2 methyl hydrogens). 3') Tho MIC of the title comix>uncl og.iinsl. Strep, pyogenes is * O.l |iy./ml. - 202 - 40532 EXAMPLE CI Using the procedure of Example C, and reacting either 6- (2-amino-2-phenylacetamldo) -2,2-dimethy1-3-(5-tetrazolyl)-penam or 6-(2-amino-2-/£-hydroxyphenyl/acetamido)-2,2-dimethyl-3-('j-tetrazolyl)penam with the appropriate isocyanate, the following compounds are prepared. The compounds are isolated as their triethylamine salts. k7-cii-conii c,h Q n o 11 ,N N - 2f>3 - Yield m.p. Infrared Spectrum (*) (°C.) CgHjNHCONH ch3nhconh £-CH3OC6H4NHCONH 63 165-70 £-ClC6H4NHCONH 39 170 (cm-1) £-ch3oc6h4nhconh 64 148-52 £-ClC6H4NHCONH 75 148-55 £-ch3c6h4nhconh 79 152-55 79 150-55 45 112-20 1785,1670, 1615, 1550, 1515 1785, 1680, 1600, 1550, 1495 1785, 1680, 1615, 1550, 1505 1785, 1670, 1600, 1550, 1505 1785, 1655, 1565, 1505 1785, 1670, 1655, 1615, 1550, 1515 1785, 1680, 1600, 1550, 1520, 1505 NMR Spectrum (DMSO-dg/DjO; ppm) MIC Strep, pyogenes (.q./ml.) 7.65-7.15(m,7H), 6.85(d,2H), 5.75- < 0.1 5.40(m,3H), 5.05(s,lH), 3.7{s,3H), 3.05(g,6H), 1.55(s,3H), 1.15(t,9H), 0.95(s,3H). 7.75-7.20(m,9H), 5.85-5.45(m,3H), < 0.1 5.05(s,1H), 3.05(q,6H), 1.55(s,3H), 1.15Ct,9H), 0.95(s,3H). 7.60-6.95(m,9K), 5.80-5.50(m,3H), < 0.1 5.lO(s,lH), 3.05(q,6H), 2.15{s,3H), 1.60(s,3H), 1.10(t,9H), 0.95(sf3H). 7.75-6.85(m,10H), 5.80-5.45(m,3H), < 0.1 5.10(s,lH), 3.10(q,6H), 1.60(s,3H), 1.15(t,9H), 0.95(b,3H). 7.45(s,5H), 5.70-5.40(m,3H), 5.1(s,lH), 50 3.1(q,6H), 2.60(d,3H), 1.60(8,3H), 1.20(t,9H), 0.95(s,3H). 7.60-7.20(m,4H), 7.55-6.75(m,4H), 5.85- < 0.1 5.40(m,3H), 5.05(8,1H), 3.70(s,3H), 3.10(q,6H), 1.60(s,3H), 1.20-tetrazolyl)penam To 0.418 g. of sodium N-(2-ethoxycarbonyl-l-methyl-5 vinyl)-2-aminoacetate in lO ml. of tetrahydrofuran is added 2 drops of N-methylmorpholine and 0.19 ml. of ethyl chloroformate with stirring. Stirring is continued for a further 30 minutes at -10°C. and then the sblution is cooled to -30°C. To this solution is then added 0.708 g. of 6-(D-2-amino-2-Io phony 1acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam dissolved in lO ml. of 1:1 tetrahydrofuran-water anc) adjusted to pH 8.7. Stirring is then continued for a further 30 minutes without cooling. At this point, the pll is adjusted to 1.5, and the reaction mixture is stirred at 0°C. for 30 minutes. The tetra-I "> liydrofuran is removed by evaporation i_n vacuo; and then the aqueous residue is washed with ether, washed with ethyl acetate, adjusted to pll 6.4 and lyophilizcd to give a white solid The solid is stirred for 20 minutes in 20 ml. of N,N-dimethyl-formamide, and the solid which does not dissolve is filtered 2D off and discarded. The filtrate is added dropwise to 200 ml. of chloroform, and the solid which precipitates is filtered off and dried giving 0.3 g. (36.6% yield) of the title compound m.p. 211-2JO°C. (dec.). IR (KBr disc): 1770 cm 1 (P-lactam). NMR (in OMSO-d ) : 9.50-9.15 ppm (d, 211), 7.40 ppm (s, 511), JL'i (>.8()-r>.3<) ppm (m, *>11), S.OO ppm (s. 111), ).»>T> ppm (s,2ll), I . r>0 ppm (s, 311), ().'>(> ppm (s, 311). - jt)5 - 40532 EXAMPLE CIII 6-/5-/2-Amlnoacotamido7-2-/£-hydroxyphenyl7acetainido) -2,2-«limothyl-3-(5-tetrnzolyl)penam The LlLle compound la prepared In 45% yield £rom 6-(2-5 amlno-2-/£-hydroxyphenyl/acetamldo)-2,2-dlme thyl-3-(5-tetrazolyl) penam and sodium N-(2-ethoxycarbonyl-l-methylvinyl)-2-aminoacetate, using the procedure of Example CII. The product has m.p. 173-188°C. (dec.). IR (KBr disc): 1785 cm"1 (B-lactam). NMR (nMSO-d6): 7.55-7.10 ppm (m, 211), 7.00-6.00 ppm (m, 211), lO 5.75-5.40 ppm (m, 311), S.IO ppm (s, 111), 3.65 ppm (m, 2H), 1.55 ppm (s, 311), 0.95 ppm (s, 3H). - 206 - 40532 EXAMPLE CIV Reaction of the appropriate 6-(2-amino-2-substltuted-.icctnmido)-2,2—«1 imethy 1-3-(5-tetrazolyl)penam or 6-(2-/2-iimi no«iceLamlilo7-2-suhst i tutcd acetamido) -2, 2-dimethy 1-3-(5-Letrazolyl)penam, with sodium N-(2-ethoxycarbonyl-l-methyl-vinyl)-2-aminoacotate, according to the procedure of Example CII, provides the following compounds: CIl I Nil I CO i Cll I Nil i CO I Cll I Nil CONH CH, m f -N \ 11 „N N r' m lo methyl O isopropyl O allyl o cyclohexyl o 3-cyclohexenyi o 15 1,4-cyclohexad ieny1 o benzyl o £-chloropheny1 o £-hydroxybenzyl o m-bromophenyl o 20 £-fluorophenyl o o-ch1orophuny1 o '), 4-»l i cli 11 >roplicny 1 o - 2<>7 - 40532 lO IS 3-chloro-4-hydroxyphenyl g-methoxyphenyl m-butoxypheny1 £- (hydroxymethyl)phenyl 3,4-dimethoxypheny1 m-tolyl 2-thienyl 3-thienyl 2-furyl 3-furyl 3-pyridy I 5-ethyl-2-thlenyl methyl phenyl £-hydroxypheny1 £-chlorophenyl m 0 O o o o o o o o o o 0 1 1 1 1 - 208 - t 4 0 5 3 2 EXAMPLE CV 0-(l>-2-/3-Aminopropionamidq7-2-phenylacetamido)-2,2-dimethyl-(5-tetrazolyl)ponam To .i sLirrird solution of o.95 ml. of ethyl chlorofor-'i m.ilc and 2 drops of N-mothylmorpholInc, in 30 ml. of tetrahydrofuran, is added 2.39 g. of N-(2-ethoxycarbonyl-l-methyl-vinyl)-3-aminopropionic acid, at -10°C. Stirring is continued for JO minutes, and then the reaction mixture is cooled to -30°C. To it is then added a solution prepared by suspending lO 3.8 g. of 6-(D-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)ponam trihydrate in 15 ml. of water and 15 ml. of tetrahydrofuran and adjusting the pH to 7.8. After the addition, the cooling bath is removed and stirring is continued for a further 30 minutes. The temperature of the reaction mixture lr> is then adjusted to 0°C., the pll is adjusted 1.5, and stirring is continued for 30 minutes. At this point, the tetrahydrofuran is removed by evaporation in vacuo, the aqueous residue is extracted with ethyl acetate, and then the pH of the aqueous residue is adjusted to 6.O. Lyophilization of the aqueous 2<> residue then affords the crude product. It is purified by stirring with 400 ml. of dimethylformamide, filtering, and adding the filtrate slowly to bOO ml. of chloroform. The purified product is filtered off. The yield is 3.30 g, mp 190°C (dec.). IR (KBr disc): 1765 cm NMR (DMSO-dg): 9.4-8.8 ppm 25 (m,2ll) , 8.0-7.1 ppm (m, iOll), 5.9-5.3 ppm (m, 3H) , 5.0 ppm (s,lll) , 3.3-2.5 ppm (m,4ll) , 1.55 ppm (s,3U) and 0.9 ppm (s,3ll). - 209 - 40532 EXAMPLE CVI 6- (l)-2-^- (Bcnzamidino) acct«-imido7-2-phenylacetamido) -2,2-dimcthyl-3-(5-tetrazolyl)penam A mixture of 1.72 g. of 6-(D-2-/2-aminoacetamidq7-2-5 phenylacetamido- 2,2-dime thyl-3-(5-tetrazoly) penam, 0.66 g. of ethyl benzimidate and 20 ml. of N,N-dimethylformamide is stirred for 1 hour at 25°C. The filtered reaction mixture is then added dropwise with stirring to a large excess of chloro form, and the solid which precipitates is filtered off. This lO affords 0.93 g. (43% yield) of the title compound, m.p. 198°C (dec.). IR (KBr disc): 1770 cm"1 (B-lactam). NMR (DMSO-dg): 9.35-9.00 ppm (m, 211), 8.00-7.15 (m, 1211), 5.95 ppm (d, 2H) , '>.■>•» - 5.3<> ppm (m, 211), '>.CK) ppm (s. 111), 4.35 ppm (3, 211), l.5() ppm (s, 311), nnd 0.90 ppm (s, 311). - 210 - 40532 KXAMI'M-: CVIX Following the procedure of Example CVI, and reacting 6 (0-2-/5-nminoacetamido/-2-phenylacetainido)-2,2-dimethy1-3-(5 tetrazolyl)penam with the appropriate imidate ester, the following compounds are prepared: Cll-CONH Nil CO o ■f s \ / UN - 211 - / 4-pyridinecarbox-3 amidinomethyl 3,5-dibromobenzamidinomethyl 2-thiophenecarboxam-idinomethyl 10 acetamidinomethyl 4-pyridinecarboxami-dinomethyl N-oxide (2-/£-chloropheny]J'-15 acetamidino)methyl £-nitrobenzamidino-methyl m-sulfamoylbenz-amidinomethyl m-cyanobenzamidino-methyl 2-benzimidazoiecarbox-amidinomethyl (tri-25 ethylamine salt) 2-pyrimidinecarbox-amidinomethyl 3-cyano-5-iodobenz-amidinomethyl Yield {%) 63 32 35 €9 22 4 = 62 51 75 59 49 56 Melting Infrared Point * Spectrum (c C.) 193 195 185 185 200 192 197 180-185 180-185 126-140 (en-1) 1770 1775 1770 1775 1775 1770 1770 1780 1785 1785 NMR Spectrum (DMSO-dg; ppra) 149-169 1785 1780 9.1-8.7(m,4H), 7.9-7.2(n,7H), 6.4-4.7(m,UH), 4.3{s,2H), 1.5(s,3H), 0.9(3,3H). 9.3-8.8(m,2H), 8.2-7.1(n,8H), 5.95-5.3(m,3H), 4.95(s,lH), 4.25(s,2H>, 1.5(s,3H), 0.9(s,3H). 9.45-8.9(m,2H), 8.15-7.9(m,2H), 7.7-7.2(m,6H), 6.0-5.4(m, 3H), 5.05(s,lH), 4.22(s,2H), 1.5(s,3H), 0.9(s,3K). 9.6-8.6(m,5H), 7.75-7.15(m,5H), 6.0-5.3(m,3H), 5.0(s,lH), 4.15(s,2H), 2.22(s,3H), 1.55(s,3H), 0.92(s,3H). 9.7-9.3(m,2H), 8.42(d,2H), 7.8(d,2H), 7.2(s,5H>, 6.0-5.3 (m,3H), 5.05(s,lH), 4.2(s,2H), 1.55(s,3H), 0.95(s,3H). 9.8-8.7(m,4H), 7.7-7.1(m,10H), 5.9-5.2(m,3H), 4.95(s,lH), 4.4-3.0(m,6H), 1.5(s,3H), 0.9(s,3H). 9.4-8.9(m,2H), 8.5(d,2H), 8.1(d,2H), 8.0-6.6(m,8H), 5.9(d, 1H), 5.65-5.4(m,2H), 5.05(s,lH), 4.35(s,2H), 1.55(s,3H), 0.9(s,3H). 8.35-7.5(m,9H), 5.85(d,2H), 5.55(m,2H), 5.02(s,lH), 4.35 (m,2H), 1.50(s,3H), 0.95(s,3H). 8.4-7.45(m,9H), 5.85(d,lH), 5.5(m,2H), 5.02(s,lH), 4.3(n, 2H), 1.5(S,3H), 0.9(e,3H). 8.0-7.2(m,9H), 5.9(d,lH), 5.55(ra,2H), 5.0(s,lH), 4.1(s,2H), 3.0lq,6H), 1.5(s,3H), 1.18(t,9H), 0.9(s,3H). 9.3(s,1H), 8.85(m,2H), 7.35(o,5H), 5.8(d,lH), 5.5(m,2H), 5.03(s,lH), 4.25(m,2H), 1.5(a,3H), 0.9(s,3H). 8.55(m,3H), 7.6(m,5H), 5.9(d,lH), 5.6(m,3H), 5.03(s,lH), 4.2(m,2H), 1.55(s,3H), 0.9(s,3H). a o w u w Melting Yield Point * m ro. 2-quinoxalinecarbox-amidinomethyl n-carbamoylbenzamidi-nomethyl 2-pyrrolecarboxamidi- nor.ethyl 2-benzthiazolecarb-oxamidinomethyl 3, 5-disulfamoyl-benzamidinomethyl 3-sulfamoyl-5-bromo-benzamidinomethyl 3-suifamoyl-5-chloro-benzamidinomethyl 3-chloro-5-cyano-benzamidinomethyl 2-benzoxazolecar-ioxamidinomethyl 53 81 83 54 212-15 31 185-92 78 196-200 71 197-200 73 203 73 199 Infrared Spectrur. (cm-1) 1785 1785 1785 1770 1667 1770 1667 1786 1681 1770 1667 1786 1681 1786 1667 *with decomposition NMR Spectrum (DMSO-dg; ppn) 9.8(s,1H) , 8.2(m,4H), 7.5(m,5H), 5.95(d,lH), 5.6(m,2H), 5.1(s,1H), 4.3(m,2H), 1.55(s,3H), 0.95(s,3H), 8.6-7 .25 (n,9H) , 5.95(d,lH), 5.56 (r.,2H) , 5.05(s,lH), 4.4(r.,2H), 1.55(s,3H), 0.9(S,3H). 7.3(m,7H), 6.3(n,1H), 5.85(d,lH), 5.5(n,2H), 5.0{s,1H), 4.25(m,2H), 1.55(s,3H), 0.9(s,3H). 0.9S(b,3H), 1.55(s,3H), 3.95(b,2H), 5.1(s,lH), 5.4-5.95(c,3H), 7.5(b,7H), 8.2(b,2H). 0.95(8,3H), 1.55(s,3H), 4.1(b,2H), 5.1(s,lH), 5.45-5.95(c,3H), 7.5(b,5H), 8.5(b,3H). 0.95(s,3H), 1.55(s,3H), 4.25(b,2H), 5.1(s,lH), 5.6(c,2H), 5.85(s,lH), 7.5(b,5H), 8.1(b,2H), 8.6(b,lH). 0.95(s,3H), 1.55(s,3H), 4.4(b,2H), 5.05(s,lH), 5.SS(c,2H), 5.8(s,lH), 7.5(b,5H), 8.0(6,2H), 8.4(b,lH). 0.95(s,3H), 1.55(s,3H), 4.25{b,2H), 5.05(s,lH), 5.5(c,2H), 5.85(s,1H), 7.4(b,5H), 8.25(b,3H). 0.95(s,3H), 1.55(8,3H), 4.3(b,2H), 5.1(s,lH), 5.55(c,2H), 5.8(8,1H), 7.2-8.2(c,9H). & o « u N 40532 KXAMPI.K CVIII KimcHdii «»i Liu? appropriate compound of formula 1 or II wherein R^ and R"* arc cach hydrogen and R* is of formula V, wherein n is 1 and Q is amino, with the requisite ethyl imidate, according to tho procedure of Example CVI, produces the following compounds R'-NII Cll- Y Cll., N.

\ // N N / - 214 - 2-(3,5-dimethylbenz-amidino)acetyl 2-(4-pyridinecarbox-amidino)acetyl 2-(acetamidinoacetyl) Melting Yield Point * * (0°C). 31 Infrared Spectrur: (cm"1) 170-186 1775 24 170-162 1785,1680 69 116-127 1770,1680 2-(2-thiophenecarbox-amidino)acetyl 2 -(4-pyridinecarbox-amidino)-3-phenyl-propionyl 2- (4-pyr:Ldinecarbox-amidino) "3-methyl butyryl 67 175-180 1780 58 172 38 1780,1680 1785,1680 * decomposition NMR Spectrum (DMSO-dg/DjO; ppn) 7. 35(s,3H), 5.77(d,lH), 5.60(d,lH), 5.20(s,lH), 4 .34 (8,2H), 2.37(s,6H), 1.67(s,3H), 1.01(8,3H). 8.40(d,2H), 7.70(d,lH), 5.83(d,lH), 5.67(d,lH), 5.30(s,lH), 4.50(8,2H), 1.67(s,3H), 1.01(s,3H). 5,83(d,1H), 5.67(d,lH), 5.30(s,lH), 4.33(s,2H), 2.40 (8,3H), 1.67 (S,3H), 1.01(s,3H). 8.03(m,2H), 7.34(m,lH), 5.78(d,lH), 5.60(d,lH), 5.19 (s,1H), 4.35(s,2H), 1.67(8,3H), 1.01(s,3H). 8.40(d,2H), 7.77(d,2H), 5.76(d,lH), 5.56(d,lH), 5.19 (s,lH), 4.33(m,1H), 2.30(m,lH), 1.60(s,3H), 1.01(s,3H). ft O « u 10 40532 KXAMP1.K CIX Using tho procedure of Example CVI, and reacting 6-(D-2- Z3-aminopropionamid2/-2-phenylacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam with the appropriate ethyl imidate, the following compounds arc prepared: CH.

R -NH f / N.

\ / ,,N N - 216 - 1 R Yield IR («) (cn"1) i 15 NJ D-2-(3-^3-pyridinecar- 63 1765 boxamidino7proplonam- ido)-2-phenylacetyl D-2-(3-pyridine-l-oxide- 82 1770 4-carboxamidino/pro-pionamido)-2-phenylacetyl D-2-(3-/2-thienylcarb 78 1775 oxamidin<27propionam- ido)-2-phenylacetyl ^ D-2-(3-benzanidino- 74 1765 i propionamido)-2- phenylacetyl 20 D-2-(3-/3,5-dibromobenzam- 82 1770 idino7propionamido)-2-phenylacetyl D-2-(3-acetamidinopropionamido) - 70 1770 -2-phenylacetyl NMR(DMSO-dg) (ppn) 0.9(s,3H), 1.55(s,3H), 2.5-3.0(.m,2H) , 3.45-4.0(n,2H), 5.0 (s,lH),5.3-5.6(ro,2H), 5.85(s,lH), 7.0-8.0(m,UH) , 8.6-9.3(m,4H).

DMSO-D,:50.9(s,3H) , 1.55(s,3K), 2.4-3.0(m,2H), 3.35-3.9 (m,2H), 5.05(s,lH), 5.35-5.65(m,2H), 5.85(d,lH), 6.4-5.1 (m,12H), 8.45(d,2H), 8.7-9.1(m,2H).

DMSO-D,+D,n: iO.95 ls,3H), 1.5(s,3H), 2.4-3.0(m,2H), 3.4-4.0(zn,2H)7u5.1(8,lH) , 7.45(s,5H), 7.8(d,2H), 8.45(d,2H! DMSOOg: 50.95 (s, 3H) , 1.55(s,3H), 2 .4-3 . ,(m,2H) , 3.4-4.0 (m,2H), 5.05(s,1H), 5.25-5.65(m,2H), 5. 5(d,lH),7.1-7.65 (m7-8H), 7.9-8.25(m,2H), 7.0-9.7 (Broad & n4-5H), DMSO D, + D2q:60.95(8,3H), 1.55{s,3H), 2.4-3.0 (m,2H), 3.5-4.05(m,2H), 5.2(s,lH), 5.45-5.9(m,3H), 7.2-7.7(m,6H), 7.8-8.25(m,2H).

DMSO-Dgs60.9(s,3H), 1.55(s,3H), 2.4-2.95(m,2H), 3.3-3.9 (m,2H), 5.05(s,lH), 5.3-5.6(m,2H), 5.85(d,lH), 7.2-8.C (11H), 8.6-10.0 (4-5H) 1.5(s,3H), 2.45-2.9 (m,2H) , 3.3-3.8 (in,2H) , 4.95(s,lH), 5.3-5.5(m,2H), 5.8(d,lH), 7.1-7.7(m6-7H)j 7.8-8.3(m,3H), 8.8-9.3 (m,2H) 0.95(s,3H), 1.55(s,3H), 2.15(8,3H), 2.25-2.8(m,2H), 3.1-3.7 (m,2H), 5.05(s,lH), 5.3-5.65(m,2H), 5.85(d,lH), 7.0-7.7(m,5H), 8.0-10.0 (5-6H) ft 0 01 u M D-2-<3-ZJ,4-dichlorobenz-amidino/propionamido)-2-phenyI-acetyl D-2-(3-/I-chlorophenyi7acet-amidinopropionamido)-2-phenylacetyl NMR (DMSO-dg) (ppn) 0.95 In 20 R m •I i>»»thy 1 () .ice t amidinomethyl lilt: ■/1 O !>cnz amidinomethyl methyl O g-chlorobenzamidinomethyl isopropyl C m-bromobenzamidinomethyl i sopropy1 O g-methoxybenzamidinomethy1 isopropyl () i,5-dichlorobenznmidinomethyl isopropyl () 2-f ur.incarbox.'imidinomethyl isopropyl () 4-pyr idinecarljoxamidinomethy I pheny1 O m-methoxybenzamidinomethyl phenyl O g-fluorobenzamidinomethyl phenyl o g-methylbenzamidinomethyl phenyl o m-methylthiobenzamidinomethyl g-hydroxyphenyl o 2-benzimidazolecarboxamidino- methyl g-hydroxypheny1 o benzamidinomethyl g- (hydroxymcthy1)phenyl o benzamidinomethyl - 210 - 40532 R' m 2-thienyl o 2-thienyl o 3-thienyl 0 5 2-furyl 0 3-chloro-4-hydroxy- 0 phenyl £-methoxyphenyI o m-tolyl o 10 phenyl o phenyl o £-hydroxypheny1 o ra-butoxypheny1 o methyl 1 15 methyl 1 isopropyl 1 phenyl 1 phenyl 1 phenyl 1 20 £-hyd roxypheny1 1 n-chloropheny1 1 z 4-pyridinecarboxamidinomethyl 2-thiophenecarboxamidinomethyl benzamidinomethyl 3,5-dichlorobenzamidinomethyl 4-pyridinecarboxamidinomethyl benzamidinomethyl 3-pyridinecarboxamidinomethyl propanecarboxamidlnonethyl butanecarboxamidinomethyl hexanecarboxamidinomethyl benzamidinomethyl acetamidinomethyl benzamidinomethyl 4-pyridinecarboxamidinomethyl butanecarboxamidinomethyl 3,5-dichlorobenzamidinomethyl 2-thiophenecarboxamidinomethyl benzamidinomethyl 4-pyridinecarboxamidinomethyl - 220 - 40532 EXAMPLE CXI 6-(0-2-/7-(4-Pyridinecarboxamidino)acetaroido]-2-(£-hydroxy-phenyl/acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam The title compound is prepared in 80% yield from 6-(D-5 2-/5-aminoacetamidq/-2-^£-hydroxypheny\7acetamido)-2,2- dimethyl-3-(5-tetrazolyl)penam and ethyl 4-pyridlnecarboximid-atc, using the procedure of Example CVI. The product has m.p. 195°C. (dec.). IR (KBr disc): 1775 cm"1. NMR (DMSO-dg): 9.3-8.8 ppm (m,4II), 8.8-7.0 ppm (m,4H), 7.75 ppm (d,2H) , 7.25 ppm lO (d,211) , 6.75 ppm (d,2II), 5.85-5.45 ppm (m,3H), 5.05 ppm (s,lH), 4.35 ppm (s,2ll), 1.55 ppm is, 311), 0.95 ppm (s,3!l). - 221 - 40532 EXAMPLE CXI 6-(D-2-/7-(4-Pyridinecarboxamidino)acetamido]-2-(£-hydroxy-phcny1/acctamido)-2,2-dimethyl-3-(5-tetrazolyl)penam The title compound is prepared in 80% yield from 6-(D-5 2-^2-aminoacetamidq/-2-^£-hydroxyphenyl7acetamido)-2,2- dimethyl-3-(5-tetrazolyl)penam and ethyl 4-pyridinecarboximid-ate, using the procedure of Example CVI. The product has m.p. 195°C. (dec.). IR (KBr disc): 1775 cm"1. NMR (DMSO-dg): 9.3-8.8 ppm (m,4H), 8.8-7.0 ppm (m,4H), 7.75 ppm (d,2H), 7.25 ppm lO (d,211) , 6.75 ppm (d,21I) , 5.85-5.45 ppm (m,3H), 5.05 ppm (s,lH), 4.35 ppm (s,2ll), 1.55 ppm (s, 311), 0.95 ppm (s,3H). - 221 - 40 532 EXAMPLE CXII 6-(0-2-/2-(3-Ethylureido)acetamido7-2-phenylacetamldo)-2,2-dimcthyl-3-(S-tetrazoly Dpenam A mixture of 1.29 g. of 6-(D-2-/2-aminoacetamido7-2- phenylacetamldo)-2,2-dimethy1-3-(5-tetrazolyl)penam, 0.23 g. of ethyl isocyanate and 15 mi. of N,N-dimethylformamide is stirred at room temperature for 45 minutes. The filtered reaction mixture is then added dropwise with stirring to 300 ml. of ether, and the precipitate which forms is filtered off.

