CA1286661C - 2,6-disubstituted penem compounds - Google Patents

2,6-disubstituted penem compounds

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Publication number
CA1286661C
CA1286661C CA000342069A CA342069A CA1286661C CA 1286661 C CA1286661 C CA 1286661C CA 000342069 A CA000342069 A CA 000342069A CA 342069 A CA342069 A CA 342069A CA 1286661 C CA1286661 C CA 1286661C
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Prior art keywords
ethyl
solution
mmol
ether
penem
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French (fr)
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Marcel Menard
Alain Martel
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Bristol Myers Squibb Co
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Bristol Myers Co
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
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    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65611—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system (X = CH2, O, S, NH) optionally with an additional double bond and/or substituents, e.g. penicillins and analogs
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/50—Improvements relating to the production of bulk chemicals
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to 2-substituted and 2,6-disubstituted penem compounds of the formula

Description

The present invention relates to certain novel 2-substituted and 2,6-disubstituted penem compounds which possess potent antibiotic activity. ~lso provided are various novel intermediates useful in preparing the bio-logically active penem derivatives and various processes for the producton of the intermediates and active compounds.
The penem ring system has the formula ', ~S~

O 7 1 ~ 2 '`, and systematically can be designated as 7-oxo-4-thia-1-azabicyclo[3.2.0]hept-2-ene. For the sake of -1- ~
;

simplicity, it is named "2-penem" in the present application and the numbering system used is as follows:

-~ ~ S

0 4 ~ 3 There is thus provided by the present invention the novel penem compounds having the formula ~N /~

wherein Z is hydrogen or an easily removable ester protecting group; X is (a) a radical of the formula (i) ~ORa in which Ra is hydrogen;
(ii) -CORb in which Rb is hydrogen, hydroxy, optionally substituted (lower) alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the alkyl group being one or more (preferably 1 or 2) of halo, hydroxy, oxo, carboxy, carb(lower)alkoxy, carbamoyl, (lower)alkoxy, amino, (lower) alkylamino, di-_ (lower)alkylamino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic rings being one or more (preferably 1 or 2) of hydroxy, , .,~
.,,. ~

(lower)alkoxy, ha:lo, (lower) alkyl, halo(lower) alkyl, methanesulfonyl, oxo, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy (lower) alkyl, sulfo or sulfo(lower) alkyl; or (iii) -OCORC in which Rc is amino, (lower)-alkylamino, di(lower)alkylamino or optionally substituted (lower)alkyl in which the lo substituents are as defined under (ii); or (b) a substituted (lower)aliphatic, (lower)-cycloaliphatic or (lower)cycloaliphatic(lower)-aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic (lower)alkyl or heterocyclicthio(lower)alkyl radical, substituents for the above-mentioned aliphatic, cycloaliphatic, phenyl or heterocyclic -groups being NR
Il (i) -CNR2R3 or -N=C-NR2R3 in which Rl is Rl hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen, (lower)alkyl, phenyl or benzyl;
(ii) -ORd in which Rd is amino, (lower)alkylamino, di(lower)alkylamino, substituted (lower)alkyl, (lower)alkenyl or optionally ring-substituted phenyl, phenyl(lower)alkyl, _ heterocyclic or heterocyclic (lower)alkyl, the substituents . ., ."

36~
on the alkyl, phenyl and heterocyclic groups being as defined under (a) (ii);
(iii) -O(CH2)nORr in which n is an integer from 1 ~- to 6 and Rr is optionally substituted (lower)alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on ~ the alkyl, pheny:l or heterocyclic groups : being as defined under (a) (ii);
(iv) -OCORr' in which Rrl is amino, (lower)-alkylamino, di(lower)alkylamino or Rr,with the proviso that Rrl may not be unsubstituted (lower)alkyl;
(v) -OS03H;
. o (vi) -OP(OH)2;
(vii) -OS02Rr in which Rr is as defined under (b) ( i ii ) ;
O
(viii) -OP (ORe) (ORr) in which Re is (lower)alkyl and Rr is as defined under (b) (iii);
(ix) -S(O)nRd in which n is 0, 1 or 2 and Rd is as defined under (b)(ii) or is in the case where NR
n=O -C-NR5R6 in which R4 is hydrogen or (lower) alkyl and R5 and R6 are each independently hydrogen or (lower)alkyl, with the proviso that Rd may not be unsubstituted phenyl;
_(x) -CORf in which Rf is amino(lower) alkyl, (lower) alkylamino (lower)alkyl, di(lower)-alkylamino(lower) alkyl, -NHNH2, -NR17NR18, 666~
-NHR19~ -S-R17, ~0(CH2)n-A-Re or ~NReRg in which R17, R18 and Re are (lower)alkyl~ R19 ; is hydrogen or (lower)alkyl, A i5 O, S, NH or -- NCH3 and n and Rg are as defined under (b) (iii) and (b)(viii);
(xi) -PO(ORW)2 in which Rw i~ hydrogen or (lower)alkyl;
(xii) -NHRh in which Rh is optionally substituted ~ phenyl, optionally substituted heterocyclic, - 10 -CH=NH, -SO3H, -OH, (lower)alkoxy, amino, (lower) alkylamino, di(lower)alkylamino, -NHCOCH3, -CS2CH3~ -S02CH3' S2 ~

S S S
-SO2NH2, -CNH2, -CNHCH3, -C-NH

NH
-C-NR7R8 in which R7 and R8 are each independently (lower) alkyl, phenyl or NH NH
NH
phenyl(lower)alkyl, -C-Rg in which Rg is (lower)alkyl, phenyl or phenyl(lower)- alkyl, O
or -C-Ri in which Ri is amino(lower)- alkyl, -NH2, (lower)alkylamino, di(lower)-alkylamino, -NH ~ , -NH-C-R1o - in which R1o is (lower)alkyl or optionally substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being NH
defined under (a)(ii), -NH-C-NH2, (lower)alkoxy, ....

~6~

-OCH2 ~ , -OCH2 ~ NO2 or -o(CH2)2Si(CH3)3;
O
(xiii) -S-C-R11 in which R11 is (lower)alkyl substituted by amino, (lower) alkylamino or d~(lower) alkylamino;
(xiv) -NRjRk in which Rj is (lower)alkyl and Rk is (lower)alkyl, (lower) alkoxy, heterocyclic, O
amino, or -C-R1 in which Ri i8 a~ defined under (b)(xii) or, when taken together with the nitrogen, Rj and Rk represent o -N ~ , providing that ~ ~
when Rk is amino or -CH2CH2NH2, Rj is methyl and also providing that Rj and Rk may not both be (lower)alkyl;
(xv) -NRj'Rk' in which Rj' is (lower)alkoxy and Rk' is (lower) alkyl, heterocyclic, amino(lower) alkyl, (lower) alkylamino-(lower)alkyl, di(lower)alkylamino(lower)-O
; - alkyl or -C-Ri in which Ri i5 as defined under (b)(xii) or, when taken together with the nitrogen, Rj' and Rk' represent O

_ O
. -- 6 --. .
, , - ,1 .

., ., , ,, ,, ~' (xvi) -NRlRmRn in which Rl, Rm and Rn are each independently (lower)alkyl or when taken together with the nitrogen, represent -N~;

(xvii) -N=CHXRx in which Rx is (lower) alkyl or optionally ring-substituted phenyl or heterocyclic, the substituents on the phenyl or heterocyclic ring being as defined under (a)(ii);
(xviii) -N=CRXRy in which Ry is (lower) alkyl or optionally ring-substituted phenyl or heterocyclic, the phenyl and heterocyclic substituents being as defined under (a)(ii), .
and Rx is as defined under (b)(xvii);
(xix) =N-Rp in which Rp is hydroxy, (lower)alkoxy, amino, di(lower)alkylamino or 20 -NH ~ ; or - NOH
(xx) C (CH2)nNR15Rl6 in which n is an integer from 1 to 6 and R15 and Rl6 are each independently hydrogen or (lower)alkyl; and Y is hydrogen or a radical selected from the group consisting of (a) _optionally substituted (lower)aliphatic, (lower)cyclo-aliphatic or (lower) cycloaliphatic : (lower) aliphatic, the substituents being one or : more of hydroxy, (lower)alkoxy, optionally substituted phenyloxy, optionally substituted : heterocyclicoxy, optionally substituted (lower)alkylthio optionally substituted ~ phenylthio, optionally substituted :'~

~'~
.

:, .
:;

heterocyclicthio, mercapto, amino, : tlower)alkylamino, di(lower)alkylamlno, (lower)alkanoyloxy, (lower)alkanoylamlno, ~ptionally substituted phenyl, optionally substituted heterocycllc, carboxy, carb (lower)alkoxy, carbamoyl, N-(lower)alkylcarbamoyl, N,N-di(lower)alkylcarbamoyl, halo, cyano, oxo, thioxo, -SO3H, -OSO3H, -SO2-(lower)alkyl, O

(lower)alkylsulfinyl, nitro, phosphono or -OP
(ORe)(ORr) in which Re and Rr are as defined above the substituents on the (lower)alkylthio group being one or more of halo, hydroxy, (lower)alkoxy, ; 15 amino, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the phenyl or heterocyclic substituents above being one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo (lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl;
(b) -ORS in which Rs i8 optionally substituted (lower)alkyl or (lower) alkanoyl or optionally substituted phenyl or heterocyclic, the substituents on the alkyl and alkanoyl being one or more of halo, hydroxy, (lower)alkoxy, (lower)alkylamino, di (lower)alkylamino, amino, oxo, (lower)alkanoylamino or optionally substituted phenyl or heterocyclic and the substituents on the phenyl or heterocyclic being one or more of hydroxy, (lower)alkoxy halo, (lower) alkyl, halo (lower) alkyl, methanesulfonyl, (lower)alkylthio, (lower)alkylamino, di(lower)alkylamino, amino, : (lower)alkanoylamino, (lower) alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl;

' ',: .''-:, l,~f~
(c) S(O)nRs in which n is o, 1 or 2 and Rs is as defined above;
(d) halo; and (e) _optionally substituted phenyl or heterocyclic in which the substituents are one or more of hydroxy, (lower)alkoxy, halo, (lower)alkyl, halo (lower)alkyl, methanesulfonyl, (lower)alkylthio, amino, (lower)alkylamino, di(lower)alkylamino, (lower)alkanoylamino, (lower)alkanoyloxy, carboxy, carboxy(lower)alkyl, sulfo or sulfo(lower)alkyl; or a pharmaceutically acceptable salt thereof, with the proviso that when Y is hydrogen, X may not be -CH20CH2CH20CH3.
The compounds of formula I wherein Z is hydrogen (and their pharmaceutically acceptable salts and physiologically hydrolyzed esters) are potent antibacterial agents. The remaining compounds are useful intermediates for preparation of the biologically active penems.
Substituent groups disclosed above for the 2- and 6-positions of the penem ring may be further defined as follows:
(a) Halo includes chlorine, bromine, fluorine and iodine. Preferred halo substituents are chlorine and fluorine;
(b) (Lower)alkyl includes both straight and branched chain saturated aliphatic hydrocarbon radicals having from 1-6 carbon atoms inclusive, e.g.
methyl, ethyl, n-propyl, isopropyl, n-butyl, _isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, etc. Preferred (lower)alkyl substituents have from 1-4 carbons and most preferably 1-2 carbons;

~' _ g _ .. ~, ,A_, ' ' ~' (c) (Lower)aliphatic is intended to include acyclic straight and branched chain saturated and -unsaturated hydocarbon radicals having from 1-6 carbon atoms inclusive. The unsaturated radicals may contain one or more double or triple bonds, but preferably contain either one double bond or one triple bond. Examples of (lower) aliphatic are methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, isobutyl, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl and 2-propenyl. The most preferred aliphatic radicals are (lower)alkyl as ln (b);
(d) (Lower)cycloaliphatic is intended to represent alicyclic saturated and unsaturated hydrocarbon radicals having from 3-8 ring carbon atoms, preferably 3-6 carbon atoms. The unsaturated ring may contain one or more (preferably one) double bond. Examples of this group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl, 1,3-cyclohexadienyl and cyclohexienyl (e) (Lower)cycloaliphatic (lower)aliphatic represents cycloaliphatic-aliphatic radicals having 3-8 carbon atoms (preferably 3-6) in the cyclo-aliphatic ring and 1-6 carbon atoms (preferably 1-4 and most preferably 1-2) in the aliphatic , ~,i,~.', ;
,~

~6f~
portion. Examples include cyclopropylmenthyl, cyclopropylethyl, cyclopropylpentyl, cyclo-butylethyl, cyclopentylmethyl, cyclohexylmethyl, _cyclopropenylmethyl, cyclopentenylethyl, cyclopropylethenyl, cyclopropylethynyl, etc. The most preferred radicals of this type are cycloalkyl-alkyl in which the cycloalkyl portion contains 3-6 carbons and the alkyl portion contains 1-2 carbons;
(f) (Lower)alkoxy includes Cl-C6 alkoxy radicals, the alkyl portion of which being defined as in (b).
Examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-pentyloxy, etc. Preferred are Cl-C4 alkoxy and most preferred are Cl-C2 alkoxy;
(g) (Lower)alkylthio includes Cl-C6 alkylthio radicals in which the alkyl portion is as defined under (b). Examples include methylthio, ethylthio and n-butylthio;
(h) (Lower)alkylamino includes Cl-C6 alkylamino radicals in which the alkyl portion is as under (b). Examples are methylamino, ethylamino, n-propylamino and n-butylamino;
(i) Di(lower)alkylamino represents di Cl-C6 alkylamino in which each alkyl is as defined under (b).
Examples are dimethylamino and diethylamino;

(j) (Lower)alkanoyloxy represents radicals of the O
_formula (lower)alkyl-C'-O- in which alkyl is as defined under (b);
(k) (Lower)alkanoylamino includes radicals of the O
formula (lower)alkyl-C-NH- in which alkyl is as under (b);
o (l) Carb(lower)alkoxy represents -C-(lower)alkoxy in which (lower)alkoxy is as under (f);
(m) Halo(lower)alkyl represents alkyl radicals in which one or more hydrogen atoms are replaced by a halogen atom;
(n) Sulfo(lower)alkyl represents - (CH2)nSO3H in which n is 1-6;
(o) Carboxy(lower)alkyl represents - (CH2)nCOOH in which n is 1-6;
(p) Phenyl (lower)alkyl represents -(CH2) in which n is 1-6;
(q) (Lower)alkylamino(lower)alkyl represents -(CH2)nNH-(lower)alkyl in which n is 1-6 and alkyl is as defined under (b);
(r) Di(lower)alkylamino(lower)alkyl represents ~ (lower)alkyl - (CH2)nN in which n is 1-6 ~ (lower) alkyl _ ~ 30 and each alkyl is as defined under (b);
o (s) (Lower)alkanoyl represents (lower)alkyl-C-in which alkyl is as under (b);
(t) N-(Lower)alkylcarbamoyl represents O
(lower)alkyl-HN-C- in which alkyl is as under (b);

.
..... .

; l~f~~l (u) N,N-Di(lower)carbamoyl represents (lower)alkyl O
N-C- in which each alkyl is llower)alkYl as under (b);
(v) Amlno(lower)alkyl represents -(CH2)nNH2 in which n is 1-6;
(w) Hydroxyamino (lower)alkyl represents - (CH2)nNHOH
in which n is 1-6;
o (x) (Lower)alkylsulfinyl represents -S- (lower)alkyl in which (lower)alkyl is as defined above under (b); and (y) (lower)alkenyl represents straight or branched unsaturated aliphatic hydrocarbon radicals con-taining one double bond and having from 2-6 carbon -atoms inclusive, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl.
The term "heterocyclic" as used herein is intended to include heteromonocyclic and heterobicyclic residues of aromatic character as well as appropriate partially or wholly saturated residues, said heterocyclic residues con-taining at least one heteroatom selected from oxygen, sulfur and nitrogen and being bonded to the penem ring carbon atom via a ring carbon atom. The preferred heterocyclic groups are either S- or 6-membered monocyclic radicals or fused 6,6 or 5,6 bicyclic radicals. Illustrative of suitable heterocyclic radicals are the following:

[~ ~;~ ~L N

~.
, ~, 12f~6~

¢~H ~ ~r~

~N ~ ~N~

~ N ~ N
H H
N _N
N ~ N_N

Nl N-1~ N I 11 ~NI
~N ~1 ~ S ~!J J~ O ~N N `S ~ ~N

~N ~ N ~N ~,N-a n d 12~6~

Similarly, the terms heterocyclic-(lower) alkyl, heterocyclic-thio-(lower)alkyl, heterocyalicoxy and heterocyclic-thio represent - (CH2)n-Heterocyclic, (CH2)n-S-Heterocyclic, -O-Heterocyclic and -S-Heterocyclic, respectively, in which n is 1-6 (preferably 1 or 2).

Since an asymmetric carbon atom is present in the 2-substituted compounds of formula I, such compounds may exist either in the form of racemic mixtures (R, S form) or as the individual dextrorotatory and levorotatory (R- and S- forms) optical isomers. Preferred are the compounds in which the configuration of the 5-carbon atom corresponds to that of natural penicillin (5R-configuration). Sub-stituents at the 5- and 6- positions of the 2,6-disubstituted penems may be in the cis or trans position in relation to one another. Where the penem 6-substituent contains an asymmetric carbon atom, the resulting isomers are identified herein as isomers A, B, C and D (see Example 58 for stereochemistry). The preferred isomer in compounds of this type is isomer B.
Separation of the various optical and geometric isomers may be carried out by conventional separation and resolution procedures well-known to those skilled in the art.
The present invention is intended to include the compounds o-f formula I in the form of isomer mixtures and also in the form of the individual separated and resolved isomers.
The pharmaceutically acceptable salts referred to above include the nontoxic carboxylic acid salts, e.g.
nontoxic metallic salts such as sodium, potassium, calcium, aluminum and magnesium, the ammonium B alt and salts with nontoxic amines such as trialkylamines (triethylamine), ,, . ,~1 ~, ,,d~

procaine, dibenzylamine, N-benzyl-~-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, N-alkylpiperidine and other amines which have been used to form salt~ of penicillins and cephalosporins. When a basic group is present, the present invention also includes the pharmaceutically acceptable acid addition salts, e.g. salts with mineral acids such as hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric or with suitable organic carboxylic acids or sulfonic acids such as trifluoroacetic, p-toluenesulfonic, maleic, acetic, citric, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic and malic. Compounds containing an acid group and a basic group can also be in the form of inner salts, i.e. a zwitterion.
Preparation of the above-described salts may be carried out according to conventional procedures for forming salts of ~-lactam antibiotics such as penicillins and cephalosporins.
The term "easily removable ester protecting group'' is one which has acquired a definite meaning within the ~-lactam and peptide art. Many such groups are known which are used to protect the carboxyl group during subsequent chemical reactions and which may later be removed by standard methods to give the free carboxylic acid. Known ester protecting groups include 2,2,2-trichloroethyl, tertiary alkyl of from 4-6 carbon atoms, tertiary alkenyl of from 5-7 carbon atoms, tertiary alkynyl of from 5-7 carbon atoms, alkoxymethyl, alkanoylmethyl of from 2-7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydry~, trityl, trimethylsilyl, triethylsilyl, ~-trimethylsilylethyl, and the like.

~36~;~

Choice of an ester protecting group is dependent on the subsequent reaction conditions the group must withstand and the condi~ions desired for removing it. Selection of a suitable group is well within the ability of one skilled in the art. For use as a chemical intermediate the most pre-ferred ester is the p-nitrobenzyl ester which can be readily removed by catalytic hydrogenation. For preparation of compounds containing functional groups reducible under such removal conditions, a preferred alternative is the ~-trimethylsilylethyl ester removable by treatment with fluoride ions. Also included within the scope of easily removable ester protecting groups are physiologically cleavable esters, i.e. those esters known in the penicillin and cephalosporin art to be easily cleaved within the body to the parent acid. Examples of such physiologically cleavable esters include indanyl, phthalidyl, t methoxymethyl, glycyloxymethyl, phenylglycyloxymethyl, thienylglycyloxymethyl or acyloxymethyl of the formula in which Y' is Cl-C4 alkyl or phenyl. Particularly pre-ferred esters of this type are methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl.
It will be appreciated that the compounds of formula I may exist in various states of solvation and the anhydrous as well as solvated (including hydrates) forms are intended ~o be within the scope of the invention.

Ik ~,, ~36~61 With respect to the compounds of formula I, the preferred compounds are those wherein Y is hydrogen or tlower)alkyl optionally substituted (preferably at the ~-carbon) by hydroxy. More preferred compounds within the above group are those wherein Y is hydroxy, ethyl or ~-hydroxyethyl. Still more preferred compounds of formula I are those wherein Y is hydrogen or ~-hydroxyethyl.
The most preferred compounds are those wherein Y is ~-hydroxyethyl.
A preferred embodiment of the present invention consists of the compounds of formula I wherein substituent X is a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl radical, the substituents for the above-named aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenyl-alkyl, heterocyclic, heterocyclic-alkyl and heterocyclicthio-alkyl radicals being NRl CNR2R3 or 1 2 3 Rl Rl is hydrogen, (lower)alkyl or phenyl and R2 and R3 are each independently hydrogen~ (lower)alkyl, phenyl or benzyl.
Within this class, the preferred compounds are those wherein Y is hydrogen, ethyl or ~-hydroxyethyl, especially those wherein Y is hydrogen or ~-hydroxyethyl and most especially those wherein Y is ~-hydroxyethyl.

12~6~61 Another preferred embodiment of the present invention consists of the compounds of formula I wherein X is a substituted (lower)aliphatic, (lower)cycloaliphatic or (lower)cycloaliphatic(lower)aliphatic radical or a ring-substituted phenyl, phenyl(lower)alkyl, heterocyclic, heterocyclic(lower)alkyl or heterocyclicthio(lower)alkyl radical, the substituents on the above-mentioned aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenyl-alkyl, heterocyclic, heterocyclic-alkyl or heterocyclicthio-alkyl radicals being -CORf in which Rf is amino(lower)alkyl, (lower)alkylamino(lower)-alkyl, di(lower)alkylamino(lower)alkyl, -NHNH2, -NR17NR18, -NHOR19, -SR17, -O(CH2)n-A-R or ~NReRg in which R17, R18, Re and Rg are (lower)alkyl, Rlg is hydrogen or (lower)alkyl, A is O, S, NH or NCH3 and n is an integer from 1 to 6.
Within this class, the preferred compounds are those wherein Y is hydrogen, ethyl or ~-hydroxyethyl, especially those wherein Y is hydrogen or ~-hydroxyethyl and most especially those wherein Y is ~-hydroxyethyl.
Still another preferred embodiment of the present invention consists of the compounds of formula I wherein X is (a) -(CH2)n~ ~ in which n is an an integer from 1 to 6, preferably 1 to 4;
(b) -(CH2)nNHOH in which n is an integer from 1 to 6, preferably 1 to 4;

--Iq--~ 2~36~6~

(c) -(CH2)nPO(O-Cl-C6 alkyl)2 in which n is an integer from 1 to 6, preferably 1 to 4 and alkyl is prefe:rably methyl, ethyl or iso-propyl; NH
Il ~ (d) -(CH2)nNH-C in which n is an : Cl-C6 alkyl integer from 1 to 6, preferably 1 to 4, and alkyl is preferably methyl or ethyl;

( ) ( 2)n \ in which n is an integer from 1 to 6, preferably 1 to 4;
O
(f) -(CH2)nOC(CH2)mNRARB in which n and m are each independently 1 or 2 and RA and RB
are each independently hydrogen or (lower)-alkyl; or (g) -(CH2)nNHCI-Rc in which n is an integer of NH
1 to 6, preferably 1 to 4, and Rc is Cl-C4 alkyl (preferably methyl or ethyl), phenyl or ~ .
(CH2)m ~ n which m is 1 or 2.