The solid is partitioned between water and ethyl acetate, and the pll is adjusted to 8.O. The ethyl acetate is removed and discarded. The pH of the aqueous phase is adjusted to 2.0, and the product is extracted into ethyl acetate. The washed (water) and dried (Na2SO^) ethyl acetate is concentrated to small volume and the product crystallizes out. It is filtered off.

The yield of the title compound is 0.74 g. (49%), m.p. 162°C. (dec.). IR (KBr disc): 1785 cm"1 (B-lactam). NMR (DMSO-d,/ o CDC13): 9.3-9.1 ppm (s,lll), 8.3 ppm (d,lH) , 7.65-7.2 ppm (m, 511), 6.3-5.5 ppm (m,5H), 5.2 ppm (s,l!I), 3.8 ppm (d,2H) , 3.3-2.9 ppm (m,2ll) , 1.65 ppm (s,3II), 1.2-0.9 ppm (m,6H) . - 222 - EXAMPLE CXIII 40532 Reaction oE 6-(D-2-/2-aminoacetamidq7-2-phenylacetam-Ido)-2,2-dimethy1-3-(5-tetrazolyl)penam with the appropriate isocyanate, according to the procedure of Example CXII, provide?; Lho following compound;;. lO ani1ino 15 2<> methylamino Yield (%) 38 33 Melting Infrared Point* Spectrum (° C.) 158 154 (cm-1) 1780 1785 NMR Spectrum (DMSO-dg? ppm) 9.3-9.0(m,lH), 8.7-8.4 (m,21l), 7 .7-6.9 (m, lOH) , 6.6-6. 3(m, 111) , 5.9-5.45 (m, 311) , 5. 2 (s, 111) , 3.95 (d,2H),1.65(s,3H), 1.05 (s, 3H) . 9.25-9.05(m,1H), 8.15(d,lH), 7.6-7.15(m,5H), 6.3-5.2 (m,511) , 5.15 (s. Ill) , 3.8 (d,2ll) , 2 .65 (d, 311) , 1.6 (s/JH), 1.05 (s, 311) . • wllh ili'iMini><licnyJ7 acetamido) -2,2-dimethyl-3-(5-tctrazol-5-yl)ponam To a stirred mixture of l.O g. of 6-(D-2-amino-2-^i-5 hydroxyphenyl7acetamido)-2,2-dimethyl-3-(5-tetrazol-5-yl)- pennm, and 0.91 ml. of triethylamine, in 20 ml. of methylene chloride, is added 3 ml. of N,N-diinethylfonnamide. This solution is then cooled to 0°C., and a solution of 0.375 g. of phenoxyacetyl chloride in lO ml. of methylene chloride is added lO dropwise. The mixture is stirred for 30 minutes after the end of the addition, and then the solvent is removed by evaporation In vacuo. The residue is dissolved in water. The aqueous solution is extracted with ethyl acetate and then acidified to pH 2.4. The aqueous phase is again extracted with ethyl acetate, 15 and the latter extract is dried using anhydrous sodium sulfate. Removal of tho solvent by evaporation JLn vacuo leaves 0.91 g. of crude product. The crude product is purified by chromatography using Sephadex LH-20 as adsorbant, and eluting with water. The yield of purified product is 0.33 g. (30%), m.p. 20 180—192°C. (dec.). IR (KBr disc): 1786, 1667, 1613 and 1515 cm"1. NMR (CDCl3/DMSO-d6) : 9.J3 ppm (d, J=7II/, 111), 8.58 ppm (d, J=81lz, 111), 7.00-7.60 ppm (m, 911), 5.90 ppm (d, J=8llz, 111), 5.60 ppm (m, 211), 5.03 ppm (s. 111), 4.65 ppm (s, 2H) , 1.57 ppm (s, 311), and 0.97 ppm (s, 3H) . - 224 - 40532 EXAMPLE CXV 6- (]>-2-I'h tha I imi do-2-pheny lace tamldo) -2,2-dime thy 1-3- (5- tetrazolyl)penam To a stirred solution of 1.07 g. of 6-(D-2-amino-2-r> pheny lacetamldo) -2,2-dimcthyl-3-(5-tetrazolyl)penam and l.(>3 ml. of triethylamine, in 20 ml. of methylene chloride, is added, at 0°C., a solution of phthalic anhydride in lO ml. of methylene chloride. The mixture is stirred at ambient temperature for 1.5 hours, and then the solvent is removed by eva-lc> poration iri vacuo. The residue is dissolved in water at pH 7.8, and the water is washed with ethyl acetate. The pH of the aqueous phase is then lowered to 2.0 and the product is extracted into ethyl acetate. The latter ethyl acetate is washed with water, dried using anhydrous sodium sulfate, and eva-IT> porated in vacuo. This affords 1.2 g. (92H yield) of the title compound, mp 185-197°C.(dec.). IR (KBr disc): 1795, 1724, and 1639 cm-1. NMR (CDCl3/DMSO-d6): 8.67 ppm (m,3H), 8.25 ppm (d, J=8llz, 111), 7.50 ppm (m,911) , 5.98 ppm (d, J=8Hz, 1H) , 5.65 ppm (m, 211) , 5.28 ppm (s,lli), 1.67 ppm (s,311), and l.lO ppm 20 (s,3Il). 40532 EXAMPLE CXVI 6-(D-2-/!-Phenylthloureido7-2-phenylacetamide)-2,2-dimethy 1- 3-(5-tetrazol)penam To a stirred solution of 910 mg. of 6-(D-2-amino-2-phenyl-5 acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, and 0.61 ml. of triethylamine, in 20 ml. of methylene chloride, is added 0.27 ml. of phenyl isothiocyanate. Stirring is continued for 2 hours at ambient temperature, and then the solvent is removed by evaporation in vacuo. The residue is dissolved in water at pH lO 7.8, and the water is washed with ethyl acetate. The pH of the aqueous phase is then lowered to 2.0 and the product is extracted into ethyl acetate. The latter ethyl acetate is washed with water, dried using anhydrous sodium sulfate, and evaporated in vacuo. This affords 707 mg. (64% yield) of the title compound IS nip 150-167°C (dec.). IR (KBr disc): 1786, 1681 and 1115 cm-1.

NMR (CIKM .j/DMSO-d ) : 'J.17 ppm (s,lll), 8.27 ppm(M,!H), (7.97 ppm ( ppm (s. 111), 3.10 ppm (q.f.ll), 1.60 ppm (s,3ll), I . 20 pi*" (t,'>||), o.'»r> ppm (s. Ill) . - 229 - 40532 KXAMPLE CXX 6-(O-2-SulfamoyI-2-phony)acetamido)-2,2-cnam A suspension of l.r» acid in 15 ml. of tiiionyl chloride is heated under reflux for 30 minutes, and then the thionyl chloride is removed by evaporation iji vacuo. To the residue is added 50 ml. of benzene and the mixture is evaporated to dryness in vacuo again. The residue is then discolved in 30 ml. of acetone, and added drop-lo wise, with stirring, at (>°C., to a solution of 0.84 g. of 6-amino-2,2-dimothyi-3-(5-tetrazolyl)penam in 25 ml. of water and 3.5 ml. of IN sodium hydroxide. During the addition, and for 30 minutes afterwards, the pH is maintained at fi.O-6.2. At this point, the reaction mixture is adjusted to pH 2.0, and 15 the product is extracted into ethyl acetate. The ethyl acetate is dried using anhydrous sodium sulfate, and then it is evaporated to dryness in vacuo. The residue is dissolved in methylene chloride containing 4.9 ml. of triethylamine. The solvent is again evaporated to dryness in vacuo, giving 1.1 g. (581 2<> yield) of the title compound as its triethylamine salt, m.p. 129-139°C. (dec.). IR (KBr dies): 1770 cm 1 (R-lactam). NMR (DMS0-d6/D20) : 7.60 ppm (m,5il), 5.90-5.40 ppm (m,3ll), 5.05 ppm (s, 111) , 1.55 ppm (s,3H), 0.95 ppm (s,31l).

Preparation of 2-sulfomoyl-2-phenyIaoctic aeid is i In-il in British Patent No. 1 ,067 . - 2 30 - 40532 EXAMPLE CXXI ft-(D-2-/2-Cuanylacetamido7~2-phenylacetamldo)-2,2-dimethyl- 3-(5-tetrazolyl)penam To a stirred solution of 405 mg. of £-nitrophenol in 10 ml. of N,N-dimethylformamide is added 620 mg. of dicyclohexyi-c.irbodiimidc followed by 410 mg. of 2-guanylacetic acid hydrochloride. Stirring is continued for 4 hours, and then to this solution is added a solution of 948 mg. of 6-(D-2-amino-2-phenylacctamido)-2,2-dimethy1-3-(5-tetrazolyl)penam triethylamine salt in lo ml. of N,N-dimethylformamide. Stirring is continued overnight, and then the filtered reaction mixture is i»ourcd into 300 ml. of ether. A gummy precipitate forms, and I ho excess solvent is removed by decantation. The gummy material i s I lien slurried in 1(X) ml. of methylene chloride containing I ml. nl triethyI.imino. This affords, after filtration, 0.4 g. (44* yield) of the title compound, m.p. 172-176°C. (dec.). IR (KBr disc): 1780 cm"1 (p-lactam). NMR tin DMS0-d6/D20):7.45 ppm (m,5ll), 5.85 ppm (d,lll), 5.55 ppm (m,2H), 5.05 ppm (s,ill), 2.70 ppm (m,4ll), 1.55 ppm (s,3il), 0.95 ppm (s,3H).

The 2-guanylacetic acid hydrochloride used in this Kxample is prepared from ethyl 2-cyanocetate in a manner analogous to that described for the preparation of 3-guanylpropionic acid hydrochloride. - 231 - ' * example cxxn ft- (l>-2-/g-fJu.micl i nobenzami.dq7-phcnylacetaniido) -2,2-dimethyl-3- (5-tetrazolyl)penam A mixture of 2.15 g. of o-guanidinobenzoic acid hydroch-V> lor ido and 75 ml. of thionyl chloride is heated under reflux for 18 hours. It is then cooled to 25°C., and concentrated to dryness i_n vacuo. The residue is washed thoroughly with ethylene dichloride. This affords 1.7 g. of £-gunnidinobonzoyl chloride hydrochloride. 1<> To a stirrod solution of 0.854 g. of 6-(n-2-amino-2-pheny- lacetainido)-2,2-dimethyl-3-(5-tetra/.olyl)iH;nam trihydrate and o.54 ml. of triethylamine in lO. ml. of N,N-dimethylformamide Is added, at ()°<*., 0.468 g. of j>-guanidinobenzoyl chloride hydrochloride. Stirring is continued for JO minutes, and tli^n lr> a further <).l 4 inl . of triethylamine and 0.124 g. of £-guanidino- benzoyl chloride hydrochloride is added. After being stirred for .j further JO minutes,the reaction mixture is filtered and the fiLtratc is added dropwise to 300 ml. of ether. The solid which precipitates is filtered off, and washed throughly with 2o methylene chloride containing trioLhyl.nninc. This affords o.8 g. (/'»•*■ yield) of tlu; title com{>ound, m.p. 1 l»6-200°C. IR (KHr disc): 1770 cm-1 (|'.-1 actam) . NMR (in DMSO-d /D. O) : 8.25-7.20 b Z ppm (in, 911), (>.(JO ppm (d,lll), 5.50 ppm (m,2ll), 5.05 ppm (s,lll), l.5o ppm (s,?ll), ppm (s,3ll). 2•> Tht; preparation of jj-guanidinobenzoic acid is described ill Nee. Tray ■ I'll i n. Pay-Has, 72, 64J (l,».'>2) . - 2J2 - h'XAMl'LK CXXIII 40532 Kcactlon of 0-in-2-amino-2-phenylacctamido)-2,2-dimethyl-I- {'i-tctr.i/.oJ y I) [H>n.im or ft- (D-2-«imino-2-/7-hydroxyphenyl7ace-I .imido)-2,2-dlmc:l.hyl-3-(5-tetrnzolylJpcnam with the appropriate acid chloride hydrochloride, according to the procedure of Kxample CXXII, provides the following congeners. Acid chlorido hydrochiorides arc prepared from the corresponding acids l>y l.hc method of llardcastie et a_l., Journal of Orqanic Chemistry, 31, 897 (1966).

CH 3 K -Nil ^ S Cll 1 () N N II - 233 - Vield Melting Point* Infrared Spectrum a1 m (°C.) (cm-1) NMR Spectrum (ppm; DMS0-dg/D20) 5 l.

D-2- (2-guar.idlnoacetagdilo)- 7-pnenylacetyl 77 166-176 1780 7.80-7.25(m,5H), 5.85(d,lH), 5.55(m,2H), 5.10 (s,lH), 4.00(m,2H), 1.50(s,JH), 0.95(S,3H), 2.

D-2-(2-/L1-i:r.idazolin-2-yla.-ino7acetar\ido) -2-phenyl- acetyl D-2- (2-/T-guar.idinophenyi7" acetamido)-2-phenylacetyl 37 170-17/ 1785 7.40(ir.,5H), 5.85(cl,lH), 5.55{m,2H), 5.05(s,lH), 4.05(m, 2H), 3.65(m,4H), 1.50(s,3H), 0.95(s,3K), 3. 53 196-200 1780 7.b0-7.05(n,9H), 5.«0(d,lH), 5.45(m,2H), 5.05 (s,1H)i 3.6(s,2H), 1.50(s,3H), 0.90(s,3H), 10 4 .

D-2-(3-guanyipropiOnamido)-2-phenylacetyl 25 180-186 1785 7.45(n,5H), 5.85(d,lH), 5.55(m,2H), 5.05(s,lH), 2.70(m,4H), 1.55(s,3H), 0.95(s,3H), i 5. 2'2~ (2-/"(X-r.ecr.ylguanyl) -amnq7aceta.-r.idc) -2-phenylacetyl 79 200-208 1772 9.70-9.05im,2H), 8.00-7.10(m,l0H), 5.95(d,lH), 5.60-5.30(m,2H), 5.00(s,lH), 4.00(s,2H), 2.75 (s,3H), 1.50(s,3H)/ 0.90(s,3H), u 15 ■u 6.

D-2- (2-/1- (suar.yl) ureidq>7-acetamido) "2-pr.enylacetyl 54 166-176 1785 7.4 5 (r., 5H), 5.80{d,iH), b.SOtm^H), 5.05(3,1:-:), 3.85(m,2H), 1.55(s,3H), 0.95(s,3H), 1 7.

D-2- (2-/3- '.;;-r:.etnylguanyl) -ureido/acetar.ido) -2-phenyl-acetyl 8d 168-171 1786 1667 0.95(s,3H), 1.55(s,3H), 2.9(s,3H), 3.85(m,2H), 5.1(s,1H), 5.4-5.95(m,3H), 7.5(m,5H), :c 8.

D-2-(2-/3-(N-ethylguanyl)-tIreid D-2-(2-£i-(N-benzylguany1)-ureido7acet:ar.ico) -2-phenylacetyl 58 165-169 1786 1681 1626 0.95(s,3H), l.S5(s,3H), 3.85(m,2H), 4.5(m,2K), 5.1(s,1H), 5.4-5.8(m,3H), 7.4(m,10H), o en u M Melting Yield Point* (*) (°C.) Infrared Spectrum (cr.~ x) NMR Spectrum (ppm; DMSO-dg/DjO) 11 12.

D-2-(2-/3-(N-p-chlorobenzyl-guanyl)ureidQ/acetamido)-2-phenylacetyl D-2-(2-/3-(N-/cyciohexylme-t.-.y]>7guanyl) ureidq7acetamidc) ■ -2-phenylacetyl D-2-(2-/5-(N-/4-pyridyl--ethyi7guanyl)ureido/acet-arcido) -2-phenylacetyl 13. D-2-(2-/3-(guanyl)ureidoj-acetamido)-2-(4-hydroxy-phenyl)acetyl 59 68 56 62 178-190 178-0.85 166-172 182-188 1786 , 1681, 1626 1786 , 1695, 1626 1786, 1681 1786, 1695, 1667 0.95 (s, 3H) , 1. 55 (s, 3H) , 3.9(m,2H), 4.5(r.,2H), 5 .15 (s,1H), 5.4-5.85(m,3H), 7.5(m,9H), 0.95 (s, 3H) , 1. 55 (n, 14H) , 3.1(m,2H), 3.9(r.,2H), 5.15(s,lH), 5.4a-5.85(m,3H), 7. 45 (n, 5K) , 0.95(s,3H), 1.55(s,3H), 3.55(m,2H), 4.55(m,2HJ, 5.1(s,1H), 5.4-5.8(n,3H), 7.45(m,7H), 8.6(m,2H) 0.95(s,3H), 1.55(s,3H), 3.8(m,2H), 5.05(s,lH), 5.4-5.8(m,3H), 6.8(d,2H), 7.3(d,2H). * with decomposition 6k O (D U N 40532 Tin: .icJil chlorido hydrochlorides used In this Kxiimplc are prepared from the correspondiny acids, us'lng thionyl chloride. 2-(Cuanylureido)acetic acid is prepared by the method of Frankel and Sheradsky, J. Chem. Soc. (London), C, 2698 (1967); 5 2-(£-guanidinophenyl)acetic acid is prepared by the method of Leanza et al., Nature 207, 1J95 (1965); and 3-guanylpropionic acid is prepared by the method of McElvain and Schroeder, J. Amer. Chem. Soc., 71, 40 (1949). - 236 - 4053: KXAMPLK CXXIV Kollowing tho procedure of Kxaaple CXXtll and reacting the -ippropr i.itc* h- (2->imino-2-uubstituteii-acctaaido) -2,2-dim-ethyl - J-( r>-tetr.jzoly I) penam with 2-guanidinoacetyl chloridc hydrochloride, tho following compounda are prepared: u7 — Nil , rn - I Nil I C-<» Nil I C - •«•« Mslll Nil X o Cll, -I'll , \ / methyl isopropyl 1 ly I cyololiexy I (-••ye lolicxeny I I , 4 -i yc IoIi.-x kI i eny I g-liytlroxypheny 1 j>-ch loropheny 1 b-bot hoxypheny1 0-fluorophenyl J,4-dichloropheny1 g-tolyI J-eh Ioro-4-hydroxypheny I 2-1hienyI 1-thienyl 2-furyl 3-pyridyl 5-tetr.»zoly I S-ethy1-2-thieny1 40832 EXAMPLE CXXV 6- (D-2-/7- (2-Kuroyl)uroido/r'>2-phenylacotaaiido)-2,2-dimethyl- 3- (5-tetrazolyl) penam To a stirred suspension of 5.0 g. of 6-(D-2-amino-2-5 phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam In 50 ml. of Methylene chloride Is added 2.72 g. of triethylamine. After IO mlnuton, tho solution is dried (Ma2S04), and then It is concent rated to dryness In vacuo giving tlic triothylamine salt of 6-(D-2-.imino-2-pheny lacctamido)-2,2-*llmothyl-3-(5-totra-IO zolyIJponam. •n. 'MB «»J. of tin* .ilrnvc Lrletliy l.imint* s.ilt, In lo ml. of M-'tliyli'nc chloride, at 0°C., In .h1Jp»I 274 n>j. of 2-furyl Isocyanate dissolve*! In a isall volume of methylene chloride.

After lO alnutes, the solvent is removed in vacuo. The residue IS partioned between ethyl acetate and water, and the pll is adjusted to 7.7. The ethyl acetate is removed and discarded. The pll of the remaining aqueous phase is adjusted to 2.S and the product is extracted into ethyl acetate. The ethyl acetate is washed with water, followed by brine, and then it is evaporated 2d to dryness |n vacuo. The residue is dissolve*! in methylene chloride containing 145 mg. of triethylamine and again the solution is evaporated to dryness _in vacuo. This affords 9 JO mg. (761 yield) of the title compound or its triethylamine salt, m.p. 90-llS°C. (dec.). IR (KBr disc): 1778 cn»~* (0-lactam). 25 NMR (inCDClj): 8.2-7.2 (m) , 6.5 (m), 6.0-5.4 (m), 1.7 (s), 1.1 (s). - 238 - kxamplk cxxvi Using the procedure of Example cxxv, and reacting either f»-amino-2,2-dimethyl-3-(5-tetrazolyl)penam or 6-(D-2-amino-2-phenylacctamido)-2,2-dimethy1-3-(5-tetrazolyl)penam with the appropriate acyl isocyanate, ncyl isothiocyanate or sulfonyl isocyanate, the following compounds are prepared \ // O UN N - 2 JO - R1 Yield (») Infrared Spectrum (cm-1) *2-(3-acetylureido)-2-phenylacetyl 98 1785, 1495 1680 *2-(3-butyrylureido)-2-phenylacetyl 1770, 1695 *2-(3-/chloroacetyi7ureido)-2-pnenylacetyl 64 1770, 1530 1695, *2-(3-/3-pyridylcarbony\7-ureido)-2-phenylacetyl 88 1785, 1495 1695, •2->(3-benzoylureido) -2-phenyl-acetyl 48 1785, 1540, 1480 1670, 1515, * 2-(3-/5,5-dibromobenzoyl7-ureido)-2-phenylacetyl 49 1770, 1560, 1670, 1490 *2-(3-/J-pyridylcarbonyl7-ureido)-2-phenylacetyl 68 1785, 1505 1670, *2-(3-propionylureido)-2-phenylacetyl 80 1770, 1540 1695, *2-(3-/cyclopropylcarbonyl7-ureido)-2-phenylacetyl 83 1770, 1695 *2-(3-/l-adamantylcarbonyl7~ ureido)-2-phenylacetyl 76 1785, 1680 *2-(3-benzoylthioureido)-2-phenylacetyl 79 1770, 1480 1680, *2-(S-ZS-furoyjythioureido)-2-phenylacetyl 73 1770, 1590, 1680, 1515, *2-(3-/p-toluenesulfonyl7~ ureido)-2-phenylacetyl 70 1800, 1600 NMR Spectrum (CDCl^j ppm) w —. M 7.4(s), 6.0-5.4(m), 5.3(s), 2.lb), 1.6(s), l.l(s). M 7.2 (s,5H), 5.8(m,3H), 5.2(s,lH), 2.2(n,2H), 1.4(s,3H), 0.9(s,3H). 7.8-7.3(m,5H), 6.0-5.5(m,4H), 5.3(s,1H) , 4.3(s,2H), 1.5 (s,3H), 1.1(s,3H). 9.0-8.0(m,3H), 7.7-7.3(s,6H), 6.0-5.3(m,3H), 1.6(s,3H), 1.2(s,3H). 8.6-7.3(m,10H), 6.3-5.7(m,2H), 5.4(s,2H), 1.6(s,3H), 1.1(s,3H). 8. 3-7.3(m,8H), 6.1-5.4(m,3H) , 5.3(s,lH), 1.6(s,3H), 1.1(s,3H). 9.0-7.3(m,9H), 6.0-5,3(m,4H), 1.5(s,3H), 1.0(s,3H), 7.7-7.3(m,5H), 6.5(m,2H), 6.0-5.3(n,5H), 1.5(s,3H), 1.3-1.0(m,6H). 7.4(s,5H), 5.8-5.2(s,4H), 1.4(s,4H), 0.9(s,7H). 7.2(s,5H), 5.8-5.2(s,4H), 1.4(s,3H), 0.9(s,3H). 7.7-7.2(8), 6.0-5,3(m), 2.05(s), 1.6(s), l.l(s). 7.7-7.0(m), 6.6(m), 6.0-5.4(m), 5.3(s), 2.1(s),1.6 (s), l.l(s). 7.9(d,2H), ".4(m,8H), 5.5(m,3H), 5.2(s,lH), 2.4(s,3H), 1.6(s,3H), 1.05(s,3H).

Yield (%) Infrared Spectrum (cm"1) NMR Spectrum (CDCl^; ppm) 3-acetylureido 3- (2-i:uroyl) ureido 3-(o-toluenesulfonyl)-ureido "2-(3-/2-phenylacety^7-ureido)-2-phenylacetyl k2-(3-/benzyloxycarbonyl7-ureido)-2-phenylacetyl »2-(3-/acetyl7thioureido) ■ 2-pheriylacetyl *2-(3-/l-methyl-5-isoxa-zolycarbonyl/ureido)-2-phenylacetyl 58 1790, 1695 10.45(s,lH), 9.35(d,lH), 5.8(m,2H), 5.35(s,lH), 2.1 (s, 3H), 1.7(s,3H), 1.15(s,3H), 60 1795, 1695 9.33(m,2H), 7.5(m,3H), 6.6(m,2H), 5.8(x,2K), 5.45 (s,lH) , 1.8(s,3H), 1.2(s,3H), 91 1795, 1695 7.7(q,4H), 7.1(d,lH), 5.8-5.4(m,2H), 5.3(s,xH), 2.4 (s,3H), 1.7(s,3H), 1.07(s,3H). 82 1770, 1685 7.7-6.9(m,10H), 5.8-5.2(m,4H), 2.0(m,2H), 1.6-0.2 (m,10H). 50 1770, 1730 7.8-6.8(m,10H), 5.9-5.2(m,4H), 2.0(s,lH), 1.9-1.0 1680 (n,15H). 79 1760, 1660 7.7-7.1(m,5H), 5.8-5.3(m,4H), 2.1(m,4H), 1.5(s,3H), 1.0(s,3H). 64 1770, 1695 7.8-7.2(m,6H), 7.0(s,lH), 5.7(m,4H), 5.3(s,lH), 2.4 (s,3H), 2.2 (s,1H), 1.5(s,3H), 1.0(s,3H).

This compound is isolated as its triethylamine salt.

This compound is isolated as its sodium salt o w u M 40532 EXAMPLE CXXVII Using the procedure of Example cxxv, and reacting 6-(2-amino-2-substituted-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)-penam or 6-(2-/2-aminoacetamidq7"-2-substituted-acetamido)-2,2-dimcthyl-3-(5-tetrazolyi)penam with the appropriate acyl isocyanate, provides the following compounds ch- I nh I co I 3-thienyl 3-ch1oro-4-hydroxypheny1 p-chioropheny1 2-thienyl 3-furyl X<> isopropyl plicny I plu*ny • jj-hyd roxypheny I 40532 55 m 2-furancarboxamido O benzamido o £-chlorobenzamido 0 n-butyramido o 3-f ur.incarboxamido O £-icxlobenzamido o benzamido o 2-furancarboxamido O benzamido 1 2-furancarboxamido 1 3,5-dichlorobenzamido benzamido 2-furancarboxamido benzamido l acetamido o propionamido o n-butyramido O n-liexanoy 1 o i >l>iiI y r.imido () mi ido | propionamido i - 243 - 10532 EXAMPLE CXXVIII ft- (l)-2-/?-Aminol>enzamido7-2-phenyiacetamido) -2,2-dimethyl-3- (5-tetrazoly1)penam A solution is prepared by suspending 1.05 g. of 6-(D-2-5 ^I-nitrobenzamido7-2-phenylacetamido)-2,2-dimethyl-3-(5-tetra- zolyl)penam in 50 ml. of water, and adjusting the pll to 7.3 using sodium bicarbonate solution. To this solution is then added 1.0 g. of 10% palladium on carbon, and the mixture is shaken under an atmosphere of hydrogen, at a pressure of ca. 40 psi, until lO hydrogen uptake ceases. The spent catalyst is removed by filtration, and the aqueous solution is lyophilized. This affords O.OI g. of crude product. A portion of tho crude product is purl I led I iirlliii l>y column rltrxm.il <><|i".i|>liy usin'j licph.idi-x 1.11-20 .11itl etuiiny wil.li water. The puri.fi.ed product. lias mp 260-272"(J. 15 lH(KBr disc): 1770 and 1626 cm ^. NMR (r^O) : 7.6-7.0 ppm (m,7!I), 6.5 ppm (d, J=9Hz, 211), 5.6-5.4 ppm (m,3H), 5.2 ppm (s,ll{), 1-4 ppm (s,31l), and 0.88 ppm (s,3H). - 244 - 40532 EXAMPLE CXXIX 6- (I)-2-/2 - (4-Ami nophonyl) acetamldo7-2-pheny lacetamldo) -2,2-<1 inn-l l»y I - 3- (5-totr.izoly 1) penam Tin* Li Lli? compound is prcp.irod in 23'i yield by hydro-cjenat ion of 6-/D-2-/2-(4-nitrophenyl)acetamidq7-2-phenylacetam-ido)-2,2-dimethy1-3-(5-tetrazolyI)penam, usiny the procedure of Example CXXV1I1 . The product has mp 260-270°C. (dec.).

JK(KHr disc): 1770, 1653 and 1515 cm"1. NMR (020): 7.6-6.8 ppm (m) , 5.6 ppm (m) , 5.2 ppm (s) , 3.4 ppm (s) , 1.3 (s) and 0.8 (s) . - 245 - 40532 KXAMPI.B CXXX ft-(U-2-Hydroxy-2-pheny lncc turn ido) -2,2-dimethy1-3- (5-tetrazoly)- penam A mixture of 0.152g of L-mandelic acid, 0.115 g of N-5 hydroxysucclnlmide and 0.206 g of N,N-dicyclohexycarbodiimide in lO ml of tetrahydrofuran in a 25 ml flask, is stirred at ambient temperature overnight, in a separate flask, ().2l(> g of {>-amino-2 , 2-dimethyl-3-(5-tetrazolyl)penam and 0.23 ml of triethylamine in lO ml of chloroform and 10 ml of methylene 10 chloride is stirred overnight. The mixture in the first flask is then filtered, and the filtrate is added slowly to the second flask. The resultant mixture is stirred for 4 hours at ambient temperature. The solvents are then removed by evaporation in vacuo, and the residue is partitioned between ethyl acetate and 15 water. The pll is adjusted to 4.7 (IN sodium hydroxide), and then the organic phase is withdrawn and discarded. The pH of the aqueous phase is then reduced to 2.0 (5% hydrochloric acid), and the product is extracted with ethyl acetate. The solvent is washed with dilute hydrochloric acid followed by brine, dried 20 using anhydrous sodium sulfate, and then it is added dropwise with stirring to 4(X) ml of hcxane. The precipitate which forms is filtered off, giving 170 mg of (>-(L-2-liydroxy-2-phenyJ acetamido) -2,2-dimethyl-3-(5-tetrazolyl)penam. NMR (in DMSO-dg): 8.16 ppm (broad singlet, III, OH), 7.47-7.04 ppm (multiplet, 611, aromatic 25 protons and NH) . 5.73-5.50 ppm (multiplet, 211, C-5 and C-6 hydrogens), 5.31 and 5.07 ppm (2 singlet, 211, C-3 hydrogen and side-chain methine hydrogen), 1.67 and 1.10 ppm (2 singlets, 611, C-2 methyl hydrogens) . - 246 - EXAMPLE CXXXI 4 0532 f>- (D-2-Hydroxy-2-phenylacctamido) -2,2-dimethy 1-3- (5-tetrazolyl) - penam The procedure of Example CXXX is repeated, except that the L-miindelic acid used therein is replaced by an aquivalent amount of D-mandelic acid. This affords a 77% yield of the title compound. NMR (in DMSO-dg): 8.40-8.20 ppm (broad doublet, 1H, Nil), 7.48-7.18 ppm (multiplet, 611, aromatic hydrogens and OH), 5.31 and 5.07 ppm (2 singlets, 211, C-3 hydrogen and side-chain metliine hydrogen), 1.65 and 1.07 ppm (2 singlets, 611, C-2 methyl hydrogens). - 247 - 4 0 5 3 2! KXAMI'M-: CXXXIl <»- (2-Car I w>xy-2-phonylacctamido) -2,2-dimethy 1-3 - (5-tctrazoly 1) - penam To a stirred solution of 150 mg of 6-amino-2,2-dimethyl-5 3-(5-tetrazolyl)penam in 5 ml of water is added dropwise dilute sodium hydroxide to give a pll of 6.1. To this solution is then added ISO mg of phenylmalonic acid, followed by 120 mg of 1-ethyl-3-(3-dimethylaminoprop-l-yl)carbodiimide. The solution is stirred for a further 3.5 hours, during which time the pH is lO maintained in the range from 6.1 to 6.3 by the dropwise addition <>l dilute hydrochloric .iciil. Al. Mils |x>inl , I lie pll I:; raised I <> I. I by llii- .in ol .s.ilur.ilcd sodium l> I c.i rlion.i l.o solul ion, .nut tho reaction mixture is extracted with ethyl acetate. The extract is discarded. The aqueous phase is then acidified to pH 2 using 15 dilute hydrochloric acid, and it is again extracted with ethyl acetate (two 30-ml portions). The latter extract is dried, and concentrated to a volume of about 25 ml. To this solution is then added a solution of 180 mg of sodium 2-ethylhexanoate in 1.25 ml of ethyl acetate. The precipitate which forms is filtered 20 off to give 176 mg of the disodium salt of 6- (2-carboxy-2-pheny 1-acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorptions at 1765 cm 1 (fl-lactam carbonyl) , 1670 cm 1 (amide I band) and 1600 cm 1 (carboxylate carbonyl) . The NMR spectrum (in D^O) shows 25 absorptions at 7.40 ppm (broad singlet, aromatic hydrogens), 5. 70 ppm (doublet., <•-') hydrogen), S.So ppm (doiihleL, (.'-(> Iiydrogi-n) , 'i.2r» ppm (2 singlcLs, C-3 hydrogen), l.So ppm (2 :singjel.:>, C-2 methyl hydrogens) and 0.95 ppm (2 singlets, C-2 methyl hydrogens) . - 248 - KXAHIM.K CXXXIII Following I.In; procedure; of lixamplc; CXXXII, and replacing I I it* pheny I hi.i Ion i <: .icld used l.li<»r<;in by .:tamido} -2 ,2-d imcthyl-3- (5- tetrazolyl)ponam To a stirred suspension of 370 mg (O.CX)2 mole) of 2-(2-5 thienyl)malonic acid (Netherlands Patent No. 6805524) in 4 ml. of water is added 480 mg. (0.002 mole) of 6-amino-2,2-dimethyl-3-(5-tctrazolyl)penam, and then the pH is adjusted to 6.5 using 20'* sodium hydroxide. The resulting clear solution is cooled to i)°C, and 384 imj . (0.(X)2 molt?) of l-ethy I-3- (J-dimethy laminopropy 1) 1<> oarbodiiinide hydrochloride is added. The solution Is stirred for 3.5 hours at 0°C, with the pll maintained between 6 and 7 using IN hydrochloric acid. At this point, the pH of the solution is then lowered to 2.0 and the mixture is extracted with ethyl acetate. The extracts are combined, dried and then concentrated to ca. 15 15 ml. To this solution is added a solution of 6f>5 mg (0.040 mole) of sodium 2-ethylhexanoate in 2.6 ml, and then the solid which precipitates is filtered off, and dried, to give 462 mg. (51% yield) of 6-(2-carboxy)-2-/2-thienyiyacetamido)-2,2-dimethyl-3-(5-tetrazoly1)penam as its disodium salt. The infrared spectrum 20 of the product (KBr disc) shows absorption bands at 1780 cm 1 (tf-lactam), 1670 cm 1 (amide I), 1615 cm 1 (carboxylate) and 1560 cm 1 (amide II). The NMR spectrum (in D^O) shows absorptions at 7.50-7.1 ppm (multiplet, thienyl hydrogens), 5.9C) ppm (doublet of doublets, C-f> hydrogen), 5.05 ppm (doublet, (.'-5 25 hydrogen), 5.40 ppm (doublet, C-3 hydrogen), L.68 ppm (doublet, C-2 methyl hydrogens) and l.OO ppm (doublet, C-2 methyl hydrogens) . - 2 50 - EXAMPLE CXXXV 40532 (i- (2-Carboxy-2-/l-thienyl7acetamido) -2, 2-dimethyl-3-(5- tetrazoly1)penam Reaction of 500 mg. (2.69 mmole) of 2-(3-thienyl)malonic acid (British Patent No. 1,125,557) with 645 mg. (2.69 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example LXXXIV, affords 810 mg. (67% yield) of 6-(2-carboxy-2-/3-thienyi7acetamido)-2,2-dimethy1-3-(5-tetra-zolyl)penam as its disodium salt. The infrared spectrum of the product (KBr disc) shows absorptions at 1775 cm 1 (R-lactam), 1670 cm-1 (amide L), 1620 cm-1 (carboxylate) and 1525 cm 1 (amide TI). The NMR spectrum (I^O) shows absorptions at 7.80-7.(H) ppm (mult iplot, thienyl hydrogens), 5.88 ppm (doublet, C-(> hydrogen) , 5.65 ppm (doublet of doublets, C-5 hydrogen), 5.4<> ppm (doublet, C-3 hydrogen), 1.60 ppm (doublet, C-2 methyl hydrogens) and l.oo ppm (doublet, C-2 methyl hydrogens). 4 0 5 3 2 KXAMI'I.K CXXXVI '• - (2 — i In I 11X -1>li<-ny I .u;i? L.mi i ■ l< i) — Z , 2-«11 nu'l.liy I - J - ('»--! i*l.r.j/o 1 y I ) - pi mi. mi To .1 stirred slurry of 24o my. of 6-amino-2,2-dimethyl-3-5 (5-tetrazolyl)penam in 5 ml. of methylene chloride is added 0.254 ml of triethylamine. This is stirred for a further 45 minutes, and then it is cooled to about 0°C. To it is then added a solution, in 6 ml. of methylene chloride, of 389 mg. of the mixed carl>onic-carboxylie anhydride formed by reacting the bis-iO triethylamine salt of 2-sulfo-2-phenylacetic acid with one equivalent of ethyl chloroformate (Nicolaus, et al., Annali di Chimica /Rome7» .53# 14 /f9637). The reaction mixture is then stirred at about 0°C for a further 1.5 hours after the addition of the anhydride solution. At this point, the reaction mixture 15 is filtered and then the solution of 288 mg of sodium 2-ethyl- hexanoate in ethyl acetate is added. The precipitate which forms is filtered off, giving the crude product as its disodium salt. The crude product is purified by dissolving it in water and adding the solution to a nilumn of 25 g of Sephadex L1I-20 20 (Pharmacia I'ine Chemicals, Inc.) made up in water. The column i s elut.ed witli water, taking fractions, and the composition of the fractions is assayed by thin-layer chromatography. The fractions containing the pure product are combined and lyophilized, giving 117 mg. of the disodium salt of 6-(2-sulfo-2-phenylace-25 tamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorptions at 1765 cm 1 (|<-lactam carbonyl) and 1660 cm-1 (amide I band) . The NMR spectrum (in DjO) shows absorptions at 7.60-7.20 ppm (multiplet, aromatic hydrogens), 5.70 and 5.50 ppm (2 multiplets, C-5 and 30 C-6 hydrogens), 5.20 ppm (multiplet, mcthine hydrogen), 5.00 ppm (singlet, C-3 hydrogen), 1.50 ppm(2 singlets,C-2 methylhydrogens) and 0.95 ppm (2 singlets, C-2 methyl hydrogens). - 2 52 - KXAMPLK CXXXVII 40532 (>-(2-/5-Indanyloxycarbonyl7-2-phenylacetamido) -2,2-dimethyl-3- (5-tetrazolyl)ponam Reaction of 592 mg. (2.0 mmole) of 5-indanyl 2-phenyl-5 malonatc with 480 mg. (2.0 mmole) of 6-amino-2,2-dimethyl-3-(5-tctrazoly Dpenam, according to the procedure of Example CXXXIV, affords 680 mg. (63% yield) of 6-(2-/5-indanyloxy-carbonyl7~2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its sodium salt. The infrared spectrum (KBr disc) of the pro-lO duct shows absorption bands at 1780 cm 1 (B-lactam) , 1705 cm-1 (ester), 1680 cm 1 (amide I) and 1565 cm-1 (amide II). The NMR spectrum (D20) shows absorption bands at 7.80-6.80 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6 hydrogens) , 5.25 ppm (doublet, C-3 hydrogen), 2.60-2.00 ppm I 'j (multiplet, C-l and C-3 indanyl hydrogens), 2.00-1.80 ppm (multiplet, C-2 indanyl hydrogens), 1.35 ppm (doublet, C-2 methyl hydrogens) and 0.90 ppm (doublet, C-2 methyl hydrogens). - 253 - 1 " " KXAMPLE CXXXVIII ft- (2-Phcnoxycarl>onyl-2-pheny lacctamido) -2,2-d imcthyl-3- (5- tetrazolyI)ponam A stirred solution of 1.80 g. of phenyl chlorocarbonyl 5 ketone (United States Patent NO. 3, 679, 801) in 20 ml. of chloroform is cooled to -40°C, and then 0.94 g of phenol is added. Stirring is continued at -40°C for a further 20 minutes, and then a solution of 2.40 g. of 6-amino-2,2-dimethyl-3-(5-tetrazoly Dpenam and 1.40 ml of triethylamine in 50 ml. of lO chloroform is added dropwise. The cooling bath is removed, and the mixture is stirred for a further 30 minutes. The mixture is filtered, and the chloroform is evaporated in vacuo to give crude ft- (2-phonoxycarbony 1-2-pheny lacctamido) -2,2-d imethy1 - 3-(r>-t olrav.o 1 y 1 ) pcn.im, as its Lr iot.hy 1 amino salt. - 2r>4 - EXAMPLE CXXXIX 40532 The procedure of Example CXXXVIH is repeated except that Mu» phenyl elil«>roi.MrlK>nyI ketene used therein is replaced hy an •'<|iiiiii.>|;ir .iiimunl. ol j>-eli 1 oroplieny I cliloro«rarl>onyl ketone, 2- ') furyl chiorocarbonyl ketene and 3-thienyl chiorocarbonyl ketene, respectively. There are produced: 6-(2-phenoxycarbonyl-2-/£-chlorophenyl7acetamido)-2-2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-phenoxycarbonyl-2-/7-furyl7acetamido)-2,2-lO dimethyl-3-(5-tetrazolyl)penam, and 6- (2-phenoxycarbonyl-2-/3-thienyl7acetamido) -2 , 2-dimethy1-3-(5-tetrazoly1)penam, respectively.

When the procedure of Example CXXXVIII is repeated, and the IS phenol used therein is replaced by an equimolar amount of the appropriate substituted phenol, the products are: 6-(2-/m-methoxyphenoxycarbonyl7~2-phenylacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2-Z-methylphenoxycarbony17-2-phenylacetamido)-2<> 2,2-dimethy1-3-(5-tetrazolyl)penam, 6- (2-/5- indanyloxycarbony l_7-2-phenylaeoLamido) -2,2-- (2-/o-f luorophenoxycarbony l7~ 2-pheny lacctamido) -2,2-dimethy1-3-(5-tetrazoly1)penam, <>- (2-/]j-ey.iiiophenoxycarl>ony l/-2-plieny lacctamido) -2 , 2-> d imel liy I -3-(5-tetrazolyl) ponam and f>- (2-/3,4-d i chlorophenoxycarbony]J-2-phony lacctamido) -2,2-dimethy1-3-(5-tetrazoly1)penam. - 2V, - *"J J " KXAMPLE CXL (>- (2-carbamoy 1-2-phenylacetnmido) - 2 ,2-dimethy 1-3- (5-tetrazoly])- penam To a stirred solution of 523 mg. (O.OOl mole) of 6 —(2— '» /£-ni trophenoxycarbonyl/-2-phenylacetamldo) -2,2-dimethyl-3-(*»—!-ol.ra'/.oly I.) pcnain and l()l. mg of triethylamine in SO ml. of chloroform i.s added 1 ml. cf a 1M solution of ammonia in methanol, at -30°C. Stirring is continued for 4 hours without external cooling and then evaporation in vacuo leaves the crude pro-lO duct as its triethylamine salt. - 256 - example cxli 40532 (D-2-su 1 Eoami no-2-pheny lace tamido) -2,2-dimethyl-3- (5-tetra- -/.oly 1) ponam to .i stirred suspension of 2.13 g. (o.(X)5) mole of ft- (D-5 amino-2-pheny1 acetamido) -2,2-d imcthyl-3- (5-tetrazolyl) penam in 50 ml. of methylene chloride is added 0.84 ml. (0.006 mole) of triethylamine. The mixture is stirred until most of the solid dissolves. To this solution is then added approximately 2 g. of pulverized Linde 4A molecular sieves, and stirring is continued lO for an additional one hour. The word 'Linde' is a Trade Mark.

The molecular sieves are removed by filtration, and the filtrate is cooled to 0°C. To this cooled solution is added, portionwise, over r> minutes, 0.84 g. (0.006 mole) of trimethylaminesulfur trioxide complex. The solution is stirred at 0°C. for 5 minutes, 1 r> and then at ambient temperature for 2.5 hours. A solution cf 2.5 g. of sodium 2-ethylhexanoate in lO ml. of 1-butanol is then added. The resulting precipitate is filtered, dissolved in 20 ml. of water and cooled to 0°C. The pH of the reaction is adjusted Lo 5.0 (glacial acetic acid) and the resulting cloudy 20 solution is stirred for 1 hour. After filtration through diato-maccous earth, the filtrate is added dropwise with stirring to 700 ml. of cold (0°C.) acetone. The resulting precipitate is collected, and dried, to yield 1.80 g. (65.3% yield) of 6-(D-2-sulfoamino-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)-25 penam as its disodium salt. Tho infrared spectrum (KBr disc) shows .absorptions at 1770 cm 1 (tf-lactam), 1660 cm 1 (amide I) and 1550 cm 1 (amide II). The NMR spectrum (DjO) shows absorptions at 7.46 ppm (S, 511 aromatic hydrogens), 5.64 ppm (q, 211, C-5 and C-f> hydrogens), 5.33 ppm) S, 111, mcLhine hydrogen ),'»• l'> 3o i>pm(3,lll, C-3 hydrogen), 1.53 r>i>in (a, 311, C-2 -methyl hydrogens) and 1 .00 ppm (S, ill, C-2 methyl hydrogens). [x]pJ = 108° (l^O) . Analysis - Calcd. for C^gll^N-jO^S^aj (percent): C, 34.85; H, 4.2<); N, 17.78; S, 11.63. Found: (Percent): 35. ()2, II, 4.31; N, 17.82; S, 1 1 .') 1 . - >',7 - 40532 EXAMPLE CXLII Reaction of the appropriate 6-(2-amino-2-substituted-ace tamido)-2,2-dimethyl-3-(5-tetrazolyl)penam with the sulfur tri oxide-trimethylamine complex according to the procedure of 5 Example CXLI, provides the following compounds: »7 mo thy I 1sopropy1 cyclopenly1 I" 3-cyclohcxeny1 1,4-cyclohexndienyl benzyl £-chlorobcnzyl £-hydroxypheny1 l<, m-methoxyphony 1 m-bromophenyI 0-fluorophenyl -j;olyl -ph}. oro-4-hydroxyphenyl 20 3,4-dichlorophenyl ^,4-dime^hoxyphenyl 1-th^enyl ^-J;hieny | ij-j-ucyl 2!» !|-pyrldyl f- - 2'i8 - KXAMI'I.I-: ext.] I [ 40532 10 f>- (n-2-/c.i rl>oxyiiK'tli()XY7acutalnAdo-2-pl»cny lacctamido) -2 , 2-dime- thyl-3-(b-tetrnzolyl)penam To a stirred solution of 2.59 g. (6.0 mmole) of 6-(D-2-.iiiii nt>-2-phony lacetamido) -2 ,2-dimethy1-3- (5-tetrazoly 1) penam Iriliydral.e and l.7(» ml. (12. 2 iiuiioJe) of triethylamine in 7() ml. ol" methylene chloride, at 0-5°C., is added a solution of 1.40 g. (12.O mmole) of diglycolic anhydride in 30 ml. of methylene chloride. The solution is stirred at 0-5°C. for 1 hour and then it is oxrrarted with 200 ml. of lni sodium bicarbonate solution. The pll of the aqueous phase is adjusted to 2.0 and the product is extracted into ethyl acetate. The solvent is dried (MgSO^), and then concentrated in vacuo, to give 820 mg. (28% yield) of the title compound. IR (Kllr disc) : 1780 cm 1 (fl-lnctam) and 1650 cm 1 amide I). NMR (in l)MKO-dj ) : 7.41 ppm (m,r>ll), r>. 55-5.')() ppm (in, ill), '>.24 ppin (:;, III), 4.1/ ppm (S, 211), 4.1<) ppm (s, 211), 1.57 ppm (s, 311), 0.99 (s, 311). - 259 - 40532 EXAMPLE CXliIV 6- (l>-2-/1 -Carboxy-2, 3-propionamido7-2-phenylacetamldo) -2, 2- d ltn<;thy 1-3- (b-totr.v/.ol-5-y 1)penam 'I'hi? LILI«» compound Ipr«>p.irrd In 737. yield from (>-(0-2-»imino-2-pheny lacctamido) -2,2-dime thy 1-3- (5-tet razolyl) penam and epoxysucclnic anhydride, using the method of Example CXLIII. JR. (KWr disc) : 1790 cm 1 (|<-lactam) and 1665 cm 1 (amide 1) . NMR (in OMSO-d6) : 7.42 ppm .5 by the careful addition of 6N sodium hydroxide. The resulting solution is treated with 1.92 g. (lO mmol) of 1-(3-dimethy-1 aminopropy1)-3-ethylcarbodiimidc hydrochloride and stirring is continued for 30 minutes, with the pH being maintained at 5.5 lO by the addition of 6.ON hydrochloric acid. A solution consisting of 2.4 g. (lO mmol) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl) penam and 3o ml. of water (adjusted to pH 7) is added to llu: firsl mentioned solution and stirring and cooling is continued l"or an hour. The aqueous solution is washed three times with l'j lO ml. portions of ethyl acetate, and is then adjusted to pll 2.5 with 6N hydrochloric acid. This solution is extracted twice with 40 ml. portions of ethyl acetate, and the combined extracts are washed with T>0 ml. of water. After being dried over anhydrous sodium sulfate, the extract is evaporated under reduced 2() pressure to furnish a colorless foam: yield 3 g. The foam is dissolved in 50 ml. of ethyl acetate and then it is treated with 2.4 g. (14.5 mmol) of sodium 2-ethylhexanoate in 30 ml, of ethyl acetate. The title compound precipitates as the sodium salt yield 3.4 g (747.) IK (Kbr) 177G, 1(>67, and 1587 cm"1 NMR (l>20): 20 7.25 ppm (s, 411), 5.70 (d, 111), 5.40 (d, 111), 5.25 (s, 111), 3.70 (s, 211), 3.60 (s, 211), 1.50 (s, 311), l.OO (s, 311). - 2(> I - 40532 kxamplk cxlvi (>- (2-Accty 1-2-phenylacetamIdo) -2,2-d imethy1-3-(5-tetrazoly) - penam To .i solution of 7(X) my (J.'>2 mmoles) of 2-carl>oxy-3- phenyl-2-propanone in 35 ml. of dry tetrahydrofuran is added 453 mg (3.92 mmoles) of N-hydroxysuccinimide (dissolved in a smal portion of dry tetrahydrofuran), followed by 811 mg. (3. ^2 iraioJ.es) of dicyclohexylcarbodiimide dissolved in a small port.on of dry tetrahydrofuran. The reaction mixture is allowed lO to stir at room temperature for approximately three hours. The reaction mixture is then filtered and the yellow filtrate is i added dropwise, with stirring, to a cooled(0°C) solution of 720 mg. (3 mmoles) of 6-amino-2,2-dimethy1-3-(5-tetrazolyl)penam and 606 mg. of triethylamine in 15 ml. of methylene chloride. 15 The resulting solution is stirred for 45 minutes, and then the solvent is removed by evaporation in vacuo. To the residue is added 50 ml. of water and 50 ml. of ethyl, acetate, and the pll Is adjusted to 7.H using sodium bicarbonate solution. The ethyl acel.jLo layer is removed and discarded. To I he aqueous phase is 2() ,|ddc<| a further quantity of el hy I acetate and the pll is adjusted to 2.5.