Within this class of compounds, the preferred members are those wherein Y is hydrogen, ethyl or ~-hydroxyethyl, preferably those wherein Y is hydrogen or ~-hydroxyethyl and most preferably those wherein Y is ~-hydroxyethyl.

,: , ' ' .

12~fi~

Other preferred embodiments of the present invention include the intermediates of the formulae:

(A) ~ _ C2R"
III
wherein Y is hydrogen or as defined above in regard to compounds of formula I, Q is phenyl or (lower)alkyl, R"
is an easily removable ester protecting group, X is 1 or 2 and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I) when x is l;

(B) Y ~ SHgCOOCH3 N ~ P(Q)3 CO2R" IIIa in which Y, Q and R" are as defined above under (A); and (C) y ~-T

N ~ P(Q)3 C2R "
IV

wherein Y is as defined above in regard to compounds of formula I, Q is phenyl or (lower)alkyl,-R" is an easily lX~36~

removable ester protecting group and T is C H O

-C-C6H5 or -C-X wherein X is as defined above in regard to compounds of formula I.
In the intermediates of formulae III, IIIa and IV, Q is preferably phenyl, R" is preferably p-nitrobenzyl and X and Y are preferably those substituent groups mentioned as being preferred in connection with the compounds of formula I. ReactiVe functional groups such as mercapto, amino and hydroxy in substituents Y and X may be protected by conventional blocking- groups during con-version of the intermediates to biologically active end-products.
Compound I may be prepared by one ox more of the reaction routes discussed below. The various synthetic routes may be divided into three main processes depending on the stage of incorporation of the 6-substituent, i.e. Y. Thus, in Process I, the 6-substituent is incor-porated in the basic starting material; Process II involves incorporation of Y at the end of the synthesis and in Process III substituent Y is incorporated in mid-synthesis.
Each of the three main processes in turn can vary in the procedure for incorporating the desired 2-substituent, i.e, X. In general, it is preferred to incorporate substituent Y in mid-synthesis and to incorporate substituent X by acylation of mercaptide intermediate III or IIIa shown below since these procedures have been found to be the most generally useful.
The steps of Process I may be seen from the following scheme: ~

1~6~6~

Process I (Variation 1): Early incorporation of 2-substituent O

Y-CH=CH-OAc CSI ~ ~ ~OAc XC-SNa >
N pH 7.5 O ~ H

O O
Y~SII-X ~ Y~,SC-X
,~ CHO ¦ SOC12 N~H 2R O ~ N ~ OH

C02R"

O
Y~SC-X p0 Y~ SIl_X
~ Cl base N ~ P03 C02R" C2R"

de-protect ~N

O
Ac = CH3C-0 = C 6H5 -6~

Process I (Variation 2): Late incorporation of 2-substituent ~ OAc CH3e-SNa Y-CH=C~-OAc CSI > ~ N~ H pH 7.5 Y ~ SAc ~ Y ~ SAc N~ C2R" ON ~ OH

Y ~ SAc P03 ~ ~ SAc MA
N ~ Cl base N ~ P03 base C2R" C2R"
, _ _ Y~ SM ~ SC-X

N~P03 C2R" C2R"

~ de-protect X-C- ~ = acylating agent MA = heavy metal salt 1~366~L

:; Process I (Variation 3): Late incorporation of 2-substituent Y ~ ~OAc 03CSNa Y-CH=CH-OAc CSI > ~ N~ pH 7.5 O H

CHO ~ sc03 SOC12 N~ 2 O N ~ OH

C2R"
3 ~ ~ SC03 MA
N ~ Cl base o ~ N ~ P03 base C2R" C2R"
o SM ~ I ~ Y ~ SC-X

, ,~N ~P 0 3 C2R" C2R"

de-protect CO R" o -~5--1~6~
In Process I a vinyl ester (Y = H or a radical as defined in connection with compounds I) containing the desired 6-substituent is converted to the optionally l-substituted 4-acetoxy-2-azetidinone by a cycloaddition reaction with chloro sulfonyl isocyanate (CSI) followed by reduction with an organic reducing agent such as sodium sulfite. The CSI reaction is conveniently carried out in an inert organic solvent such as diethyl ether at a temperature of OC or below. The reduction step may be conducted in an aqueous or aqueous-organic reaction mixture at a temperature of 0 or below and at a slightly basic pH.
Following formation of the 4-acetoxy-2-azetidinone, Process I may be separated into three different paths. In one route (Variation 1), the O
azetidinone is reacted with a thiolic acid X-C-SH wherein X
is as defined in connection with compounds I, or a salt thereof, in a suitable solvent (e.g. aqueous or aqueous organic). Displacement of the acetoxy group results in incorporation of the desired 2-substituent in the azetidinone at this stage. The displacement reaction is ; preferably carried out at room temperature or below and at a slightly basic pH ( ~7.5). When Y ~ H, cis and trans isomers of the resulting azetidinone are preferably separated (e.g.
by chromatography) at this point in the process. Variations 2 and 3 depicted above convert the 4-acetoxy-2-azetidinone into the 4-acethylthio-2-azetidinone and 4-tritylthio-2-azetidinone products, respectively, by nucleophic dis-placement~with thioacetic acid or triphenylmethyl mercaptan (or a salt thereof such as the sodium salt), respectively.

,j.....
~, ~2~36~

The 4-thio azetidinone iB next reacted with a o glyoxylate ester HC-CO2R" wherein R~' i6 an easily removable ester protecting group such as p-nitrobenzyl or trimethyl-silylethyl, or a reactive oxo derivative thereof such as ahydrate, in an inert organic solvent (e.g. benzene, toluene, xylene, and the like) and preferably at an elevated temperature (e.g. 50C. up to most preferably reflux temperature). When a hydrate of the ester is employed, resulting water may be removed azeotropically or with molecular sieves. The hydroxy ester product is formed as a mixture of epimers which can be optionally purified as by chromatography or used directly in the next step.
Conversion of the hydroxy ester to the corresponding chloro ester is achieved by reaction with a chlorinating re-agent (e.g. SOC12, POCl3, PC15, and the like) in an inert :
organic solvent (e.g. tetrahydrofuran, diethyl ether, methylene chloride, dioxane, and the like) in the presence or absence of a base, preferably an aliphatic tertiary amine (e.g. triethylamine) or a heterocyclic tertiary amine (e.g. pyridine or collidine). The reaction is advantageously run at from about -10C. to room temperature.
Chloro ester product is obtained as a mixture of epimers which can optionally be purified before use in the next step.
The phosphorane intermediate may be obtained by reaction of the chloro ester with a suitable phosphine (preferably triphenylphosphine or a tri(lower)alkyl phosphine such as triethylphosphine or tri-n-butyl phosphine) ,~., 1~366~
in an inert organic solvent such as dlmethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (e.g. hexa~e, cyclohexane, benze;ne, toluene, and the like) in the presence of a base, preferably an organlc tertlary amine such as triethylamine, pyridine or 2,6-lutidine. The reaction is advantageously carried out at temperatures from room temperature to the reflux temperature of the solvent system.
At this stage the process again diverges into two routes. In Variation I (where the 2-substituent has already been incorporated), the phosphorane intermediate is converted to the desired penem by thermally cyclizing in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent system. Most conveniently, the cyclization is carried out under reflux conditions. Suitable inert organic solvents t include aliphatic, cycloaliphatic or aromatic hydrocarbons (e.g. benzene, toluene, hexane, cyclohexane), halogenated hydrocarbons (e.g. methylene chloride, chloroform, carbon tetrachloride), ethers (diethyl ether, dioxane, tetrahydrofuran, dimethoxyethane), carboxylic acid amides (e.g. dimethylformamide), di C1-C6 alkylsulfoxides (e.g.
dimethylsulfoxide) or a Cl-C6 alkanol (e.g. methanol, ethanol, t-butanol), or a mixture thereof.
In variations 2 and 3 the phosphorane is converted to a heavy metal mercaptide of the formula ~ 2~36661 ~S- _ q~

C2R ~ X
III
or /sHgcoocH3 n N ~P ( Q ) 3 C2R "
IIIa wherein Q is preferably phenyl or (lower)alkyl, x is 1 or 2 and M is Cu(II), Pb(II) or Hg(II) when x is 2 or Ag(I) when x is 1. Mercaptide formation is accomplished by reaction of the phosphorane with a salt of Hg(II), Pb(II), Cu(II) or Ag(I) or with (methoxycarbonyl)mercury(II) acetate in a methanol-containing solvent and ln the presence of an organic or inorganic base such as aniline, pyridine, collidine, 2,6-lutidine, an alkali metal carbonate, and the like. A p~eferred base is pyridine. The reaction may be carried out at room temperature or, if desired, with moderate cooling or heating. The anion (A) of the heavy metal salt may be any anion which gives a soluble salt in the selected solvent, e.g. N03 , CH3C00 , BF4 , F , C104 , N02-, CN0-, etc. The mercaptide intermediate is then reacted with an acylating agent capable of introducing the moiety X-C- wherein X is the desired penem ~6~;6~

2-substit~ent. The acylating agent (X-C-O) may be the acid O
X-C-OH or a reactive functional derivative thereof such as an acid halide (preferably acid chloride), acid azide, acid anhydride, mixed acid anhydride, active ester, active thioester, etc. Acylation is conducted in an inert solvent (e.g. a halogenated hydrocarbon such as methylene chloride or an ether such as dioxane, tetrahydrofuran or diethyl ether) and, when an acid derivative is used, in the presence of an acid acceptor such as a tri(lower)alkylamine (e.g. triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine. When the free acid is employed, the acylation is conducted in the presence of a suitable condensing agent, for example a carbodiimide such as N,N'-dicyclohexylcarbodiimide. Acylation of the mercaptide can be achieved over a wide temperature range, but is preferably carried out from about -20 to +25C.
Following acylation, the resulting phosphorane is cyclized as described above to give the desired penem ester.
Formation of the phosphorane via the mercaptide intermediate (Variations 2 and 3) has been found to result in product of much better purity than that obtained by the more conventional route of Variation 1.
Once the carboxyl-protected penem is formed, the protecting group may be removed by conventional deblocking procedure~ (e.g. hydrolysis, hydrogenation or photolysis) to give the de-blocked penem. Removal of the p-nitrobenzyl ester, for example, may be achieved by catalytic hydrogenation in the presence of a noble metal catalyst such as palladium or rhodium, including derivatives thereof such as oxides, hydroxides or halides, said catalyst being optionally supported on a conventional carrier such as carbon or diatomaceous earth. A non-reducible aqueous or non-aqueous inert solvent such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane is used. Hydrogenation may be conducted at atmospheric or elevated pressure and is conveniently run at room temperature for a period of from about 1-5 hours depending on the solvent and catalyst used. If an equi--valent weight of a base such as an alkali metal or alkaline earth metal hydroxide or an amine is employed during the hydrogenation, the product may be recovered in the form of a carboxylic acid salt. Removal of the ~-trimethylsilyl-ethyl ester, another useful protecting group, is conveniently achieved by treatment with a source of fluoride ions. Other ester protecting groups can be similarly removed by methods well-known to those skilled in the art.
In a second main process (Process II), the reaction sequence is as shown below:

~6'.i6~

Process II (Variation 1): Early incorporation of 2-substituent o ~OAc XC-SNa CH2=CH-OAc CSI ~ ~ pH 7.5 O O
Il 11 SC-X ~ ~SC-X >
CHO ¦ SOC12 N~ C2R" O - N ~ OH

~rSC-X ' p0 ~S ll_X ,~

N ~ Cl base N ~ P03 C2R" C2R"

~N ~ bas > ~ f ~ .X
C 2 C2R"

Y~S
de-protect ~ N ~ X

CO

-3~-12~6G6~
.

~ Process Il (Variation 2): Late incorporation of 2-substituent .

CH2=cH-oAc CSI > ~ ~ pH 7.5 >
O H

~ SAc CHO ~ SAc SOC12 O ~H C2R o N ~ OH

SAc ~ ~ ~ p03 base C2R" C 2 SM ~ ~ SC-X
N ~ P03 ~

C2R" C2R"

.

~N ~ base > ~ ~ X

C2Rn o C2R"

~ S
- de-protect ~ ~
o co2 ~ Z ~3~

Process II (~Jariation 3): Late incorporation of 2-substituent OAc03CSNa CH2-CH-OAc CSI~ ~ N~ pH 7.5 O H

SC03 CHO ~ SC03 SOC12 N~ CO2R" ~

C2R"

SC0~ ~ ~ ~ p03 base N ~ P03 ~ 5C-X

C2R" C2R"

~ base ~ cO2XR"

de-protect ~ N

co2 .

-3't-~2~366~L

As can be seen Process II is substantially the same as Process I (except that Y must be H) up through the thermal cyclization step which produces the 2-substituted penem. A 6-substituent, however, if desired, is now in-corporated at this stage by reaction of the 2-penem with a suitable electrophile in an inert solvent (e.g. tetrahydro-furan, diethyl ether, dimethoxyethane, and the like) and in the presence of a strong base. In this procedure the 2-penem can be reacted in the form of the free acid (obtained by de-blocking as described above) in the presence of about two equivalents of base or, alternatively, a suitable 2-penem ester may be used in the presence of about one equi-valent of base. Any ester inert to anion chemistry (the reaction involves anion formation with base followed by reaction of the electrophile with the penem anion) may be employed, e.g. (lower)alkyl such as methyl, ethyl, n-propyl or t-butyl, phenyl, trichloroethyl, methoxymethyl, silyl such as trimethylsilyl or t-butyldimethylsilyl, and the like. Penem esters having activated methylene groups such as p-nitrobenzyl are not suitable and, if the 2-penem ester is of this type, it must be first de-blocked and either used as the free acid or converted to a suitable ester. The particular base used is not critical and the usual strong bases such as sodium hydride, phenyl lithium or butyl lithium are suitable. Most preferably, however, a lithium disilylamide or a lithium dialkylamide such as lithium di-cyclohexylamide (LDCA), lithium diethylamide, lithium di-methylamide or lithium di-isopropylamide (LDA) is used.

The electrophile is selected so as to generate the desired Y-substituent upon reaction with the anion and may be, for example, a halogen (e.g. Br2, I2), an alkyl halide (e.g. CH3I) or a similar halide such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenyl-(lower)alkyl, heterocyclic, heterocyclic-thio, heterocyclic-thio-(lower)alkyl, or heterocyclic-(lower)alkyl, halide, a tosylate or mesylate (e.g.

3 2 2 ~ CH3, CH3CH2S2CH3~ ~ SO2 ~ SO2 0CH2CH2CH20SO2CH3, etc.), an epoxide (e.g. ~ ), an S
episulfide (e.g. ~ ), an aldehyde (e.g. CH3CHO, C6H5CH2CHO), ~o a ketone (e.g. CH3COCH3, ~ ) or an ester (e.g.

CH3CH2COOCH3 or C6H5COOCH3). Representative examples of other suitable electrophiles are shown below:

CH2=CH-CH2Br 1~` 1 Br CH3CCH=CH2 ; ~ Br Br CH3CH-CH3 Q

o Cl 0CH2Br HCHO 0C-CCH2Br 0~o CH2SCH2Cl 36~

0CH=CHCHO 0 ~

CH3CCH2C1 ~ ~ C-CH Cl.

A most preferred electrophile is acetaldehyde which gives rise to the hydroxyethyl 6-substituent. Introduction of the 6-substituent by this process is preferably carried out with cooling (e.g. -80 to OC.) according to the general procedure described in Canadian Journal of Chemistry, 50(19), 3196-3201 (1972).
After formation of the desired 2,6-penem, any ester protecting group may be removed as discussed above to give the de-protected product.
The third main reaction process (Process III) can be understood from the following scheme:

Process III (Variations 1 and 2):

sc03 sc03 H O N~

Y ~ Y~SC03 base N~B

de-protect / \ MA/base -3~--~ ~6~61 ~SC03~f M
N~ N\B

~ C~oH20R " ~ X- C ~

~Sc03 ~SC-X
o N~_OH ~N

\ / SOC12 / de-protect o~Cl ~ SC-X

C2R"

~,~ b0se f~o \ / CO 2 R "

P03 Y~5~:X

C02R"
C2R"
~/base ,¦ SOC12 -3~-lZr~66~;1 ~_~ , SM S C - X

o~ ~Z 03 ~N~_ Cl CO R"
2 C2R"
O
\ / X-C- ~3 ~ base 03~ ~r ~ p03 C2R" C2R"

Y

~X Yo~N ~x C2R " CO 2R "

~ de-protect~ de-protect Y
.X

CO ~ O

_ _ .
B = blocking group for ring nitrogen ~f3~661 The 4-tritylthio-2-azetidinone of Process III
is formed as described in Process II (Variation 3). The ring nitrogen of the azetidinone is then protected by a conventional easily removable blocking group such as triorganosilyl (e.g. trimethylsilyl or t-butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, and the like. Introduction of the desired Y-substituent at the l-position of the azetidinone is then achieved by reaction of an appropriate electrophile with the N-protected azetidinone in the presence of a strong base (reaction con-ditions as described above in connection with Process II).
At this point the process diverges into two routes depending on the time of de-blocking the azetidinone.

In one route the N-protected intermediate is de-blocked by conventional procedures (e,g. acid hydrolysis) and then converted to the 2,6-penem via ester formation, chlorination of the hydroxy ester, conversion of the chloro ester to a phosphorane, conversion of the phosphorane to a heavy metal mercaptide, acylation of the mercaptide with X-C- ~ , thermal cyclization of the resulting phosphorane to give the 2,6-penem ester and removal of the carboxyl-protecting group. Reaction conditions for these steps are as disclosed in connection with Process II (Variation 3).
An alternative route involves the steps of converting the N-protected azetidinone to a heavy metal mercaptide, acylating the mercaptide with the moiety X-C- ~9 , removing the N-protecting group, reacting the ~S~~

12~

de-protected azetidinone with the glyoxylate ester, chlorinating, reacting the chloro ester with the phosphine to give the phosphorane, cyclizing the phosphorane to give the penem ester and removing the carboxyl-protecting group to give the 2,6-penem. Reaction conditions for these steps are as disclosed previously.
In preparing the 2-penem or 2,6-penem compounds according to the above processes, free functional groups in substituents X or Y which do not participate in the reaction may be temporarily protected in a manner which is itself known, such as free amino groups by acylation, tritylation or silylation, free hydroxyl groups, for example, by etherification or esterification, mercapto groups by esteri-fication, and free carboxyl or sulfo groups, for example, by esterification, including silylation, After the reaction has taken place, these groups can, if desired, be liberated, individually or jointly, in a manner which is itself known.
Additionally, it is possible in compounds of formula I to functionally modify the 2- and/or 2,6-substituents during or at the conclusion of the reaction procedures according to known processes to obtain other substituents included within the scope of the present invention. Thus, for example, carbonyl groups can be re-duced to alcohol groups, unsaturated aliphatic groups can be halogenated, amino groups can be alkylated or acylated, nitro groups can be converted to hydroxyamino and amino groups, hydroxyl groups can be etherified or esterified, etc.
The penem free acid compounds may be converted to pharmaceutically acceptable salts thereof or to easily 12~ 6~

removable esters thereof (particularly physiologically cleavable esters). Salts may be formed by reaction of the free acid with a stoichiometric amount of a suitable non-toxic acid or base in an inert solvent followed by recovery of the desired salt as by lyophilization or precipitation.
Esters (in particular physiologically cleavable esters) may be prepared in an analogous manner to preparation of the corresponding esters of penicillins and cephalosporins.
Resulting mixtures of isomers can be separated into the individual isomers according to known methods. Mixtures of diastereomeric isomers, for example, can be separated by fractional crystallization, adsorption chromatography (column or thin-layer) or other suitable separation methods.
Resulting racemates can be resolved into the antipodes in the customary manner, for example by forming a mixture of diastereomeric salts with optically active salt-forming reagents, separating the diasteromeric salts and converting the salts into the free compounds, or by fractional crystal-lization from optically active solvents.

Accordingly, the present invention also provides for a process for the preparation of the compounds of formula I which comprises cycli~ing a compound of the formula y S--C -X

N ~ P(Q)3 C2R"

1~66~1 wherein Q is phenyl or (lower~alkyl, Rll is an easily remo~able ester group and X and Y are as defined above in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent removing by methods known per se the removable e~ter group and,optionally, other protecting groups; and, if Y is hydrogen and when desired, converting the product to any other desired product where Y is not hydrogen by treating said product with a corresponding electrophile in an inert solvent in the presence of a strong base.
The present invention also comprises those em-bodiments according to which--compounds used as intermediate products are used as starting materials and the remaining process steps are carried out with these, or the process is discontinued at any stage, Furthermore, starting materials can be used in the form of derivatives or can be formed during the reaciton.
The free acid penem compounds provided by the present invention and pharmaceutically acceptable salts .;, -~13-and physiologically cleavable esters of said acids have been found to be potent broad-spectrum antibacterial agents useful in the treatment of infectious diseases in animals, including man, caused by both Gram-negative and Gram-positive organisms. The compounds are also of value as nutritional supplements in animal feeds and as agents for the treatment of mastitis in cattle.
The 2-penem acids (and physiologically cleavable esters and pharmaceutically acceptable salts thereof) pro-vided according to the present invention (i.e. compounds of general formula I wherein Y = H) possess antibacterial activity per se and are also useful intermediates (preferably in their carboxyl-protected form) for preparing the 2,6-disubstituted penems I via anion formation and reaction with an electrophile.