The ethyl acetate is removed, washed with water, washed with sodium chloride solution, and then dried using anhydrous sodium sulfate. To £hc dried solution is added 0.42 ml. (3 mmole) of 2't tr4etjiylamine, and then the solvent is removed giving the title ! compound as its triethylamine salt. The yield is 540 mg. (36%). IR (CIIC13 solution) s 1780 cm"1. NMR (CDC13) : 7.6-7.2 ppm (m,5II), 6.0-5,6 (m, jll) , 5.4 ppm (a. III), 3.4-3.1 ppm (q, 611), 2.2 ppm (s, 111), '1.8 ppm (s, ill), I.(>-1.1 (in, *» 11) and I .<) ppm (:;,Ill). - 262 - KXAMIM.K CXLVII (>-l'henylpyruvnmido-2 ,2-dimethyl-3- (5-tetrazolyl) penam 40532 To a stirred solution of 960 mg. (4 mmole) of 6-amino-2, 2-dimethyl-3-(5-totrazolyl)penam and 1.2 g. (12 mmole) of 5 triet.hylnmine in 20 ml. of methylene chloride, is added a solu tion of 728 mg. (4 mmole) of phenylpyruvoyl chloride in 5 ml. of methylene chloride, at 0°C. The cooling bath is removed, and when the reaction mixture has attained room temperature, the solvent is removed by evaporation ^n vacuo. The residue is lO partitioned between ethyl acetate and water, the pH is adjusted to 7.8, and then the ethyl acetate layer is separated and discarded. The pll of the residual aqueous phase is adjusted to 2.5, and the product is extracted into ethyl acetate. The ethyl acetate is washed with water, followed by brine, and then dried 15 using sodium sulfate. To the ethyl acetate is added 404 mg. of I r i<*thy lami ne, ami then 'he solvent is evaporated to dryness in vacuo. This affords 1.26 g. (657. yield) of the title compound as its triethylamine salt. IR (KBr disc): 1760 and 1670 cm NMR (in CDC 1 •}) : 7.4-7.0 ppm (m, 511); 6.0-5.2 ppm (m,31l), 3.6 20 ppm (s,2!l), 1.6 ppm (s,3II), 1.1 ppm (s,311). - 2<<~i - 40532 EXAMPLE CXLVIII Following the procedure of Example CXLVII, and reacting either 6-nmlnn-2,2-dimethyl-3-(r>-Letrnzolyl) pennm or 6-(D-2-.1111 i no-2-pheny I .icrol.iin ido), 2-d iim'l.hy I - 3- tcLrazol y I) pen.un w| I pre 1 llif .ipprnpr i .it <_• acid chloride, Um I ■>! lowing compounds .»rc M|"ed: : n \ II —n n + (CII3Cil2) -jNlt - 264 - Yield Infrared Spectrum 1 R (%) (cm ) NMR Spectrum* (CDCl^j ppn) 5 ethoxycarbonyl 60 1780, 1515, 1710, 1270 5 .9-5.4 (r.) , 5.38(s), 1.7(s), l.l(s). benzoyl 85 1785, 1670 8 .4-7. 5 (r.) , 5.9-5.4(m), 5.38(s), 1.8(s), 1.2(s) • acetyl 58 1785, 1640 1700 6 .0-5.4(n) , 3,2(s) , 3.1(s) . 10 2-benzoylformamido)-2-phenylacetyl 66 1785, 1600 1670 8 . 2 - 7 .2 (r., 10K), 5.8(m,3H), 5.4(s,lH), 1.4(s,3H) , 0.9(s,3H). 2-(acetylformamido)-2-phenylacetyl 37 1785, 1680 7 .4(s,5H), 5.8-5.2(m,4H), 2.4(s,3H), 1.4(s,3H), 1.0(s,3H). 2- (ethoxycarbonylforrr.-amido)-2-phenylacetyl 78 1785, 1680 9 1 .1-9.2(s) .5(8), 1. , 8.8-8.1(3), 7.7-7.l(m), 5.9-5.2(m), 0(s) . 4.6-4.0(q), 15 2-(phenoxycarbonyl-amido)-2-phenylacetyl 60 1785 , 1600 1725, 5 . 8-5 . 2 (r*;, 4 K), 1.5(s,3H), 1.0(s,3H). 2-(ethoxycarbonyl-amino)-2-phenylacetyl 80 1785, 1680 7 1 .5-7.2(s, . 9(s,3H), 1H), 6.9-6.4(m,5H), 5.7-5.4(m,4H), 4. l.l(s,3H). 3-3.9(q,2H), 20 2-(benzyloxycarbonyl-amino)-2-phenylacetyl 35 1785, 1680 7 1 .4(s,5H), .0(s,3H). 7.3(s,5H), 5.8-5.1(m,4H), 3.2-2.8(q, 2H), 1.9(s,3H), *the absorption bancs due to the triethylamine have been omitted from this tabulation. i* o w u 13 40532 EXAMPLE CXLIX 6- (l)-2-/2-carl>oxy-3- (2-thienyl) acrylamidq7-2-phenylacetamido) - 2.2-dimethy 1-3- (0-tetrazolyl)penam To 20 ml. of water at ca. 0°C., is added 0.99 g. (5 5 mmole) of (2-thienyl)methylenemalonic acid followed by 1.86 g. (5 mmole) of 6-(j)-2-amino-2-phenylacetamido)-2,2-dimethy 1-3-(5-tctrazolyl)penam, and the pll raised to 7.7. When a clear solution is obtained, the pll is lowered to 6.0, and 0.96 g. (5 mmole) of l-ethyl-3-(3-dimethylaminopropyl)carbodiimide is added. The lO mixture is stirred at ca., 0°C. for 3 hours, with the pH being maintained at 6.0 by the addition of 6N hydrochloric acid. At this point, the pll is again raised to 7.7, and the reaction mixture is exLrurLed with ethyl acetate. Tho extract;; are discarded, and the residual aqueous phase is acidified to pit 2.(>. 10 The product is extracted into ethyl acetate, and then the extract is treated with 1.4 ml. (10 mmole) of triethylamine. The solvent is removed by evaporation iri vacuo, which affords 1.8 g. (55% yield) of tho title compound as its triethylamine salt. IR (CI1C13 solution): 1780, 1660 and 1600 cm-1. NMR (in 2() CDCl.j) : 11.6- lO.Qppm (s,lH), 8.5 ppm (s,lll), 7.8-6.9 ppm (m, 911), 5.9-5.3 ppm (m,4H), 1.6 ppm (s,3H), l.O ppm (s,3H).

In like manner, starting with (£-chloropheny1)methylene-maIonic acid, there is prepared, in 71% yield, 6-(D-2-/2-carboxy-2-(£-chIorophenyl)aerylamidcj7-2-phenylacetamido) -2,2-25 dimethyl-3-(5-tetrazolyl)penam triethylamine salt. IR (KBr disc): 1780, 1070 and 1600 cm *. NMR (in CDCl^): 10.5-9.0 ppm (m,lll), 8.1-7.1 ppm (m,l01l), 5.9-0.3 ppm (in,411), 1.6 ppm (s,3H)» i . 1 ppm (s, 311) .

KXAMI'I.K CI. <>- (IJ-2-AI lo|>l»e».nn ido-2-pheny I .ice lam ido) - 2 , 2 —<1 imethy 1 -3- (5- t r» e razo I y 1) penam To a stirred solution of 1.12 g. (3 mmole) of 6-{D-2-amino-2-phenylacetamldo) -2,2-dimethyl-3-(5-tetrazolyl)penam .ind 0.40S ml. of triethylamine in 6 ml. of water is added portionwise, during lO minutes, 0.512 g. (3.5 mmole) of N-methyl-N-nitrosobiuret. Stirring is continued for a further 2 hours, and then the pH is adjusted to 2.0. The product is extracted into ethyl acetate, and then the extract is treated with 0.42 ml. (3.0 mmole) of triethylamine and then evaporated to dryness Iji vacuo. This affords 1.4 g. (84% yield) of the title compound as its triethylamine salt. IR (KBr disc): 1785, 1695 and 1540 cm"1. NMR (in CDCl-j) : 9.4-8.4 ppm (m) , 8.3 ppm (s), 7.7-7.1 ppm (m), 7.1-6.7 ppm (m), 5.9-5.3 ppm (m), 5.3-5.0 ppm (d), 4.5-4.1 ppm (d) , i.6 ppm (s), 1.O ppm (s). 40532 EXAMPLE CLI 6-(3-Aminomethyl-2-pheny1isocrotonamldo)-2, 2-dimethyl-3-(5- tetrazolyl)penam To a stirred solution of 720 mg. (3 mmole) of 6-amino-2, 5 2-dimethyl-3-(5-tetrazolyl)penam and 0.84 ml. (6 mmole) of triethylamine in 15 ml. of methylene chloride, at -20°C., is added 706 mg. (3 mmole) of 3-azidomethyl-2-phenylisocrotonoyl chloride (Tho Journal of Antibiotics, Tokyo, 24, 626 /I9717) dissolved in ml., of meLhylono chlorido. Tho cooling is l<> removed, and l.hc reaction mixture is KLirrod as it warms I o room temperature and then for a further 15 minutes. The pll of the reaction mixture is then adjusted to 7.8, and it is extracted with ethyl acetate. The ethyl acetate is discarded, and the pll of the residual aqueous phase is lowered to 2.5. 15 It is then re-extracted with ethyl acetate, and to this second extract is added 3 mmoles of sodium 2-ethyihexanoate. The solvent is then removed by evaporation iji vacuo leaving a gummy solid (1.12 g .) .

The above solid is dissolved in 35 ml. of water, and 500 2<) mg. of l.O'i pal 1 adium-on-carbop is added. The mixture is then liydrogenated in a Parr hydrogenator, under 20 p.s.i. pressure, at 25°(*. , for 1(> hours. At this point, the catalyst is removed by filtration, and the filtrate is acidified to pH 2.0 It is filtered, and the pll of the filtrate is raised to 5.7. 25 The filtrate is lyophilized, to producc 900 mg. (87% yield) of the title compound. IR (KBr disc): 1770 cm 1 (fl-lactam). - ^bts - EXAMPLK CLI I auajrf 6 - (2,2-Dimethyl-5-oxo-4-pheny1-1-imidazolidinyl)-2,2-dimethy1- 3-f5-tetrazolyl)penam A mixture of i.O g (2.34 mmole) of 6-(D-2-amino-2-5 phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam, 0.654 ml (4.86 mmole) of triethylamine and 100 ml of anhydrous acetone is stirred at ca. 25°C for 24 hours. At this point, the solvent is removed by evaporation in vacuo, leaving 1.10 g of 6-(2,2-dimethyl-5-oxo-4-phenyl-l-imidazolldinyl)-2,2-dimethyl-3-(5-lO tetrazolyl)penam, as its triethylamine salt. The infrared spectrum (KBr disc) shows absorptions at 1786 cm 1 (fj-lactam) and 1709 cm 1. The NMR spectrum (DMS0-dg/D20) shows absorptions at 7.76-7.15 ppm (multiplet, 5H, aromatic hydrogens), 5. 22 ppm (singlet, 1H, imidazolidine methine hydrogen) 5.78 and 15 5.lO ppm (two doublets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 4.69 ppm (singlet, 311, C-3 hydrogen), 3.10 ppm (quarter, 6H, J = 8 Hz, N-CH2-CHj), 1.62 ppm (singlet, 3H, imidazolidine methyl hydrogens), 1.50 ppm (singlet, 3H, C-2 methyl hydrogens) 1.40 ppm (singlet, 3H, imidazolidine methyl hydrogens), 1.21 20 ppm (triplet, 9H, J = 8 Hz, N-CI^-CH^) and 0.98 ppm (singlet, 3H, C-2 methyl hydrogens). - 269 - 40533 EXAMPLE CLI 11 (>-(2,2-Dimethyl-5-oxo-4-/£-hydroxyphenyl7-l-lmidazolidinyl)-2, 2-dlmethvl-3-(5-totrazolvl)penam Reaction of 6-(D-2-amino-2-/£-hydroxyphenyl7-2-phenylace-5 lamldo)2,2-dimethyl-3-(5-tetrazolyl)penam, with acetone and triethylamine, according to the procedure of Example CLII affords 6-(2,2-dimethyl-5-oxo-4-/£-hydroxyphenyl/-l-imidazoli-dinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam as its triethylamine salt;. The infrared spectrum (KBr disc) shows absorption bands l<> .il 17 tt*» mil ' (('.-lactam) and HiHli cm '. Tim NMR spectrum (DMSO-d^/D^O) shows absorptions at 6.82 and 7.35 ppm (quartet, 411 aromatic hydrogens), 5.16 ppm (singlet, ill, imidazolidine methine hydrogen), 5.71 and 5.07 ppm (two doublets, 211, J = 4 llz, C-5 and C-6 hydrogens), 4.52 ppm (singlet, 311, C-3 hydro-15 gen), 3.07 ppm (quartet, 611, J = 8 Hz, N-Cllj-Cll^) , 1.60 ppm (singlet, 311, imidazolidine methyl hydrogens), 1.43 ppm (singlet, 311, C-2 methyl hydrogen) , 1.36 ppm (singlet, 311, imidazolidine methyl hydrogens), 1.16 ppm (triplet, 9H, J = 8 llz, N-Cllj-CHj) and 0.97 ppm (singlet, 311, C-2 methyl hydro-20 gens). - 270 - EXAMPLK CLIV 40532 Following the procedure of lixnmple CLII, and reacting the appropriate 6-(2-amino-2-substituted-acetamido)-2,2- dimethyl-3-(5-tetrazolyl)penam with the requisite aldehyde or 5 ketone, the following compounds are prepared: 6- (2,2-dimethyl-5-oxo-4-/£-fluorophenyl,7-l-imidazo-lidinyl) -2,2-dimethyl-3- (5-tetrazolyl) penam, 6- (2,2-dime thy l-5-oxo-4-/o-ch loropheny 17-1-imidazo-lidinyl) -2,2-dimethyl-3- (F-tetrazolyl) penam, lO 6- (2,2-dimethyl-5-oxo-4-/m-bromophenyl7-l,"frai<1azo- 1 idinyl)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2,2-diethyl-5-oxo-4-^m-hydroxyphenyl7-l-imidazo-lidinyl)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2-ethyl-5-oxo-4-/£-hydroxyphenyl7-l-imidazolidinyl)-15 2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2,2-dimethyl-5-oxo-4-/m-tolyl7-l~imidazolidinyl)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2,2-dimethyl-5-oxo-4-^£-amyloxyphenyl7-l~imidazo- lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, 20 6-(2,2-dimethyl-5-oxo-4-/m-butoxypheny l7~l-imidazo- 1idinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2,2-dimethy1-5-OXO-4-/£-methoxyphenyl7-l-imidazo-lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-ethyl-2-methyl-5-oxo-4-/£-n-hexyloxyphenyl7~l- 25 imidazolidinyl)-2,2-dimethy1-3-(5-tetrazolyl)penam, 6- (2 ,2-dime thy 1-5-oxo-4-/£-isop ropy lpheny 17"-1 - imidazolidinyl) -2,2-d imethy 1-3- (5-tetrazolyl) penam, 6- (2,2-dimethyl-5-oxo-4-/p-methylthiophenyl/-l-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, 30 6-(2,2-dimethyl-5-oxo-4-cyclopropyl-l-imidazo- lidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2,2-dimethyl-5-oxo-4-cyclopentyl-l-imidazolidinyl)-2,2-d imethy1-3-(5-tetrazoly1)penam, 6-(2,2-dimethyl-5-oxo-4-cyclohexyl-l-imidazolidinyl)-35 2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(2,2-dimethyl-5-oxo-4-cyclohepty1-1-imidazolidinyl)-2,2-dimethy1-3-(5-tetrazoly1)penam, 6-(2,2-dimethyl-5-oxo-4-/2~thienyl7~l~imidazolidiny1)-2,2-dimethyl-3-(5-tetrazolyl)penam, 40 6-(2,2-dimethyl-5-oxo-4-/3-thienyl7~l~imidazolidinyl)- 2,2-dimethyl-3-( 5-tetrazoly Dpenam, - 271 - I ' ' 4 0 5 :i 2 6-(2,2-dimethy1-5-oxo-4-/2-fu» »_7 -imidazolidinyl)-2,2-dlmothyl-3-(5-totr.izolyl) p. ft-(2,2-dimethy1-5-oxo-4-/3-fury\7-l-imidazolidinyl)-2, 2-dJmothyl-3-(5-totrazolyl)penam, 5 0- (2,2-c|lmotJiyJ.-5-oxo-4-/3-pyridyl7-l-imidazol id iny I) - 2,?-djmathyl-3-(5-totrazolyl)penam, and 6-(2,?-dJmethyl-5-oxo-4-/5-ethyl-2-thienyl7-l-imidazo-li4inylK-2,2r-d|methyl-3- (5-tetrazolyl) penam, fj-(2, J-dimet{*yJ.-5-oxo-4-/3-isothiazolyl7-l-imidazolidinyl) JO ^ ,^-^mt|thyl-3-(5-tetrazolyl) penam, 6-(2,imethyl-5-oxo-4-/5-isothiazoly17-l-imidazolidinyl) 2, jm^tfry lr3- (5-tetrazolyl) penam, 6 -12, % -*d ijne t|iy - 5-oxo- 4 -/3 - ch loro-4 - hy droxy ph eny l7~ 1 -J.ipjda^oli fj-j^,2-tlimothyl-5-oxo-4-^'3,4-dimethoxyphenyl7-l-imida- zoj Idjny I) -2',2-dimothy 1-3- (5-totrazolyl) ponam, ! j (1- {2 , 2—1( I mi" l |iy I -5-OXO-4-/l-mo L hy I -<1-mo Uioxy pheny l_7~ I -'im M.izol Id i ny I ) -2, 2-d i moLhy 1 -3- (r.izolyl) pon.im, t • - 212 - 40532 KXAftl'I.K Cl.V l»-(5-Oxo-4-phony I -1 - Imidazolidinyl) -2,2-d imethy 1-3- (S-tetr.i- zolyl) i>cnam To 7 ppm and 1.06 ppm (2 singlets, 611). - 274 - KXAMPI.K CLVI I 40532 Following the procedure of example CLV, and reacting the appropriate 6-(2-amino-2-substituted-acetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam with the requisite aldehyde, the following 5 compounds are prepared: 6-(5-oxo-4-/£-chlorophenyl7-l_in»idazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, 6-(2-methyl-5-oxo-4-/3-chloro-4-hydroxyphenyl7-l-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam, lO 6- (5-oxo-4-/jj>-n-hexy lpheny 17-I-imidazolidinyl) -2,2- dimethyl-3-(5-tetrazolyi)penam, 6-(2-methyl-b-oxo-/m-n-propylthiophenyl7-l-imidazoll-diny1)-2,2-dimethy1-3-(5-tetrazolyl)penam and 6-(2-ethyl-5-oxo-Z£-n-hexylthiophenyl/-l-imidazolidinyl)-15 2,2-dimethy1-3-(5-tetrazolyl)penam, 6-(5-oxo-4-/2-thieny47-I-imidazolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam and 6- (5-oxo-4-/!J~thienyl7~l_imidazolidinyl) -2,2-dimethyl-3- (5-tetrazolyl)penam, 20 respectively - 275 - 40532 KXAMIM.K CI.VLU 0- (ZTiexahydro-l-a/.epiny Umcthyleneamino) -2,2-dimethyl-3- (r.-teLra/.olyl )pcnnm To n stirred solution of 1.2 g (5 mmoles) of 6-amino-2, 5 2-dimethyl-3-(5-tetrazolyl)penam, 1.0 g (10 mmole) of triethylamine and 30 ml of dichloromethane, cooled to 0°C, is added O. 54 g (5 mmole) of chlorotrimethylsilane. After 15 minutes, 0. 86 (5 mmole) of l-(dimethoxymcthyl)hexahydroazepine (British Patent No. l,2*)3, 590) is added, and stirring is continued for lO a further 1 hour. The volatile components are removed by evaporation i_n vacuo, and then the residue is extracted with 25 ml of acetone. The insoluble material is filtered off, and the acetone is evaporated in vacuo to a yellow foam, which changes to a white powder on trituration with ether. This affords 1.44 15 g (82% yield) of 6-(/JTexahydro-l-azepinyi7methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum of the product (KBr disc) shows absorption bands at 1795 cm-1 (B~ luctam), 1706 cm 1 and 1645 cm The NMR spectrum (CDCl^) shows absorption bands at 8.00 ppm (singlet. 111, N-CH=N), 20 5.90 and 5.60 ppn (two doublets, 211, J = 4 llz, C-5 and C-6 hydrogens), 5.40 ppm (singlet, HI, C-3 hydrogen), 3.90-3.50 (multiplet, 411, CM^-N-CHj) , 2.00-1.50 ppm (multiplet, 1111, C-2 methyl hydrogens and /CH^ 4 ;>n(l 1 • 2D ppm (sing Let, 111, C-2 ineLhyl hydrogens). Examination of the product by Lhin-25 layer chromatography (0.2M NaOAc: acetone; l:f») showed a single spot (K( o.23). - 270 - EXAMPLE CLIX 40532 6-(/Dime thy laminq7mt; thyleneamino)-2,2-dimethy1-3-{5-tetrazolyl)- pert am Reaction of N,N-dlmethylformamide dimethyl acetal with 5 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CLVIII, on a 5 mmole scale produces 1.47 g (89% yield) of product. The product is a 3:1 complex of 6-(/Simethylamino^methyleneamino)-2,2-dimethyl-3-(5-tetrazolyl)-penam with triethylamine. The infrared spectrum of the product lo (KBr disc) shows absorption bands at 1780 cm 1 (f}-lactam), 1710 cm 1 and 1640 cm The NMR spectrum shows absorptions at 8.00 ppm (singlet, 1H, N-CH=N), 5.80 and 5.50 ppm (two doublets, 2H, J = 4 Hz, C-5 and C-6 hydrogens), 5.30 ppm (singlet, 1H, C-3 hydrogen), 3.40-3.00 ppm (multiplet, 811, N(C1Lj)2 and N-CH-,-15 CHj), 1.70 ppm (singlet, 3H , C-2 methyl hydrogens), 1.30 ppm (triplet, 311, N-CHj-CH^), 1.70 ppm (singlet, 3H, C-2 methyl hydrogens). When examined by thin-layer chromatography (0.2M NnOAe: .uretom;; 1:6), showed a single spot (R^ 0.26). - 277 - 40532 KXAMIM.K CLX (t-{l)-Z-^J>inM't.hy I .imlnoincthy lent Mini no7~2-phony l-»«:otam I do) -2 ,2- <1 imcthyl-3- ('>-!.<• I-r.v/.oly L) pcn.un To stirred solution of 3.73 g. (lO mmole) of 6-(D-2-5 amlno-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam and 2.02 g. (20 mmole) of triethylamine in 50 ml. of methylene chloride, at 0°C., is added 1.08 g. (10 mmole) of trimethyl-silyl chlorido. Stirring is continued for 20 minutes at 0°C., and limn 1.2 y. (JO mmole;) of N,N-d iinethy 1 formamido dimethyl U> acet.il is added. Stirring is continued for a further 2 hours, and then 2 ml. of methanol is added. The solvents are removed by evaporation _in vacuo, and acetone is added to the residue. After filtration, the filtrate is evaporated to dryness. This latter residue is dissolved in 25 ml. of methylene chloride 15 containing 1.4 ml. of triethylamine, and then the solution is added dropwise with stirring to 400 ml. of ether. The solid which precipitates is filtered off, giving 4.83 g.(90% yield) of the title compound as its triethylamine salt. IR (KBr disc): J786, 1710 and 1052 cm *. I.MR (in l)2°) : 7.8 ppm (s,lll), 7.0 ppm 20 (s,r>ll) , O.O ppm (d,21l), r>.8 ppm (c 1, 211) , r>. 5 ppm (s,lll), 5 . 4 ppm (:;,lll), 3.'i ppni (q,0II), 3.2 ppm (s,6/l), 1.8 ppm (a,'ill), 1.4 ppm (L , *> 11) , and 1.2 ppm (s,3ll). - 278 - 40532 EXAMPLE CLXI 0- (l)-2-Z2- (/nex.ihydro-l-azepinyl7methyleneamino) acetamido7~ .icetamido)-2-dimethy1-3-(5-tetrazolyl)penam A procedure analogous to that of Example CLX is used to obtain the title compound from the reaction 1.07 g. (2.5 mmol) of 6-D-/2-(2-aminoacetamido) -2-phenylacetamidq7-2,2-dimethy 1-3-(5-tetrazolyl)penam and 0.43 g. (2.5 mmol) of 1-(dimethoxy-methyl)hexahydroazepine. The product is isolated as its triethylamine salt: yield O.68 g (43%); IR (KBr) 1780 and 1695 cm *; NMR (DjO) 8.05 ppm (s,lH), 7.75 (s,5H), 6.0-5.6 (m,2H), 5.50 (s, III) , 4.50 (s,2H) , 4.20 (s,lH) , 4 .05-3.65 (m,4H) , 3.4 (q,61t), 2.35-1.75(m,8H), 1.70 (m,8H), 1.70 (s,3H), 1.55 (t,9H), l.lo (s, 311) . - 279 - 40532 EXAMP.LK CLXI I (i- (12-2-/nimothy laminomethyleneaminq7-2-/£-hydroxypheny V7~ .icqtamldo) -2.2-dimothy 1-3- (5-tetrazoly 1) penam To a stirred solution of 1.95 g. (5 mmole) of 6-(D-2-5 ami ri"-2-/£-hydroxyphenyl/ncetamido)-2,2-dimethy1-3-(5-tetrazolyl) penam and 0.5 g. (5 mmole) of triethylamine in 12 ml. of methylene chloride, at 0°C., is added 0.6 g. of N,N-dimethyl-form.imlde dimethylacetal. Stirring is continued for 1 hour at 0° C., and then the reaction mixture is poured into 100 ml. of ether. lO This causes a gummy solid to precipitate. The solvent is decanted from the solid, and then the solid is dissolved in 50 ml. of methylene chloride and 2 ml. of triethylamine. The solution is IreaLed with activated charcoal, filtered, .and then added drop-wise L<> I'M) ml. of ether. The solid which precipit.'ites Is re-1'j dissolved in methylene chloride containing triethylamine, again treated with activated charcoal, and again added dropwise with stirring to ether. The; solid which precipitates is filtered off, giving 4 50 my. (17% yield) of the title compound as its triethylamine salt. IR (KBr disc): 1786, 1715 and 1652 cm *. NMR (in 20 D^O-NallCO^) : 7.7 ppm (s,lll), 7.3 ppm (d,2H), 6.9 ppm (d,2ll), 5.8 ppm (d, HI) , r>. 5 ppm (d,lll), 5.3 ppm (2s, 211), 3.2 ppm (q,6ll), 3.1 ppm (s,61l) , 1.3 ppm (t,9II), l.O ppm (s,3ll).