The active compounds provided by the present in~
vention may be formulated as pharmaceutical compositions comprising, in addition to the active ingredient, a pharma-ceutically acceptable carrier or diluent, The compounds may be administered both orally and parenterally. The pharmaceutical preparations may be in solid form such as capsules, tablets or dragees, or in liquid form such as solutions, suspensions or emulsions. In the treatment of bacterial infections in man, the active compounds of this ~r~66~;~

invention may be administered orally or parenterally in an amount of from about 5 to 200 mg./kg./day and preferably about 5 to 20 mg./kg./day in divided dosage, e.g. three or four times a day. They are administered in dosage units containing, for example, 125, 250 or 500 mg. of active in-gredient with suitable physiologically acceptable carriers or diluents.
The present invention also provides a method of combatting bacterial infections in animals, particularly warm-blooded animals, which comprises administering an acid of formula I or a physiologically cleavable ester thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to an infected host in an amount sufficient to com~at such infection, Illustrative examples of the preparation of starting materials and end-products of the present invention follow. All temperatures are in degrees Centigrade. For the sake of convenience, certain abbreviations are employed in the examples, Definitions of the less obvious of these abbreviations are as follows:
CSI chloro sulfonyl isocyanate pet. ether petroleum ether b.p. boiling point n,m.r. nuclear magnetic resonance h hour ether diethyl ether (unless otherwise indicated) ~t5 ~2~36~61 Celite Trademark of Johns-Manville Products Corporation for diatomaceous earth psi pounds per square inch r.t. room temperature PNB p-nitrobenzyl m.p. melting point LAH lithium aluminum hydride n-BuLi n-butyl lithium MIBK met~yl isobutyl ketone Et C2H5-Tr C( 6 5)3 Me CH3-THF tetrahydrofuran Ph phenyl DMF dimethylformamide TEA triethylamine PNBG p-nitrobenzylglyoxylate THP tetrahydropyranyl TFA trifluoroacetic acid HMPT (or HMPA) hexamethylphosphorus triamide EtOAc ethyl acetate DMSO dimethylsulfoxide Ac CH3CO-Ms CH3SO2-DMAP 4-dimethylaminopyridine Py pyridine LDA lithium diisopropyl amide q6-3fi661 EXAMPLE ~

2'-(2'-Die~hyl~hos~hQno-~'-ethyl)~enem-3-carboxyl1c Acid -~S ~ 1l (CH2)2P-(oEt)2 Ol O
(EtO)2-P-(cH2)2co2cH3 ~ (EtO)2P-(cH2)2co2H

o O
Il 11 (EtO)2P-(CH2)2COC1 ) (Eto)2-p-cH2)2cosH

A mixture of 1 (11.2 g, 50 mmoles) and 5N NaOH (10 ml) was stirred and cooled (ice-bath) for 15 min and at room temperature for 15 min. The mixture was extracted with ether and the extract discarded. The aqueous solution was acidified with 5N HCl and extracted wht CH2Cl2 to give after drying and evaporation of ~olvent 10.0 g (95%) of oil 2, nmr ~ (CDC13), 4.1 (4H, m), 1. 8 - 2. 9 (4H, m) 1. 2 (6H, t).
~ o a cooled (ice-bath) solution of ~ (2.26 g, 10.76 mmoles) was added dropwlse oxalyl chloride (2.74 g, 1.88 ml, 21.5 ~moles). ~he mixture was kept at room temperature for 6 h and then it was ~2~3666~

evaporated to d~ness. The traces of (COCl)2 were removed azeo-tropically with benzene to give 2.4 g (quantitative yield~ of c-ude 3.IP. v C 1800; 1735 cm . n~r ~ 4.3 (4H, m!, 3.0 - '-7 (2H, m) 2.0 - 3.0 (2H, m), 1.4 (6H, m). This was treated with H2S/TEA in a standard procedure to glve 1.9 g (80~.) of oil 4 estimated to be 80% pure. Nmr: ~ 4.1 (4H, q), 2.7 - 3.5 (2H, m), 1.7 - 2.5 ~2H, m) 1.33 (6H, t).

(EtO)2~-(c~2)2cs ~ (CH3)2~(OE )2 ~ O
NH 4 o~ N

To 4 (1.9 g, 8.4 mmoles) was added under N2 lM
solution of NaHCO3 (10 ml), followed by addition of 5 (0.813 g, 6.3 mmoles) in H2O ~3 ml). The pH of the mixture W2S adjusted to 7-8 by adding more NaHCO3. After standing for 4 h the mixture was extracted with CHC13 to give after drying and con-centration 1.05g (56.4~ based on 5) of solid 6, m.p. 64-67, nmr ~ 7.7 (NH), 5.3 (lH q), 4.2 (4H,) 3.8 (lH q) 3.5 (lH, q), 2.6-3.2 (2H, m) 1.7-2.4 (2H, m), 1.3 (6H,) (CH2)2~(OEt)2 S (cH2)2-P-(OEt)2 NH ~

A mixture of 6(260 mg, 0.88 mmole) and p-nitrobenzyl glyoxalate (198 mg, 0.88 mmole) was refluxed in benzene (6 ml) under a Dean Stark apparatus for 16 h to give after eva~oration of benzene 453 mg of heavy oil 7, nmr ~ 8.3 (2H, d) 7.6 (2H, d) 5.3-5.7 (4H,) 4.9 (OH), 4.2 (4H,) 3.55 (lH g), 3.4 (lH, gj, 2.5-3.2 (2H, m) 1.7-2.5 (2H, m) 1.3 (6H) 5 ~ (CH2)2~O~t)2 ~ 5 ~ (CH2)2 -(~t~2 ~N ~ H O N ~ Cl o PNB

A crude 7 (504 mg, 0.88 mmole) was dissolved in LM
solution of pyridine in THF (0.9 ml). To this was added dropwise with stirring and cooling (ice-bath) lM solution of SOC12 in THF (0.9 ml) and the mixture was stirred in the cold for 15 min and at room temperature for 40 min. To it was added benzene (10 ml), and the solid was filtered off. The filtrate was concentrated in vacuo to give 463 mg (quantitative yield) of crude 8, r~r ~ 8.3 (2H, d), 7.6 (2H, d), 6.1 (lH, s), 5.7 (lH, m), 5.3 (2H, d), 4.2 (4H), 1.8-3.6 (6H, m) 1.3 (6H).

(CH2)2~-(OEt)2 5 ~ (CH2)2-P-(OEt)2 N ~ 1 ~

~119-~36~

To a solution of crude 8 (463 mg, 0.88 mmole) in THP (4 ml) was added triphenylphosplline (236 mg, 0.9 mmole) and 2,6 lutidine (96 mg, 0.9 mmole) and the mixture was al-lowed to stand at room temperature for 65 h. Then it was fil-tered, the filtrate concentrated and the resiclual oil chromato-graphed on a silica gel column with ethyl acetate-296 EtOH as eluent, to give 203 mg (30.6%) of oil 9, which solidified on standing, m.p. 126-128C.

F~s ~ (CH2)2$(OE-)2 ~~(CH2)2P(OEt)2 CO PNB

A solution of 9 (470 my, 0.635 mmole) in toluene (30 ml) was refluxed for 5 h followed by concentration and chromatography on silica gel-ethyl acetate to give 167 mg (569~) of 10 as oil, IR 1795, 1710 cm nmr 0 8,3 (2H, d) 7.7 (2H, d) 5.7 (lH, m), 5.38 ~2H, d) 4.1 (4H) 1.8-3.8 (6H, 1.35 (6H).

(CH ) -~-(OEt) ~N-- ~ 2 ~ 2 ~366f~;3L

To a solution of 10 (59 mg, 0.126 mmole) in THF (3 ml) and ether (1 ml) was added NaHC03 (9 mg, 0.107 mmole), water (1 ml) and 10% pd.celite (60 mg) and the mixture hydrogenated at 30 psi for 2 h. The product was isolated as usual to give 36 mg (86%) of 11 as oil, IR (CHc13) 179g, 1730, 171~ cm~l, nmr ~ 9.0 (CO2H), 5.6 (lH, m) 4.4 (4H), 3.6 (lH, q), 3.15 (lH, q) 1.7-3.0 (4H, m), 1.3 (6H).

..~

i6~1 ~Q~
6-Acetoxymethyl-2-methyl~e~m-3-C~ Q~ a9ia ~cO ~ ~ CH3 N 4~

. _ .. .. _ Preparation of 1,3-diacetoxypropene (Ref. L.W. McTeer U.S. 2,866,813. CA 53 9063) Ac20 CH2=CH-CHO ---~AcOCH2CH=CH-OAc + CH2=CH-CH(OAc)2 Preparation of catalyst: A solution of boric acid (6.2 g) and oxalic acid (12.6 g) in water (44 ml) was evaporated to dryness to give the solid catalyst.
Procedure: Acrolein (140 g; 2.5 mol) was mixed with acetlc anhydride (256 g, 2.5 mol) at r.t. A 5 ml portion of this mixture was transferred to a one-liter Erlenmeyer flask and treated with a few drops of catalyst, prepared by dissolving 1.0 g of solid catalyst in 5 ml acetic anhydride. A vigorous exothermic reaction set in ~ - .

~6~i1 and the reaction mixture was kept at a temperature of 40 -60 (controlled by cooling with ice-bath), and the rest of the acroleinacetic anhydride mixture wa~ introduced into the flask in portions of 10 to 15 ml followed by a few drops of catalyst. The resulting mixture was distilled to remove unreacted starting material B followed by 1,l-diacetoxy-propene. The product 51.6 g (13.06%) was obtained next, b.p. 54 - 57C/ 1.2 mm. NMR: ~ (ppm, CDC13) 7.4 (H, d, J = 12), 5.3 - 5.8 (H, m), 4.5 (2H, d, J = 7) 2.16 (3H, s), 2.05 (3H, s). IR: vc=O 1770, 1750, vc=O 1680.

CS~ OAc ~ OAc AcOCH2CH=CH-OAc ) AcO ~ AcO ~ NH
~ NH
1 0 2a 2b PROCEDURE:
CSI (16.92 g; 0.12 mol) was added dropwise to cooled (ice salt bath, -15C) 1 (18.96 g; 0.12 mol). The pale yellow mixture was kept at 5 for 5 h whereby it changed to deep yellow. This was diluted with ethyl acetate (20 ml) , cooled to -30C, and added in portions to a cooled (ice salt bath) mixture of water (3.4 ml); ice (17.0 g) NaHC03 (0.3g) and Na2 S03 (3.4 g). After addition, the resulting mixture was stirred vigorously for 20 min and some additional NaHC03 was added to keep pH at 7-8. The layers were separated, and aqueous layer was extracted with ethyl acetate (2 x 50 ml).
The combined organic phase was dried (Na2S04; NaHC03; 1:1).
It was filtered and evaporated to give 17.4 g of an oil.
This was distilled under high vacuum (0.01-0.05 mm) in a hot air bath. (temp. 55 - 85) to remove 1. The undistilled light brown oil was cooled, taken up in ether and filtered over celite-charcoal to give, ~;
.li,l~

after evaporation to dryness 5.28 g (22%) of 4:1 mlxture of 2a and 2b (determined by nmr) as colourless oil. NMR: 7.25 (H, NH), 6.0 (0.25H, d, J = 4.3), 5.8 (0.75H, d, J = 15.), 4.5 (0.5H,- d, J = 6.5), 4.4 (1.5H, d, J = 4.5), 3.8 (0.25H, m), 3.5 (0.75H, m), 2.13 (3H, s), 2.1 (3H, 8).
IR: c=o 1780, 1740.

A c O~ 3 I
~ NH

2 AcO~ Ac~SAcAcS ~--`~OAc o ,~ O ~ 0~

3a 3b 3c PROCEDURE
Sodium thioacetate was prepared by addition of thioacetic acid (2.22 ml, 2.363 g) to a solution of IM
NaHCO3 (31.0 ml) under nitrogen. This was added to a cooled (ice bath) solution of 2 (5.2 g; 25.9 mmoles) in water (20 ml) and stirred for 4 h at room temperature. Some acetone (20 ml) was added to render the reaction mixture homogeneous. The mixture was concentrated in vacuo to remove acetone and then extracted with methylene chloride. The extract was dried and evaporated to give 5.6 g of a mixture of isomers (83.14%) of 3a and 3b. The NMR
spectrum of the crude oil showed that there were one trans and two cis compounds present in the mixture. A sample (550 mg) was chromatographed on silica gel (30 g, 10~ H20) and eluted with benzene-ether-methanol to give 200 mg of a mixture of 3a and 3b in the ratio 7:1, followed by 150 mg of an unknown cis compound (~ 5.55, d, J = 4.3) to ,, v `

which structure 3c was tentatively assigned. NMR: 6.78 (H,NH), 5.52 (0.17H, d, J = 4.3), 5.18 (0.83H, d, J = 1.5) 4.37 (2H, d, J = 4.5), 3.45 (H, m), 2.35 (3H, s), 2.05 (3H,s). I~: Vc=O 1765, 1740, 1600 cm.~1 AcO ~ 02N ~ OH2C02CH¢o~)~ ~ SAc N O ~ N-CH-OH

PROCEDURE:

A mixture of crude 3 (2.17 g; 10 mmoles) and p-nitrobenzyl glyoxylate (2.5 g; 11 mmoles) in benzene (200 ml) was refluxed 20 h under a Dean Stark water collector followed by concentration in vacuo to give 3.4 g of crude 4 as oil. This was used as such without further purification.
NMR: ~ 7-5 - 8.5 (4H), 5.2 - 5.8 (4H), 3.4 - 5.1 (4H), 2 -2.4 (6H). IR: VC=O 1665, 1740, 1740, 1730, 1700.
AcO ~ SOC12 AcO ~ SAc N-CH-OH ~ N-7H-Cl PROCEDURE:
To a cooled (ice-bath) solution of crude 5 (3.3 g; 7.75 mmoles) and pyridine (0.67 g; 8.5 mmoles) in benz~ne (20 ml) was added dropwise thionyl chloride (1.01 g; 8.5 mmoles) in benzene (10 ml) and the mixture stirred at the above temperature for 15 min and at r.t. for 15 min. The benzene solution was decanted, and the residual semi solid washed three -r ~
~1 36~6~L
times with 15 ml portions of benzene. The combined benzene solution was evaporated to give 1.90 g of crude 5 (55%).
NMR: ~ 7.5 - 8.5 (4H), 6.12 and 6.2 (lH), 5.66 (lH, m), 5.4 (2H, d, J_- 6), 4.3 - 4.7 (2H, m), 3.63 (H, m) 2.4 (3H, d), 2.1 (3H, s). IR: Vc=O 1765, 1740, 1730, 1700.

AcO ~ Ac 3 Aco~SAc ~ N-FHCl Dioxa~e ~ N -C=P(~) 10CO2?NE 2 PROCEDURE:

15 A mixture of crude 5 (1.90 G; 4.27 mmoles) triphenylphosphine (1.572 g; 6 mmoles) and 2,6-lutidine (0.642 g; 6 mmoles) in dioxane (20 ml) was heated at 55 for 18 h. It was cooled, filtered and evaporated to give 3.8 g of a crude dark oil. This was chromatographed on silica gel to give 1.2 g (42%) of 6.

AcC~SAc AcO~--~N--F=p(~p) 3 o~ ~
256 2 7 ~o2PNe PROCEDURE:
A solution of crude 6 (1.20 g; 1.79 mmoles) in toluene (15 ml) was refluxed for 5 h. it was cooled and evaporated to give an oil which was chromatographed on SiO2 ;, , .
., ~36~à61 (30 g) and eluted with benzene to give 0.4 g of 7 (57%) .
Anal- Calc'd for C17H16N207S C 52.04; H 4.11; N 7.14.
Found: C 51.77; H 4.08; N 7.30.
Sepa~ation of the cis and trans isomers was achieved through careful chromatography on silica gel (60 g) eluting with benzene. cis-isomer: ~ (ppm, CDC13): 7.5-8.5 (4H, aromatics), 5.67 (lH, d, J = 5, H-5), 5.28 (2H, AB quartet, benzyl), 4.33 (2H, d, AcOCH2), 4.20 (lH, dt, H-6), 2.31 (3H, s, CH3), 2.0 (3H, s, CH3CO). VC=O 1770, 1740, 1730 10 cm~l.
trans isomer: ~ (ppm, CDC13): 7.5-8.5 (4H, aromatics), 5.53 (lH, d, J = 2, H-5), 5.30 (2H, AB quartet, benzyl), 4.32 (2H, d, AcoCH2), 4.27 (lH, dt, J = 5, J - 2, H - 6), 2.31 (3H, s, CH3), 2-0 (3H, s, CH3CO). VC=O 1770~ 1740~ 1730 cm~1.

~S t Ac(~ ~CH AC~ CH
~ N _~ 3 NaHC03 C2Na C02PNa PROCEDURE:
To a solution of trans 7 (119 mg; 0.3 mmole) in ethyl acetate (15 ml) and water (7 ml) was added NaHCO3 (25.2 mg, 0.3 mmole), and Pd/C (110 mg) and this was hydrogenated 4.5 h at 30 psi. The mixture was filtered and layers separated. The aqueous layer was washed with ether and then lyophilized to give 40 mg of solid 8 (48~).

12~366~1 ~

V 1765, 1740, 1600 cm . ~ (ppm, D2O): 5.52 (lH, H-5~, 4.85 (2H, AcOCII2), 4.0 (lH, 1i-6), 2.65 (3H, CH3), 2.40 (3H, CH3CO).

CH3 ~ ;3 C2Na C02H

PROCED~R~:
To a solution of crude trans 8 (100 mg) in cold water (2 ml) was acidified with cold lN HCl and extracted with CHC13. The extract was dried (Na2SO4) and evaporated to give 30 mg of a pale yellow solid. M.P. 111-113 with decomposition. IR:
V 1780, 1750, 1680. (Neat). IR: (XBr): v 1775 (Strong), 1745, 1670.

Treatment of cis paranitrobenzyl 6-acetoxymethyl-2-methyl-penem-3-carboxylate according to the above procedure gives the cis sodium salt and free acid.

- 5~-36~63~

ExamDle 3 Potassium 6-(2'-Hvdroxvisopropyl)-2-methylpenem-3-carboxylate (anion process) \y~OH

C02~C
. _ _ FNr~ 3 LDA HO~f ~

02H + C02K

1 4a A solution of acid 1 (116 mg, 0.627 mmoles) in anhydrous THF (4cc, freshly distilled over LAH) was added dropwise at -78C
to a THP (2cc) solution of LDA (from diisopropylamine, 70.7 mg, 98 ~1, 0.699 mmoles, and n BuLi 1.6 M, 0.440cc, 0.704 mmole stirred at -78C for 30 min). The mixture was stirred for 5 min. followed by successive addition of diisopropylamine (70.7 mg, 98 ~1, 0.699 mmole) and 1.6 M n BuLi (0.440cc, 0.704 mmole) at -78. It was then stirred for 10 min. at -78 and treated rapidly with acetone (5cc). The mixture was allowed to react with acetone for 10 min. It was acidified (pH=2) with 1~ HCl, diluted with ethyl acetate (40 cc) and washed with brine (3 x 20 cc). It was dried over Na2SO4. Solvent evaporation gave a crude residue (3a) which was taken up in CH2C12 (crude yield 90 mg). The crude acid was dissolved in cold MIBK (2 cc) and treated dropwise with potassium 2-ethyl hexanoate. It gave two batches of potassium salt (36.4 mg, 26%) as a cis and trans mixture, the trans isomer being predominant.

~.~f~566~;

6) 60 ~1H~ d~ JS-6 cis = 4~H-5)~ 5.55 ~lH, d~

J 6 t = 2, H-5), 3-93 (lH~ d~ J6--5 cis 4' )' ~lH, d, J6-5 trans = 2, H-6), 3.50 ~b.s.,OH), 2.34 (3H~ s, CH3), 1.47, 1.40 (6H, 2s, 2CH3), 1.35, 1.32 (6H, 2s, 2CH3) V (nujol mull) 1765, 1582, VOH 3600 - 3100 W ~EtOH) Amax 257 ~ = 3920), 300 ~E = 4020).

Example 4 Potassium 6-Hydroxybenzyl-2-meth-~lpenem-3-carboxylate (anion process) ~ H
HO X ~ 8~

-~H
CH3 ~ HO ~ XH3 1 4b A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous THF (6 cc, distilled over LAH) was added dropwise to a cold (-78) THF (2cc) solution of LDA made from diisopropylamine (84 ~1, 60.6 mg, 0.599 mmole) and 1.6 M n-BuLi (0.380 cc, 0.608 mmole). The mixture was stirred for 5 min, followed by successive addition of diisopropyl amine (84 ~1, 60.6 mg, 0.599 mmole) and 1.6 M n-BuLi (0.380 cc, 0.608 mmole). It W2S then stirred for 7 min at -78 and treated rapidly with benz-aldehyde (300 yl). The mixture was allowed to react at -78 for 20 min. It was acidified with 1~ HC1 (pH-2), diluted with ethyl acetate (40 cc), washed with 1:1 H2O-brine (3 x 20 cc) and brine (1 x 20cc) It was dried over Na25O4. Solvent evaporation gave a residue which was dissolved in MIBK (2cc). It was treated dropwise with potassium 2-ethvl -6~ -hexanoate. It gave 4b (35 my) in 20% yield as a diastereoisomeria mixture. ~ : (ppm, DMSOd6) 7.95 (5H, s, H-aromatic) 5.57 (d, J5-6 trans = 1.5, H-5), 5.45 (d, J
5-6 trans - 1.5, H-5) 5-35 (d, J5-6 cis = 4~ H 5)~ 5-0 ( ~
C-H hydroxybenzyl), 4-25 (dd, J6-5 cis = 4, J 6-C-H
hydroxy benzyl = 10, H-6), 3.90 (m, H-6), 3.65 (b.s., OH), 2.35 (3H, 2s, CH3) Vc=O ("NUJOL MULL")* 1760, 1590, vOH
3600 - 3100. UV (H2O) max 252 ( s = 5,100), 296 (~ =
3,300)-Exam~le 5 Potassium Ç-Thiomethyl-2-methyl~e~em-3-carboxylate (anion Drocess ) SMe ~ ~ CH3 N ~

S SMe S

1 4c A solution of acid 1 (100 mg, 0.540 mmole) in anhydrous THF (5cc, distilled over LAH) was added dropwise to a cold (-78) THF (2cc) solution of LDA made from diisopropylamine (84 1, 60.6 mg, 0.599, mmole) and 1.6 M
n-Butyl lithium, (0.380 cc, 0.608 mmole). The mixture was stirred for 7 - 8 min, followed by successive addition of diisopropylamine (84 ~l, 60.6 mg, 0.599 mmole) and 1.6 M
n-Butyl lithium (0.380 cc, 0.608 mmole). It was then stirred for 7 min at -78 and treated rapidly, with methyl thiomethylsulfonate (300 ~ l, excess). The mixture was allowed to react at -78 for 5 min. It was acidified with 1%
HC1 (pH-2), diluted with ethyl acetate (40 cc) , washed with 1:1 H2O-brine (3 x 20 cc) and brine (20 cc).
*Trade Mark ., .

~ ~fi~l The organic solution was dried over Na2SO4. Solvent evaporation gave a residue which was dissolved in cold MIBK
(2cc). The cold solution wa~ treated dropwise with potassium 2-ethylhexanoate. It gave ~ (40 mg)in 28% yield as a 8:3 mixture of cis and trans isomers (decomp.) 115 120) ~ (ppm, DMSOd6 ) 5.85 tlH, d, J5-6 ci8 = 4, H 5) , 5-57 (lH~ d~ J5-6 trang = 1-5, H-5), 4.87 (lH, d, J6-5 cis =
4, H-6), 4.72 (lH, d, J6-5 tran8 = 1.5, H-6), 3.42 (b.s., OH), 2.37 (s, SCH3), 2.33 (s, CH3), 2.25 (8, SCH3). Vc=O
("NUJOL MULL)* 1770, 1600, UV (H2O) ~max 252 ( ~= 4200), 297 ( F = 3700) Example 6 l-(~-Nitrobenzvloxycarbonylmethvltriphenylphosphoranyl)-4-tsilver me~captidyl)-2-aze~idinone ~ SAg N ~P ~ 3 STr OAc Na0Me ~ H

0 H o A methanol (90cc) suspension of triphenylmethyl mercaptan (13.8 g, 0.05 mmole) was degassed for 0 . 5 hour with a nitrogen stream. The mixture was cooled down at O and sodium hydride (2.4 g, 0.05 mole, 50%
oil dispersion) was added portionwise. The resulting solution was stirred for 5 min and 4-acetoxyazetidinone (7.7 g, 0.059 mole) in water (55 cc) was added rapidly.
Precipitation of 4-triphenyl methyl mercaptoazetidinone (2) occurred immediately. The * Trade Mark . .~ , ~
,. . ..

~6~
mixture was stirred for 4 h at room temperature. The solid was filtered off, washed with water and di6solved in methylene chloride. The methylene chloride solutlon was washed with diluted HCl, water, aqueous sodium bicarbonate water and brine and dried over MgSO4, (89.8%, m.p.: 146.5 - 147.5C) Anal. Calc'd for C22H19NOS: C, 76.49; H, 5.54; N, 4.05; S, 9.28 Found: C, 7.54; H, 5.60; N, 4.00; S, 9.36.
~ (ppm, CDC13) 7.60 - 7.10 (15H, m, H-trityl), 4.62 (lH, bS, NH), 4-40 (lH~ dd~ J4-3 trans = 3 ~ J4-3 cis = 5~ H-4)~3-24 (lH~
ddd~ Jgem = 15~ J3_4 ci6 = 5, J3_NH = 1.8, H-3), 2.81 (lH, ~ gem 15~ J3_4 trans = 3-0, J3_NH = 1.2, H-3) Vc=O (CHC13) 1760, VNH 3340 F' ? ~ ~S~ OH ~ S~

Hydrated p-nitrobenzyl glyoxylate t4.54 g, 0.02 mole) and azetidinone 2 (6.90, 0.02 mole) were refluxed in benzene through a Dean Stark condenser filled with 3A
molecular ~ieves for 24 h. Further glyoxylate (2 x 454 mg, 2 mmoles) wa6 added with reflux period (18 h) after each addition. The mixture was diluted with ether, washed with 5% aqueous HCl, water, aqueous 5% NaHCO3 water and brine. It was dried over MgSO4 (12 g, quantitative) A small fraction of the epimeric mixture was separated on a ~ilica gel plate (CH2Cl2- ether 6:4) Isomer A:
Rf = 0.87, m.p. = 170.5 - 171.5 ~6~61 ~ (ppm, CDC13) 8.07 (2H, d, J=9, Hm aromatic), 7.45 tpart of d, Ho aromatic), 7.40-7.00 (15H, m, Trltyl), 5.25 (2H, s, CH2-PNB), 4.75 (lH, s, H-C-O), 4-37 tlH, dd, J3_4 trans= 3 J3-4 cis ~-4, H-3), 2.83 (lH, dd, Jgem = 16, J4-3 CiB = 4~
H-4), 2.10 (lH, dd, Jgem = 16, J4-3 trans = 3~ H 4)~ 1-42 (b.s., OH).
c=o (CHCl3 1770, 1760 (shoulder), vNO2 1525, vOH 3475.

Isomer B:
10 Rf 0.75, m.p. = 152 - 153 ~ (ppm, CDC13), 8.13 (2H, d, J = 9, Hm aromatic), 7.47 (,2H, d, J = 9, Ho aromatic), 7.40 - 7.00 (15H, M, trityl), 5.30 (3H, s, CH2-PNB, H-C-0), 4.45 (lH, t, J = 3.5, H-4), 2.90 -15 2.70 (2H, AB part of ABX, H-4), 1.55 (b.s., OH).
vc=o(CHC13) 1767, 1755 (shoulder), vNO2 1525, CH

STr SOCl2 STr ~ pyridine ~

A cold (-15) THF (150 cc, dried over molecular sieves) solution ~f azetidinone 3 (12 g, 21.7 mmoles) was treated with pyridine (1.9 g, 24.1 mmoles, 1.94 cc) and dropwise with thionyl chloride (2.86 g, 24 mmoles, 1.88 cc) under a nitrogen atmosphere. The mixture was stirred for 45 min at -15. The precipitate was filtered off and washed with benzene. Evaporation of solvent gave a residue which was ,"~ ~
,-~, . .

taken up in benzene and treated with activated charcoal (11.7 g, 94%, crystallized out from chloroform).
~(ppm, CDCl3) 8.17 (2H, d, J = 8, Hm aromatic), 7.67 - 7.00 (17H, m, ~o aromatic, Tr-H), 5.80 (8, H-C-Cl), 5.37, 5.33 (2s, H-C-Cl, CH2-PNB), 4.81 (lH, m, H-4), 3.27 - 2.40 (2H, m, H-3) c=o (KBr film) 1785, 1770 vN0 1525.

STr ~ ~3P

A THF (100 cc, distilled over LAH) solution of chloroazetidinone 4 (11.6 g, 20.2 mmole~) was treated with triphenyl phosphine (7.86 g, 30.0 mmoles) and 2,6-lutidine (2.36 g, 2.56 ca, 22.0 mmoles). The mixture was refluxed for 72 h. The precipitate was filtered off and washed with ether. The organic solution was washed with 2% aqueous HCl and 5% aqueous bicarbonate and dried over MgSO4.
Evaporation of solvent gave a residue which was purified through silica gel pad (200 g). The desired phosphorane was eluted with 30,40 and 50% ether-benzene (11.4 g, 70.4%, m.p.: 201-202).
Anal. Calc'd for C49H40N205SP: C, 73.57; H, 5.04; N, 3.50;
S, 4.01.
Found: C, 73.58; H, 4.91; N, 3.44; S, 3.87.
Vc=O (CHCl3 1740, ~phosphorane (1620, 1610), VN0 1525.

3fi6~

T-03 ,__~SAg ~3 pyridine ~ ~ 3 4-Tritylmercapto azetidinone 5 (1.6 g, 2 mmoles) t was dissolved in CH2Cl2 (20 cc) and the solvent was flushed down at 55-60. Phosphorane 5 at 55 - 60 was dissolved in preheated (55-60) methanol (32 cc). Immediately after the obtention of a methanolic solution of 6 it was treated with a preheated (55 - 60) mixture of methanolic 0.15 M silver nitrate solution (16 cc, 1.2 eq) and pyridine (174 mg, 178 l, 2.2 mmoles, 1.1 eq). The warming bath was then immediately removed. The mixture was stirred at room temperature for 2 h and at OC for 1 h. The silver mercaptide 6 was filtered off, washed twice with cold tO) methanol and three times with ether. (1.12 g, 84.5%, m.p.:
130-135 dec-.).

Vc=O (CHCl3) 1795, 1725 (shoulder), v phosphorane (1620, 1605), vN02 1530.

6f~
Example 7 1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl)-4-- ~silver mercaptidyl)-2-azetidinone) SCOC~13 K2C03,AgNO3 SAg 1~' ~ 1~
o ~ - C=PPh3 MeOHO ~ N` C=PPh3 10COOPNB COOPN~

A solution of phosphorane 7 (1.796 g, 3.0 mmoles) in chloroform, (3ml) was diluted with methanol (90 ml), lS cooled at OC under nitrogen atmosphere and treated successively with silver nitrate (0.51 g, 3.0 mmoles) and potassium, carbonate (0.33 g, 2.4 mmoles). The reaction~
mixture (protected from light) was stirred at oc for 15 min., then the cooling bath was removed and stiring was continued for 3 h. The reaction mixture was cooled down to -10C, stirred for 1 h and filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.91 g, M.P.: 138 - 145C dec, 96~. I.R. ("NUJOL")* cm~1: 1748, 1620 and 1605. An analytical sample was obtained by, preparative TLC (ethyl acetate); M.P.: 140 - 5C dec, calc'd for C30H24N2O5SPAg: C, 54.31; H, 3.65; N, 4.22; S, 4.83.
Found: C, 54.11; H, 3.48; N, 3.92; S, 4.62.
Example 8 1-(p-Nitrobenzyloxycarbonylmethyltriphenylphosphoranyl-4-(silver mercaptidyl~ -2-azetidinone A. Use of aniline as base . .
SCOCH3 Aniline, AgNO3SAg 1~' . ....... ~ r~
~ N MeOH ~ N ~
35 Cl PPh3 C=PPh3 COOPNB COOPN~

* Trademark ~r36~1 A solution of phosphorane 7 (1.8 g, 3.0 mmoles) in chloroform (4 ml) was diluted with methanol (90 ml), cooled to -15C under nitrogen atmosphere and treated successively with silver nitrate (0.56 g, 3.3 mmoles) and aniline (1.5 ml, 16.5 mmoles). The reaction mixture (protected from light) was stirred at -15C for 0.5 h and then the cooling bath was removed and stirring was continued for 24 h. The reaction mixture was cooled to -10C
and stirred for 1 h before being filtered; the silver mercaptide was successively washed with cold methanol and ether; 1.55 g, M.P. 114-5C dec. 77.9%. IR ("NUJOL")*cm 1;
identical to compound of Example 7.

Silver-l-(Paranitrobenzyl 2'-~riphenyl~hosphoranylidene-2'-ace~ate)-2-azetidinone-4-thiolate B. Use of 4-dimethylamino~yridine (DMAP~ as base SCOCH SAg r~' 3 AgN3/DMAP I _,/
20 ~L N ~ C H 2 C 1 2 / C 3 3 3 ~-- N ~ ~1) 3 A solution of the above S-acetyl phosphorane (17.96 g, 30 mmol) in methanol and dichloromethane (1:2, 450 ml) was purged with nitrogen (5-10 min), cooled to 5C
and treated successively with silver nitrate (5.35 g, 31.5 mmol) and 4-dimethylaminopyridine (3.85 g, 31.5 mmol). The ice-bath was removed and the solution refluxed vigorously for 2 h and then stirred at room temperature for 1 h. The colored reaction mixture was treated with charcoal, filtered and evaporated. The residue was redissolved in the minimum amount of dichloromethane and added dropwise, with stirring to cold methanol (300 ml). The precipitated silver salt was collected by filtration, washed with ether and 35 dried; 18.1 g (91%); ir (CHC13) vmax: 1745 (C=O of B-lactam) and 1607 cm~1 (C=O of ester).
* Trademark .~

i66~
Silver~ a~Lnitrobenzyl 2'-trihenyh~b~9 -2"-aoeta~e)-2-C. Use of di~zabicycloun~ecene (D~U~ a~ ba.~e ~COCH3 AgNo3 ~ SAg DBU, MeOH ~

The above S-acetylphosphorane (36. 0 g, O. 060 mol) 10 was dissolved in methylene chloride 120 ml. The solvent was evaporated in order to obtain an oil. The resulting oily residue was dis601ved in warm (35C) methanol (240 ml) and treated rapidly with a methanolic (420 ml) solution of silver nitrate (10-68 g. O. 0628 mol). The resulting solution 15 (or su6pension) was stirred at room temperature for 5 min, cooled down (ice-bath) and a DBU (8. 96 ml, O. 060 mol):
solution in methanol (20 ml) was added over a 5 min period.-~The mixture was stirred for 5 min. The solid was filtered, washed once with cold (0C) methanol and ether and 20 dried under vacuum; 37. 0 g (93%); ir ("NUJOL NAILL")* vmax (c=O) and 1600 cm 1 (phosphorane) D. Use of pyrrolidine as base Silver 1~ aranitrobenzyl 2'-trlphenylphosphora}
idenç-2"-aceta~e)-2-azetidinone-4-thiQlate SCoCH
SAg Pyrrolidine I
AgNO3 ~
~ - N ~ ~ N
O f=PPh ~-PPh3 COOPNB COOPNB
To a cold (0C) solution of 4-acetylthio -1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate) -2-azetidinone(O. 60 g, 1. 0 mmol) in CH2C12 (2 ml) was 35 added MeOH (4 ml), a solution of AgN03 in MeOH (O. 14N, 7. 86 ml, 1. 1 mmol) and a solution:. of pyrrol-*Trade Mark ~ ,,.~, idine tO.92 ml, 1.1 mmol) in MeOH (2 ml~. The cooling bath was removed and the reaction mixture was stirred for 1.75 h, cooled to -10C, stirred for 0.25 h and filtered. The solid was washed~with cold MeOH and dried in vacuo; 0.548 g, m.p.
115C, 82.4%. ir ("NUJOL")* vmax: 1775 (C=O) and 1600 cm 1 (aromatics).
Exam~le Mercuric (II)-~2'-Triphenyl~hos~horanylidene-2'_-acetatel -2-azetidinone-4-thiolate STr H g ( OA c ) 2 O~N \C

S)2Hg 1 l A solution of I (2.4 g, 3 mmoles) in dichloromethane (15 ml) was cooled to 5C and treated with a solution of mercuric acetate (0.525 g, 1.65 mmole) dissolved in methanol (15 ml). After stirring at 5 ~or 2 h, the solvent was evaporated and the residue redissolved in dichloromethane and washed with cold water. The organic solution after being dried (MgS04) and treated with charcoal, was evaporated to give a foam which crystalized when triturated in ether. Yield: 1.73 g (91~) M.P. 123 -127C, I.R. (CHC13) 1745 cm 1 (vc=O e lactam) 1608 cm l (phenyl) *Trade Mark ;6~
Ex~ampl~_10 2-Methyl~enem-3-~ni~Qk~nzyl~d~Q~Lg~Q
(from mercaptide ~;ermediate) , S ) 2 H g ~ SCOCH~
~ PPh 2CH3COCl ~/
N ~ p y r i d i n e ~ N ~ 3 II III

A solution of II (262 mg, 0.2 mmole), acetyl chloride (35 mg, 0.44 mmole) and 2 drops of pyridine in 10 ml of dichloromethane was stirred at 5C for 1 h. The precipitated mercuric chloride was then filtered off and the filtrate waæhed successively with cold dilute hydrochloric acid, sodium hydroxide and finally brine. The organic solution was submitted to a stream of hydrogen sulfide for 2 minutes at 5C and stirred at that temperature for an additional 10 minutes in order to precipitate the last traces of mercuric salts. Some charcoal was added to the black mixture which was then filtered through a pad of celite. Evaporation of the clear filtrate left 193 mg (80.7%) of III as a foamy material.
I.R. (CHC13) 1755 (, Vc=O B-lactam) 1692 (v ) 1620 (phenyl). SCOCH3 r r ~ CH3 Phosphorane 111 (75 mg, O. 126 mmole) in toluene (10 cc) was refluxed over a 2. 5 h period under nitrogen atmosphere. Solvent evaporation and purification of the residue afforded a crystalline derivative (25 mg, 63%) whose physical and spectral data were in complete agreement with those of the title product.
Product IV may if desired be subjected to catalytic hydrogenation (30% Pd on "CELITE")* to produce the corresponding 3-carboxylic acid product.
*Trade Mark ~3666~L
Example 1 2-Aminome~hylpenem-3-carboxyli$ Acld from me~Q~p~de~int~mediate) f~ CH2NH2 COOH
1 0 ,_ _ SCOCH N
~SAg ClCOCH2N3 ~--f 2 3 ~ N!

~N ~ C H 2 C 1 2 o ~C- P P h 3 f=PPh3 A solution of silver mercaptide 1 (1.25 g, 1.99 mmole) in dichloromethane (15 ml) kept under nitrogen atmosphere was cooled at 0C and treated dropwlse with a 2M
solution of azidoacetyl chloride in dichloromethane (1.13 ml, 2.26 mmoles). The reaction mixture was stirred at 0C
for lh; the cooling bath was removed and stirring was continued for 5 h. The reaction mixture was filtered over a "CELITE"* pad and the 601ids were wa6hed with dichloromethane (35 ml). The filtrate and washings were combined, washed with sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to an orange syrup which was purified by column chromatography (30 g of silica gel 60, eluate; ether-2%
ethyl acetate *Trade Mark . .

(200 ml), ether -6% ethyl acetate (200 ml) and ether-20%
ethyl acetate (500 ml), fraction slze: 10 ml). The combination and evaporation of fractions 49-80 gave a yellow powder; 0.13 g, M.P. 61-70, 60.8%.

F~ To i ~ e n e ~N ~ C H 2 N 3 Cl=PPh3 COOPNB
COOPNB

A solution of phosphorane 2 (0.593 9, 0.93 mmole) in toluene (20 ml) was heated at 105C for 1 h, cooled to 23C
and concentrated to a semi-crystalline compound which was purified by column chromatography (12 g of silica gel 60, Eluate: benzene (100 ml), benzene-2% ether (100 ml) and benzene-4% ether; fraction size: 10 ml). The combination and evaporation of fractions 18 - 26 gave a yellow syrup which crystallized on standing; 0.18 g, M.P.: 127-8C, 53.7%. NMR
(CDC13, ~ 8.22 (2H, d, JHO, Hm = 8-8 Hz~ P
nitrobenzyl), 7-60 (2H, d, JHm, Ho = 8-8 Hz~ Hm of p nitrobenzyl), 5.71 (lH, dd, J5,6 cis = 3-6 Hz~ J5,6 trans = 2.1 Hz, H-5), 5.33 (2H, center of ABq, Ja b = 14.0 Hz, CH2 of p-nitrobenzyl), 4.58 (2H, center of ABq, Ja b =
15.0 Hz, CH2on C-2) 3.88 (lH, dd, J6,s cis = 3-6 Hz~ Jgem =
16.5 Hz, H-6 cis) and 3-55 (lH, dd, J5,6 trans = 2-1 hz~
Jgem=16 5 Hz, H-6 trans) I.R. ("NUJOL")* cm 1 2115 and 2090 (N3), 1780 (c=o of B-lactam) and 1685 (c=o of p-nitrobenzyl ester).
An analytical sample was obtained by preparative T.L.C.;
M.P. 127-8C, calc'd for C14H11N5O5S: C, 46.54; H, 3.07; N, 19.37; S, 8.87. Found: C, 46.43; H, 3.08; N, 19.37; S, 8.90.

*Trade Mark ~, .~ I
,i ~, ., lZr~

CH2N 30~ Pd/ "CE~,ITE'' r~~ ~ CH NH
3 THF, e th er, H 20 a~ N ~ 2 2 COOPNB COOH

To a solution of penem 3 (0.18 g, 0.5 mmole) in tetrahydrofuran (6 ml) was successively added ether (6 ml), water (6 ml) and 30% palladium on ~ CELITE" * (O. 18 g). The reaction mixture was hydrogenated under 30 p.s.i. at 23C
for 2.5 h and filtered over "CELITE"* pad; the pad was washed with water and the filtrate and washings were combined, washed with ether-THF mixture and lyophilized to give 30 mg, 30%, of compound 4. [Water and ether insoluble compound were diss 01 ved in chloroform and the organic solution was washed with water and dried over anhydrous sodium sulfate. The evaporation of solvent under reduced pressure gave 77 mg (42.8%) of starting material 3]. NMR
(DMSO d-6) ~:5.7 (dd, J5-6ci8 - 3-5 Hz~ J5-6trans = 1-5 Hz~
H-5)- I. R. ("NUJOL")* cm 1 1775 (c=o of B-lactam) and 1615, 1585. U.V. ~H20 m : (F=2320) and 307 (~=2685).
max Title product 4 was also obtained from intemediate 3 by the following route:

1 ~-- ~ CH2N3 H2,Pd/D-E~ ~ ~ CH2NH2 30 o~L_ ~ ~ THF, E~er, O~N ~

3 q To a solution of penem 3 (2.4 g, 6.89 mmoles) in tetrahydrofuran-ether-water mixture (1:1:1, 165 ml) was added 30% palladium on diatomaceous earth (4.8 g). The reaction mixture was hydrogenated under 45 p.s.i. at 23C
for 2.5 h and *Trade Mark 6~
filtered over celite pad. The filtrate and washlngs were combined, washed twice with ether, centrifugated and filtered several times to give a clear solution which was lyophilized; 0.622 g, 45%. The crystallization of the compound was induced by the addition of water (0.8 ml); the suspension was centrifuged and the water was removed leaving an orange solid. This solid was washed twice with water and a slightly yellow solid was obtained after drying: 0.273 mg, 19.8%. UV~ 2 : 307 (~ =4318) and 257 max (~ =2650). Some crude starting material (1.2 g, 50~) was recovered. The compound (50 mg) can also be purified by column chromatography ["SEPHADEX" *GIO, column size: 1.6 x 100 cm, flow rate: 10 ml/h, eluent: distilled water, fraction volume: 1.5 ml, detector: refractive index3.

UV~ : 307 (~=3597) and 255 (E=2424).
max The stability of the compound in aqueous solution was checked by:
UV: 6 h 307 (~=3545 and 255 (F =2773) 21 h 307 (~=3467) and 255 (~=2411) 28 h 307 ( =3337) and 254 (~=2398) 46 h 307 (F =3259) and 254 (~=2398) 70 h 307 (~=3076) 94 h 307 (~=2842) 170 307 (~=1900) A sample of compound 4 was kept at 23C for 3 days and the UV was taken: UV~ 2 :307 ( =3055) and ( =2008).
max Compound 4 was converted as described below to two additional 2-penem derivatives.

*Trade Mark Ç3~

S\ ~ Nal~CO3, H 2O ~ ; ~ 2 ~ I ~CH2NH3 CH C-OEt 5 C:)G91a(3 A suspension of compound 4 (50 mg, 0.25 mmole) in distilled water (0.5 ml) was treated with one equivalent of sodium bicarbonate (21 mg) followed by the addition of ethyl acetimidate (21. 8 mg, 0. 024 ml). The reaction mixture was stirred at 23C for 20 min and lyophilized 10 giving 52 mg of a yellow solid. NMR (D2O) ~: 5.7 (m, H-5) and 2.23 (b.s., CH3 of amidine). I.R. (KBr)cm 1 1772 (c=o of B-lactam). U.V. ~D20 m~ : 305 (~=3116) and 253 max 15 ( =2525). The compound 5 was applied on a column ("SEPHADEX")*G10, column size: 1.6 x 100 cm 1 Eluent: H2O, detector: I.R. fraction size: 1.6 ml) and lyophilization of appropriate fractions gave 23 mg 45% of slightly yellow 20 powder U.V.~ 2 m~: 303 (~=2960) and 248 (F=2885).
max 2 . ~ (~) NaHCO , H O S H
~cH2NH3 3 2 ~ ~ CH2N=C +6NaCI

O ~~ C ~ N ~ ~NH2 4 c~) H- -OEt 6 COO(~la(~) A suspension of compound 4 (50 mg, 0.25 mmole) in distilled water (0-5 ml) was treated with sodium bicarbonate (21 mg, 0.25 mmole) and stirred for 1.5 min before the addition (2 min) of a mixture of sodium bicarbonate (126 mg, 1.5 mmole) and ethyl formimidate hydrochloride (164 mg, 1.5 mmole). The reaction mixture was stirred for 10 min at 23C and lyophilized giving an orange powder. U.V. ~H2m~: 304 (~=2300).
*Trade Mark m a x . .~

E x a m p 1 e 12 Sodium 2-Hydroxyaminopropylpenem-3-carboxylate NHCH
N ~
CO Na 1 ) NaOH S ~
02N/--~02E~ 2) HCl conc 2 C02H

To a cold 5% aqueous solution of sodium hydroxide (320 ml) was added ester 1 (21.6 g, 0.134 mole). The resulting mixture was stirred at room temperature for 2 h and then concentrated to 250 ml and acidified wilh concentrated HC1.
The mixture was extracted with ethyl acetate (4 x 200 ml) and the organic extracts were dried over sodium sulfate.
Concentration on rotary evaporator left an oil. Yield 13.2 g (75%).