In like manner, starting with 6-(D-2-/2-aminoacetamidq7- 2-phonylacetamldo)-2,2-dimethyl-3-(5-tetrazolyl)penam, there is 25 prepared a 2')v. yield of a 2:1 complex of (>-(0-2-/2-(dimethy 1- .iiii i noiwt hy J i-ne.inii no) acetaniido7~2-pheny I - (2-Phony 1 .icot.imido) -2,2-dimethy 1-3- (l-/pivuloy ioxymethyl/-• <;Lr.izoI -5-yI)pon.im and 6- (2-Phonyl«icet.imi EXAMPLE CLXIII B (>- (2-Phenylacetamido) -2,2-dimethyl-3- (l-/27-/5-phthalidyl7~ tetrazol-5-yl)penam Reaction of 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-15 tetrazolyl)penam sodium salt with 3-bromophthalide, according to the procedure of Example CLXIII, produces the title compound as a mixture of isomers, m.p. 70-85°C., yield 91%. IR (KBr disc) 1785, 1675 and 1500 cm"1. NMR (CDCl-j) : 8.05-7.10 (m, 911), 6.55-6.20 (m, 211), 5.80 (m, 2H) , 5.20 (m, 1H) , 3.60 (s, 211) , 1.60 20 (s, 311), and l.OO (s, 3H) ppm. - 283 - 4 0 5 3 M KXAMPLE CLXIV Reaction of the appropriate 6-acylamino-:>, 2-dimethy 1-3-(5-tetrazolyl)ponam with tlie requisite alkanoy ioxyalky 1 or with 3-l>rnmophthnl ide, according to the procedure of Example CLXIII, '» |>r«>v lili'.s t.lu* I ol lowing congcncrs. Ill oarli case, the product i;» .i mixture i>l monn.i I ky latcd compounds, in which the a I kanoy loxy-nlkyi or phthalidyl substituent is located at either the 1- or the 2-position of the tetrazole ring. 6-acetamido-2,2-dimethyl-3-(l/27-acetoxymethyltetrazol-lO .5-yl)penam 6-propionamido-2,2-dimethy1-3-(l-/2/-isobutyryloxymethyl-tetrazol-5-yl)penam, 6-(2-phenylacetamido)-2,2-dimethyl-3-(1/27-propionyloxy-methyitetrazol-5-yl)penam, 15 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(l/27~n-hexanoyl- oxymethyltetrazol-5-yl)penam, 6-(2-cyclohexanecarboxamido)-2,2-dimethy1-3-(1/2J-pivaloyloxymethy1tetrazol-5-yl)penam, 6- (2-£-chlorophenylacetamido) -2,2-dimethyl-3- (l/2/-acetoxy-20 methyltetrazol-5-yi)penam, 6- (2-m-methoxyphenylacctamido) -2 , 2-dimethyl-3- (1/2.7-pro-pionyloxymethy1tetrazol-5-y1)penam, (>- (2-/3-ch I <>ro-4 -hydroxypheny l7acetnmido) - 2 , 2-d i methy 1 -3 - (I /2_/-pi v.i.loy loxymethy 1 tetrazol-5-yl) penam, 25 6- (2-/2-tli ieny 17acct.imido) -2 , 2-dime thy 1-3- (l-/27~acetoxy- methy itctrazol-5-yl)penam, 6-(J-furancarhoxamido)-2,2-dimethy1-3-(i-/27-n-butyry1-oxymethy I tetrazol-5-y 1} i->enam, 6-(2-phenyIpropionamido)-2,2-dimethy1-3-(l-/27~pivnloy1-30 oxymethy1tetrazol-5-yl)penam, 6-(2-phenoxyacetamido)-2,2-dimethy1-3-(i/27~pivaloyloxy-methyltetrazol-5-yl)penam, - 2H4 - 4 0532 6-ncctamido-2,2-dimethyl-3- (i/27-/I-acetoxyethy l7tetrazol-■j-y Dpenam, 6-(2-cyclohexylacetamldo)-2,2-dimethyl-3-(l/27-/I-pro-pionyloxyethyl7tetrazol-5-yl)penam, 5 6- (2-phenylacetamido(-2,2-dimethyl-3- (l/!£7-/l-pivaloy- loxyethy\/tctrazol-5-yl)penam, 6-(2-phenoxyacetamido)-2,2-dimethy1-3-(l/27-/l~n-hex-anoyloxyethyl7tetrazolyl)penam, 6-(2-/3-thieny17acetamido)-2,2-dimethyl-3-( lo acetoxyethyi/tetrazolyl)penam, 6-propionamido-2,2-dimethy1-3-(1/27-phthalidyltetrazol- 5-y Dpenam, 6-(2-phenylacetamido)-2,2-dimethyl-3-(l-Z^Z-phthalidyl-tetrazol-S-yl) penam, 15 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(l/^7-phthalidyl- tetrazol-5-yl)penam, 6- (2-/3-hydroxyphenyl/acetamido) -2, 2-dimethy 1-3- (1 l'2j~ phthalidyltetrazol-5-yl)penam, 6-(2-/2-furyl7acetamido)-2,2-dimethy1-3-(l/£7~phthalidyl-20 tetrazol-5-yl)penam and 6-(2-^5-methy1-2-thienyIZacetamido)-2,2-dimethy1-3-(1/^7" phthalidyltetrazol-5-yl)penam, respectively. - 285 - . 4 0 5 3 3 • _ * KXAMPLF. CLXV 6-Amino-2 ,2-dimethy1-3- (2-/pivaloyloxymethyl/tetrazol-5-yl) - penam To a stirred solution of 0.932 g. (7.21 m mole) of quino-5 line in 8.0 m.l. of chloroform is added 0.840 g. (4.05 m mole) of phosphorus pentnchloride. The suspension is cooled to -15°C., and then 1.81 g. (3.84 m mole) of 6-(2-phenylacetamldo)-2,2-dimethy1-3-(2-£pivaloyloxymcthyl7tetrazol-5-yl)penam is added. Stirring is continued for a further 30 minutes, at ca. -5°C., and then 2. l.O 15 q. (35.7 m inole) of n-propanol is added. Stirring is continued for a further 30 minutes, again at ca. -5°C., and then 25 ml. of 0O:lO isopropyl ether-acetone is added, followed immediately l>y a solution of 1.35 g. of sodium chloride in 6.02 ml. of wntcr. The temperature rises to 15°C. and then it is lowered 15 again to -15°C. Tho precipitate which has formed is filtered off and dried, giving 1.33 g. (38'A yield) of 6-amino-2,2-dimethyl-3-(2-/pivaloy loxymethyl^tetrazol-r>-y 1) penam hydrochloride. The infr.ired sped, rum (Kllr disc) show:; .il>:;orpt. i ons .it |7Kr> em ' (|.-I .icl .mi) . 11 >■ I I V'.O (Mil ' (iT.li'i). Tin- NMU :: | • I i i iiii (l)MSO-il ) 20 shows absorptions .it 6.70 ppm (singlet, 211, pivaloyloxy methylene hydrogens), 5.75 ppm (doublet, HI, C-5 hydrogen), 5.50 ppm (singlet, 111, C-3 hydrogen), 5.70 ppm (doublet, III, C-6 hydrogen), 1.75 ppm (singlet, 311, C-2 methyl hydrogens), 1.20 ppm (singlet, OH, ^t-butyl hydrogens) and l.lO ppm (singlet, 3H, 25 C-2 methyl hydrogens). - 2 86 - 4 0 5 3 2 EXAMPLE CI.XVI f>-Amino-2,2-dimethyi-3-(l-/pivaloyloxymethyJ7tetrazol-5-yl - penam The title compound is prepared as its hydrochloride, in 5 90% yield, from 6-(2-phenylacetamido)-2,2-dimethy1-3-(l-/pivaloy-loxymethyl7tetrazol-5-yl)penam, using the method of Example CLXV. The infrared spectrum (KBr disc) shows absorptions at 1780 cm 1 (B-lactam) and 1740 cm-1 (ester). The NMR spectrum (DMSO-dg) shows absorptions at 6.71 ppm (singlet, 2H, pivaloyl-lO oxy methylene hydrogens), 5.88 ppm (singlet, 1H, C-3 hydrogen), 5.83 ppm (doublet, 1H, C-5 hydrogen), 5.20 ppm (doublet, 1H, C-6 hydrogen), 1.80 ppm (singlet, 3H, C-2 methyl hydrogens), 1.20 ppm (singlet, 9H, t-butyl hydrogens) and 1.16 ppm (singlet, 311, C-2 methyl hydrogens) . - 287 - 4 0 5 3 2 KXAMIM.K CbXV I1 (I?-'*-Am '^ — • 'VI re >xy pheny I_/Vn:«,l..un i xyiii' • l.liy \Ji.i -I. r.i/.n I -5-y I ) penam To a st. irreel suspension of 287 my. (l.O m mole) of sodium 5 JY-(2-methoxycarbonyl-l-methylvinyl)-D-2-amino-2-(g-hydroxy- phenyl)acetate (Long, et. al., Journal of the Chemical Society London7, Part C, 1920 Z1971/) <"*nd 1 drop of N-methylmorpholine in 6 ml. of ethyl acetate, is added 0.97 ml. (1.03 mole) of ethylchloroformate, at -15°C. Stirring is continued for a further lO 30 minutes at -15°C. This mixture is then added to a pre-cooled (-15°C.) suspension of 390.5 mg. (l.O m mole) of 6-amino-2,2-dimethyl-3-(2-/pivaloyloxymethy1/tetrazol-5-yl)penam hydrochloride in 2 ml. of ethyl acetate containing 101 mg. (l.O m mole) of triethylamine. The reaction mixture is then stirred at -15°C. 15 for I hour followed by 5°C. for J hour. The; ethyl acetate is removed l>y ev.i|>or.il Ion _i_n v.icuo, and the wli i te solid thus obtained i s suspended In LO ml. of 1:1 wa t.er-tetrahydrofuran. The suspension is cool eel to 0°C. , anel the;n its pll is adjusted to 2.1. The suspe;nsion is stirreel at 0°C. for 45 minutes, with further 20 acid being addeel lo maintain the pll at 2.1 as necessary. At this point, the tetrahydrofuran is removed by evaporation in vacuo, the resielual aqueous phase is saturated with sodium chloride;, and the product is extracted into ethyl acetate. The ethyl acetate is dried and evaporated i^n vacuo giving, after triturat-25 ion of the residue with ether, 425 mg. (81% yield) of 6-(D-2- amino-2-/£-hydi-oxyphenyl/acetamido)-2,2-dimethy1-3-(2-/pivaloy-lejxymethyl_7tetrazol-5-yl) penam hyelrochlor ide. The infrared spectrum (KUr disc) shows absorptions at 1780 cm * ((-".-lactam) 1755 cm ' (ester), L682 cm 1 (amide l). The NMR spectrum (l)MSO-3t) ei^) shows absorptions at 7.00 ppm (quartet, 411, aromatic hydroejens) , 6.59 ppm (singlet, 211, pivaloyloxy methylene), 5.52 ppm (multiplet, 211, C-5 anil C-6 hydrogens), 5.22 ppm (singlet, ' BK - 40532 III, side chain mothinc hydrogen) 5.00 ppm (singlet, HI, c-3 hydrogen), 1.47 ppm (singlet, 311, C-2 methyl hydrogen), 1.07 ppm (singiet, 911, t-butyl hydrogens), and 0.96 ppm (singlet, 311, C-2 methyl hydrogens). 5 The MIC of the title compound against Strep, pyogenes is 0.39 jig./ml. - 289 - 1 4 0 53:2 KXAMI'M-: CI.XVIII 6-(n-2-Ami no-2-^>-hydroxypheny l_7acetamido) -2 , 2-d imethy1-3-(I-/pivaloy1oxymethyl/tetrazoI-5-yl)penam The title compound is prepared as its hydrochloride, in 5 50% yield, from 6-amino-2,2-dimethyl-3-(l-/pivaloyloxymethyl/~ tetrazol-5-yl)penam, using the procedure of Example CLXVII. The infrared spectrum of the product (KBr disc) shows absorptions .it 1780 t:»i * (lactam) and 1680 cm * (amide I). The NMR :;p<>«-|.ruiii (UMiJO-il ) shows absorptions al. 7.0'» ppm (qiiartt:l., 411, 1() aromatic hydrogens), 6.55 ppm (singlet, 211, pivaloyloxy methylene hydrogens), 5.61 ppm (multiplet, 311, C-3, C-5 and C-6 hydrogens), 5.06ppm (singlet. 111, side-chain methine hydrogen). 1.55 ppm (singlet, 311, C-2 methyl hydrogen), 1.10 ppm (singlet, 311, C-2 methyl hydrogen), l.lO ppm (singlet, 9H, t-butyl 15 hydrogens) and 1.03 ppm (singlet, 3H, C-2 methyl hydrogens). - 2MO - EXAMPLE CLXIX d J Using the procedure of Example CLXVII, reaction of the appropriate O-ninino-2,2--Ainlno-2 , 2-d i me thy 1-3- (1 -pi v.'iloy loxymethy I LeLrazol -S-y 1 ) - penam and C>-Amino-2,2-d Lmethyl-J- (2-pl va lay I oxyinethy 11 otra/.o I - r>-y I) - penam To a stirred suspension of 2.40 g. of 6-amino-2,2-dimethyl-3-(b-tetrazolyl)penam in 15 ml. of N,N-dimethylfor-mamidc, is added 2.8 ml. of triethylamine. Stirring is continued for a further i5 minutes, and then 2.68 g. of chloromethyl pivalate is added. The mixture is stirred at ambient temperature for 5 hours, and then it is diluted with 100 ml. of water. It is Ihon extracted wltli othyl acetate. Tho extract Is washed wiLli water, dried using anhydrous sodium sulfate, and then LI is evaporated in vacuo to give a mixture of the title compounds. The individual isomers are obtained by chromatographic separation of the crude product. - 202 - EXAMPLE CLXXI 4 0532 0- (2-/"3- (2-^£-Ch loropheny l7acet imidoyl) ureidq7acetamido) -2,2-dimethyl-3-(5-tetrazolyl)penam To a stirred solution of 480 mg. of 6-amino-2,2-dimethyl-0 3-(5-tetrazolyl)penam and 404 mg. of triethylamine, in 6 ml. of N»N-dimethylformamlde, is added 650 mg. of 2-(3-/2-(£-chloro-phenyl)ncotimidoyl7ureido)ncetyl chloride hydrochloride. Stirring is continued for 1 hour, and then the reaction mixture is filtered. The filtrate is added to 300 ml. of ether, and the lO solid which precipitates is filtered off. The solid is washed thoroughly with methylene chloride, and dried, giving 585 mg. of the title compound, m.p. 150-162°C. IR spectrum (Nujol mull) 1780 cm (R-lactam) . NMR spectrum (DMSO-dg) : 8.90 ppm (d,lH), 8.00-7.20 ppm (m,8H), 5.80-5.20 ppm (m,3H), 4.10-3.60 ppm (m, 15 411), 1.65 (s,31I), 1. lO ppm (s,3II). - 293 - KXAMPM-: cr.XXII Using tho procedure of Example CLXXI, and reacting either 6-ainino-2,2-d imethy1-3-(5-tetrazolyl)penam or 6-(D-2-amino-2-phenyLacctamido)-2,2-dimethy1-3-(5-tetrazolyl)penam with the appropriate acid chloride hydrochloride, tin* following compound: are produced.

N N N N II - 2fM - Melting Infrared Yield Point* (%) (°C) 2- (3-/Eenzimidoyl7ureido) -5 acetyl 2-(3-/p-methoxvbenz imidoy17-ureido)acetyl 2-(2-/3-(2-^£-chloropheny^7-acetimidoyl)ureidQ/acet-K* amido)-2-phenylacetyl 2-(2-/7-(benzimidoyl)ureido7* acetamido)-2-phenylacetyl 2-(2-/7-(£-methoxybenzini-15 doyl)ureido/acetamido-2-phenylacetyl 81 153-164 71 162-168 50 160-169 45 160-166 64 168-174 Spectrum (cm"1) 1780 1775 1780 1775 1775 NMR Spectrum (DMSO-dg? ppn) 8.90(d,1H), 8.70-7.20(m,9H), 5.80-5.20(m,3H), 4.10-3.70(m,2H), 1.65(s,3H), 1.10(s,3H). 8.80(d,lH), 8.05-6.20(m,8H), 5.75-5.15(n,3H), 4.05-3.70(m,5H), 1.65(s,3H), 1.05(s,3H). 9.40-9.20(m,1H), 8.80(d,lH), 8.40-7.10In,13H), 5.90-5.15(m,4H), 4.05-3.70(m,4H), 1.55(s,3H), 1.00(s,3H). 9 .40(d, 1H) , 8 .60(d, 1H) , 8.10-6.00(m,HH) , 5.90-5.10(m,4H), 4.00-3.60(m,2H), 1.55(s,3H), 1.00 (s,3H). 9.40(d,1H), 8.70(d,1H), 8.10-6.30(m,13K) , 6.00-5.10(m,4H), 4.10-3.70(m,5H), 1.55(s,3H), 1.00 (s.3H). *with decomposition b O at u 10 • 40532 KXAMPLK CLXXIII 6-(3-PhonyLureLdo)-2,2-dimethy1-J-(5-tetrazoLy L) pcn In like manner, using ethyl isocyanate, there is obtained a 70% yield of 6-(3-ethylureido)-2,2-dimethyl-3-(5-tetrazolyl) -penam triethylamine salt, m.p. 80-90°C. IR spectrum (KBr disc): 1/85 cm ^ (['.-lactam). 1668 cm ^ and 1570 cm ^. NMR spectrum 20 (DMSO-d^) : 7.8() ppm (m,HI), 6.50 ppm (m,2II), 5.60 ppm (m,2Il), 5. LO ppm (s,Lll), 3.10 ppm (q,8ll), I. GO ppm (s 311), 1.40-0.70 ppin (in, 1511) . - 2y6 - 40532 EXAMPLE CLXXIV Reaction of 6-(D-2-amino-2-phenylacetamldo)-2,2-dimethyl-3-(5-tetrazoiyl)penam with the appropriate acid chloride, according to the procedure of Example CXLVII, provides the following 5 compounds, which are isolated as the free acids by elimination of the final triethylamine treatment.

CH- R1-NII.

,/ \ II N N - 297 - Melting Infrared Yield Point Spectrum in i 15 |NJ VC 00 25 2-(2-phenylacetamido)-2-phenyl-acetyl 2-benzanido-2-phenylacetyl 2-aceta.Tiido-2-phenyl acetyl 2-butyramido-2-phenylacetyl 2-(2-furancarboxamido)-2-pftenylacetyl 2-(2-thiophenecarboxamido) • 2-phenylacetyl 2-(2-£2-thienyl/acetamido) ■ 2-phenylacetyl 2-(3-pyridinecarboxamido) • 2-phenylacetyl 2-(2-pyrrolecarbOxamido)-2-phenylacetyl (») 77 65 74 74 73 88 69 62 58 (° C.) (cm-1) NMR Spectrum (DMSO-d6/CDCl3; ppm) 130-140 1800,1655, 1515 145-165 1785,1640 1515 140-160 1790,1655, 1525 146-160 1795,1695, 1650 143-165 1795,1665 1600,1515 130-155 lbOO,1695 1640,1540 1505 134-148 1795,1655, 1530 164-185 1785,1660, 1600,1530 170-195 1795,1695, 1640,1560 1515 O -talc. 42 (r., 1H) , 8 .07 (d, 1H) , 7.33(m,10H), 5.73(d,lH), 5.63(n,2H), 5.10(s,lH), 3.67(s,2H), 1.67(s,3H), 1.06(s,3H). 8.20(d,lH), 7.90(n,3H), 7.50(m,8H), 6.00(d,lH), 5.60(n,2H), 5.23(s,lH), 1.53(s,3H), 1.03(s,3H). 8.10(d,1H), 7.40(n,5H), 5.8(d,lH), 5.60(m,2H), 5.20(s,lH), 1.67(s,3H), 1.08(s,3H). 8.84(t,1H), 8.07(d,1H), 7.50(m,5H), 5.90(d,lH), 5.70(m,2H), 5.27(s,lH), 2.27(t,2H), 1.87(m,5H), 1.07(n,6H). 8.60(n,1H), 7.90(d,1H), 7.6-7.0(m,7H), 7.5(c,lH), 6.00(d,1H), 5.60(m,2H), 5.23(s,lH), 1.58(s,3H), 1.03(s,3H). 8.50(m,1H), 8.10(d,1H), 7.80-7.00(m,8H), 5.95(d, 1H), 5.60(m,2H), 5.10(s,lH), 1.60(s,3H), 1.10(s, 3H) . 8.91(n,1H), 8.33(d,1H), 7.50-7.10(m,5H), 6.90(n, 2H), 5.75(d,lH), 5.60(n,2H), 5.20(s,lH), 3.83 (s,2H), 1.60(s,3H), 1.05(s,3H). 9.10(s,1H), 8.70(m,3H), 8.30(m,lH), 7.50(m,7H), 6.00(d,1H), 5.67(g,2K), 5.20(s,lH), 1.60(s,3H), 1.05(s,3H). 10.80(s,lH), 8.60(d,1H), 7.90(d,lH), 7.30(m,5H), 6.90(t,2H), 6.20(m,2H), 5.23(s,lH), 1.53(s,3H), 1.00(s,3H).

U Me-ting Yield Point R1 (%) (° C.) 2-(2-/3-bromophenyi7acetamido)- 75 140-162 2-phenylacetyl 2-(2-^5-raet:hoxyphenyl7acet- 70 134-150 amido)-2-phenylacetyl 2-(4-pyridinecarboxamido)- 52 160-180 2-phenylacetyl 2-(2-/T-nitrophenyl7acet- 49 145-170 amido)-2-phenylacetyl 2-(2-/2-furyl7acetamido)- 73 165-184 2-phenylacetyl 2-(4-nitrobenzamido)-2- 81 160-178 phenylacetyl 2-(2-phenoxyacetamido)- 77 120-128 2-phenylacetyl 2-(2-cyanoacetamido)-2- 135-145 phenylacetyl 2-(2-azidoacetamido)-2- 41 138-147 phenylacetyl Infrared Spectrum (cm"1) NMR Spectrum (DMSO-dg/CDCl^; ppn) 1800,1647 8.83(m,1H), 8.35(d,lH), 7.35(m,9H), 5.6(m,3H), 5.2(s,1H), 3.6(s,2H), 1.6(s,3H), 1.05(s,3H). 1798.1652 8.67(m,lH), 7.83(d,lH), 7.4(m,7H), 6.95(d,2H), 5.9(d,1H), 5.67(m,2H), 5.32(s,lH), 3.88, 3.73(s,2H), 1.7 (s,3H), 1.12(s,3H), 1795,1653 8.83(m,3H), 8.2(q,4H), 7.4(m,5H), 6.0(d,2H), 5.6 (m,2H), 5.2(s,lH), 1.6(s,3H), 1.05(s,3H). 1795,1667 8.6(m,1H), 8.07(d,lH), 6.8-7.6(m,10H), 5.9(d,lH), 5.6(m,2H), 5.2(s,lH), 4.6(m,2H), 1.6(s,3H), 1.07 (s,3H). 2250,1790 9.1(d,IK), 7.45(m,5H), 5.75(d,lH), 5.630n,2H), 5. 1667 15(s,1H), 3.80(s,3H), 1.6(s,3H), 1.03(s,3H). 2100,1795 7.5(m,5H), 5.93(d,lH), 5.73(m,2H), 5.17(s,lH), 1667 4.12(s,2H), 1.67(s,3H), l.l(s,3H).

O a u to 40532 KXAMI'I.K CI.XXV (> - (2-Pheny lacctamido) -2,2-dimet'-y 1-3- (l-/4-benzyloxybenzyi7- tetrazol-5-yl)penam To a stirred solution of 189 mg of 6-amino-2,2-dimethy1-5 3-(l-^3-benzyloxybenzyl7tetrazol-5-yl)penam in 4 ml of chloro form, is added, .iL ambient temperature, O.OJ8 ml of pyridine followed by O.OS7 ml of phcnylaectyl chlorido. Stirring is continued for a further 4b minutes, and then the reaction mixture is diluted with 25 ml of chloroform and then washed with lO water. The organic phase is dried using anhydrous magnesium sulfate and then evaporated ijn vacuo. The residue is 209 mg (86% yield) of 6-(2-phenyiacetamido)-2,2-dimethy1-3-(1-^T- benzyloxybenzyl/tetrazol-5-yl)penam. The NMR spectrum (in CDC13 shows absorptions at 7.50-6.70 ppm (multiplet, aromatic hydro-15 gens), 6.4 ppm (doublet, amide hydrogens), 5.80-5.20 ppm (multi plet, benzyl hydrogens and C-5 and C-6 hydrogens), 5.10 ppm (singlet, C-3 hydrogens) 5.05 ppm (singlet, benzyl hydrogens), 3.60 (singlet, phenylacetyl methylene hydrogens), 1.30 ppm (singlet, C-2 methyl hydrogens) and 0.8b ppm (singlet C-2 20 methyl hydrogens).