,~,, . .1,"
,~, "

~f~6~

2 CO2H + SOCl2 2 COCl A solution of acid 2 (13.2 g, 0.1 mole) in SOC12 t25 ml) was stirred for 2 h at 30C. After evaporation of thionyl chloride, the residue was distilled under vacuum T =
76-78C (P=0.2 mm Hg). Yield 8.8g (58.3%) as a colourless liquid: n.m.r. (CDCl3) ~ ppm:2.40 (2H,m,B-CH2); 3.15 (2H, t, ~ -CH2); 4.50 (2H, t, r-cH2) i.r. (neat): 1550 cm 1 (VN0 ); 1790 cm~1 (VC=O~ acid chloride).
S ~ N02 ~ 1) H25/Et3N , f a O. COCl ~Ac - _ 2) NaHCO3/ ~ N

A solution of ~ (19.46 g, 0.128 mole) in methylene chloride (200 ml) was added rapidly to a cold (0-10) stirred solution of triethylamine (36 ml, 0.256 mole) in methylene chloride (500 ml) which had been saturated at 0-51 with H2S. The mixture was stirred at -10 for 1 h and then a stream of nitrogen was passed throuqh the solution to eliminate the excess of H2S. The mixture was washed with 10% HC1, the organic extract was concentrated to about 150 ml and then sodium bicarbonate (10.9 g) and water (500 ml) was added. The pH was adjusted to about 7.5 with NaHCO3 or HC1. The resulting mixture was cooled to 0C and 4-acetoxy-2-azetidinone (16.8 g, 0.13 mole) in water (20 ml) was added with vigourous stirring. After 4 h the mixture was extracted with ethyl, acetate. ~he extracts were washed with 10% HC1, sat. NaHC03, brine, dried (Na2SO4) and evaporated. The residue was purif:Led by column chromatography (SiO2 ; eluent: ether then ether-ethyl acetate 5%) giving an oil which crystallized in ethyl acetate-hexanes yielding 4 (3.5 g, 12.5%) as a white powder. (m.p. 45-47,C).
~H( C02P~B

A mixture of azetidinone 4 (1.09 g, 5 mmoles) and p-nitrobenzyl glyoxylate hydrate (1.2 g, 5.25 mmoles) in benzene (100 ml) was heated at reflux with a Dean-Stark trap o filled with 4A molecular sieves for 18 h. Evaporation of the solvent gave the glyoxylate adduct 5 (2.1 g) as an oil.

~ ~ 2 SOCl2 ~ ~ N02 25 O~ ~C0 ?Ns Y ~H -Cl H 2 ~2PNB

Azetidinone glyoxylate 5 (2.1 g) was dissolved in tetrahydrofuran (50 ml) and pyridine (0.57 ml, 7 mmoles) was added to the solution. The mixture was cooled to OC and SOCl2 (0.5 ml, 7 mmoles) was slowly added. The mixture was stirred 1 h at OC and then filtered before evaporation to dryness. Filtration of this material over a pad of silica gel with CH2Cl2 gave a foam; yield 1.9 g (85%).

1~36~

a~ ~--~N 2 ¢) 3 ~ ~f ~--N ~ C~~-Cl 2,6-lutidine C=P~
CO2PNa 12PNa To a solution of chloroazetidinone (6.2 g, 14 mmoles) in THF (300 ml) was added triphenyl phosphine (5.5 g, 0.02 mole) and 2,6-lutidine (2.4 ml, 0.02 mole). The mixture was heated at 45C for 20 hours. Lutidine hydrochloride was filtered off and washed with ether. The filtrate was then evaporated. The residue was purified by chromatography through a silica gel column and eluted with dichloromethane and dichloromethane-ethylacetate (1:1). Evaporation of eluent gave a white solid (2. 9 g, 30%.) ~ Toluene ~ ~ N0 ~ ~3 C02PNs C022~

Phosphorane l (2.0 g, 3 mmoles) in toluene (150 ml) was refluxed for 2.5 h. Bvaporation of solvent afforded an oil which was purified by chromatography through a silica gel column and eluted with dichloromethane and dichloromethane-ethylacetate (9: 1) - Evaporation of the solvent gave a syrup which crystallized in ethylacetate-hexanes as a white solid (0. 82 g, 40. 7%) 66~

~ --\NO 30% Pd/DE
J_N ~ 2 THF-E~ER-H20-NaHC0 CO 2 ~B
8 ~ ~/V\NHCH

C2Na To a solution of ester 8 (50 mg, O. 127 mmole) in a tetrahydrofuran-ether mixture (2:3, 25 ml) was added water (10 ml), sodium biaarbonate (10 mg, O. 127 mmole) and 30%
palladium on diatomaceous earth (50 mg). The reaction mlxture was hydrogenated under 50 p. s.i. for 3 h at 25C, filtered over a celite pad and washed with ether. Aqueous solution was lyophilized yielding a yellow powder (30 mg) of hydroscopic compound.

~3~61 Example 13 6-EthYl-2-aminomethylpenem-3-carboxylic Acid (cis and trans isomers) 10 C~N--~ ~112NU2 2 a. Silver cis and trans 3-ethyl-l-(p-nitrobenzvl-2'-triphenylphosphoranylidene-2'-acetate)-2-azetldinone-4-thiolates A solution of cis and trans 3-ethyl-l-(p-nitrobenzyl-2'-phosphoranylidene-2'acetate)-4-acetylthio-2-azetidinones o (1.88 ~., 3.0 mmoles; ~xample 1, structure 7) in chloroform (4 ml.) was diluted with methanol (90 ml.), cooled to 0 and treated successively with finely powdered silver nitrate (0.51 g., 3.0 mmoles) and potassium carbonate (0.33 g., 2.4 ~moles). The miiture was stirred vigorousl~ 15 ~in.
at 0, 3 h at room temperature and 1 h at -10C. The precipitated silver mercaptide was collected by filtration, washed with methanol and with ether and dried in a vacuum.
The title product was obtained as a grevish solid, m.p.
112-135 d. vC=O 1750, 1620, 1605.

b. Cis and trans 3-ethvl-1-~n-n trobenzvl-2'-~hosphoranvlidene-. .
2'-acetate)-4-azidoacetvlthio-2-azetidinones A solution of the above crude mercaptide (1.31 g, 2 mmoles) in dichloromethane (15 ml) was cooled to 0 and treated, under a nitrogen atmosphere, with a 2r1 solution of azidoacetyl chloride in dichloromethane (1.13 ml, 2.26 mmoles). The mix-ture was stirred at 0 for 1 h and at room temperature for 5 h. The insoluble silver salts were removed by filtration over Celite and ~ashed with dichloromethane. Lhe combined filtrates were washed with dilute sodium bicarbonate solution and water, dried and concentrated. The oilv residue was purified by chromatography over silica gel (35 g) eluting with ether-ethyl acetate. The pertinent fractions were concentrated to give a mi.~ture of cis and trans acylated compounds as a semi-solid; 0.62 mg. v (CDC13): 2105, 1760, 1690, 1621 c~ .
c. Cis and trans ~-nitrobenzyl-2-azidor~ethYl-6-ethylpenem-3-_ _ carboxylates ~-solution of the above crude phosphorane (0.60 g) in o ~Z~36~6 ~

toluene (30 ml) was ~ept at 105 for 1 ;1, cooled and concentrated to leave an oily residue which was purified by colwnn cnromato-graphy over silica gel (20 g) eluting witn increasin~ pro~or-tions of etner in benzene. T.~e pertinent fractions were concentrated to give both the cis and trans isomers.
cis isomer: ~ (ppm, CDC13): 8.25 (2~1, d, J = 8.8, ~o of paranitrobenzyl), 7.65 (2~, d, ~m), 5.93 (lH, d, J = 4.1, H-5), 5.38 (2H, AB quartet, J = 14.0, benzyl), 4.68 ~2H, AB quartet, J = 15.0, CH2-.~3), 3.4 (lH, m, h-6), 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3).
trans isomer: ~ (ppm, CDC13): 8.18 (2~, d, J = 8.8, Ho), 7.59 (2H, d, Hm), 5.52 (lH, d, J = 1.4, H-5), 5.33 (2H, AB ~uartet, J = 14.0, benzyl), 4.58 (2~, A3 quartet, J = 15.0, CH2-i~3), 3.7 (lH, dt, J = 1.4, J = 7.4, ~-6), 1.9 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2C~3).

d. Trans 2-Aminomethyl-6-ethylpenem-3-carboxylic Acid A mixture of the above trans p-nitro benzyl ester (0.20 g, 0.5 mmole), THF (6 ml), ether (6 ml), water (12 ml) and 30% palladium on celite (0.20 g) was reduced at 23 for 2.5 h at an initial hydrogen pressure of 30 psi. Tl~e catalyst was removed by filtration over celite and washed with water. The combined filtrates were washed with etAer-THF and lyopnilized to give the crude trans acid (12 mg). Chromatography over a column of Sephadex G-10 eluting witn water gave the pure trans acid (6 mg) as a Aygroscopic powder. vC=O 1775, 1615 cm 1.
AmaX = 306 (f - 3465). ~ (ppm, D2O-DMSO): 5.40 (lH, d, J =

2.0, H-5), 2.0 (2H, m, CH2CH3), 1.1 (3h, t, J = 7.4, CI12CH3).

~g5~

e. cis 2-~minomethyl-6-ethylpenem-3-carboxvlic ~cid Reduction of the cis-p-nitro~enzyl ester as descri~ed above for the trans-ester ga~e thé cis-acid as a yellowish hygroscopic power (13~) v~=O 1775, 1615 cm 1. ~ma~ 304 (~=3563). ~(ppm, DzO-DMSO): 5.75 (lH, d, J = 4. O, H-5), 2.0 (2H, m, CH2CH3), 1.1 (3H, t, J = 7.4, CH2CH3).

/~t Example ~X~
The following compounds may be prepared according to tne yeneral procedure of Example ~

~ S
N ~

Acylating Agent Y X Z

CH3COCl -c~3 -CH3 Na, H

Ac20 -CH3 -CH3 Na, H

3 2 2CH3 -c~3 -c~3 Na, H

2 5 1 -CH3 2 5 Na, H
0CH2COCl -CH3 -CH20 ~a, ~

00CH2cOcl -c~3 -C~200 Na, H

COCl -CH3 ~ Na, H

COCl -CH3 ~ Na~

(CF3CO~20 -CH3 -CF3 Na 2 5 2 OCl -c~3 -CO2Et Na ~COCl -C~3 ~ ~ Na, H

CH3 ~CH3 --~6 -1'~3~

Acylating Aqent Y X Z

~ C~2COCl -C~3 ~5 Na, ~i 3( 2)2COCl -CH3 -(CH2)2NH2 N3(CH2)3COCl -CH3 -(CH2)3NH2 H
NC(CH2)2CoCl -CH3 -(CH2)3NH2 H
02N(CH2)3COCl -CH3 -(CH2)3NHOH Na, H
3(CH2)4COcl -CH3 -(CH2)4NH2 H
N3(CH2)20CH2COCl -CH3 -CH20(CH2)2NH2 3( 2)2 C 2 Cl -CH3 -CH2S(CH2)2NH2 AcNH(CH2)2C02C02Et -CH3 -(CH2)2NHAc Na, H
CH3COC1 2 5 -C~I3 Na, H
2 5C 2 5 2 5 Na, H
0CH2COCl -C2HS -CH2~ Na, H
00cH2COCl -C2H5 C 20 Na, H
COCl -C2H5 ~ Na, H
N3(CH2)2COCl C2H5 -(CH2)2N~2 H
N3(CH2)3COCl -C2H5 ( 2)3 2 H
2 ( 2)3 -C2HS -(CH2)3NHOH Na, N3(CH2)4COCl -C2HS (CEI2)4~1H2 CH3COCl iso-C H7 -CH3 Na, H
C2 5COCl iso-C3H7 -C2H5 Na, H
COC1 iso-C3H7 ~ Na, H
COCl iso-C3H7 ~ Na, H

~ COC1 iso-C3H7 ~ iNa, H

0CH2COCl iso-C3H7 -CH2~ ~ia, H

3 2 iso-C H 2 2 -~7 -o ~f3~6~

N3(CH2)2COCl iso-C H (C~l2)2'~ 2 3(C~12)3COCl iso-C3H7 -(CH2)3NH2 H
2 ( 2) 3 Cl iso-C3H7 -(CH2)3NHOH Na, H.

Example ~
cis- and trans-6-Acetoxymethvl-2 aminomethvlpenem-3-carboxYlic A _ C

a) 3-Acetoxymethyl-4-tritylthio-2-azetidinones (cis and trans isomers) A solution of a mixture of cis and trans 4-acetoxy-3-acetoxymethyl-2-azetidinone (4.7 g, 25 mmoles) (Example 2, structure 26) in water (200 ml) was added rapidly to a vigorously stirred solution of sodium triphenylmethyl mercaptide (from triphenylmethyl mercaptan, 55.2 g; and sodium hydride, 9.6 g, in methanol, 300 ml). The mixture was stirred at room tempera-ture for 4 h and the solids were collected by filtration, washed with water, and dissolved in dichloromethane. The solu-tion was washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, dried and concentrated to leave 85% of a solid which was used as such in tne next experiment.

b) cis and trans 3-Acetoxymethyl-l-(p-nitrobenzyl-2'-hydroxy-2'-acetate)-4-tritvlthio-2-azetidinones A solution of the above azetidinone (8.0 g, 20 mmoles) and p-nitrobenzyl glyoxylate (4.54 g, 20 mmoles) were refluxed in benzene (100 ml) through a Dean-Star~ water separator filled 1~6~
with 3A molecular sieves. After 24 h a second quantity of p-nitrobenzyl glyoxylate (4.54 g) was added and the reflux continued for a further 24 h. The mixture was diluted with ether, washed with 5% aqueous hydrochloric acid, water, aqueous 5% sodium bicarbonate and water. Drying and cbncentration left 100% of the crude isomeric mixture as an oil.

c) cis and trans 3-AcetoxvmethYl-l-p-nitrobenzyl-2'-chloro-2'-acetate)-4-tritYlthio-2-azetidinones A solution of azetidinones from part b(l2.2 g, 20 mmoles) and pyridine (1.9 g, 24 mmoles) in dried THF (150 ml) was cooled to -15 and treated dropwise with thionyl chloride (2.86 g, 24 mmoles) under a nitrogen atmosphere. The mixture was stirred 45 min at -15, the precipitate was removed by filtration and washed with benzene, and the filtrates were concentrated to leave a semi-solid (95%).

d) cis and trans 3-Acetoxymethyl-l-(p-nitrobenzYl-2'-tri~henYl-Phosphoranvlidene-2'-acetate)-4-tritylthio-2-azetidinones A mixture of azetidinones from step c (12.6 g, 20 mmoles), triphenylphosphine (7.8 g, 30 mmoles) and 2,6-lutidine (2.6 cc, 22 mmoles) in THF (100 ml) was heated under reflux for 80 h. The insoluble material was removed by filtration and washed with ether. The filtrates were washed with 2% aqueous hydrochloric acid,` 5% aqueous sodium bicarbonate and water, dried and concentrated. The residue was dissolved in benzene, filtered slowly through a pad of silica gel (250 g) and the pad was eluted with increasing proportions of ether in benzene. Concentration of the pertinent fractions gave a mixture of the title compounds (65%)- VC=O 1740, Vc=pO3 1620, 1610, vNO2 1525 cm~l.

.~

~2~366~

e) Silver cis and trans 3-Acetoxvmethvl-1-(-nitrobenzyl-2'-triphenvl~hosphoranvlidene-2'-acetate~-2-azetidinone-4-thiolates The crude azetidinones from step d (8.5 g, lo mmoles) were dissolved in hot methanol (55-60). A hot solution (55-60) of silver nitrate (2.04 g; 12 mmoles) and pyridine (0.87 g, 11 mmolesj in methanol (80 ml) was added. The mixture was allowed to cool down to room temperature in 2 h and stirred a further 1 h at 0~. The silver mercaptide was collected by filtration, washed with ice-cold methanol and then with ether (5.7 g, 82%, melts with decomposition). vc=O 1745, 1740, 1625 cm~1.

f) cis and trans 3-AcetoxYmethvl-4-azidoacetYlthio-1-(p-nitrobenzyl-2'-tri~henylphosphoranvloidene-2'-acetate)-2-azetidinones The above silver mercaptide tfrom step e; 1.4 g, 2 mmoles) in dichloromethane (15 ml) treated as described in Example 28 with azidoacetylchloride (2.3 mmoles) gave 0.78 g of a yellow powder.

g) cis and trans 6-Acetoxvmethyl-2-azidomethvl~enem-3-carboxylic Acid p-Nitrobenzvl Esters A solution of the above crude phosphorane (0.70 mg) in toluene (35 ml~ was kept at 105 for 1 h, cooled and concentrated to leave an oil which was purified by chromatography over silica gel (25 g) eluting with increasing proportions of ether in benzene. The pertinent fractions were concentrated to give the cis and trans-isomers of the title compound.

6~

cis isomer: ~ (ppm, CDC13): 8.5-7.5 (4H, aromatics), 5.67 (lH, d, J = 5, H-5), 5.31 (2H, AB quartet, Cli2-benzyl), 4.50 (2H, A~ quartet, CH2N3), 4.33 (2H, d, AcOCH2), 4.26 (lH, dt, H-6), 2.0 (3H, s, CH3).

trans isomer: ~ (ppm, CDC13): 8.5-7.5 (4H, aromatics), 5.62 (lH, d, J = 2, H-S), 5.33 (2H, A3 quartet, CH2-benzyl), 4.40 (lH, dt, H-6), 4.50 (2H, A~ quartet, CH2~3), 4.27 (2H, d, AcOCH2), 2.0 (3H, s, CH3).

h) trans 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic A _ Hydrogenation of the above trans isomer by the procedure described in Example 28 gave the title compound.
vc=O 1775, 1740, 1616 cm 1. ~max 304 (~ = 3192).

i) cis 6-Acetoxymethyl-2-aminomethylpenem-3-carboxylic A _ Hydrogenation of the corresponding cis isomer as described in Example 28 gave the title compound as an unstable hygroscopic semi-solid.

_ q/_ ~2~366~

Example ~
The following compounds may be prepared according to the general procedure of Example ~ .

~N--~
CO2 z Acylating Agent Y X Z
CH3COCl -C~20Ac -CH3 H
C~H5COCl C 2 -C2H5 H
COCl -CH2Ac ~ H
COCl -CH2Ac ~ H

~ OCl -CH2Ac ~ H

3( 2)2 2 -(CH2)2~H2 H
N3(CH2)3COCl C 2 -(CH2)3NH2 H
N3(CH2)4COCl C 2 -(CH2)4NH2 H
02N(C 2)3 C 2 -(CH2)3NHOH H
CH3COCl -(CH2)2OAC -CH3 H

COCl -(CH2)20Ac ~ H
3 2 -(CH2)20AC 2 2 H
3t 2)2C ( 2)2 -(CH2)2~H2 H
N3(CH2)3COCl -(CH2)20AC (C 2)3 2 H

-3 -Cli-OAc -CH3 H

3 2 -C~.-OAc ~2 2 li _q,~,_ 1~36~
Exam~le 17 _ cis an~ trans 6-(l'-Hydroxy-1'-ethyl)-2-meth~lpenem-3-carboxylic Acld. Sodlum Salts IH
(Y = -CH-CH3; X =-CH3) To a solution of 2-methylpenem-3-carboxylic acid (100 mg, 0.54 mmoles) in THF (8 ml) was added diisopropyl-amine (0.08 ml, 0.57 mmoles) at 0 and n-butyl lithlum (0.75 ml, 1.20 mmoles) at -78. After stirring 2 min at -78, ~,~r~6fi~il freshly distilled acetylaldehyde (0.5 ml) was added and stirring was continued for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was acidified with O.lN hydrochloric acid (18 ml) and extracted with ethyl acetate (3 x 20 ml). Concentration of the dried ethyl acetate phases left an oil (49 mg). The oil was dissolved in methylisobutyl ketone and treated with an excess of sodium methylhexanoate in the same solvent.
Addition of ether precipitated the title compounds as a white amorphous solid (25 mg). ~ (ppm, D20): 5.6-5.83 (lH, m, H-5, cis and trans), 2.27 (3H, s, CH3 ), 1.22 and 0.90 (3H, 2d, CH3).

Example 18 cis 6-(1'-HydroxY-l'-ethyl)-2-methylpenem-3-carboxylic Acid Sodium Salt (isomer "D") 2-Methylpenem-3-carboxylic acid (100 mg) was treated with LDCA and acetaldehyde as described in Example 17. The residue (58 mg), obtained after concentration of the dried ethyl acetate phases, was extracted with ether and the ether solution concentrated to an oil (48 mg). This oil was con-verted to a sodium salt with sodium methyl hexanoate as described in Example 17. This yielded 29 mg of a white solid which was identified as cis-6-(1'-hydroxy-1'-ethyl)-2-methyl penem-3-carboxyllc acid, sodium salt, contaminated with a little sodium 5-methyl-1,3-thiazole-4-carboxylate. ~ (ppm, DMS0-d6): 5.5 (lH, d, J = 4.1, H-5), 2.22 (3H, s, CH3), 1.02 (3H, d, J = 5.5, CH3).

1~36~;61 ExamDle 19_ cis a~d traB~
6-t2'-Hydroxy-2'-p~o~yl)-2-e~lylpenem-3-carboxylic 5Acids. Potassium Salt~s (Y = (CH3)2 C-; X = -C2H5) OH

Substitution in the general procedure of Example 3 for the 2-methylpenem-3-carboxylic acid used therein of an equimolar amount of 2-ethylpenem-3-carboxylic acid gave a mixture of potassium salts. ~ (ppm, DMSOd6 ): 5.60 and 5.56 (lH, 2d, J = 4 and J = 2, H-5), 3.92 and 3.60 (lH, 2d, J = 4 and J = 2, H -6), 2.88 and 2.86 (2H, 2q, CH2-CH3), 1.47, 1.41, 1.36 and 1.32 (6H, 4s, CH3), 1.2 and 1.4 (3H, 2t, CH2CH3)- ~ max 257 (~ = 3705) and 302 ( F = 3815) 20Example 20 cis and trans 6-1'-Hydroxy-l carbQxYlic Acid. Sodium Salts To a solution of 2-methoxymethylpenem-3-carboxylic acid (see Preparation 6; 116 mg, 0.55 mmoles) in THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at O and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78. After stirring 2 min at -78 freshly distilled acetaldehyde (0.5 ml) was added and stirring was continued for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (0.lN, 18 ml) and extracted with ethyl acetate (3 x 20 ml).
Concentration of the dried ethyl acetate phases left an oil (53 mg) which _ 9s _ g~

36~
was converted to a mixture of the sodlum ~alt~ of the tltle compounds as described in Example 17. White amorphous hydro-scoplc powder (21 mg). ~ (ppm, D2O): 5.7-5.85 (lH, m, H-5, cis and tran~) 3.38 (3H, 28, OCH3 1.22 and 0.92 (3H, 2d, S CH3). vC=O 1770, 1600 cm 1 Example 21 cis and tran6 6-Acetyl-2-methvlpenem-3-carboxylic Acid.
Sodium Salts 15 (Y = -C-CH3; X = -CH3) To a solution of 2-methylpenem-3-carboxylic acid (100 mg, 0.54 mmoles) in THF (10 ml) was added diisopropylamine (0.08 ml, 0.57 mmoles) at O and n-butyl lithium (0.75 ml, 1.20 mmoles) at -78. After stirring for 2 min at -78, ethyl acetate (1 ml) was added and stirring was continued for 10 min. The reaction mixture was quenched with a saturated ammonium chloride solution (10 ml) and washed with ethyl acetate. The aqueous layer was carefully acidified at O with 0.lN hydrochloric acid and extracted rapidly with ethyl acetate (3 x 20 ml). Concentration of the dried extracts left an oil (36 mg) which was converted to the title compounds as described in Example 17. ~ (ppm, D2O): 5.90-6.10 (lH, 2d, J = 4, J = 2, H-5), 3.8 (lH, m, H-6 cis and trans3, 2.34 and 2.27 (3H, 2s, CH3), 2.12 and 2.0 (3H, 2s, CH3).