- VH> - 40532 UXAMI'LK CLXXVI Reaction of the appropriate 6-amino-2,2-dlmethyl-3- (1-substituted-tetrazol-5-yl)penam with the requisite acid chloride according to the procedure of Example CLXXV provides tho following compounds: CH, RX-NH r o ,2^ M N R iO 15 20 25 10 15 acetyl acetyl propionyl acryloyl cyclohexanecarbony1 benzoyl £-chlorobenzoy 1 m-broraobenzoyl o-fluorobenzoy1 2-phenylacetyl 3-phenylpropiony1 2-(£-tolyl)acetyl 2-(£-isopropylphenyl)acetyl 2-(m-chlorophenyl)acetyl 2-(3,5-dibromophenyl)acetyl 2,6-dimethoxybeni.oyl 2-(£-chlorophenoxy)acetyl 2-thienylcarbonyl 2-(3-thienyl)acetyl 2-(2-furyl)acetyl 2-(3-pyridyl)acetyl 2-(5-tetrazolyl)acctyl 2-azido-2-phenylacetyl 2-(£-cyanopheny1)acetyl dodccanoyl acryloyl A^-octenoyl A J4-undecenoyl 12. ■dodecenoyl 2-(phenylthio)acetyl £-methoxybenzy1 m-ethoxybenzyl £-acetoxybenzyl £-benzyloxybenzyl benzyl 2-furylmethyl 3-furylmethyl m-propionoyloxybenzyl £— i sopropoxybenzy1 £-hydroxybenzyl £-methoxybenzyl o-methoxybenzyl 2-furylmethylbenzyl £-n-butoxybenzyl pivaloyloxymethy1 o-acetoxybenzyl £-methoxybenzyl o-methoxybenzyl £-methoxybenzyl £-hydroxybenzyl £-n-hexy1oxybenzy1 2-furylmethyl £-methoxybenzyl £-benzyloxybenzyl £-methoxybenzyl £-ethoxybenzyl o-methoxybenzyl m-methoxybenzyl 2-f uryime t hy1 £-methoxybenzyl - 301 - 4 0 5 3 2 2 -pliiMiy 1 acety I 2-phenylacety I 2-phenoxyacetyL 5 2-phenoxyacetyi 2-(2-thienyi)acetyl 2-(3-thienyl)acetyl 2, 6-diethoxybenzoy1 2-(2-thienyl)acetyI IO 2-ethoxy-l-naphthoyJ 2-n-butoxy-l-naphtlu>y 1 4-isothiazole carbonyl 2-cyclohcptylacety1 2-(cyclohex-3-enyl)acctyl 15 3-phenylpropiony1 2-phenylthioacetyl 2-(2-furyl)acetyl 2-(1-pyrazolyl)acetyl 2-(1-pyrrolyl)acctyl 20 2-(l,2,4-triazol-l-yl)acetyl 2-(3-sydnonyl)acetyl 2-(2,4-dimethylthiazol-5-yl)-acetyl 2-bromoacetyl 25 2-bromoacetyl 2-phenylacetyl cycloheptatrieny1carbonyl 2-phenylacetyl 2-phenoxyacetyl 30 2-(3-thienyl)acetyl 2-(3-chlorophenyl)acetyl 2-phenylacetyl 2-phenylbutyryl 2-phenoxyacetyl 35 2-phenylthioacctyi 2-phenylacetyl 2-thieny1acety1 3-thienylacetyl 3-thienylacetyl 40 2-bromacetyl 2-chloroacetyl 4-bromobutyryl 2-(4-fluorophenyl)acetyl phenoxycarbony1 4 5 benzyloxycarbonyl 2-(4-fluorophenyl)acetyl 2,6-diethoxybenzoy1 2-(4-pyridylthio)acetyl 5-methyl-3-pheny1-4-isoxazoiyi-50 carbonyl 2-cyanoacetyl 2-(5-tetrazolyl)acetyl 2-(1-tetrazolyl)acetyl 2-azido-2-phenylacetyl 55 2-sulfo-2-phenylacetyl 4-methy1-1-(2,6-dichloropheny1) - 5-pyrazoly1carbonyl 4-phenylbenzyI <11 pheny lme thy 1 3-chlorobenzyi 3-chloro-4-methoxybenzyl 2,4-dimethoxybenzyl 4-n-hexylbenzyl 4-fluorobenzyl 3.4-dimethoxybenzy1 1-phenylethyl 4-nitrobenzy1 1- (4-meLlioxyphenyi) ethyl 3.5-dichlorobenzyl 3-chloro-4-ethoxybenzyl 4-isopropylbenzyl 4-iodobenzyl 4-me thoxyme thoxybenzyl 4-n-hexylbenzyl 4-n-hexyloxyben2y1 4-biphenylylmethyl 4-bromopheny1 2-formloxybenzyl 1-(4-chlorophenyi)butyl 4-ethylbenzyl 4-(n-hexyloxymethoxy)benzyl 3-formy1oxybenzy1 diphenylmethyl 4-(2-chlorophenyl)benzyl 4-(4-tolyl)benzyl 2-(4-methoxyphenyl)benzyl cooc2h5 COOCH3 cooc2h5 cooc2ii5 coo-n-c(;lI3 COOCII2C6H5 cooc6h5 COO-24-(n-C4ll9)C6H47 coo-Z"4-no2c6h4/ COO-(3-BrC6H4J C00-/4-(i-C3H70)C6H47 COO-(2,4-Cl2C6H3) coo-(2-ch3oc6h4) C00-Z"4-(n-C6H130)C6H37 coo-(2-fc6h4) COO-(2-CH3C6ll4) COO-/"4 - (t-C4II9) C6H47 COO-fl ,4- (NO.,) 2c6»137 cooch3 cooc2h5 C00-n-C4lIg C00CIUC6IIc C00-/2-N02-4-(C3H70)C6H37 COOC2lI5 - K>2 - 40532 12 A -dodecenoyl acryloyl cyclbutylcarbonyl 5 2-phenylacetyl 2-phenoxyace ty1 2- (3-thlcny1)ace ty1 2-cyanoacctyl 2-(2-fluorophenyl)acetyl IO 2-(3,4-dichlorophenyl)acetyl 2-(3-bromophenyl)acetyl 2-(3-tolyl)acetyl 2-(4-isopropylphenyl)acetyl 2-(4-amyloxyphenyl)acetyl 15 acryloyl 2- (4-cyanophenyl)acetyl 2-(2-furyl)acetyl ethoxycarbonyl acetyl 2C) butyryl benzoyl cyclopentanecarbonyl 1,4-cyclohexadienylcarbonyl 2-(2-tetrazolyl)acetyl 25 2-(4-chlorophenyl)thioacetyl 2-phenylacetyl 2-(2-thienyl)acetyl 2-(3-thienyl)acetyl 2-phenoxyacetyl 30 2-bromoacetyl 1,4-cyclohexadienylcarbonyl COOCH2C6H5 coocghc cooc2h5 so2ch3 S02CH2(CH2)4Cn3 S0,CH,C-Hc so^cJs6 5 so2-Z"4-no2)c6h47 S02-(4-BrC6h4 S02-(2-ClC6h4) so2-/2-c2h5)C6h4) s02-/3-(n-c4H9)CfiH4) so2-3-(ch3o)c6h4/ S02-(2,4-Cl2C6H3T S02-/3-CH3-4-TCH30)C6H,7 S02-/2,4-TN02)2C6H,7 S02-/2-CH30-5-(N02rC6H37 S02-CH2-(4-ClC6H4f SO'-CI^-(2-BrC6H4) SC>2CH2-(3-CH3C6H4) so2c2h5 S02CtH5 S02-/^-(n-C4H90)C6H47 SO,C6HC phthalL dyl - 303 4 0532 EXAMPLECLXXVII Reaction of the appropriate 6-amino-2,2-dimethyl-3-(1-substituted tetrazol-5-yl)penam with the requisite soditun N-(2-methoxycarbony1-1-methy1vinyl)-2-amino-2-substituted-ace-tate, accordiny Lo tho procedure of Example CLXVII, affords I. ho foltowjny oonyonors: N N 2 / R 7 2 R lo I r> methyl i sopropy1 cyclopentyl 1,4-cyclohexadieny1 phenyl phenyl phenyl phenyl phenyl £-hydroxypheny1 £-hydroxyphcny1 3-chloro-4-hydroxypheny1 2-thieny] 3-thienyl 2-furyl £-methoxybenzyl ^-hydroxybenzyl 2-fury1mothy] £-me thoxybenzy1 ^-hydroxybenzyl £-methoxybenzy1 £-acetoxybenzyl m-ethoxybenzy1 £-hydroxybenzyl £-methoxybenzy1 benzyl £-methoxybenzyl £-hydroxybenzyl 2-fury]methyl 2-furylmethyl - K)<1 - R 4 0 5 3 2 4-me thoxyphcny1 4 -N,N-d imethylam i nopheny1 4-nitrophenyl 5 3-pyridyl 4-f1uorophcny1 phenyl benzyl 3-indolymethyl IO 2,4-dichlorophenyl 3-bromophenyl 3-tolyphcnyl 2-methoxyphenyl 4-(n-butoxy)pheny1 15 3,5-dimethoxyphenyl 4-isopropylthiophenyl 4-methylthiophenyl 3-furyl 4-methylthiophenyl 20 cycloheptyl cyclohexyl 3-chloro-4-methoxybenzyl 3-chlorobenzyl diphenylmethyl 4-benzyloxybenzy1 1-phenylethyl 4-phenylbenzyl 2,4-dimethoxybenzyl 4-iodobenzyl 4-n-hexylbenzyl 1-(4-chloropheny1)buty1 4-bromopheny1 4-ethylbenzyl 2-formyloxybenzyl 4-biphenylyImethy1 phenyl-(4-methoxyphenyl)methyl 1-(4-methoxyphenyl)e thy1 4-nitrobenzy1 2-fluorobenzyl 1-phenylbutyl 4-methoxybenzyl 25 to 3r> 4n ■>ii phenyl 3-thienyl 1,4-cyclohexadienyl p-hydroxyphenyl 3-chloro-4-hydroxyphenyl phenyl phenyl 4-chlorophenyl cyclohexyl 3-thienyl phenyl methyl n-octyl cyclopropyl Ap propenyl A -butenyl 5-ethyl-2-thienyl 4-dimethylaminophenyl phenyl phenyl 2-thienyl methyl n-buty1 dodecyl cyclobutyl 4-hydroxyphenyl 3-chloro-4-hydroxyphenyl 2-butenyl 2-chloropheny1 4-methoxyphenyl 4-n-hexoxyphenyl 4-isopropylthiophenyl COOC2H5 c00ch3 cooc2h5 cooc6h13 cooc6hs cooch,c6h,-coo-/4-tch3)c,h47 coo-/2- (ch3o) cgh,j) coo-/2-no2-4-(c3h70)c6h37 c00-/2 , 4 - (no-,) 2 c6 h37 coo-/2-fc6h47 coo- (3-brcghjj) COO-/"4- (n-C4H9) C6H4/ COO-'/3-Cl-3-CH3ct H3/ COO-COO-i-C3H7 COOCH, SOjCH^ s°2^2 5 N s02-n-c6jil3 so2c6h5 so2ch2c6h5 so2ch2c6h5 s°2C6"b SOjJCIUJ^CIU so2_/3-(n° j<:6ii47 .so2-(4-nrcni4) s02-(2-C2lI5C6H4) s02-/^-(n-C4h9)C6H47 - 30b - 40532 3,4-dimethoxyphenyl 3-bromophenyl 4-fluorophenyl 5 2,4-dichlorophenyL 3-furyl 5-ethyl-2-thienyl 1 ,4-cyclohexadlenyi phenyl lo 2-thienyl I,4-eyelohox.nl ienyI 4-hydroxyphenyl 3-chloro-4-hydroxypheny1 methyl 15 propyl phenyl 4-hydroxyphenyI 3-chloro-4-hydroxyphenyl 2-thlenyl 2o 3-thienyl 1,4-cyclohexadieny L 3-pyridyl cyclohexy 2-cyclohexeny1 25 2-furyl 2-isothiazolyl 4-methoxyphenyl 3-fluorophenyl 4-tolyl 30 5-ethyl-2-thieny1 S02-/3-(CI!30)C6H4/ 501-P^-CUCf. 502-/3-C»3-4-(ch3o) C6II3/ Hi) S02~/2 , 4-(N02) 2^-6H37 S02-/"2-CU30-b-{N027C6H .7 S02-(3-FC6H4) S°2C2l,r1 phthalidyl acetoxymethyi propionoxymethy1 isohutyryloxymethy1 acetoxymethyi 1-(acetoxy)ethyl n-hcxanoyloxymethyi 1-(n-hexanoyloxy)ethyl pivaloyloxymethyl 1-(acetoxy)ethyl 1-(butyrloxy)ethyl 1-(propionyloxy)ethyl n-pentyloxymethy1 pivaloyloxymethyl acetoxymethyi 1-(pivaloyloxy)ethyl pivaloyloxymethyl pivaloyloxymethyl - 300 40532 EXAMPLE CLXXVIII 6-(2-Phenylacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam To a stirred suspension of 2.4 g of 6-amino-2,2-dimethy1-3-(5-tetrazolyi)penam in 50 ml of chloroform is added 2.8 ml of 5 triethylamine. Stirring is continued for a further 15 minutes, and then tho solution thus obtained, is cooled to 0°C. To this solution is then added 1.08 g of trimethylsilyl chloride. The cooling bath is removed, and the reaction mixture is stirred for a further 1 hour at ambient temperature, to give a chloro-lo form solution of the mono-trimethylsilyl derivative of 6-amino-2,2-dimethyl-3-(r>-tetrazoiyl)penam. This latter solution is then recooled to 0°C, and 1.56 g of phenylacetyl chloride is added dropwise, with stirring. The cooling bath is removed, and the mixture is stirred for I hour at ambient temperature. The chloro-15 form is then washed with water, dried using anhydrous sodium sulfate, and concentrated to dryness in vacuo. This affords crude 6-(2-phenylacetamido)-2,2-dimethy1-3-(5-tetrazolyl)penam. - 307 - 40532 KXAMI'l.i: CI.XXIX When Liu; procedure of Kx.imple CIiXXVIII in repeated, except Hint the trimethylsilyl chloride used therein is replaced by an equimolar amount of triethylsliyl chloride and tri-n-butyl-5 silyl chloride, respectively, the product in each case is 6-(2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. The intermediate products in these experiments are the mono-triethyl-silyl and the mono-tri-n-rbutylsilyl derivative of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, respectively. - tntl - 40532 EXAMPLE CLXXX 6-(2-Phenoxyacetamido)-2,2-dimethy1-3-(5-tetrazolyl) penam To a stirred suspension of 2.4 g of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 50 mi of chloroform is added 4.2 ml 0 of triethylamine. Stirring is continued for a further 15 minutes, and then the solution thus obtained is cooled to 0°C. To this solution is then added 2.16 g of trimethylsilyl chloride. The cooling bath is removed, and then the reaction mixture is stirred at ambient temperature for 1 hour and then it is re-lO fluxed for 1 hour. It is then cooled to ambient temperature giving a chloroform solution of the bis-trimethylsilyl derivative of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam. This latter solution is then cooled to 0°C, and 1.72 g of phenoxyacety1 chloride is added dropwise with stirring. The cooling bath is 15 removed, and the mixture is stirred for 1 hour at ambient temperature. The chloroform is then washed with water, dried using anhydrous sodium sulfate, and then evaporated to dryness in vacuo. This affords crude 6-(phenoxyacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam. - 309 - 40532 KXAMI I.K CI.XXXI TIh.mi the pruocduri; oT l-:x.iui|> 1»■ (.'I.XXX Is ropoatod except l.haL trimotliylsi lyl chlorido used therein if. replaced by an equimolar amount of triethylsily1 chlorido and triisopropyl-silyl chloride, respectively, the product in each case is 6-(2-phenoxyacetamido)-2,2-dimethyl-3-(b-tetrazolyl)penam. The intermediate products in these experiments are the bis-triethyl-silyl and the bis-triisopropyl derivative of 6-amino-2,2-dimethyi-3-(5-tetrazolyl)penam, respectively. - 3i(> - 4 0 5 3 2 example clxxxii 6-(D-2-Amino-2-/?-hydroxyphenyl/acetamido)-2,2-dimethyl-3- (5-totrazolyl)penam, Potassium Salt To a stirred solution of 1.94 g. 6-(D-2-amino-2-/S-5 hydroxyphenyl/acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam in lOO ml. of methanol, cooled to -30°C., is added dropwise 5 ml. of a 1.ON solution of potassium hydroxide in methanol. The mixture is allowed to warm to 0°C., and then it is added dropwise with stirring to 700 ml. of ether. The solid which precipitates lO is removed by filtration and dried under high vacuum. This affords 1.65 g. (76% yield) of the title potassium salt, m.p. i85°C. (dec.).

When the above procedure is repeated, except that the potassium hydroxide used therein is replaced by an equimolar 15 amount of sodium hydroxide, the product is the sodium salt of T»- (D-2-ami no-2-/4-hydroxypheny 1/acetamido) -2 ,2-dimethy 1-3- (5-tetrnzolyl)penam. -311- KXAMI'Mi Ct.XXXIIl (>- (O-2-Amino-2-/^-hydroxypheny 1 ./."icetamido-2, 2-d imothy1-3- (b-tetrazolyl) ponum Calcium Salt 'I'o a stirred solution of 2.0 y. of (i-(D-2-amino-2-/5-S hydroxypheny1/acetamido) -2,2-d imethy 1-3- (!>-tetrazolyl) penam in 20 ml. of dimethylformamldo is added a turbid solution of 0.19 g. of calcium hydroxide over 5 minutes. The mixture is heated at 35-40°C. for J hour, and then an additional 30 ml. of dimeth-yiformamide is added. Heating at 3b-40°C. is continued for a lO further 30 minutes, and then the cooled solution is added drop-wise to 700 ml. of ether. An oil precipitates. The solvent is decantcd off and to the rnsidue is added 100 ml. of ethanol, followed I >y KM) ml. of ellier. The oil slowly solidifies and I lien it i s recovered hy filtration arid dried under high vacuum. This lb affords 1 . 4y (f>7v, yield) of the title calcium salt. - iU - 4 0 5 3 2 EXAMPLE CLXXXIV G-(2-Phenylacetain ido)-2,2-dimethy1-3-(5-tetrazolyl) penam A flask containing 965 mg. of 6-amino-2,2-dimethy1-3-(l-/^-mc;thoxybenzy.iytetrazol-5-yl) penam £-toluenesulfonate, 40 5 drops of anisole, and 5 ml. of trifluoroacetic acid is immersed in a water-bath maintained at 35-40°C. The progess of the reaction is followed by removing samples at intervals, and recording their nuclear magnetic resonance spectra. After about 25 minutes, the removal of the 4-methoxybenzyl group is found to IO be approximately 90% complete. At this point the reaction solution is added to a rapidly-stirred, ice-cold solution of IO ml. of pyridine in 50 ml. of chloroform. Stirring is continued for 5 minutes, and then 0.24 ml. of phenylacetyl chloride is added. The cooling bath is removed and the reaction mixture is stirred 15 for a further 20 minutes. A lOO-ml. portion of water is added, and the pll of the aqueous phase is then adjusted to 2.5 by the dropwise addition of 0.5 N hydrochloric acid. The chloroform layer is separated off, washed with saturated brine, dried using anhydrous sodium sulfate and then it is evaporated to 20 dryness iri vacuo. The crude product thus obtained is re-dis-solved in chloroform, and the solution is divided into two equal portions. To one of these portions is added an equal volume of water. The layers are stirred vigorously and the pH of the aqueous phase is raised to 6.9 by the dropwise addition of 25 O. IN sodium hydroxide solution. The chloroform is separated off and discarded, and then an equal quantity of fresh chloroform is added to the aqueous phase. The layers are stirred vigorously and the pll is adjusted to 2.5 using dilute hydrochloric acid. The chloroform is separated off, washed with saturated 30 brine, dried using anhydrous magnesium sulfate and then evaporated to dryness iri vacuo. - 31 i 40532 This affords 107 my. of an oily residue. Tho residue is redissolved in 3 ml. of chloroform which is then added dropwise to 30 ml. of hcxane. The fluffy white solid which precipitates is filtered off, giving 80 mg. of 6-(2-phenylacetamido)-2,2-5 dimethyl-3-(5-tetrazolyl)penam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1795 cm 1 (fl-lactam carbonyl), 1660 cm 1 (amide I band) and 1510 cm-1 (amide II band). The NMR spectrum (in CDC1), shows absorption bands at 7.20 ppm (broad singlet, aromatic hydrogens), 5.55 ppm (multi-lO plot, C-5 and C-6 hydrogens), 5.15 ppm (singlet, C-3 hydrogen), 3.GO ppm (broad singlet, benzyl hydrogens), 1.40 ppm (singlet, C-2 methyl hydrogens) and 1.05 ppm (singlet, C-2 methyl hydro-yens) . - 31A - 40532 example CL.xxxv Using the procedure of Kxamplc CLXV, and utilizing as starting material an appropriate 6-acylamino-2,2-dimethyl-3-(l/2/-substituted tetrazol-5-yl)penam chosen from those in Example CLXIV, the following compounds are prepared: 6-amino-2,2-dimethyl-3-(l/2/-acetoxymethyl-tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(l/^/-isobutyryloxymethyl-tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(l/^/-propionoxymethyl-tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(l flj-n-hexanoy1 oxy -methyltetrazol-5-yl)penam, 6-amino-2,2-dimethy1-3-(l-/2/-/I-acetoxyethyl7-tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(l/27-/l~ProPionyloxy-ethyl/tetrazol-5-yl)penam, 6-amino-2,2-dimethyl-3-(1/27-/1-pivaloyloxy-ethyl7tetrazol-5-y Dpenam, 6-amino-2,2-dimethyl-3-(l/27-/l-n-hexanoyloxy-methyl7tetrazol-5-yl)penam and 6-amino-2 , 2-dimethyl -3- - (l/2/-phthalidy 1 tetrazol -5-y1)penam, respectively. - 315 - 4 0 5 3 'i KXAMI'I.K CLXXXV1 HiMction of the appropriate 6-acylamino-2,2-dimethy1-3-(l/27-substituted tetrazol-5-yl)penam compound, chosen from those in Kxamples CLXIX and CLXXVII with sodium N-(2-ethoxy-5 carbony1-1-methyivinyl)-2-aminoacetate, according to the procedure of Kxample CLXVII, produces the following compounds: G- (2-/2-ami noacotam ido./-2-pliony lacctamido) -2,2-d imethy! -3- (J -/3-me thoxybenzy 1 _/tetrazol.-5-yl) penam, 6- (2-/2-aminoacetamido/-2-/3-hydroxyphenyl7acetamldo) -IO 2,2-dimethy 1-3- (l-/methoxycarbony]l7t.etrazol-5-yl) penam, 6-(2-/2-aminoacetamidq7-2-/3-chloro-4-hydroxy7acetamido) 2,2-dimethy1-3-(l-/ethoxycarbonyl/tetrazol-5-yl)penam, 6-(2-/2-aminoacetamido7-2-/2-thienyl/acetamido)-2,2-dimethyl-3-(l-/ethylsulfonyl/tetrazol-5-yl)penam, 15 6-(2-/2-aminoacetamidq7-n-valeramido)-2,2-dimethyl-3- (l-/n-hexylsulfonyl7tetrazol-5-yl)penam, 6-(2-/2-aminoacetamido/propionamido)-2,2-dimethyl-3-(i-/acetoxymethyl/tetrazol-5-yl)penam, 6-(2-/2-aminoacetamidq/-2-phenylacetamido)-2, 2-dimethyl-2() 3-(i-/isobutyryloxymethyl/tetrazol-5-yl)penam, 6- (2-/2-aminoacetamidq7-2-/3-chloro-4-hydroxypheny l7~ ace t.am ido) - 2 , 2-d imethy 1 -3 - (1-/1- (aco t.oxy) othyl/tetrazol- 5-y1)ponam, <>- (2-/2-.mi i noacotam ido/-2-/2-f ury i/aoot.ani i do) -2,2-2't d i im.'lliy I — t — ( 1 -/h-ponLy I oxymoLhy L7l ptrazo I - r>-y 1 ) pon.ini, 6- (2-/2-.imi noacotam ido/-2-/2-eye 1 olioxy 1/acetamido) -2,2-d inn;thy 1 - 3- (1-/1- (propiony 1 oxy) othy l/teLrazol-5-y 1) ponam G-(2-/2-am inoacetamido/-2-phonylacctamido)-2,2-dimothy]-3-(2-/pivaloy1oxymethy 1 _/«_etrazol-5-y1)penam, '}() 6- (2-/2-.1111 i iio. ii-otami do/-2-/2-1 li iony l/acelami do) -2,2- d imethy I - I - (2-^p i v.i J oy 11 ixymel hy iyi el r.i/.ol -r>-y 1 ) penam and (>- (2-/2-.imi no.tcetaniidq/-2-/'3-cli loro-4-hydroxyphcnyl7-acetamido)-2,2-dimethyi-3-(2-/pivaloyloxymethy1/tetrazol 5-yl)penam, ,r' respectively. - 316 - 40332 KXAMPLE CLXXXVII 6-(D-2-/1-(2-Furoyl)ureidq/-2-phenylacctamido)-2,2-dimethyl-3- (1-pivaloyloxymcthyltetrazol-5-y Dpenam To a stirred solution of 455 mg. of 6-(D-2-amino-2-5 phenylacctamido)-2,2-dimethyi-3-(1-pivaloyloxymethyltetrazol-5-yl)penam in 20 ml. of methylene chloride, at 0°C., is added 137 mg. of 2-furoyl isocyanate dissolved in 5 ml. of methylene chloride. The cooling bath is then removed, and stirring is continued for 2 hours. The solvent is removed in vacuo and the IO residue is partitioned between ethyl acetate and water at pH 7.5. The ethyl acetate is removed and discarded. The pH of the remaining aqueous phase is adjusted to 2.5 and the product is extracted into ethyl acetate. The ethyl acetate is washed with water, followed by brine, and then it is evaporated to dryness 15 i_n vacuo. This affords the title compound. - 317 - 40532 EXAMPLE CLXXXVIII Tho procedure of Examp.le CLXXXVII is repeated, except tlie 6- (n-2-amino-2-phenylacctamido) -2,2-dimothy 1-3- (1-pivaloyloxymethyl tetrazol -5-yl) pen.im used therein is replaced by the 5 appropriate 6-(r>-2-amino-2-phenylacetamido)-2,2-dimethyl-3-(1/2/-substituted tetrazol-5-yl)penam, nnd the 2-furoyl isocyanate is replaced by the requisite isocyanate. This affords: 6-(D-2-/5-(2-furoy1)ureido/-2-phenylacetamldo)-2,2-dimethyl-3-(1-/1-acetoxy)ethyl/tetrazol-5-yl)penam, 10 6-(D-2-/3-benzoylureidq/-2-/2-thienyl7acetamido)-2,2- dimethyl-3-(2-/pivaloyioxymethyl/tetrazol-5-yl)penam and 0-(n-2-/3-(3-thieny1)ure ido/-2-/3-chloro-4-hydroxypheny l/7icol.imido) -2 , 2-d imelliy 1 -3 - (2-^piva l.oy loxyme LIiy 1 )-'' t el.r.izo I-r>-y I ) penam, respectively.

- JIB - <10532 KXAMl'l.K CLXXXIX Kc.u-L I on oT Lho nppropr 1.11.»• pon.im compound froin those listed in Kxiimplcs CLXIX nnd CLXXVII with tho appropriate aldehyde or ketone, according to the procedure of Example CLII, 5 produces the following compounds: 6-(2,2-dimethyl-5-oxo-4-phenyl-l-imldazolidinyl)-2,2-dimethy1-3-(l-/pivaloyloxymethy 1/tetrazol-5-yl) penam, 6-(2,2-dimethyl-5-oxo-4-/4-hydroxyphenyl/-l-imi-lo dazolindinyl)-2,2-dimethyl-3-(l-/acetoxymethyl7- tetrazol-5-yl)penam, 6-(2-methyl-5-oxo-4-/2-thienyl7-l-imidazolindinyl)-2,2-d imethyl-3-(l-/n-hexanoyloxymethyl/tetrazol- 5-yl)penam, 15 6-(2,2-dimethyl-5-oxo-4-/3-chloro-4-hydroxyphenyl/- imidazolindinyl) -2,2-dimethyl-3- (1-/"W.;c.-»toxy)ethyi7-tetrazol-5-yl)penam, 6-(2,2-diethyl-5-oxo-4-/5-thienyl/~l~in»idazolidinyl)-2,2-dimethyl-3-(1-/1-(n-hexanoyloxy)ethyl7tetrazol- 20 5-yl)penam, 6-(2,2-dimethyl-5-oxo-4-phenyl-l-imidazolindinyl)-2,2-dimethyl-3-(1-phthalidy1tetrazol-5-yi)penam and 6-(2,2-dimethy1-5-oxo-4-pheny1-1-imidazolindiny1)-2,2-dimethyl-3- (2-/pivaloyloxymethyl/tetrazol-5-25 yl)penam, respectively. - 31'J - EXAMH.K CXC The following ingredients are blended together in the indicated proportions by wci'jlif. niiciii.:;. 1*.

Tapioca starch Magnesium stearate 6-(D-2-Amino-2-phenylacetamido) -2,2-dimethy1-3-(5-tetrazolyl)penam tt <>.<> i :t. *, 6.5 lOO.O After the composition is thoroughly blended, tablets are punched from the mixture, each tablet being of such size as to contain lOO mg of the penam compound.

Tablets are also prepared containing respectively 50 and 250 mg of active ingredient, by selecting the appropriate proportions of penam compound and cxcipient blend in each case. 320 4 0 S 3 2 example cxci The following ingredients are blended together in the indicated proportions by weight.

Calcium carbonate 17.6 5 Dicalcium phosphate 18.8 Magnesium trisilicate 5.2 Lactose, U.S.P. 5.2 Potato starch 0.8 6-(D-2-Amino~2-/3-thienyl/ IO acetamido)-2,2-dimethyl-3- (5-tetrazolyl)penam 50.0 The throughly-mixed pharmaceutical composition is filled into soft gelatin capsules, such that each capsule contains lOO mg of active ingredient. 15 Capsules are also prepared containing respectively 50 and 250 mg of active ingredient by varying the proportions of penam compound and excipient blend. - 321 - 40532 KXAMPLK CXCII The sodium salt of 6-(D-2-amino-2-^p-hydroxyphenyl7ace-tamido)-2,2-dimethyl-3-(5-tetrazolyl)penam is throughly mixed and ground with sodium citrate (4% by weight). The ground, dry 5 mixture is sterilized and packed into sterile vials, which are then stoppered with serum caps under sterile conditions. When it is intended to use this preparation, sufficient sterile water is injected into the vials to dissolve the contents, and give a solution containing 25 mg/ml of active ingredient. For Lo p.irenLcr.i I use;, Liu: solution is withdrawn from Lho vials using ii hypodermic syringe.

In a similar manner, by varying the amount of water added, solutions containing respectively 10, 50, 100, and 200 mg/ml of active ingredient are prepared - 322 - 40532 EXAMPLE CXCIII In vitro .intlb.ietcrinl .ictivltics for n number of the compounds of this Invention ore; presented below.

In Table II, the minimum inhibitory concentrations (MIC's) 2 '> of compounds of formula I, wherein R is hydrogen, against a strain of Streptococcus pyogenes, are reported; and in Table III, minimum inhibitory concentrations of compounds of formula 2 I, wherein R is hydrogen, against a strain of Staphylococcus aureus, are presented. Because of the tautomeric nature of such to tetrazoln derivatives, referred to hereinbefore, each of the preparations tested also contains some of the corresponding compound of formula II, wherein R"* is hydrogen.

TABLE II . MIC (pg/ml) vs. 15 R Strep, pyogenes 2-phenylacetyl )>-2 - (2-/]>-methoxyben/.am ldo7'icolamido) -2-plieny 1 acety 1 O. 1 l»— 2 — (2-/T>utyriiml) -2- (]_>_liy 11 • >xy| >ln -iiy 1 ) .n •< -1 y 1 |)-2 - (rnz.mi i 11 1 in i/.ii •<■ 1 . nil i di >) - 2-1 >ln • 11y 1 .it -i •! y 1 •■(). • <). • i >. ii. 1 1 1 1 2 'j n-2-(2-^3-pyr Idi necarboxam idi.no/acotami do) -2-plienyl acety I -chlorophenyi) acetamidino/acetamido) -2-phenylacetyl 0. 2 30 D-2-(2-^£-nitrobenzamidino/acetamido) -2-phenylacetyl - 40532 TADLK 11 (continued) MIC (yg/ml) vs.Strep.

R Pyogenes D-2-(2-/2-benzimidozolecarboxamidinp7~ 5 acetamido)-2-phcnylacetyl <0.1 D-2-(2-/2-pyrlmidinecarboxamidino/- acetamido)-2-phenylacetyl 0.78 l>—2—(2-/3-cyano-5-iodobenzamidino/- acetamido)-2-phenylacetyl <0.1 lO 2-(3,5-dimethylbenzamidino)acetyl 0.39 2-(4-pyridinecarboxamidino)acetyl <0.1 2-(acetamidino)acetyl <0.1 2-(2-thiophenecarboxamidino)acetyl <0.1 2-(4-pyridinecarboxamidino)-3-phenylpropionyl O.2 15 D-2-(2-/4-pyridinecarboxamidino/acetamido)- 2-(^-hydroxyphenyl)acetyl <0.1 D-2-(2-/3-ethylureido/acetarnido)-2-phenylacetyl <0.1 D-2- (2-/3-phenylureidp/acetamido) -2-phenylacetyl <0.1 D-2-(2-/3-methylureidp7acetamido)-2-phenylacetyl <0.1 2C) D-2-(3-guanylureido)-2-phenyincctyl <0.1 D-2-ureido-2-phenylacety1 O.l 2-sulfamoyl-2-phenylacetyl <0.1 D-2-(£-guanidinobenzamido)-2-phenylacetyl 1. 56 D-2-(2-/guanidino/acetamido)-2-phenylacetyl <0.1 25 D-2-(2-/£-guanidinophenyl7acetamido)-2-phenylace- ty1 1.56 D-2-(3-/guany l/propionamido)-2-phenylacetyl <0.1 D-2-(2-/N-methylguanidinp7acetamido)-2- phenylacetyl <0.1 30 D-2-(2-/3-(guany1)ureido/acetamido)-2- phenylacetyl 3.12 327 4 0 5 3 2 TAHLH I I (cont i nued) ^ MIC (iig/ml) vs.Strep R pyogenes D-2-(3-/2-furoy/ureido)-2-phenylacetyl <0.1 5 2-(3-acetylureido)-2-phenylacetyl <0.1 2-(3-butyrylureido)-2-phenylacetyl <0.1 2-(3-/chloroacetyl/ureido)-2-phenylacetyl 0.2 2-(3-/3-pyridylcarbonyl/-ureido)-2-phenylacetyl O.l 2-(3-benzoylureido)-2-phenylacetyl <0.1 lO 2-(3-/3,5-dibromobenzoyl/-ureido)-2- phenylacetyl <0.1 2-(3-/3-pyridylcarbonyl/-ureido)-2-phenylacctyl O.2 2-(i-propiony]ureido)-2-phcnylacety1 <0.1 2-(3-/cyclopropylcarbonyl/-ureido)-2-phenylacetyl<0.1 15 2-(3-/l-adamantyIcarbonyl/-ureido)-2-phenylacetyl<0.1 2-(3-benzoylthioureido)-2-phenylacetyl 1.56 N-acetylcarbomoyl 1.56 N-(2-furoyl)carbamoyl 1.56 N-(£-toluenesulfonyl)carbomoyl 1.56 20 2-carboxy-2-phcnylacetyl 0.002 2-carboxy-2-(2-th ienyl)acctyl 0.1 2-carboxy-2-(3-thienyl)acetyl 0.1 2-sulfo-2-phenylacetyl 200 2-(5-indanyloxycarbonyl)-2-phenylacetyl <0.1 25 D-2-sulfoamino-2-phenylacetyl 12.5 phenylpyruvoyl <0.1 328 - 40532 TADLH 1I (continued) I MIC (pg/ml) vs.Strep.

R pyogenes phenylglyoxyloyl <0.1 5 D-2-(benzoylformamido)-2-phenylacetyl 25 D-2-(acetylformamido)-2-phenylacetyl 50 D-2-(ethoxycarbonyIformamido)-2-phenylacetyl <0.1 D-2-(phenoxycarbonylformamido)-2-phenylacetyl 25 D-2-(ethoxycarbonylamino)-2-phenylacetyl 6.25 IO D-2-(benzyloxycarbonylamino)-2-phenylacetyl <0.1 D-2-(2-carboxy-3-/2-thienyl/acrylamido)-2- phenylacetyl <0.1 D-2-(2-carboxy-3-/£-chlorophenyl/acrylamido/- 2-phenylacetyl ' <0.1 15 D-2-allophanamido-2-phenylacetyl <0.1 3-aminomethyl-2-phenylisocrotonoyl 12.5 D-2-(dimethylaminomethyleneamino)-2-phenylacetyl<0.1 D-2-(dimethylaminomethyleneamino)-2-(n-hydroxy- phenyl) acetyl *" <0.1 20 2-(3-/2-(£-chlorophenyl)acetimidoyl/ureido)- acetyl 100 2-(3-/benzimidoyl/ureido)-acetyl <0.1 2-(3-/£-methoxybenzimidoyl/-ureido)acetyl 0.1 2-(2-/3-(2-/£-chloropheryl/-acetimidoyl)- 25 ureido/acetamido)-2-phenylacetyl <0.1 2-(2-/3-(benzimidoyl)ureido)-2-phenylacetyl O.78 2- (2-/3- (£-methoxybenzimidoy 1) ureidq/acet.nmi(io- 2-phenyl.icetyl 1.56 3-phenylcarbamoyI ^O.l JO 3-ethylcarbamoy1 <0.1 D-2-(2-phenylacctamido)-2-phenylacetyl <0.1 - 329 - 40532 i TADLK 11 (continued) MIC (pg/ml) vs.Strep. pyogenes D-2-(benzamido)-2-phenylacetyl <0. 1 5 D-2-(butyramido)-2-phenylacetyl O. 39 D-2-(2-furancarboxamido)-2-phenylacetyl 0. 1 D-2-(2-thiophenecarboxamido)-2-phenylacetyl <0. 1 D-2 - (2-/"2-thieny l/acetarnido) - 2-phony lacoty 1 O. 1 D-2 - ( 3-pyr id Inccarlioxamido) - 2-pheny 1 acety I «). 1 JO D-2-(2-pyrroLecarboxamido)-2-phenyl.neety L <0. 1 D-2-(2-/2-quinoxalinecarboxamidino/-ncetamido) -2-phenyiacetyl 0. 1 D-2- (2-/in-carbamoylbenzamidino/acetamido) -2-phenylacety1 <0. 1 - 3 30 - 40532 TABLE II (continued) MIC (jig/ml) vs.

U-2-(carboxymethyl)acetamido-2-phenylacetyl 0.2 5 D-2-(4-carboxy-2,3-epoxypropionamido)-2- phenylacetyl 0.2 2- (4-nminomethylphenyl) acotyl <0. 1 2-(2-/carl>oxymethyl7phenyI)acety1 0.2 2-.»mino-2- (4-aminophenyl) acety 1 0.039 IO u-2-amlno-2- (3-aminophenyl)acetyl D-2-acetyl-2-phenylacetyl 0.004 2-(4-/2-azidoethoxy/phenyl)acetyl <0.1 D-2- (3-/"2- (guanylthio) acetyl/ureldo) -2- phenylacetyl 0.004 IS D-2-(3-phcnylthioureido)-2-phenylacetyl <0.1 D-2-phthalimldo-2-phenylacetyl 0.004 D-2-(4-aminobenzamido)-2-phenylacetyl <0.1 D-2-(2-/4-aminophenyl/acetamido)-2-phenylacetyl <0.1 D-2-(2-phenoxyacetamido)-2-(4-hydroxyphenyl)acetyl 0.2 20 D-2-(3-/5-(N,N'-diethylguanylthio)acetyl^ureido)- 2-phenylacetyl 0.004 2-ethoxy-l-naphthoyl <0.1 DL-2-amlno-2-(m-nitrophenyl)acetyl 0.004 DL-2-amino-2-(£-sulfamoylphenyl)acetyl <0.1 25 U-2-arnino-2-(£-fluorophenyl) acetyl 3.12 D-2-amino-2-(2-furyl)acetyl 0.39 D-2-amino-2-(2-tetrahydrofuryl)acetyl <0.1 D-2-amino-2-(3-pyridyl)acetyl <0.1 D-2-amino-(4-aminophenyl)acetyl 0.39 30 D-2-amino- (3-aminophenyl) acetyl <-0.01 2-(2-/aminomethyl7phenylthio)acetyl 1.56 2-(3-/2-aminoethoxy/phenyl)acetyl <0.1 2-(4-/2-aminoethoxy/phenyl)acetyl <0.1 D-2-(2-chloroacetamido)-2-phenylacetyl <0.1 35 D-2-(2-chloroacetamido)-2-(2-furyl)acetyl -O.l D-2-(&,N'-dimethylamidinothio7ncetamido)-2- phenyTncetyl 0.004 - 331 - 4 0 5 3 £ TABLE tI (continued) MIC (|iq/ml) vs, l<' iil. rep, pyor.jr.-no: l>-2- (2-/pontamolhy Leneamid inoth iol/-5 acetamido) -2-plienylacetyl D-2-(2-/2-benzimidazoylthiq/acetamido)-2-phenylacetyI D-2-(2-/>l,N,-diethylamidinothio/ncetamido)-2-phenylacetyl IO D-2-(2-/N,N'-dibutylamidinothio/acetamido)-2-phenylacetyl D-2 - (2-/4-oxo-A2-imidazolin-2-ylthio/-acetamido)-2-phenylacetyl D-2-(2-/amidinothio^acetamido)-2-15 phenylacetyl D-2-(2-/2-imidazolylthio/acetamido)-2-phenylacetyl D-2-(3-aminopropionamido)-2-phcnylacetyl 2-(phony 1thio)acety1 2() 0-2- ( 2-/phony I t li i o/acu t.im i do) -2-phc -ny 1 aeot.y 1 2-(ethylthio)acoty1 D-2- (2-,/othy 1 tlii o/acetamido) -2-pheny 1 acety 1 3- (niothoxycarbonyl) butyryl D-2-(3-/methoxyca rbony L/bu tyram ido)-2-2'> phenylacetyl 1- (ethoxycarbony J ) acoty 1.

D-2-(2-/ethoxycarbonyl/acetamido)-2-plienylacetyl 2-(bcnzylthio)acctyl 30 D-2- (2-/benzylthio/acetamido) -2-phenylacetyl D-2-(3-benzamidopropionamido)-2-phenylacety1 D-2-(3-/4-chlorobcnzamido/propionamido)-2-phenylacetyl D-2-(S-ZS-chlorobenzamido/propionamido)-2-phenylacetyl 35 D-2-(3-/2-furancarboxamido/propionamido)-2-phenylacety1 . 1 ■ o. 1 ■ o. 1 f>. 2 5 <>. 2'> o. 39 I O. 2 o. 78 R Strep.pyogenes D-2-(3-acetamidopropionamido)-2-phenylacetyl <0.1 5 D-2-(3-benzamidinopropionamido)-2-phenyl acetyl 3.12 D-2-(3-/5,5-dibromobenzamidino/propionamido)-2-phenylacetyl <0.1 D-2-(3-acetamidinopropionamido)-2-phenylacetyl <0.1 IO D-2-(3-/3,4-dichlorobenzamidino/propionamido)- 2-phenylacetyl 0.78 D-2-(3-/4-chlorophenyl/acetamidinopropionamido)-2-phenylacetyl 1.56 D-2-(2-/3-(N-methylguanyl)ureido/acetamido)-2-15 phenylacetyl <0.1 D-2-(2-/3-(n-ethylguanyl)ureido/acetamido)-2-phenylacetyl <0.1 U-2-(2-/3-(N-bcnzylguanyl)ureido/acetamido)-2- j^heny lacetyl O.l 20 D-2-(2-/2-benzthiazolecarboxamidino/~acetamido)- 2-phenylacetyl <0.1 D-2-(2-^t5-disulfamoylbenzamidino]- acetamido)-2-phenylacetyl 0.004 D-2-(2-/3-sulfamoy1-5-bromobenzamidino^acctamido-25 2-phenylacetyl 0.004 D-2-(2-/3-chloro-5-cyanobenzamidino/acetamido)-2-phenylacetyl 0.004 D-2-(2-/2-benzoxazolecarboxamidino/acetamido)-2-phenylacetyl 0.39 30 D-2-(2-/3-sulfamoyl-5-chlorobenzamidino/acetamido)- 2-phenylacetyl C.004 D-2- (3-/4l-pyridinecarboxamidino) propionamido) -2-phenylacetyl <0.1 D-2-Q-pyridine-l-oxide-4-carboxamidino/propion-35 amido)-2-phenylacetyl 3.12 D-2-(3-/2-thienylcarboxamidino/propionamido)-2- phenylacetyl <0.1 D-2-(2-/3-(N-£-chlorobenzylgu anyl)ureido/acetamido) -2-phenylacetyl 0.39 - 333 - 40532 TAHI.I-: I I (con t i nucil) I MIC. (|iy/ml) vs.

K Strep, pyogenes I)-2-(2-/3-(N-/cyclohexyImethy1 /yuany L)ureido/-5 acetamido)-2-phenylacetyl 0.2 D-2-(2-/3-(N-/4-pyridyImethy1/guanyl)ureido/acetamido) -2-phenylacetyl 0.004 D-2-(2-/3-(guany1)ureido/acetamido)—2—(4— hydroxyphenyl)acetyl 0.004 lO D-2- (3-/2-phenylacetyi^/ureido) -2- phenylacetyl <0.1 D-2-(3-/benzyloxyearbony1/ureido)-2- phenylacetyl 0.004 D-2 - (3-/acety l/tli ioureido) -2-pheny lacetyl 3 .2 |r> D-2- (3-/3-methyl-5-isoxazolylcarbonyl/ureido)- 2-phcnylacetyl <0.1 D-2-(2-/4-bromophonyl^acetamido)-2-phenylacetyl O.2 0-2-(2-/4 -methoxypheny1/acotami do)-2-phony1auoLy1 O.l D-2-(4-pyridinecarboxamido)-2-phenylacety1 3.12 Uo D-2-(2-/4-ni trophenyl/acetamido) -2-phenylacetyl <0.1 D-2-(2-/2-furyl/acetamido)-2-phenylacetyl <0.1 D-2-(4-nitrobenzamido)-2-phenylacetyl 0.004 D-2-(2-phenoxyacetamido)-2-phenylacetyl 0.004 D-2-(2-cyanoacetamido)-2-phenylacetyl 0.004 ;>r> D-2-(2-azidoacctamido)-2-phenylacetyl 0.2 D-2-(2-/3-(guanyl)ureido/acetamido)-2-(4- hydroxyphenyl)acetyl 0.004 D-2-(3-/guanyl/uro ido)-2-(4-hydroxypheny1)acety1 O.OD4 D-2 - ( 2-/3-l>pn'/.oy I uroi do/acet .mi i d< >) - 2- phony I act ■ I y I • (). I l,) D-2- ( 2-/3-mot hanosu I fony I uro i ilo/aoot.iiii i ) phenylacetyl 0.2 D-2-(3-/3-ethy 1thioureido/propionamido)-2- O.39 phenylacetyl D-2-(3-/3-phenylthioureido/propionamido)-2-•»>■) phenylacetyl 1.56 D-2-(3-/3-methylureido/propionamido)-2- phenylacetyl <0.1 D-2-(3-/3-phenylureido/propionamido)-2- phenylacetyl <0.1 - 334 - 40532 tami.i-: i i i MIC (pg/ml) vs.

D-2-nmino-2-(£-methoxypheny1)acetyl <0.1 5 2-nminoacetyl 200 D-2-amino-3-(3-indolyl)propionyI 6.25 D-2-nmino-2-(3-thienyl)acetyl <0.1 2-(2-/4-pyridylthio/acetamido) -2-phenylacetyl 100 d-2-(methanesulfonamido)-2-phenylacetyl 1.56 IO D-2-(propanesulfonamido)-2-phenylacetyl 0.78 D-2-(£-chlorobenzenesulfonamido)-2-phenylacetyl 1.56 D-2-(£-nitrobenzenesulfonamido)-2-phenylacetyl 1.56 D-2-(a-toiuenesulfonamido)-2-phenylacetyl 0. 39 D-2-(2-/3,5-dibromobenzamidino/acetamido)-2-phenyl- 15 acetyl 1.56 D-2-(2-/acetamido/acetamido) -2-phenylacetyl 1.56 2-(4-pyridinecarboxamido)-3-methylbutyryl 50 D-2-(2-/guanyl/acetamide)-2-phenylacetyl 12.5 D-2-(2-/A ^-imidazolin-2-y1/acetamido)-2-phenylacetyI 3.12 20 2-(3-/2-furoyl/thioureido)-2-phenylacetyl 0.78 2-(3-/£-toluenesulfonyi/-ureido)-2-phenylacetyl 6.25 L-2-hydroxy-2-phenylacetyl <0.1 D-2-hydroxy-2-phenylac/j*-yl <0.1 D-2-(2-/3imethylaminomethyleneaminq7acetamido)-2- 25 phenylacetyl 6.25 D-2-(acetamido)-2-phenylacetyl O. 78 D-2-(2-/2-pyrrolecarboxamidinq/acetamido)-2-phenyl- 50 acety i - 335 - 4 0 5 3 2 Minimum inhibitory concentrations of other compounds of this invention are presented in Table IV.

TAOLK IV MIC (iig/ml) vs.

^ Compouxul Strep, pyogenes 6-(5-oxo-4-pheny1-1-imidnzolidinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam 6.25 6-(5-oxo-4-/£-hydroxyphenyl/imidazolidinyl)-2, 2-dimethyl-3-(5-tetrazolyl)penam 6.2 5 lo 6-(2,2-dimethyl-5-oxo-4-phenyl-l-imidazoli- dinyl)-2,2-dimethyl-3-(5-tetrazolyl)penam 1.56* 6- (2, 2-dimethyl-5-oxo-4-/g-hydroxyphenyJ>/-l- imidazoIidinyl)-2,2-dimethy1-3-(5-tetrazolyl)- penam 0.78* 15 6-(/hexnhydro-l-nzepinylytacthylenenmino )-2,2- dimethyl-3-(5-tetrazolyl)penam 50 6- (/- (O-2-.imino-2-/jj-hydroxypheny l^acetamido) -2,2- dimethy1-3-(2-pivuloyloxymethy1tetrazol-5-yl) - penam O. 3<) *MIC against Staph. aureus - 3 if. - 40532 KXAMI'f.K CXCIV (»-Amino-2 ,2-d imethy 1-3- (l/2/-triphenyImethyItetrazol-5-yl) - penam To a stirred slurry of 240 mg. ofi 6-amino-2,2-dimethyl-5 3-(5-tetrazolyl)penam in 1.5 ml. of dry, ethanol-free chloroform, is added 0.36 ml of triethylamine. The mixture is stirred until a cloudy solution is obtained and then ca. 200 mg. of anhydrous sodium sulfate is added. Stirring is continued for a further 15 minutes and then the mixture is filtered. To the filtrate is IO added 278.5 mg. of triphenylmethyl chloride, and the reaction mixture is stored at ambient temperature for 4.5 hours. At this point, the solvent is removed by evaporation iji vacuo, leaving the crude title product as a mixture of isomers as indicated. The crude product is re-dissolved in a small volume 15 of chloroform and then adsorbed on a small column of silica gel. The column is eluted with chloroform and the first 20 ml. of eluate are collected and evaporated to dryness iri vacuo. A small volume of ether is added to the residue, and the mixture is again evaporated to dryness i_n vacuo. The latter residue is 20 washed with ether, to give 357.4 mg. (77% yield) of a white solid. The NMR spectrum (CDCl-j) shows absorptions at 7.15 ppm (broad singlet), 5.70 ppm (doublet), 5.35 (singlet), 4.55 (doublet), 1.60 (singlet) and 1.10 (singlet). - 337 - 40532 EXAMPLE CXCV Reaction of 6-amino-2 ,2 -•') lmethyl-3- (5-tetrazolyl)penam with a substituted triphonyImethyi chloride of formula (R"*)''-Cl, according to the procedure of Example CXCIV, affords in each case a mixture of the corresponding 6-amino-2,2-dimethyl -3-(l-/substituted triphenyImethyl7tetrazol-5-yl)penam and 6-amino-2,2-dimethy1-3-(2-/substituted triphenyImethy 1/tetra-zol-5-yl)penam compounds. In this way, the following mixtures are produced: CH anil CH N N 338 40532 (R5)'' d iphenyI(2~£luoropheny1)methyl diphenyl(3-chloropheny1)methyl diphenyl(4-bromophcnyl)methyl 5 diphenyl(2-ethylphenyl)methyl diphenyl(4-n-propyIphcny1)methy1 diphenyl(3-sec-butylphenyl)methyl diphenyl(4-ethoxyphenyl)methyl dipheny1biphenylylmethy1 IO phenyldi(3-tolylJmethyl phenyldi(3-chlorophenyl)methyl phenyl(4-chlorophenyl)(4-methoxyphenyl)methyl phenyldi(biphcnylyl) methyl tri(4-tolyl)methyl 15 (4-isopropylphenyi)di(3-methoxyphenyl)methyl The mixtures are separated into the two isomers by chromatography. - 339 - 40532 KXAHPIJi CXCVt b- (2-Phenoxy.icut-imlclo) -2,2-d Imothy 1-3-11/2/~ tr Iphcny Imothy I -tetrazol-5-yt)penam To .i Htlrr<> 40533 KxmPLK cxcvt h- l2-Phennxyacwt-yl)|> rciuvol by evaporation In vacuo. Thin iffonln the title rud(ja >un>t at a aiiiure of I ■ i — in as IS indicated.