,.~

~J~6 Example 22 The following compounds may be prepared according to the ge~eral procedures of Examples 3-5 and 17-21.

S
/~ x ~__ N ~
CO2 z X Y Z

-CH-nBu Na -CH3 o -C-0 Na -CH3 -CH20H Na -CHCF3 Na -C-CH3 Na -C-CH3 Na -CH-CH3 Na -C(CH3)2 K

-C-CH3 Na x y z 8H Na -C(CH3)2 K

-CH20CH3 0 s -C-CH3 Na -C-0 Na 2 3 OjH
-CHCH3 Na 3~ ~ OH
-CH -C ~ -C-(CH3)2 K

~ ;~J36~
Example 23 The following compounds may be prepared according to the general procedure of Example 3.

~ /~x N ~
CO2 z :~ Y, Z
OH
~H -CHCH3 Na _ 99 _ ~'~r~fi~6~ ~' ' ' ' x y z -OH
-H -CH-~ K
0~
6 4 3 Na OH
-H -CH-n-C El Na OH
-H -CH-CF Na -H -CH20H Na -H -C-CH3 Na o -H -C-~ Na OH
-CHCH3 Na OH
-CEI-~ K
jo -C-CH3 Na OH
-CH-CH Na OH
2 0 . -CH-CH ~a 0~
C 2~ -CH-~ X
OH
-CH200 -C}~(CH3)2 _loo--O lzJ3666 ~y Example ~

2-(4'-Phthalimido-l'-butyl)oenem-3-carboxylic Acid "N il--TEA HzS ~ ~ H

To a solution of triethylamine hydrosulfide, previously prepared by bubbling H2S gas through a methylene chloride (200 ml) solution of triethylamine (8.8 ml, 63.7 mmoles), was added dropwise a methylene chloride (75 ml) solution of 1 (Gabriel Ber. 41, 2010) (10.65 g, 40.2 mmoles), at 0C over a 30 min period. The mixture was stirred at 0C for 15 min and 2 h at room temperature. The Organic solution was diluted with methylene chloride (125 ml) and washed with lN HCl (2 x lS ml), water (2 x 15 ml) and brine. It was dried over MgS04 and the solvent was flashed down to give 10.5 g (100%) of 2 as a white solid. m.p.: 93-94C n.m.r. (CDC13) ~ 7.5 - 8 (4H, m), 4.47 (lH, broad s), 3.5 - 3.9 (2H, m), 2.5 - 2.9 (2H, m), 1.4 - 1.9 (4H, m). Anal. calc'd for C13H13NO3S: C, 59.29; H, 4.97; N, 5.32;

S, 121t. Found: C, 58.92; H, 4.91, N, 5.42; S, 12 31.

--tO~ ~

~ 2~36-~6~L

P.c ~~--s~
rNf ~ ~aHC03 3 F~ J---J

A suspension of 2 (3.04 g, 11.6 mmoles) in a solution of IM sodium bicarbonate (11.6 ml) was stirred at room temperature under nitrogen for 15 min. To it was added 3 (1.5 g, 11.6 mmoles) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted with methylene chloride.
The organic phase was dried and evaporated in vacuo to give 3.82 g of solid 4; m.p.: 95 - 96C; i.r. (CHC13) 1775, 1710 cm~1. n.m.r. ~ 7.8 (4H, d, J = 2Hz) 7.05 (]-H, broad s), 5.25 (lH, dd, Jcis = 5Hz, Jtrans = 3Hz), 3.5 - 3.0 (2H, m) , 1.5 - 2.0 (4H, m) Anal. calc'd for: C16Hl6N204S: C, 57.62; H, 4.85; N, 8.43; S, 9.64. Found C, 57.43; H, 4.82; N, 8.44; S, 9.71.

~6~

C8_co2cH2~>N02 C02CH 2~No2 A benzene solution (30 ml) of 4 ~3.0 g, 9.04 mmoles~ and p-nitrobenzyl glyoxalate (2.22 g, 9.8 mmoles) was refluxed under a Dean-Stark condenser filled with 3A mole-cular sieves for 21 h. Evaporation of the solvent afforded 5.4 g of 5 as an oil (100%). i.r. (neat) 3200 - 3600, 1770, 1710, 1525 cm n.m.r. (CDC13) ~ 8.21 (2H, d J = 9Hz), 7.75 (4H, d J = 2Hz), 7.52 ~2H, d, J = 9Hz, 5.52 (lH, broad s), 5.32 (3H, 2s), 4.55 (lH, broad s), 3.5 - 3.7 (2H, m), 3.45 (lH, gem cis SHz) 3.02 (lH, dd, J = 15Hz J
= 3Hz), 2.4 - 2.9 (2H, m), 1.4 - 2.0 (4H, m) ~ SOC12 ~f ~

C2CH 2~Ho2 C02CH 2~02 Azetidinone glyoxalate 5 (4.9 g, 9.05 mmoles) was treated at 0C with thionyl chloride (15 ml) at 0C
for 0.5 h and at room temperature for 1 h. The excess of thionyl chloride was codistilled with benzene in vacuo to --Jo3--12~3~i661 afford 6 as a yellow syrup ~5.0 g, 100~) n.m.r. (CDCL3) ~ 8.2 (2H, d, J = 9Hz), 7.72 (4H, broad 5), 7.60 (2H, d, J = 9Hz), 6.1 ~lH, broad s), 5.50 - 5.85 (lH, m), 5-32 t2H, 2s), 3.4 - 4.0 (2H, m), 3.1 - 3.3 (lH, m), 2.8 -3.05 (lH, m), 2.50 - 2.85 (2H, m), 1.5 - 1.9 (4H, m).

~3P
C02CH2~No2 C02CH2~No2 A solution of 6 (21.6 q, 38.8 mmoles) in tetrahydrofuran (85 ml, distilled over ~AH) was treated with triphenyl phosphine (10.2 g, 38.8 mmoles) and 2.6-lutidine (5.0 ml, 42.9 mmoles) for 18 h at 40C. The mixt~re was diluted with benzene-ether 1:1 (30 ml), washed with water, lN HCl, saturated NaHC03, brine and dried over MgSO4. Evaporation of the solvent afforded a dark brown oil.
It was passed through a silica gel (700 g) column (benzene-ether) to give 16.0 g (53~) of 7 as a thick oil. NMR (CDC13) ~ 8.2 (2H, d, J = 9Hz), 7.8 (8H, d, J = 2Hz), 7.52 (16H, broad s), 5.2 (lH, broad s) 4.78 (lH, 2s), 4.30 - 4.52 (lH, m), 3.5 - 3.8 (2H, m), 2.8 - 3.5 (2H, m), 2.1 - 2.9 (4H, m), 1.5 - 1.9 (4H, m) 1~36661 5 F~ 3 ~ ~N
C2CH 2~No2 2 2 2 A solution of phosphorane 1 (5.0 g, 6.4 mmole6) in toluene (35 ml) was refluxed for 3 h. Evaporation of the solvent gave a residue which was passed through a silica gel (100 g) column. Elution with benzene followed by ether gave 600 mg of the ester 8 as oil i.r. (neat 1790, 1710, 1520 cm 1 n.m.r. (CDC13) ~ 8.22 (2H, d, J = 9Hz), 7.82 (4H, d, J = 2Hz), 7.65 (2H, d, J = 9Hz), 5.69 (lH, dd, Jci8 =
4Hz, Jtran8 2Hz), 5.35 (2H, 2s), 5.12 (lH, dd, Jgem = 16Hz, Jci8 = 4Hz), 3.50 (lH, dd, Jgem = 16Hz~ Jtrans = 2Hz)~
3.1 - 3.8 (2H, m), 2.5 - 3.0 (2H, m), 1.4 - 2.0 (4H, m).
O o ~ ~0~) C2CH No2 C02H

A two phase mixture made of ester 8 (196 mg, 0.
39 mmole) in ether (2 ml) , tetrahydrofuran (4 ml) and sodium, bicarbonate (32 mg, 0.39 mmoles) in water (2 ml) was hydrogenated on 30~ Palladium on Diatomaceous earth (190 mg) in a Parr shaker at 40 p. B. i. H2. After 4.5 h it was filtered over "CELITE"* pad and the pad was washed with water and tetrahydrofuran. The filtrate and washings were combined and the organic phase was *Trade Mark ~.

~2r~3666~ ~

separated. The aqueous solution was washed with ether, aci-dified with lN hydrochloric acid (3 x 0.4 ml) and extracted (after each acid portion added) with ethyl acetate ~4 x 2 ml).
The organic extracts were washed with brine, dried Gver MgS04 and the solvent was removed by evaporation to afford the acid 9, 67 mg (47%), as a yellow solid. i.r. ~nujol) 1775, 1705, 1690 cm 1.
n.m.r. (DMS0) ~ 7.92 (4H, s), 5.71 (lH, dd, J i ~ 4Hz, Jt = 2Hz), 3.90 (lH, dd, J = 16 Rz, Jcis = 4Hz), 3.47 (lH, dd~

J = 16 Hz, J = 2Rz), 3.3 - 4.3 (3R, m), 2.7 - 3.05 2H, m), gem trans 1.5 - 2.0 (4H, m).

--lo6--~f~6~i6~L
Example 2 Sodlum 2~-(Aceton~ln~h~L-n~ ~nem-3-~1kQ8yLL~
o ~ H 3 C2Na ~
r--f~ 2 3 ~ sCOCH2--C--C~3 Ketal 1 (2.0 g, 4.54 mmoles) was treated at 0 with 95% TFA (20 cc) for 15 min. The mixture was diluted with brine and extracted with methylene chloride (4 x 30 cc).
The methylene chloride extracts were washed with, water-brine (3 times) and brine, and dried over MgSO4 (1.44 g, 80%).
~ (ppm, CDC13) 8.27 (2H, d, J = 9, Hm aromatic), 8.60 (2H, d, J = 9, Ho aromatic), 5.70 - 5.25 (m, CH2- PNB, H-C-O, OC~ ~
H-4, _C=C ), H OH
4.75 (lH, bs, OH), 3.76 (center of ABq, CH2-CO), 3.47 (part of a dd~ J3_4 ci~ = 5~ H-3), 3.05 (2H, 2dd, Jgem = 15, J3_4 trans = 3, H-3), 2.30, 2.28 (1.67H, 2s, CH3), 1.98 (1.33 H, s, CH3) VC=O (CHC13) 1780, 1755, v NO 1525.
N__OCH
0 l~ 3 Il ~SCOCH -C-CH
~ ScocH2ccH3 ~ 2 3 ~ N~fpH ~ N~H

C02PNB ` co2P~a ~.~J~

A methylene chloride (50 cc) solution of ketone 2 tl.44 g, 3.63 mmoles) was treated at O under nitrogen atmosphere with methoxyl amine hydrochlorlde (334 mg, 1.1 eq.).
Triet~yl amine (367 mg, 0. 51 cc, 1 eq.) was then added dropwise to the mixture. It was then stirred at room temperature for 18 h. The reaction mixture was diluted with methylene chloride, washed with water-brine (2 times), brine and dried over MGSO4 (1.52 g, 98%).
~ (ppm, CDC13) 8.12 (2H, d, J=8, Hm aromatic), 8.40 (2H, d, J = 8 Ho aromatic), 5.50-5.05 (4H, m, CH2- PNB, H-4, H-C-O), 3.80-3.60 (m, OCH3, part of H-3 cis, part of OH), 3.55-270 (m, part of H-3 cis, H-3 trans, CH2CO, part of OH), 1.97, 1.90, 1.88 (3H, 3s, CH3) VC=O (CHC13) 1770, 1750, 1690.

N~OCH3 N`~ OCH3 ¦~' OH SOC12 ~ 2 3 a~N~ pyrLdlne ~ N~Cl A cold (-15C) THF (20 cc, distilled over LAH) solution of azetidinone 3 (1.52 g, 3.57 mmoles) was treated dropwise with pyridine (325 mg, 0.332 cc, 4.10 mmoles, 1.15 eq) and thionyl chloride (488 mg, 0.299 cc, 4.10 mmoles, 1.15 eq) under nitrogen atmosphere. The mixture was stirred for 15 min at -15. The solid was filtered off and washed with benzene. The resulting solution was evaporated down.
The residue was taken upon benzene and treated with charcoal (1.2 g, 76%) ~ (ppm, CDC13) 8.23 (2H, d, Hm aromatic), 7.80 (2H, d, Ho aromatic), 6. 12, 6.08 (lH, 2s, H-C-Cl) , 5.75 - 5.55 (lH, m, H-4), 5.40, ........

~6~
5. 30 (2H, 2s, CH2- PNB) , 3.95 - 3.80 (3H, 3s, OCH3) 3.80 - 2.95 (4H, m, 2H-3, CH2-CO), 2.00 - 1.85 (3H, 4s, CH3) vc=O (CHC13) 1790, 1765 (shoulder), 1700, v NO 1530.

N~OCH3 N~OCH3 ~FN~C1 ~L N~P~3 0 pNa ~ 5 A THF (20 cc, distilled over LAH) solution of chloroazetidinone 4 (1.2 g, 2.70 mmoles) was treated with triphenyl phosphine (1.06 g, 4.05 mmoles 1.5 eq) and 2,6-lutidine (318 mg, 0.346 cc, 2.97 mmoles, 1.1 eq). The mixture was stirred for 4 days at room temperature under nitrogen atmosphere. It was diluted with ethyl acetate, washed with 2% aqueous HCl, H20, 2% aqueous NaHC03, water and brine. The solution was then dried over MgS04 and the solvent was evaporated. Crude 5 was purified on silica gel (10 times by weight) column (ethyl acetate, 770 mg, 25 45%).
vc=o (CHCl3) 1755, 1695, v 1630 - 1610, ~ NO 1525.

S COCH - C - Cl~ ~ C H - C - C H

N~P3 Toluene O N ~
r co PNB
Co2PNB 2 .
:

J~
Phosphorane 5 (700 mg, 1.05 mmole) was refluxed in toluene for 4.5 h. Toluene evaporation afforded a residue which was passed through a silica gel (1:15 ratio) column (4% ether-~enzene). It gave 6 as a crystalline material (251 mg, 62%, m.p. 116-125) Anal. calc'd for C17H17N3O6S: C, 52-17;
Found: C, 51.15; H, 4.18; N, 10.33.
(ppm, CDC13) 7.70 (2H, d, Hm aromatic), 7.12 (2H, d, Ho aromatic), 5.00 (2H, s, CH2PNB), 4.85 (lH, m, H-5), 3.75 - 2.70 (7H, m, CH30, CH2, H-6), 1.77, 1.72, 1.65 (3H, s, CH3)-v c=o (CHCl3) 1787, 1742, 1705, NO2 1530.

U.V. (EtOH) ~max 318 (E = 8420), 262 (~ = 12,539) .

OCH3 H ~ CH -C-CH
2 3 NaHC03 N~ 2 3 20 CO2PN~ C02Na A mixture of ester 6 (151 mg, 0.386 mmole) in THF (20 cc), ether (40 cc) and NaHCO3 (32 mg, 0.381 mmole) in water (20 cc) was shaken ln a Parr hydrogenator for 3 h at 35 p.s.i. H2, using 30% Pd on "CELITE"* (200 mg) as catalyst. The catalyst was filtered off and washed with water and ether. The resulting aqueous mixture was washed with ether (3 x 60 cc) and lyophilized (32 mg, 30%).
~ (ppm, DMSO) 5.50 (m, H-5), 3.75 (s, OCH3), 0.77 (s, CH3).
Vc=O ("NUJOL MULL")* 1770, 1600, 1400.
U.V. (H2O) max 300 ( F = 2,800) , 255 ( F = 2,400).
*Trade Mark 12r3~61 Example ~P
The following 2-penem compounds may be prepared by acylation of l-(p-nitrobenzyloxycarbonylmethyltriphenyl-phosphoranyl)-4-(silver mercaptidyl)-2-azetidinone with the appropriate acylating agent followed by cyclization and deblocking steps. The general reaction scheme is shown below:

O O
SAg or ~ SCOR

2. RCOCl ~

Co2pNB C02PNB

S\ H2/30% Pd/diatomaceous ~R earth >

r, S
¦ ~ R
~----N ~

for variation 1: use RCO2~ + iBuCOCl for variation 2: use HCl + PC15 + RCO2H

12~3666~

Acvlatinq Agent ~ethod Product NH-(c}l2)4-co2H 1 2-(4-Aminobutyl)penem-3-carboxyllc acld 0C~12OCONH-CH-co2~l 1 2-(1-Aminoethyl)penem-3-(both D and L) carboxylic acid 0CH2OCONH-CH-CO2H 1 2-(1-Aminopropyl)penem-3-(both D and L) carboxylic acid CEI_cH3 0cH2ocoNH-cH-co2H 1 2-(1-Amino-2-methylpropyl)-(both D and L) p~nem-3-carboxylic acid 0CH2OCONII-CH-CO2H 1 2-(1-Aminobenzyl)penem-3-(both D and L) carboxylic acid 0CH2OCONH-CH-CO2H 1 2-(1-Amino-2-phenylethyl)-(both D and L) penem-3-carboxylic acid CH2OCH20-NO2-p ~CH20CONH-CH-C02H 1 2-(1-Amino-2-hydroxyethyl)-(both D and L) penem-3-carboxylic acid 0CH2OCONH-CH-CO2H 1 2-(1-Amino-2-carboxyethyl)-(both D and L) penem-3-carboxylic acid CH2coNH
0CH2OCONH-CH-CO2H 1 2-(1-Amino-2-carbamoylethyl)-(both D and L) penem-3-carboxylic acid 0CH OCONH-CH-CO2H 1 2-(1-Amino-3-methylthiopropyl)-(both D and L) penem-3-carboxylic acid (CH2) 4NHCo2CH2Ç5 0CH2OCONH-CH-CO2H 1 2-(1,5-Diaminopentyl)penem-(both D and L) 3-carboxylic acid 0cH2ocoNcH2co2H 1 2-[(Methylamino)methyllpenem-3-carboxylic acid CH
0cH2ocoNcH2cH2co2H 1 2-~2-(Methylamino)ethyll-penem-3-carboxylic acia ~13~

Acylatinq Agent Method Product 0CH20CONCH2CH2C1~2C02H 1 2-[3-(Methylamino)propyl]-penem-3-carboxylic acid C11~3 0cH2ocoNcH2cH2cH2cH2co2Ei 1 2-[4-(methylamino)butyl]-penem-3-carboxylic acid Cl 2H5 0CH20CONCH2Co2H 1 2-[(Ethylamino)methyl]penem-3-carboxylic acid f2H5 0cEl2ocoNcH2cH2co2H 1 2-[2-~Ethylamino)ethyl]penem-3-carboxylic acid f 2H 5 0CONCH2CH2c~2co2H 1 2-[3-(ethylamino)propyl]-penem-3-carboxylic acid 0CH20CONCH2CH2CH2CH2C02H 1 2-[4-(Ethylamino)butyl]-penem-3-carboxylic acid 0CH20CONCH2C02H 1 2-[(Phenylamino)methyl]-penem-3-carboxylic acid 0cH2ocoNcH2cH2co2H 1 2-[2-(Phenylamino)ethyl]-penem-3-carboxylic acid 0cH2ocoNcH2cH2cH2co2H 1 2-[3-(Phenylamino)propyl]-penem-3-carboxylic acid 0cH2ocoNcH2cH2cH2cH2co2H 1 2-[4-(Phenylamino)butyl]-penem-3-carboxylic acid CH3CONHCEi2C02H 1 2-[(Acetylamino)methyl]-penem-3-carboxylic acid CH3CONHCHzCH2C02H 1 2-[2-(Acetylamino)ethyl]-penem-3-carboxylic acid CH3cON C 2C 2C 2C 2 1 2-~3-(Acetylamino)propyl]-penem-3-carboxylic aci G
~1/3 .