In like Manner, acylatlon of &-d*lno-2,2-dinethy 1 - 1- (I -triphenylaethyItetrazol-S-yiIpenoa with prtenoxyacety1 chloride provides |2-|>*u.-noayacetu*i- , 2-d la>ithy l - I -„'U I 2-t r Ipheny Inethy I let r j;ul-->-y i) i*-rt.un with (rfu-nosyjcetyl chloride provide* b-(2-phenii)xy>u'etiiaitlu)>.>,i>t)taethyl>l-f.'-t r n-heny In*-thy I tetrazol -'»-y I ) pervao.

J4«> IO 40833 EXAMPLE CXCVII Acylatlon of the 6-*alno-2,2-d laethy1-3-(l-/subatituted trlpheny laethy 1/tetraxol-S-yl )pci\4a and 4-*ialno-2#2-dlaethyl-3-(2-/kubet1tuted trlphenylaethyl/tetrasot-S-yl)pena» alxturta of Kuaplo CXCV with pheaosyacetyl chloride, according to tho procedure of Buaplt CXCVl, provides, la each case, alaturea of the corresponding t-t 2-phenoxyacetamido)-2, 2-d laethy I-3- (I'-Zkubatltuted tr Ipheny laethy l/tetrazol-S-y Dpenam aad »-|2-P*»eneayecctas»ido)-2#2-dlaethyl-3-«2-/subetltuted tr1phenyl-aethyj/tctraxol-S-y Dpenaa ccspwuids. la thia way, the follow-log alstures aro produced.

CM, c^H^ocUjCom r / o )t-f |BS»•* jik! Cll, C(ns0CU2C0MH. r /■ \ e^n. 1—' \rV* - 141 - 40533 i»-ny I (/-f lu»r»>i>hony I )a«>lhy I d1phony1(J-ch loropheny Dae thy 1 d1pheny1(4-brnaophcny1)aethy1 * diphenyl|2-ethylphenyl)aethy1 diphenyl(4-n-propyIphenyllaethyl diphenyl(1-eec-butylphenyllaethy1 diphenyl (4-ethoxyphenyDaethyt d1pheny1btpheny1ylaethy1 lo phenyldi t l-tolyIlaethyl phenyldi (J-chlr»rop«*enyD*«thy I I'hunyl |4-chlortipht*nyl ) 14 -»•( ikiiy|itu'ny I )s»«-ihy I |ihcnyltli (lii|ihcny ty I liwthy I trl(4-totyl|nethyi 1*> 14 - losipropy lpfta-ny I )dl ( )<«ethokyphenyUa.-thyl - I4w» 40533 example cxcviii k-(2-Phnnniyacot.isi(lo) -2,2-d laethy 1 - J-(5-totrazolyl )penaa To a ntlrrcd solution of 1.17 g. of 6-(2-phenoxyace-iaaldo)-2,2-dlauthyl-)-( l/V-tr tphenylaethyltotrasol-S-yl) -*> pvnoa In 20 al. of acetone is .uklcd l.O al of water followed by 50 ay. of g-toluenesulfonic acid aonohydrato. The alxture la stirred at oatotent teaperature for one hour, and then the solvent la reaove*! by evaporation In vacuo. To the realdue Is added V) al. of water and SO al. of ethyl acetate. Tho pM Is IO adjusted to 7.0, the layers are separated* and the ethyl acetate la discarded. Fresh ethyl acetate Is added to the resuming aqueous phase, and the pM is adjusted to 2.O. The ethyl acetate layer is reaoved, washed wil'i water, and dried usiiuj .inhytlruu& &'>11 u» -sulfate. Evaporation of the solvent In v.K"uo IS leaves the crude title product. - j41 - 40533 EXAMPLE CIC Mhcn cach of th* 6-(2-phcnoxyacetaaido)-2,2-dincthyl'-)-(I-/substituted triph*nylaothyl/t«tr«xol-S-yDporvaa and 6-(2-phennxyaccta»i«lo)-2#2-dincthyl-3-(2-/Wuhatitutsd trlphenyl-'» Mthyiytetr.ixol-S-yDpen.MB Mixtures, solectrtl fraa those In towepl» CXCVl I, .ire (ub)ect«l to the reaction conditions of IfrMple CXCVl 11, the product in each esse Is 2- (ph«noxyac«tM-|ilo)-2,2-diMethyt-)-(S-tetrasolyt)pen4n. 144 4 0 5 3 2 KXAMPij; »:c h- (Tr ipfw-ny lM»*thy l.mino) -2, 2-dl»?th*/l- I- (l/V*plvj loy loxy- aethyitetraxol -S-yl )poiuiai To 4 stirred solution of 9)2 Mg. of 6-(trIpheny1-S Methyla»lno)-2,2-dtaothy l-)-^-tetraxolyl)ponaa and o.2i ail. of trlathylMlne in IO «l. of diaothyiforaoalde, at 0°C. la added JOl mq. of chloroaisthyl plvalate. The cooling bath la rwovad after IS Minutes and th* reaction Mixture is stirred at tWtoicnt tuatmratuf for 2 hours. At this point tho solvent lo is rcsPveU by evaporation under liiqh vacuu* and to the residue Is irtrlsfl water and ethyl acetate. The pit Is adjusted to 7.0 and tho water u removed and discarded. The ethyl acetate Is washed with water, dried usiiMf anhydrous todlus sulfate and evaporated to dryncs* in vacuo. This at lord* the title product IS as a Mixture of jauacra 4S indicated. The individual laaawra can be obtained by chraautcwjr-»|>hy.

- US - KXAMl'U: tX'l '•-Anlnirit, /•<) tat.-i.tiy 1 - J- (l/^/-pi v.i loypxyaicthy I tet r.i/ol -5-y 1) - pcnuai The title product ii propared as its £-toluenoaulfonate salt, by tro.itln9 6-(triphcnytanthylaaino)-2,2-di•ethyl-)-ll/V',*^»lv.llny••*yl.•-tr.l*ol-^-y» with g-toluc-ncaul fonw in .iii-ii>n>a| •• o>r«li(V| (•• iIm- •»! k«' XX. - 146 - 40533 PREPARATION /-( l-/irHuthii*yl« n*i«ii To 14.iO g. of the above product in 175 m1. of sthanol, at -7S°C., is JiUed 11 Ml. of liquid ammonia. The cooling bath lo is then removed, and the reaction mixture is stirred overnight. Tbe solvent is removed by evaporatioo ,in vacuo, leaving an oil, which solidifies on trituration with hexane. After drying* the *olld Me|()hs 1?..' «|. •»«*! hu* M.p. SS-8s°C.

The latter solid is stirred xith Ux> ■1. of 4N hydro-IS chloric acid overnight, to effect hydrolysis. The product filtered off and dried giving 11.OS g.( m.p. 2U-21S°C.

This latter product is stirred with S.20 9. of phosphorus pentachloride tn 12S Ml. of Methylene chloride overnight, and then the solid which is out of solution is filtered off. It is 20 re-suspended tn i2S m1 . of Methylene chloride, S.20 g. of phosphorus pentachlorlde is added, and it is again stirred overnight. The solid is again filtered off, giving S.22 g. of 2-()-/g-methoxybenzimtdoyl/ureidolacetyl chloride hydrochloride, m.p. 14fc-l->2°c. IR spectrum (Nujol Mull): 1790 cm'1. 25 In like manner, ethyl benzimidate is converted into 2-(3- /fcenzusidoy(/ureido)acetyI chloride hydrochloride.

Ethyl 2=»£=chloropheRyI)JcetiMidate is converted into 2-(J-/2-<£-chloropheny1)acetiMiUoyl/ureido)acetyt etiloride hydro- U7 - 10533 chlorido usliwj tho abovo proo.-Uuro, oxcopt th.it the hydrolysis step Is carrtul out usinq IN tuMltum hydroxide and dlaethoxy-ethuno (3x1), followed by acidification with 4N hydrochloric .tcid. - 348 - 40898

Claims (3)

1. CLAIMS t 1. A paixk derivative of fenuUi or tho salts thsrsof t wtenln 1^ ii u ulno or substituted amino group, which substituted isiao group Is R*-KH-. or fcj " 5"~ or (R^)'NH* or is a precursor for a tetrazolyl group which it -C - H - C* or -C - MH - c • • Ual o and R2 or R* is hydrogen, trialkylsilyl having frra one to four carbon a*cas xn each of said alkyl group*;, alkanoyloxymethyl having fron three to eight carbon at cos, 1-(alkanoyloxy)ethyl hav:n? froa four to nine carbon atoms, phthalidyl or a tetrazolylpenaa nitrogen protecting group removable froa spocific corpound of said formula; - 349 - 40832 Ual is CI or Drs is An acyl group of an organic carboxylic acids lo an osiino protecting groins oc hereirtosfore defined thianyl, fury!, pyridyl, thiazolyl, isothiazolyi, tetraeolyl, tfianlyl, imidazolyl, pyrazolyl, substituted phenyl, substituted thimyl, substituted furyl, substituted pyridyl, substituted thiasolyl, substituted isothiazolyi, substituted triavolyl, *ul>s .ituted IsiJaiolyl or substituted pyrazolyl, turlt zubatl lutu) i»>ioty being substituted by u)> to two r»f fluoro, cbloto, brosio. hydroxy, alkyl having froa one to six carbon atnuc, alkoxy having fro* on* to six carton atoms and alkytthio having frun one to six carbon atonsi carton atons, or taken together vith tho nitro-jon atom t«» which they are attached fots a pyrroli«uno. norpUol ino. ptf*i tdlfu > or i»i icyclohept.i.i t*yl «jto«;-, ar.«! C it a tel • .1 zolyl peiuutt nitrogen protectirm group or a «jrou|» ruadily convertible to a tetrazolyl penja protecting group and providing that when Hy is a precursor for a tetrazolyl group My Bust be fK*)'-KH-.

2. A penaat derivative according to claim 1. vheroi.\ is .

3 A penast derivative accordinc to clain 1, wherein - 3"So - 40833 to eight cur boa atoaa, 1-(alkanoyloxy) othyl having froa four to nine caxboa atons or phthalidyl. 4* A penaa derivative according to olaia 1, wherein ** *• ^>« - CH - »-and l' or lJ la hydrogen, olkanoyloxyaethyl having frca throe to eight carboo ateas. I-(alkanoyloxy)ethyl having frca four to nine carbon a toss or phthalidyl. 5. A penaa derivative according to elala 1, vheroln IO R, ie amino. 6. A penaa derivative according to elaia 2. wherein R* i» hytlicwjen. trialkylailyl having ttorn one to four carbon atoae, in each of said alkyl groups, alkanoyloxyaethyl having froa three to eight caebmt atoaa. 1-(alkanoyloxy)ethyl IS froa four to niv; carbon atrma. phthalidyl or am! K? is hydro«jen. trialJty\zi lyl having froa one to four carbon •"tui: in cach of k.u0 alkyl >«-. , 1 - (alkanoyl a::y) e thy I 1' 20 Kavliyj ;«'«.» ;rat to ;iinC C.ilgliS'i", p-ht'iai iuy I » ~C!' ■-'! "Q*!f i -r.o-,-R,4« - JSl - 40832 io IS 20 or whcroSn and arc each selected fro* th* group consisting of hydrogon, fluoro, chloro, broao, alkyl having froa one to four carbon atom, alkoxy having froa cno to four carbon io t io » s«lcct«d froa nitro. fluoro. chloro. broao, alkyl having froi.. ono to four carbon atoas and alkoxy having fro-w one to four carbon atom; R* and R*7 arc cach hydrr*;en, hydroxy, nitro, fluoro, <*bluro, broao. irnVn, alkyl having froa ono to six carbon atou, alkoxy having from on* to six carbon atom*, alkanoyloxy having froa two to seven carbon atoaa. fornyloxy. alkoxyaethoxy having from two to seven carbon atoms, phenyl or bonnyloxy: and R*® is hyarrKjen, alkyl having from one to foui carbon or phenyl. 7. A ilcriv-.ti/c jccoi'vliiiq to cither of claimr. 2 or 6. wherein is vhi rtin .1^ is 7 n— ll I c I 0 - 352 - 40533 whoroin n is 0 or lj R7 is hydroqon, alkyl having froa ono to twlvo carbon atoms, alkanyl having froa two to twelve carbon atoms, cycloalkyl having froa threa to seven carbon atoma, cycloalkenyl having fro* five to eight carbon atoms, cyclo-heptatrlenyl, 1,4-cyclohexadienyl, 1-aainocycloalkyl having from four to seven carbon atoms, cyanomethyl, S-aothyl-3-phenyl-4-iscxasolyl, 3- (o-chlorophenyl) -4-isoxa- solyl, 5-»ethyl-3-(2.4-dichlorophenyl)-4-isoxazoiyi, S-»othy1-3- (2-chloro-C-f luorophenyl)-4-isoxazolyl, J-alkoxy-l-naphthyl having from one to four carbon atoms in said alkoxy, phenyl. phtnosy, ptesnylthio, pyridylthio. benzyl, sydnonyl. thianyl, furyl, pyridyl. thiazolyl. ftaothiasolyl, pyrimidinyl, tatraiolyl, triazolyl. imida-xolyl, pyrazolyl. substituted phenyl, substituted phenoxy, substituted phenyltKio, substituted benzyl. substituted thienyl, substituted furyl, substituted pyridyl. substituted tetrazolyl, sub::i'.uted thiazolyl. substituted Isothiazolyi. substituted pyrimidinyl. substituted tii-acolyl, substituted imidazolyl and substituted pyrazolyl. each substituted aoiety beinq substituted by up to two ■embers selected from tho group consisting of fluoro, chloro, broao, hydroxy, hydroxymethyl. amino, M.N-Jialk/l-amlno having from one to four carbon atoms in each of said alkyl groups, alkyl having from one to four carbon atoos. aminoaethyl. aminoethyl, alkoxy having froa one to four carbon ato-ns, slkylthio having fro» one *o four r^rbon atoms, 2-iBiiioeihoxy or K-alkylomino having frost or.c to four carbon atossi and 0 is hydrogen, alkyl having from one to six JSl - 40538 carbon atoms, hydroxy, asldo. carboxy. sulfo. carbamoyl, phenoxycarbonyl. indanyloxycarbonyl. sulfoaaino, asinoaathyl. aaino or MH- (CO-CHj-IOD^-CXJ-Xi wherein S is alkyl having froa on* to six carbon •tost, phnyl. sobstitatad phony i. furyl, tlii any 1. pyridyl, pyrrolyl, aalno, V-alkyl-amlno having from onm to six carbon atoas. anilino, sobstitatad anilino, guaaidiao. seylaaiao having fvosi two to sovsn carbon atoss, bansaaido. substituted btniuldo. thlophenecarboxaaido. furancarboxaaido, pyridinacarboxaaido. aainoa«thyl. guanidlnosMthyl. alkano-cerboxaaldosMthyl having (tea threa to sight carbon a toss, bensaaidfnoswthyl. (substituted b«nsaaidino)aethyl, thio-phenecarboxa**'dinoaethyl, furjens n is I; R7 is phenyl, sydnonyl, thienyl. I* furyl. pyridyl. thiazolyl. isothiazolyi. pyrinidinyl. tetrazol yl. tri azolyl. iaidaxolyl. pyrazolyl. said substituted phenyl, said substituted triazolyl. said substituted thienyl, n.tid substituted furyl. said substituted pyridyl. said substituted thiazolyl, said substituted isothiasolyl, said substituted 20 pyrinidinyl. said substituted tetrazolyl. said substituted iaidazolyl or said substituted pyrazolyl; and 0 is amino. 14. K penaa derivative according to claim 7. wheroin or R5 is hydrogen; n is 1; R7 is phenyl, said substituted phenyl or thienyl; and 0 is amino. 25 15. a pcnan derivative according to claim 14, wherein r' is phenyl. 1C. A ponan derivative iccordinq to claim 14. wherein R7 is 4-hy-Ji oj.y-j,hi-»!yl. 17. A iVriv.itivo accoitli:i-i to claim 14. wlu-j. iu is 3-dtlortj--t-l:yJroxyp!u-:iyl. - 35r> - 40533 18. A penaa derivative* according to claia 7, vhtroin 2 \ 7 R or * lii hydro«jcn; n ir. li R is phonyl, said nubatitutcd phenyl or ihltmyli and o i«- Mii-CCO-cilj-NH)^-CO-*, wherein 1 is Miaowthyl. 19. A penaa derivativo according to clala 7, who re in R3 or is hydroqeni n it li R7 is phenyl, said substituted phenyl or thienylt and 0 is Mil-(CO-CUj-KHJ^-CO-I, wherein S is guanidino. 20. A penaa derivative according to olaia 19, wherein a is 1 and l' is 4-hydroayphenyi. 21. A penaa derivative according to claia 7, wherein R* or l' in hydrogen; n is It R* is phenyl, said substituted phenyl or thienyl; and 0 is tftl-tCO-CUj-Nlll^-CO-*, wherein m is 0 and Z i v pyritlinocjrbo*cj*i(iino«ethyI or pyrrolocarfcox-untdtaaaeth'/l. 22. A penaa derivative according to clala 21. wh»rain R7 i» 4-hydr^xyvhenyl or.J s i'. 4-pyridinecarboxaaudinoaethy 1. 23. A penaa derivative according to claia 21. wherein R7 is 4-hydro*yj»fienyl ind Z is 2-pyrmlecarboxaaidlnoaethyl. 24. A penaa derivative according to claia 5, wherein n2 or R* is ►^dr«ser>. 25. A penaa derivative according to claia 5, wherein R* or R* l» trialkylrilyl having frca one to four carbon atom#, alkanoyloxy*?!thy 1 havi.uj from three to eight carbon atoms, 1-(alkanoyl .'xylethyl h--vm»j frca four to nine carbon atoti:, phthalidyl -tnU - 356 - 4059a wherein P**, and ft** irt each hydroqen, fluoro, chloro. brow, alkyl hawtnq froa on* to four carbon atou, alkoxy having froa one to four carbon a tons or phenyl. 24. A penam derivative according to claia S, of the (orwla wherein II2 is -CC-CM-O-R14, -SO^-R14 or (R*)'i viwrcin is alkyl having froa one to four IO carbon atnex. benzyl, phenyl or phenyl substituted by up to two aoietic* selccteJ froa nitro, fluoro. chloro, brooo. alkyl havinq froa one to four carbon atoas and alkoxy havinq froa one to four carbon atoeta: and (3®)s is selectcc! froa the qroup consisting of - 35? - 40833 IO IS wterela M* and >n each Mlaetad txmi hydrogen, hydroxy, nitro, fluoro, chloro, bromo, lodo# Alkyl btvlag froa on* to •lx carbon mtommf alkoxy having froa om to ill carbon aUM. alkanoyloxy having froa two to aavan carbon atou« forayloxy. alkoxyaathoxy having froa two to aavan carbon ttcaa, phanyl and baasyloxyt l" ia hydrogen, alkyl having froa ooa to four carbon atom or phenyl: R« and V** are each aelacted froa hydrogen and ■ethyli and X ia oxygen or sulfur. 27. A pena* derivative according to claia 2%, wherein ** ia m4r. 2t. A penaa derivative according to claia 1 of forvula (rV-I or tho aalts thereofi wherein (R*)' ia ar d»ino protecting group; and Ry I • R* Nr3 CI 0 wherein R2 or is hydrogen, trialkylsilyl having froa one to four carbon atoms in each of said alkyl groups: alkanoyl- - 358 - 40B31 oxyanxhyl having froa thro# to tight carbon atoaii 1-(alkan-(tyloiy)etliyl having froa four to nine carbon atoas, phthal-idyl or a tetrasolylpenaa nitrogen protecting group removable froa said cwyound of Mid formulai and 0' is a tetrasolylpenaa nitrogen protecting group or s group which is readily convertible to s tetrasolylpenaa nitrogen protecting group. 29. A penaa derivative according to elaia 21. wherein (I®)' is trialkylsilyl having froa one to four carbon atone in each of said alkyl groups or wharein I . ft** and ft2* are each hydrogen, fluoro, chloro. broao, alkyl having froa one to four carbon atoms, alkoxy having froa one to four atoms or phenyl. 30. A pen-rn derivative according to either of claims 28 and 29, wherein By is -OM-G' or -C-NH G' • a ci o wherein R2 or C* is -CHjCIIjY, -C(-O)-O-R14. -S02-!>14 or (ft6)*, when in Y is cyano, alkoxycarbonyl having from two - 359 - 4003a to nevon carbon atone, phenoxycarbonyl, alkyIsulfonyl having frun ona to »it carbon a tons pltonylsulfonyl or wherein and It*' ara each solected froa tha group consisting of bydrog*n, alkyl having froa on* to four carbon atoas, bensyl or phenyl) 1^* Is alkyl having froa on* to six carbon atoM, bansyl, phenyl or phenyl eubstitutod by up to two solatia* •elected froa nitro. fluoro, chloro, broao. alkyl having froa one to four carbon atona or alkoxy having froa one to four carbon atoMi and*V ia ■s^-GC wherein and k*7 are each selected froa hydrogen, hydroxy, nitro, fluoro. chloro. bewo, lodo, alkyl having fron on* to aix carbon atone, alkoxy having from one to six carbon aton*. alkanoyloxy Ktvlng fron two to seven carbon atons, fornyloxy. alkujtynethoxy having fron two to seven carbon atona, phenyl and benxyloxy; I11 i. selected fron the group consisting of hydro gen, alkyl having froa one to four carbon atoas and phenylt and B2® are each selected hydrogen or nethylt and X is oxygen or sulfur. 31. A penaa derivative according to any of claims 28, 2» and 30, wherein I*5)' is triphenylaethy1. 32. A pcnan derivative according to any of claieis 26, 25, 30 and 31. wherein R* or C* ia the said |R°) "»». A derivative according to claia 28. wherein 360 - io 1% 40538 (I®) * la trialkylsilyl having froa om to four oarbon •teas in each of said alkyl groups; and IL ia rj vhsrein k2 or R* ia trialkylsilyl having froa ono to four eartoon atoas ia each of Mid alkyl groups* >4. A asthod of pro paring a penaa derivative of foraalei ^ or tho salts thereof; Ktenia is aaino or substituted aaino which substituted aaino qroup is I1- KB- or i^io or .12 nvp5* or (K ) '-Mll- -CH-N- Ry is a tetrasolyl group which ia X or o. :o or a precursor for a teti aolyl group which is -C-fi-C' or -C-KM-C' • m Hal 0 and R2 or »3 is hydrogen, trialkylsilyl having fron one to four carbon *toc*s in each of said alkyl groups, alkanoyloxy-sethyl having froa three to eight carbon atoas. I-(alkanoyloxy ) a thy 1 having froa four fo nine carbon atoms, phthalidyl or - 361 - 40533 a tetrasolylponaa nitrogen protecting group rawvabla froa a ifi««ific compound of said Consular ■al is CI or Bri IT1 is an acyl group of an organic carboxyllc acidi ) !**)• la an aaino protecting group for a specific compound of said foraula, •• la phenyl. 1,4-cyclohexadlenyl, 3-sydnonyl, thienyl, furyl. pyridyl* thlasolyl. lsothlasolyl, tetrasolyl. triasolyl, laidasolyl, pyrasolyl, substituted phenyl, sub-10 stltuted thlenyl. substituted furyl. substituted pyridyl. substituted thiasolyl, substituted lsothlssolyl. substituted triasolyl, substituted iaidasolyl or substituted pyretolyl. each substituted aoitty being substituted by up to two aea-bers selected fro* fluoro. chloro. broao. hydroxy, alkyl IS having froa one to lii carbon atoas, alkoxy having froa o..; to six caxbor atoas and alkylthio having fro* one to >ix carbon atiaai I® and 1^® are hyUroqon. nothyl or ethyl» 1^ and h** aro oaeh alkyl having froa one to six 20 carbon atoas. or taken together vith the nitrogen atoa to which they are attached are one of the group pyrrolidine, aorpholino, piporidino or *zacycloheptan-l-ylt and G' is a tetrazolyl penaa nitrogen protecting group or a group readily convertible to a tetrasolyl penaa nitro-2S gsa protecting group snd providing that when fty is a pre cursor for a tetrasolyl group, R,, mint bo wherein there is included in the synthesis of a coepound according to fOTRUlsS 3t Ofl& Of thfi StOpS* a) converting a -COOH group At 3-position of a precursor into a group By by one or more steps. -162 - 4093a (b) acylating an amino group at a 6-position of tho ponaa r.tructnro with an acylating agent in ono or aoro reaction steps to form a grouping for Hy of 39. A asthod according to claim 34, of preparing a penaa derivative of formula a*-. or a salt thereoft whore ia is hydrogen or aa amino protect lag group, and as is ;o - ^o., wherein X2 or I1 is hydrogen, trialkylallyl having from ono to four ccrbon atom in each of said alkyl groups, alkanoyl* oxymethyl having from threo to eight carbon atoms, l-(alk;noyl< oxy)ethyl having from four to nino carbon ateaa, phthalidyl or a tetr&xolylpenam nitrogen protecting group removable fx eta said ecxwfouiid of said formula) wherein there ia included a step of converting the COOH group of a ponam entachloride or phosgeno. in th»< pttt«tnce of at least about I aole of a tertiary amine, to produce the penaa derivativo with the -C(Cl) "W-G* group. 39. A He thod according to claia 36. wherein the punaa derivativo with the •CtCU-H-C' group is contacted with a 20 source of asida loo to produce a penaa derivativo of formula 40. A aethod according to claia 34, of nwiking a pcnan derivativo of forwula - 364 - IO I* 20 or a aolt thereof1 wherein It* la an acyl group of an organic carboxylio add* and It, ia X3 or whorein t* or 1® ia hydroocn, trialkylsilyl having froa ono to foor earben ateaa in each of aald alkyl groups. alkanoyl' oxyaethyl having froa threo to eight carbon ateaa* I-(alkanoyloxy jc thy 1 having froa four to nine carboo atoaa* phthalidyl and a tetrasolylpenaa nitrogen protecting group roaov-able froa s->id ceopound of said foraulai characterized in that it ineludoo the step oZ acylating a penaa derivative of foraula or a salt* or a silylated derivative thereof, with an organic acid acylating i^nt. 41. A actho.1 according to claim 40. wherein the amino group t>t the penaa derivative of the foreula —s.. is first eo.»vcstrtl into a (trialkylsilyl)aaino «jioup havinn froa one to four carbon atuas in each of said alkyl groups. - 365 40532 42. A p*nnm derivative According to claim I, substantially