~2~36C~

Acylatinq Aqent Method Product -CH3CONHCH2CH2CH2CH2C02H 1 2-[4-(Acetylamino)butyl]-penem-3-carboxylic acid C6H5CONHCH2C02H 1 2-[(Benzoylamino)methyl]-penem-3-carboxylic acid C6H5coNHcH2cH2co2H 1 2-[2-~Benzoylamino)ethyl]-penem-3-carboxylic acid 6 5 2 2 2C02H 1 2-[3-(Benzoylamino)propyl]-penem-3-carboxylic acid C6H5coNHcH2cH2cH2cH2co2H 1 2-[4-Benzoylamino)butyl]-penem-3-carboxylic acid 0cH2ocoNHcH2coNHcH2co2H 1 2-[(Glycinamido)methyl]-penem-3-carboxylic acid 0cH2ocoNHcH2coNHcH2cH2co2H 1 2-[2-(Glycinamido)ethyl]-penem-3-carboxylic acid 0cH2ocoNHcH2coNHcH2cH2cH2co2H 1 2-[3-(Glycinamido)propyl]-penem-3-carboxylic acid H2ocoNHcH2coNHcH2cH2cH2- 1 2-[4-(Glycinamido)butyl]-CH2C02H penem-3-carboxylic acid H2NcoNHcH2co2H 1 2-(Ureidomethyl)penem-3-carboxylic acid H2NcoNHcH2cH2co2H 1 2-(2-Ureidoethyl)penem-3-carboxylic acid 2 2 2C 2C2H 1 2-(3-Ureidopropyl)penem-3-carboxylic acid H2NCONHCH2CH2C~2CH2C02H 1 2-(4-Ureidobutyl)penem-3-carboxylic acid 1 Xf~ ~ 6 ~
Acvlatina AaentMethod Product CH3~HCONHCH2C02H 1 2-~(Methylcarbamoylamlno)-me~hyl~penem-3-c~rboxylic ~cid CH3NHCONHCH2CH2C02H 1 2-[2-(.~ethylcarbamoylamino)-methyl]penem-3-carboxylic acid CH3NHCONHCH2CH2CH2C02~ 1 2-[3-~Methylcarbamoylamino)-propyl]penem-3-carboxylic acid CH3NHcoNHcH2cH2cH2c~2co2H 1 2-[4-(~lethylcarbamoylamino)-butyl]penem-3-carboxylic acid 0tJHCONHCH2CO H 1 2-[(Phenylcarbamoylamino)-mF_hyl]penem-3-carboxylic acid 0~HcoNHcH2cH2co2H 1 2-[2-Phe~.ylcarbamoylamino)-ethyl]penem-3-carboxylic acid 0NHcoNHcH2cH2c~2co2H 1 2-[3-(Phenylcarbamoylamino)-propyl]?enem-3-carboxylic acid ~NHcoNHcH2c~2c~2cH2co2H 1 2-[4-(Phenylcarbamoylamino)-butyl]penem-3-carboxylic acid CH3CONHCONHCH2C02H 1 2-[(Acetylcarbamoylamino)-methyl]?enem-3-carboxylic acid CH3CONH CONHCH2CH2C02H 1 2-[2-(Acetylcarbamoyla~ino)-ethyl~penem-3-car~oxyl~c acid CH3coNHcoNHcH2cH2c~2co2H 1 2-[3-(Acetylca-bamoylamino)-propyl]penem-3-car~oxylic aci_ CH3C0 2 2 2 2 2 1 2-[4-~cetylca_bamoylamino)-butyl]penem-3-carboxylic acid 0CONHCONHCH2C02H 1 2-[(Benzoylcarbamoylamino)-metnyl3penem-3-carboxylic acid ~36~

Acylatinq Aqent Method Product 0CONHCONHCH2C~2CO2H 1 2-- [2- (Benzoylcarbamoylamino~-ethyl]penem-3-carboxylic acid 0COI~HCONHCH2CH2CH2CO2~ 1 2- [3-~Benzoylcarbamoylamino)-propyl]penem~3-carboxylic acid 0CONHCONHCH2CH2CH2CH2CO2H 1 2- [ 4-tBenzoylcarbamoylamino)-butyl]-penem-3-carboxylic aci~

CH3OCONHCONHCH2CO2H 1 2- [ (Carbomethoxycarbamoyl-amino)methyl]penem-3-carboxylic acid CH3OCONHCONHCH2CH2CO2H 1 2- [2-(Carbomethoxvcarbamoyl-amino)ethyl]penem-3-carboxylic acid CH3ocoNHcoNHcH2c~l2cH2co2H 1 2-[3-(Carbomethoxycarbamoyl-~mino)propyl]penem-3-carboxylic acid CH3ocoNHcoNHcH2cH2cH2cH2co2~ 1 2-[4-(Carbomethoxycarbamoyl-amino)butyl]penem-3-carboxylic acid (cH3)3si(cH2)2ocoNHcoNHcH2co2H 1 2-[t2-trimethylsilylethyloxy-carbonylcarbamoylamino)-methyl]penem-3-carboxylic acid 3 3 2)20-ONHcoNHcH2- 1 2-[2-(2-trimethylsilylethyl-CH2C02H oxycarbonylcarbamoylamino)-ethyl]penem-3-carboxylic acid 3 3 2)2 CoNHcoNHcH2 1 2-~3-t2-trimethylsilylethyl-2c~2co2H oxycarbonylcarbamoylamino)-propyl]penem-3-carboxylic acic fi~

Acylating Aqent Method Product (CH3)3si(cH2)2ocoNHcoNHcH2- 1 2-[4-(2-Trimethylsilylethyl-CH2CH~CH2C02H oxycarbonylcarbamoylamino)-. butyl]penem-3-carboxylic acid CH3S2CNHCH2C02H 1 2-[(Methylthiothiocarbonyl-amino)methyl]penem-3-carboxylic acid CH3s2cNHcH2cH2co2H 1 2-[2-(~ethylthiothiocarbonyl-amino)ethyl]penem-3-carboxylic acid CH3S2cNHcH2cH2c 2 2 1 2-[3-(~ethylthiothiocarbonyl-amino)?ropyl]penem-3-carboxylic acid CH3s2cNHcH2cH2cH2cH2co2H 1 2-[4-(Methylthiothiocarbonyl-amino)butyl]penem-3-carboxylic acid CH3S02NHCH2C02H 1 2-[(Methanesulfonylamino)-methyl]penem-3-carboxylic acid CH3S02NHCH2CH2C02H 1 2-[2-(Methanesulfonylamino)-ethyl]penem-3-carboxylic acid CH3S02NHCH2CH2CH2C02 1 2-[3-(Methanesulfonylamino)-propyl]penem-3-carboxylic acid CH3SO2N~CH2CH2CH2CH2C02 1 2-[4-(1~ethanesulfonylamino)-butyl]penem-3-carboxylic acld 0S02NHCH2Co2H 1 2-[(Benzenesulfonylamino)-methyl]penem-3-carboxylic acid AcYlatinq A~ent Method Product ~HcNHcH2cH2co2~ 1 2-[2-(N-~ethylthiocarbamoyl-amino)ethyl]penem-3-carboxylic acid H3CNHCNHCH2C~2CH2C2H 1 2-[3-(N-Methylthiocarbamoyl-amino)propyl]yenem-3-carboxylic acid H3cNHcNHcH2cH2cH2cH2co2H 1 2-[4-(N-Methylthiocarbamoyl-amino)butyl]penem-3-carboxylic acid 0NHcNHcH2co2H 1 2-[(N-Phenylthiocarbamoyl-amino)methyl)penem-3-carboxylic acid 0NHcNHcH2cH2co2H 1 2-[2-(N-Phenylthiocarbamoyl-amino)ethyl]penem-3-carboxylic aci~

0NHcN~cH2cH2cH2co2H 1 2-[3-(N-Phenylthiocarbamoyl-amino)propyl~penem-3-carboxylic acid H2cH2cH2co2H 1 2-[4-(N-Pnenylthiocarbamoyl-amino)butyl]penem-3-carboxylic acid 1I NHCH2C2H 1 2-[(Guanylamino)methyl~-~ penem-3-carboxylic acid ~ 1l 2 2 2 1 2-[2-(Guanylamino)ethyl]-HO ~ ~ penem-3-carboxylic acid NHCH CH CH C02H 1 2-[3-(Guanylamino)propyl]-2 2 2 penem-3-carboxylic acid ~O~
HO

~11~~

~2)~366~l Acylatinq Aqent Method Product N 1l NHCH2CH2CH2CH2C02H 1 2-[4-(Guanylamino)butyl~-~o~N penem-3-carboxylic acid ~ ~ 1 2-[(Acetimidoylamino)metnyl]-H3CJI N-CH2C02H penem-3-carboxylic acid " -CH2CH2C02H 1 2-[2-(Acetimidoylamino)ethyl]-penem-3-carboxylic acid CH2CH2cH2c 2 1 2-[3-(Acetimidoylamino)propyl]-penem-3-carboxylic acid -cH2cH2cH2cH2co2 1 2-[4-(Acetimidoylamino)butyl]-penem-3-carboxylic acid N ~ O
N CH2C 2 1 2-[(Formimidoylamino)methyl]-penem-3-carboxylic acid " -CH2CH2C02H 1 2-[2-(Formimidoylamino)ethyl]-penem-3-carboxylic acid CH2C 2 2 2 1 2-[3-(Formimidoylamino)propyl~-penem-3-carboxylic acid -CH2CH2C~l2cH2c02 1 2-[4-(Formimidoylamino)butyl]-penem-3-carboxylic acid 02NCH2C02 1 2-[(Hydroxyamino)methyl]-penem-3-carboxylic acid 02NCH2CH2C02H 1 2-[2-(Hydroxyamino)ethyl]-penem-3-carboxylic acid 02NcH2cH2cH2cH2co2H 1 2-[4-(Hydroxyamino)butyl]-penem-3-carboxylic acid _//~

l~S~

Acvlatinq AqentMethod Product IOCH3 2[(Methoxyamino)methyl]-(cH3)3si(cH2)2ocoN-cH2oo2H * 1 penem,3-carboxylic acid (CH3)3SI(cH2)2000N-CH2CH2C02H * 1 2-[2-(Methoxyamlno)ethyl]-penemr3-carboxylic acid ~CH3 (CH3)3Si(CH2)20a)NCH2CH2cH2c02H * 1 2-[3-(~5ethoxyamino)propyl]-penem,3-carboxylic acid (cH3)3si(cH2)2oooNcH2cH2cH2cH2co2H * 1 2-[4-(methoxyamino)butyl]-penem-3-carboxylic acid lH2 (cH3)3si(cH2)2ocoNcH2co2H * 2 2-[(Hydrazino)methyl]penem-3-carboxylic acid ~H2 (cH3)3si(cH2)2ocoNcH2cH2co2H * 2 2-[2-(Hydrazino)ethyl]penem-3-carboxylic acid (CH3)3SI(CH2)20C~ cH2cH2cH20o2H * 2 2-[3-(Hydrazino)propyl]penem-3-carboxylic acid (cH3)3si(cH2)2oooNcH2cH2cH2cH2oo2H * 2 2-[4-(Hydrazino)butyl]penem-3-carboxylic acid Nl(CH3)2 (cH3)3si(cH2)2ocoNcH2oo2H * 2 2-[(2,2-Dimethylhydrazino)-methyl]penem,3-carboxylic acid I (CH3)2 (CH3)3Si(CH2)2OcONCH2CH2co2H * 2 2-[2-(2,2-Dimethylhydrazino)-ethyl]penemr3-carboxylic acid 1~6~

I (CH3 ) 2 (CH3)3Si(CH2)20CONcH2cH2cH2oo2H * 2 2-[3-(2~2-Dimethylhydrazino)-propyl]penem-3-carkoxylic acid I (CH3)2 (cH3)3sI(cH2)2oco~cH2cH2cH2cH2oo2H * 2 2-[4-(2,2-Dimethylhydrazino)-kutyl]penem-3-carboxylic acid * use trimethylsilylethyl instead of F~3 in azetidinone intermediate and deblock with r.

- 120(a) -1~6~

Acylating Aqent Method Product CH3coNHNHcH2co2H * 2 2-[t2-Acetylhydrazino)methyl]-penem-3-carboxylic acid CH3coNHNHcH2cH2co2H * 2 2-[2-(2-Acetylhydrazino)-ethyl]penem-3-carboxylic acid CH3CONHNHCH2c 2 2 2 * 2 2-[3-(2-Acetylhydrazino)-propyl]penem-3-carboxylic acid CH3coNHNHcH2cH2cH2cH2co2H * 2 2-[4-(2-Acetylhydrazino)-butyl]penem-3-carboxylic acid (cH3)2NcH2co2H 2 2-[(Dimethylamino)methyl]-penem-3-carboxylic acid H3)2NcH2cH2co2H 2 2-[2-(Dimethylamino)ethyl]-penem-3-carboxylic acid (CH3)2NC 2 2 2 2 2 2-[3-(Dimethylamino)propyl]-penem-3-carboxylic acid (CH3)2NCH2cH2cH2cH2co2~ 2 2-[4-(Dimethylamino)butyl]-penem-3-carboxylic acid CH3coNcH2co2H 1 2-[(N-Methylacetamido)methyl]-penem-3-carboxylic acid CH
CH3CONCH2CH2C02H 1 2-[2-(N-Methylacetamido)ethyl]-penem-3-carboxylic acid CH3coNcH2cH2cH2co2H 1 2-[3-(n-Methylacetamido)propyl]-penem-3-carboxylic acid CH
CH3CONCH2CH2CX2CH2C02H 1 2-[4-(N-Methylacetamido)butyl]-penem-3-carboxylic acid 1~3666~l Acylatinq Aqent Method Product 2 2 1 2-[(Phthalimido)methyl]penem-3-carboxylic acid -CH CH CO H 1 2-[2-(Phthalimido)ethyl]-2 2 2 penem-3-carboxylic acid 1 2-[3-(Phthalimido)propyl]--CH CH CH CO H
2 2 2 2 penem-3-carboxylic acld . 1 2-[4-(Phthalimido)butyl]-~ -CH2CH2CH2CH2CO2H penem-3-carboxylic acid 0CH2OCONHCH2CH2OCH2co2H 1 2-[(2-Aminoetnoxy)methyl]-penem-3-carboxylic acid 0cH2ocoNHcH2cH2scH2co2H 1 2-[(2-Aminoethylthio)methyl]-penem-3-carboxylic acid C~ 02CH20 0cH2ocoNHcH2c~2NcH2co2H 1 2-[(2-Aminoethylamino)methyl]-penem-3-car~oxylic acid 0CH2OCONHCH2CH2NCH2co2H 2 2-[N-(2-Aminoethyl)-N-methylamino]methylpenem-3-carboxylic acid 0CH2OCONH ~ CH2CO2H 1 2-(p-Aminobenzyl)penem-3-carboxylic acid CH2co2H~
0CH2ocoNH ~ 1 2-(o-Aminobenzyl)penem-3-carboxylic acid 0cH2ocoNH ~ CO2H 1 2-(p-Aminophenyl)penem-3-carboxylic acid ~_~C02H
0CH2OCONH ~ 1 2-(m-Aminophenyl)perem-3-carboxylic acid - /:2 ;L-~2~fi~

Acylatinq Aqent Method Product 0CH20CONH ~ 1 2-(o-Aminophenyl)penem-3-carboxylic acid 0CH20CONHCH2 ~ C02H 1 2-[p-(Aminomethyl)phenyl]-penem-3-carboxylic acid ,_~C02H
0CH2ocoNHcH2 ~ ~ 1 2-[m-(~minomethyl)phenyl]-penem-3-carboxylic acid C2H ~
0CH20CONHCH2 ~ 1 2-[o-(Aminomethyl)phenyl]-penem-3-carboxylic acid ~fi~

Example ~
The 2-penem products listed below as the triethylamine salts are treated with (C~3)3N So3 in CH2C12 solution at 0.
Addition of sodium 2-ethylhexanoate in l-butanol to the re-action solution results in precipitation of the indicated products as disodium salts.

Starting Material Product CH2)nNH2~1--~(C~2~n-NHS03Na O O
C02N(C2H5)3 C2Na Exp. A n = 1 A. n = 1 Exp. B n = 2 B. n = 2 Exp. C n = 3 C. n = 3 Exp. D n = 4 D. n = 4 2~
Example ~' The following 2-penem products may be prepared from the indicated starting materials by the procedure ~ ~ (CH2)nN(CH3)2 > N ~ 2 2 ~fi~

H2/Pd ~ ~(C~12)n ( 3 3 Starting Material Product (C32)nN(CH3)2 ~ ~ (C~lz)n ( 3)3 Exp. A n = 1 A. n = 1 Exp. B n = 2 B. n = 2 Exp. C n = 3 C. n = 3 Exp. D n ~ 4 D. n = 4 Examp le ~r The following 2-penem products may be prepared from the indicated starting materials by the procedure SAg Sco(cH2) + Cl(C~2)nCCl ~N ~ p~3 CO PNB
Co2PNB 2 ~/~5-~2~fi~

s ~3 s (CH2)nCl ~ (CH2)n~~

Co2pNB Co2pNB

¦ deblocking ~deblocXing (C~2 ) nC~( CH 2 ) n ~) co2~ C2 Starting Material Product tCH2) nC1 ~ (CH2) n~

Exp. ~ n = 1 A. n = 1 Exp. B n = 2 B. n = 2 Exp. C n = 3 C. n = 3 Exp. D n = 4 D. n = 4 5o Example ~r The following 2-penem products may be prepared from the indicated starting materials by the procedure . 2~3fi66~L

o o o o ,o 11 11 ~SC-(CH2)m-C R TFA ~ ~/SC ( 2)m N`~OH ~/
CO Z
C2 z B 2 O N
H2NB SC (CH2)m co2%

~ SC~ (CH2)m .C-R , 1- ~3P
SOC12 1 1 . >
,~ N C 1 2 .
'1/

S ~B
~ ~ \ 11 L~ ~(CH2)m-C R

OH
~(C~I2)m N ~

m = 0-2 z = - (C~2~ 2Si (C~3~ 3 R = ~I, C~3 B = O (CH2) 2 ( 3 3 -/d 7 -12~36661 Starting Material Product l ~ ~) OH
SC- (CH2)m-C-R S~ N
L N~r OH ~ (CH2)m C R

EXP. A R = H m = 0 A. R = H m = 0 EXP. B R = H m = 1 B. R = H m = 1 EXP. C R = H m = 2 C. R = H m = 2 EXP. D R = CH3 m = 0 D. R = CH3 m = 0 EXP. E R CH3 E. R = CH3 m = 1 EXP. F R 3 F. R = CH3 m = 2.

Substitution in the above procedure of H2NOCH3 for t~e H2NO (CH2) 2Si (CU3)3 USed therein reSU1tS in fOrmatiOn Of the fO11OWing ~roducts.
r ~ S~ llOCI~3 ,Ll ~(CH2) m~C~R

EXP. A m = 0 R = H
EXP. B m = 1 R = H
EXP. C m = 2 R = H
EXP. D m = 0 R = CH3 EXP. E m = 1 R = C~I3 EXP. F m = 2 R = CH3 ~ ~666~L

Substitution in the above procedure of (CH3)3Si-(CH2)20CONHNH2 for the ~2NO(CH2)2Si(CH3)3used therein re-sults in formation of the following products, ~(CH2 ) m~C~R

Exp. A m = O, R = H
~Exp. B m = 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3 Exp. E m = 1, R = CH3 Exp. F m = 2, R = CH3 Substitution in the above procedure of (CH3)2NNH2 for the H2No(CH2)2Si(CH3)3 used th~rein results in formation of the following products:

~_~ S~ , NN(CH3)2 ,~N ~ ( CH 2 ) m~C~ R

co2~

Exp. A m = O, R = H
Exp. B m - 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3 Exp. E m = 1, R = CH3 Exp. F m = 2, R = CH3 .

~ 2~6~61 !

Substitution in the above procedure of (CH~)3Sl(C~2)2OCOM-NH2 for the H2MO(CH2)2Si(CH3)3 used therein results in formation of the following products:

~~ ~(CH2)m~C~R
N ~

Exp. A m = 9, R = H
Exp. B m = 1, R = H
Exp. C m = 2, R = H
Exp. D m = O, R = CH3 Exp. E m = 1, R = CH3 Exp. F m = 2, R = CH3.

_13O -~:2r~6~6~L
Exam~le 31 ~( ~ )2 ~SAg 1~' 5 ~H 2C 1 ~p + C lCOCH 2CH 2Cl ~
C02PNB co2pNa II I ~ I c A solution of I (1.1 g, 1.6 mmole) and II (0.16 ml, 1.6 mmole) in methylene chloride (30 ml) was cooled in an ice bath and treated dropwise with lM solution of pyridine in methylene chloride (1. 7 ml, 1. 7 mmole). The resulting reaction mixture was stirred at room temperature for 1 h and then filtered over celite* and washed with methylene chloride. The filtrate and washings were combined and washed successively with lN HCl (5 ml), water (5 ml), lM
NaHC03 (5 ml) and brine, and then dried (MgS04) and evaporated in vacuo to give III 900 mg ( 87% ) as an amorphous solid. It was used in the next step without further purification. IR (CHC13) 1755, 1690 cm 1 NMR (CDC13) ~ 8. 22 (2H, d, J=9 Hz), 7. 55 (15H, m), 6. 72 (2H, d, J=9 Hz), 5. 7 (lH, m), 5. 0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4H, m).
*Trade Mark 12~6~

~ ~ ~ ~2Cl+ ~ ) p C02PNB ~ 5 ~ ~(--<)2 III IV ~ ~ ~
1 0 C02PN~

A mixture of III (1.3 g, 2 mmoles) and LY (0.65 ml, 3 mmoles) wa6 heated at 80C for 4 h. The reaction mixture was diluted with methylene chloride (10 ml) and washed with water (2 x 5 ml). Organic layer was dried -~
(MgS04) and evaporated in vacuo to give y, 1.4 g (90%), as an amorphous solid. lt was used in the next step without further purification. IR (CHC13) 1755, 1690 cm 1 NMR
(CDC13) ~ 8.25 (2H, d, J=9 Hz), 7.55 (lS H, m), 6.8 (2H, d, J=9 Hz), 5.7 (lH, m), 5.1 (2H, 2s), 4.72 (2H, dq J=12 Hz, J=6 Hz), 2.6 14H,m), 1.4 (6H, 8), 1.28 (6H, s).

25 ~ 5 ~ ~t ~ )2 ~3 Co2pNB ~ ~( ~ )2 v VI
A solution of y (1.6 g, 2.06 mmoles) in toluene (60 ml) waæ heated under reflux for 5 h.
The solvent wa6 evaporated in vacuo and the residual oil was chromatographed on silica gel column l~r366~;1 (30 g). Elution with benzene followed by ether removed first unpolar material and then ethyl acetate gave VI, 620 mg (62%) as a white solid, m.p.: 83-40C from ether, IR (CHC13- r 1790, 1710 cm~1 NMR: (CDC13) ~ 8.2 (2H, d, J=9 S Hz) , 7.6 (2H, d, J=9 Hz) 7.5 (2H, 8) 5. 65 (lH, dd, Jtrans = 4 Hz, Jcis = 2 Hz), 5.22 (2H, 2s), 4.75 (2H, dq J=12 Hz, J=6 Hz) 3.85 (lH, dd, Jgem = 15 Hz, J trans = 4 Hz)~ 3-5 (lH~ dd~ Jgem = 15 Hz, JciB = 2 Hz), 2.8-3.3 (2H, m), 1.4 (6H, s), 1.28 (6H, s).

~ ~ ~(-<)2 ~ F~ ~ 2 C02~NE~ C02H

Vl VII

To a solution of VI (200 mg, 0.4 mmole) in tetrahydrofuran (8 ml) and ether (4 ml) was added sodium bicarbonate (34 mg, 0. 4 mmole) , water (4 ml) and 30% Pd/
"CELITE"* (200 mg) followed by hydrogenation 2h at 40 p.s.i.
The mixture was filtered and layers were separated. The aqueous phase, after washing with methylene chloride (2 x 5 ml) , was cooled with ice, acidified with lN HCl (1 ml), and extracted with chloroform (5 x 5 ml). Organic extracts were dried (MgSO4) and evaporated in vacuo to give VII, 76 mg (52%) , as an oil. IR (CHC13) 1790, 1710 cm 1. NMR
(CDC13) ~ 9.5 (lH, ws) , 5-65 (lH, dd, Jtrans = 4Hz~ Jcis =
2 Hz), 4. 72 (2H, d~ J=12 Hz, J=6 Hz) 4.2- 5.1 (2H, m), 3.4-4.1 (2H, m), 2.7-3.4 (2H, m), 1.35 (6H, s), 1.25 (6H, 8).
*Trade Mark . . --~, ,~.

i6J~
Exam~l~ 32 ~ ~ ~P(o _ lo ~5 q + Clc~c~2)3R(oc2H5)2 - R
C2 PNB ~5 ~/( CH2) 3P (OC2H5 2 l l 1 5 1 2 ~ N ~P ~t~ 3 co2P~a To a cooled (ice bath) mixture of 1 (1.324 g, 2 mmoles) and 2 (0,54 g, 2.2 mmoles, crude) in CH2C12 (15 ml) was added dropwise 1 M solution pyridine /CH2C12 (2.2 ml, 2.2 mmoles). The mixture was stirred at r.t. for 1 h and filtered over "CELITE"*. The filtrate was washed successively wlth 0.5N HC1, H20, 0.5 M NaHC03 and brine. It was driad (MgS04) and filtered over "CELITE"* charcoal to give after evaporation to dryness 0.9 g of an oil. The oil was chromatographed on SiO2 (10% H20) and eluted with ethylacetate to give 0.5 g of 3. (32.8%). NMR
~ (ppm, CDC13) 7.0-8.4 (m, l9H), 4.8-5.8 (3H, m), 4.1 (4H, ~), 3.3-4.2,(2H, m) 2.7 (2H, m),1.9 (2H, m), 1.3 (6H, t).

*Trade Mark 1.28~
~S~@ (OEt)2 ~P
- ~02PN3 ~ ~\~ (OLt) ~ 022~3 3 (0.4 g, 0.52 mmole) in toluene (35 ml) was refluxed for 4 h and evaporated to dryness to give an oil which contained 3, 4 and 3P=O. This was chromatographed on sio2 (10% H2O) and eluted with EtOAc to give 0.1 g of pure 4, followed by 0.15 g of 3 and 4. NMR ~ (ppm, CDC13), 8.3 (2H, d), 7.67 (2.H, d) , 5.7 (H, q) , 5.33 (2H, d) , 4. 2 (4H, q) , 3.83 (H, q), 3.4 (H, q), 2.9 (2H, m), 1.9 (2H, m), 1.3 (6H, t). IR (neat) 1790 cm~l (~-lactam) 1710 cm~l (ester).
S ~ ~OEt)2 N ~
0 2PN ~ ( O- t ) A mixture of 4 (0. 1 g, 0. 207 mmole) , 30% Pd/
"CELITE"* (0.1 g) and NaHCO3 (17 mg, 0.207 mmole) in THF (10 ml), ether (5 ml) and water (5 ml) was hydrogenated at an initial pressure of 40 psi for 2 h. It was filtered over "CELITE"* and the layers separated. Basic aqueous layer was washed well with ethylacetate and acidified with lNHCl. It was extracted with CH2C12 and dried (MgSO4). The CH2C12 solution was evaporated to give 48 mg of 5 (66. 5%) .

IR spectrum ~ 1790 (~-lactam) ~ 1700 (-C-OH).

*Trade Mark lX8666~
Exam~le 33 ~ S~P (OMe) 2 C2 N~

0 o= + (~'~10~3~ F~S ~Oi~le)2 2 _ _ CO~P~B
A mixture of 1 (1.07 g, 1.66 mmole) and 2 (0.42 g, 3 mmoles) in CH2Cl2 (3 ml) was heated at 80 for 5 h. The crude oil was chromatographed on SiO2 (3% H2O) and eluted with ether, ether-ethylacetate (1:1) and ethyl acetate: 5% EtOH to give 1.0 g of 3 (82%). The oil crystallized on standing, M.P. (ether) 138-40.
NMR ~ (ppm, CDC13) 8.2 (2H, d) 7.0-8.0 (17H, m), 4.6-5.5(3H, m), 3.8 (3H, s), 3.6 (3H, s), 1.5-3.5 (6H, m).

O ~ ~0 2(OM~ R IC~e)2 3 (0.5 g, 0.69 mmole) in toluene (30 ml) was refluxed for 4 h. It was evaporated to dryness, chromatographed on SiO2 (3% H2O) and eluted with Et2O:
EtOAc (1:1) followed by EtOAc: 10% EtOH to give 0.18 g of 4 (58%). NMR ~ (ppm, CDC13, 8.25 (2H, d), 7.6 (2H, d), 5.65 (H, ~), 5.3 (2H, d), 3.8 (3H, s) 3.6 (3H, s), 2.7-3.6 (2H, m), 1.5-2.5 (4H, m).

~0 ~86~6 Oc~s~ 30% Pd/ "(~ELITE"*
N ~ NaHC03 C2 P `'3 4 F~/R(O~e) 2 1 5 C2Na A mixture of 4 (50 mg, 0.112 mmole), NaHCO3 (9.12S mg) and 30% Pd/"CELlTE"*(50 mg) in THF (5 ml), Et2O
(2.5 ml) and water (2.5 ml) was hydrogenated at an initial pres~ure of 40 psi (for 2 h). It was filtered o~er "CELITE"* and the layers separated. The basic aqueous layer was washed well with EtOAc and lyophilized under high vacuum to give 28 mg of ~. (75.9%) (hygroscopic). IR (KBr) 1770 cm~1 (B-lactam), 1610 cm~l (-COO~).

*Trademark ~X~6~i6~

Example 34 (l'R.5R.6R? and (l'S.5S.6S) 6-(1'-HydroxY-l'-ethyl)-2-methylpenem-3-carboxylic Acid (isomer Dl (illustrates most preferred Process of introducinq 6-substituent in mid-synthesis OH

10o co2Na~ K

A. Preparation of 4-Tritylthio-2-azetidinone Intermediates 151. 1-(Trimethylsilyl)-4-tritylthio-2-azetidinone 20- sc~3 sc~3 c L N ~ ~ ~ Si(Me) A solution of 4-tritylthio-2-azetidinone (345 mg, 1 mmole), 1, 3, 3, 3, -hexamethyldisilazane (80 mg, 0. 5 mmole) and chlorotrimethylsilane (55 mg, 0.5 mmole) in dichloromethane (20 ml) was heated under reflux for 18 h. Concentration of the reaction mixture left virtually pure title compound.
~ (ppm, CDC13): 7.32 (15H, m, aromatics), 4.22 (lH, dd, H-4), 2.67 (lH, dd, J = 4.1, J = 16, H-3), 2.22 (lH, dd, J = 2.2, J =
16, H-3), 0.3 (9H, s, CH3).

,,.,,i, . . . .

~X86~6~
2. 1-tt-ButYldimethvlsilyl~-4-trity~hio-2-azetidinone SC~3 ~ C~3 ~N ~ O ~ N~Si/ cH3 C(CH3)3 Triethylamine (1.62 ml, 11.6 mmoles) was added dropwise in 5 min to a cooled (O) and stirred solution of 4-tritylthio-2-azetidinone (3.5 g, 10.1 mmoles) and chloro-t-butyldimethylsilane (1.68 g, 12.7 mmoles) in DMF (35 ml). The reaction mixture was stirred at room temperature for 18 h, diluted with water (250 ml) and ether (200 ml). The organic phase was washed with water (3 x 50 ml), dried and concentrated to leave an oil (4.33 g). Crystallization from pentane gave a total of 4.1 g(89%) of the title compound as a white solid, m.p. 113-4. ~
(ppm, CDC13 ): 7.45 (15H, m, aromatics), 4.2 (lH, dd, H-4), 2.63 (lH, dd, J = 4, J = 16, H-3), 2.13 (lH, dd, J = 2, J = 16, H-3), 1.0 (9H, s, t-Bu), 0.35 (6H, s, Me).
Vc=O 1735 cm 1 Anal. calc'd for C28H33, NOSSi-: C, 73.15; H, 7.24;
N, 3.05; S, 6.97%. Found: C, 73.27; H, 7.32; N, 2.97; S 6.94%.

l~&f~
3. 1-Methoxvmethyl-4-tritylthio-2-azetidinone SC~3 ~ iC~3 ~ H 0 C~2oC:~3 A solution of 4-tritylthio-2-azetidinone (1.38 g, 4.0 mmoles) in THF (lO ml) was added to a well stirred suspension of sodium hydride (200mg of commercial 50%, 4.1 mmoles, washed with pentane) in THF (10 ml) maintained at -15. Methanol (12 drops) was added and the mixture was stirred at -15 for 0.5 h.
Methoxymethyl bromide (0.58 g, 4.6 mmoles) was added and the mixture was stirred for 2h, diluted with ether, washed with water and brine, dried and concentrated to leave an oil (1.72 g).
Crystallization from pentane gave a white solid (1.41 g) m.p 72-76 ~ (ppm, CDC13 ): 7.3 (15H, m, aromatics), 4.4 (3H, m, NCH2O
and H-4), 3.22 (3H, s, CH3 ), 2.76 (2H, m, H-3).

4. 1-(Methoxyethoxymethyl) -4-tritYlthio-2-azetidinone sc~3 sc~3 ~ _ ~ ~
N~ o~ N o To a suspension of tetrabutylammonium bromide (322 mg, 1 mmole) and potassium hydroxide (85%, 70 mg, 1.1 mmole) in dichloromethane (10 ml) cooled to 5 was added with vigorous stirring 4-tritylthio-2-azetidinone (345 mg, 1 mmole) and methoxyethoxymethyl chloride (187 mg, 1.5 mmole). The mixture was stirred at room temperature for 2 h, the ",~

solvent was evaporated and the residue partitioned between water and ethyl acetate. The dried organic phase was concentrated to leave a viscous oil (415 mg). Purification by column chromato~raphy on silica gel eluting with ether (5%)-dichloromethane gave the title compound (206 mg, 48%) as an oil. ~ (ppm, CDC13): 7.30 (15H, m, aromatics), 4.57 (2H, AB
quartet, N-CH20), 4.46 (lH, dd, H-4), 3.50 (4H, s, OCH2CH2O), 3.30 (3H, s, CH3), 2.75 (2H, m, H-3).

5. 1-(2'-Tetrahvdropvranyl)-4-tritylthio-2-azetidinone SC~3 ~ c~3 ~ , n ,~ N~ ~N~ t n-Butyl lithium (1.6M, 1.6 ml, 2.56 mmoles) was added dropwise to a solution of 4-tritylthio-2-azetidinone (863 mg, 2.5 mmoles) in THF maintained at -78. After stirring for 15 min, 2-chlorotetrahydropyran (560 mg, 4.7 mmoles) was added and the reaction mixture was allowed to come to room temperature in 1.5 h. The reaction solution was diluted with ethylacetate, washed with brine, dried and concentrated to leave an oil (635 mg).
Column chromatography on silica gel eluting with dichloromethane-ether gave a mixture of the isomeric title compounds contaminated with a little starting material. ~ (ppm, CDCl3 ): 7.28 (15H, m, aromatics) , 4.4 (H, dd, H-4), 2.9-2.2 (2H, m, H-3) , 4.1-3.2 and 2.2-0.7 (tetrahydropyranyl).

1~8~6~
B. Prep~E~tion of 3-~l'-Hydroxy-1'-ethyl) -l-m~thoxym~hyl-4-tri~ylthio-2- azstidinQ~L

H
~3 N ~(~ O

a) (1'S 3S.4R and l'R.3R 4S)i6Omer ~isomer C¦

A 6olution of lithium diisopropyl amide was prepared in THF (5 ml) at -78C from n-butyl lithium (1.6M, 1.0 ml, 1.6 mmol) and diisopropylamine (0.25 ml, 1.84 mmol). After 30 min a solution of 1-methoxymethyl-4-tritylthio-2-azetidinone (491 mg, 1.42 mmol) in THF (6 ml) was added dropwise and the solution was stirred for 15 min. Acetaldehyde (3.0 ml) was added dropwise, followed, after 20 min, by water (30 ml). The mixture was acidified to pH 3 with 2% HCl and extracted with ethyl acetate (5 x 20 ml). The combined organic phases were washed with brine, dried and concentrated to leave an oil which crystallized upon trituration with ether: 440 mg, 80%, mp 188.5-9C; 1 Hmr (CDC13) 25 ~:7.3- (15H, m, aromatics), 4.37 (2H, ABq, N-CH2O), 4.32 (lH, d, J=2, H-4), 3.17 (3H, s, OCH3), 3.32-2.70 (2H, m, H-3 and H-5), and 1.12 ppm (3H, d, J=7, CH3); Anal. calcd for C26H27N03S: C 72.02, H
6.28, N 3.23, S 7.39; found: C 71.99, H 6.02, N 3.21, S 7.40%.
b) (~'_S, 3S. 4R and 1'R. 3R. 4S) and rl'R. 3S. 4R and l'S. 3R. 4S) (isomers C and B).
A solution of lithium diisopropyl amide (0.482 mmol) i6 prepared at -78C in dry ether (3 ml) from butyl lithium 0.191 ml of 2.52 M æolution in hexane, 0.482 mmol) and diisopropyl amine ..~

~8~
(0.067 ml, 0.482 mmol). After 20 mi.n, a solution of t4R and 4S) 1-methoxymethyl-4-tritylthio-2-azetidinone (0.171 g, 0.439 mmol) in a mixture of dry ether (lml) ancl dry THF (1 ml) was added dropwise a~d the resulting clear solution was stirred at -78C for 15 min. A solution of tetrabutyl ammonium fluoride l0.96 ml of a 0.5M solution in THF, O. 48 mmol) was then added. A precipitate was formed with the generation of a slight pink colour. After 5 min at -78C, the reaction mixture was quenched with freshly distilled acetaldehyde (0.2 ml, excess), and the stirring continued for 15 more min. The work-up was done by adding to a saturated solution of ammonium chloride and extracting with ethyl acetate (2 x 25 ml). The combined organic phases were washed with brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under vacuum gave an oil (0.228 g) which was chromatographed on 10 g of silica gel A mixture of benzene and ethyl acetate (6:4)gave 0.106 g (62% recovery) of substrate and a mixture of the two isomer alcohols which were separated by chromatography on thick laye~
plates (same solvent-system). The alcohol with the high Rf (0.033 g, 17 %) was identical to the above isomer (isomer C): mp 188.5-189C (Ether-dichloromethane); The alcohol with low Rf (0.030 g, 16%) (isomer B), was obtained as an oil which crystallized with difficulty from hexanes: mp 94-95C.
ir (CH2C12) ~max : 3600 (OH), 1760 cm~l (C=O); 1Hmr (CDC13) ~:6.9-7.5 (15H, m, aromatics), 4.2 (2H, center of ABq, J=11.5, CH2- O-CH3), 4.28 (lH, d, J=2.0, 4-H), 3.65 (lH, center of a broad sextet, H-l'), 3.3 (lH, dd, J3,4 trans= 2-5~ J3,1 = 5-5~ H3)~ 3-15 (3H, s, O-CH3), 1.55 (lH, broad s, OH-l'), 1.05 (3H, d, J=6.5, H-2'); ~a~l- calcd for C26H27N03S: C 72.02, H 6.28, N 3.23, S
7.39; found: C 71.77, H 6.36, N 3.15, S 7.43%.

' ~28666~

C. Preparation o~
trans 3-Acetyl-l-methoxymethyl-4-tritylthio-2-azetidinone EtOA ~ CH3 ~

Lithium diisopropylamide was prepared under a nitrogen atmosphere at -78C in the usual manner from diisopropylamine (0.34 ml, 2.4 mmol) and n-butyl lithium tl.l ml of a 2.2M solution in hexane, 2.4 mmol) in THF (3 ml). A solution of l-methoxymethyl-4-tritylthio-2-azetidinone (0.78 g, 2 mmol) in THF (3 ml) was added dropwise and, after stirring at -78C for 20 min, ethylacetate (0.53 g, 6 mmol) was added in one portion and stirring continued for 0.75 h at -78C. The reaction mixture was diluted with ether and washed with an ammonium chloride solution, water and brine, dried and concentrated to give an oil (0.7 g). Purification was achieved by chromatography over silica gel (20 g) eluting with increasing amounts of ether in benzene. The pertinent fractions were concen-trated to give the title material as a colorless oil (0.32 g, 37%);
IHmr (CDC13) ~:7.7-6.8 (15H, aromatics), 4.85 (lH, d, J=2, H-4), 4.5 (2H, s, N-CH2-0), 3.9 (lH, d, J=2, H-3), 3.22 (3H, s, CH3) and 2-0 ppm (3H, s, CH3); ir vmax: 1770, 1710 cm 128~i~i161 D. Preparation of trans 3-Acetyl-l-(t-butyldimethylsilyl)-4-trltylthio-2-azetidinone - ~ Si EtOAc ~ ~ Sl~
3 2 \(CH3)2 Diisopropyl lithium amide was prepared in the usual manner from diisopropylamine (0.18 ml, 1.24 mmol) and n-butyl-lithium (0.78 ml of a 1.6M solution in hexane, 1.24 mmol) in THF
(8 ml). A solution of l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (0.46 g, 1 mmol) in THF (8 ml) was added dropwise at -78C. After a 5 min stirring period,ethyl acetate (1 ml) was added in one portion and the mixture was stirred 3 h at -78C.
The mixture was acidified with cold hydrochloric acid (0.5N) to pH 6 and extracted with ethyl acetate (2 x 20 ml). The combined organic phases were dried and concentrated to give an oil (0.5 g) which crystallized from pentane: 200 mg total, 40%; mp 122-4C;

ir v : 1750, 1710 cm ; lHmr (CDCl ) ~: 8-7.1 (15H, m, aromatics), max 3 4.83 (lH, d, J=2,H-4), 3.38 (lH, d, J=2, H=3), 1.80 (3H, s, CH3), 0.92 (9H, s, Bu and 0.3 ppm (6H, s, CH3).

E. ~re~aration of trans-l-(t-Butyldimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone o SC~3 H~ ~3 ~Si (CH3) 2 S\i(CH3)2 t-Bu t-Bu To a cooled (-78C) solution of diisopropylamine (0.34 ml, 2.4 mmol) in tetrahydrofuran (5 ml) was added dropwise, under N2, a _l~5~

1~6~Gl solution of 1.5 M n-BuLi (1.6 ml, 2.4 mmol). After stirring for 30 min, a solution of 1-(t-butyldimethylsilyl)-4-tritylthio-2-azeti-dinone (1.0 g, 2.18 mmol) in tetrahydrofuran (5 ml) was added dropwise and stirring was maintained for 30 min. Ethyl formate tO.8 ml, 9.9 mmol) was added and the cooled solution was stirred for 10 min. The reaction mixture was washed successively with cold lN hydrochloric acid (5 ml), lM sodium bicarbonate (6 ml), water (10 ml) and brine. The organic layer was dried (MgSO4), evaporated and crystallized from pentane to give 810 mg (76%) of formate as a white solid mp 132-3C; ir (CHC13) : 1760, 1715 cm ; IHmr (CDC13) ~: 9.0 (lH, d, J=1.25 Hz), 7.30 (15H, m), 4.7 (lH, d, J=1.5Hz) and 3.5 ppm (lH, t, J=1.5 Hz).
NOTE: a) diisopropyl amine was distilled over CaH and stored on KOH
b) tetrahydrofuran was distilled over L.A.H. and stored on molecular sieves 3A
c) ethyl formate was stirred at room temperature with K2CO3, then distilled over P2O5 d) n-BuLi was titrated with lN hydrochloric acid F. Preparation of l-(t-Butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinones. (4 isomers).

OH
~5i/ C~51~

(Me)2 \(Me)2 n-Butyllithium (1.6M, 3.4 ml, 5.44 mmol) was added in 5 min to a solution of diisopropylamine (0.847 ml, 6.23 mmol) in THF (30 ml) maintained at -78C. After 0.5 h a solution of l-(t-butyldimethylsilyl)4-tritylthio-2-azetidinone (2.0 g, 4.4 mmol) in THF (20 ml) was added; after 15 min acetaldehyde (10 ml) was ~ C~

~2~

added in one portion; after another 15 min water tlOO ml) was added.
The mixture was acidified ~pH 5-6) with dilute hydrochloric acid and extracted with ethyl acetate (3 x 30 ml). The organic phases were washed wi~h brine, dried and concentrated to leave an oil which was found to consist of a mixture of four isomers by tlc (labelled isomers A,i3,C,D by decreasing order of polarity).
Crystallization of the oily residue in ethyl acetate-pentane gave isomers i3 and C as a white solid and left A and D in the mother-liquors. The four pure compounds were obtained by preparative chro-matography (~aters, 500) of the above solid and mother-liquors. The relative proportions were: A, 1796i B, 329~; C, 39%; D, 12%. In the above reaction, when ether was substituted for THF and the re~ction quenched after 1 min at -78C, the relative proportions of A,~3,C, and D were:
12.9, 30.5, 38.2 and 18.4%. In ether, when the reaction was allowed to come to 20C in 2 h before quenching, the proportions were: 13.4, 24.6, 44, and 1896. When one molar equivalent of anhydrous magnesium bromide was added to the reaction mixture, the proportions changed to:
19.2, 19.7, 30.1 and 31P6.

somer A: This isomer possesses a cis-stereochemistry at C -C . It is a racemic mixture composed of the (l'S, 3R, 4R) and the (l'R, 3S, 4S ) enantiomers. Compounds later derived from compound A are referred to as "Isomer A". They consist of an enantiomeric mixture and possess the same configuration at Cl" C3 and C4. Compounds derived from compound A, through a reaction that proceeds with inversion of configuration, will be referred to as "Isomer D" if the inversion takes place at Cl, and as "isomer C" for the inversion, at C3 mp 152-3C;
lHmr (CDC13) ~: 8.0-6.8 (15H, m, aromatics), 4.30 (lH, d, J=5.5, H-4), 3.78 (lH, m, H-l'), 3.10 (lH, dd, J=5.5, J=10, H-3), 1.22 (3H, d, J=6.5, CH3), 0.95 ~9H, s, Bu), 0.27 (6H, 2s, CH3). _ nal. calcd for:
C 30H37NO25i: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71.28, H 7.41, N 2.48, S 6.19%.
"~ 7 12~6~

Isomer B: This isomer posseses a trans-stereochemistry at C3-C4. It is a racemic mixture composed of the (l'R,3S,4R) and the (l'S,3R,45) enantiomers. Compounds with the same configuration at Cl" C3 and C4 are referred to as "Isomer B" ir (CHCl ) v : 1745 cm (C=O); mp ' 3 max 158-9C; lHmr (CDC13) ~: 7.60-7.10 (lSH, m, aromatics), 4.02 (lH, d, J=0.8 H-4), 3.32 (lH, dd, J=3.0, J=0.8, H-3), 3.55-3.15 (lH, m, H-l'), 0.88 (12H, CH3, and t-Bu), 0.16 (6H, s, CH3);

Isomer C: This isomer possesses a trans-stereochemistry at C3-C4.
It is a racemate formed of the (l'S,3S,4R) and the (l'R,3R,4S) enantiomers. Compounds with the same configuration at Cl" C3 and C4 are referred to as "Isomer C". mp 134-6C; IHmr (CDC13) ~: 7.60-7.10 (lSH, m, aromatics), 4.32 (lH, d, J=1.8, H-4), 3.02 (lH, dd, J=2.7, J=1.8, H-3), 3.0-2.5 (lH, dq, J=2.7, J=6, H-l'), 1.02 (3H, d, J=6, CH3), 0.95 (9H, s, t-Bu), 0.27 (6H, s, CH3); ir (CHC13) V : 1735 cm 1 (C=0) max Isomer D: This isomer possesses a cis-stereochemistry at C3-C4.
It is a racemate composed of the (l'R,3R,4R) and the (l'S,3S,4S) enantiomers. Compounds with the same configuration at Cl" C3 and C4 are referred to as "Isomer D". mp 171-2Ci Hmr (CDC13) : 7.80-6.90 (15H, m, aromatics), 4.70 (lH, d, J=4.5, H-4), 3.02 (lH, dd, J=4.5, J=0.5, H-3), 2.39 (lH, dq, J=0.5, J=6.5, H-l'), 1.0 (3H, d, J=6.5, CH3), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CH3). Anal. calcd for C30H37NO2SSi: C 71.52, H 7.40, N 2.78, S 6.36%. found: C 71-27, H 7.43, N 2.51, S 6.31%.

-J'f~

128~

O OH

b) ~ SC~3 4 ~ ~ SC~3 ~ Si/ O ~ Si \Me2 \Me2 2 trans isomers A solution of trans 3-acetyl-1-(t-butyldimethyl-silyl)-4-tritylthio-2-azetidinone (1.0 g, 2 mmoll in THF (30 ml) was added dropwise, under a nitrogen atmosphere, to a cooled (0) and stirred suspension of sodium borohydride (0.38 g, 10 mmol) in THF (120 ml). The ice bath was removed and the mixture was stirred at room temperature for 4 h. It was poured into ice-cold hydrochloric acid (lN, pH 6), stirred for 15 min and extracted with ether (3X). The combined ether extracts were dried and concentrated to give an oil (1.04 g) which was crystallized in pentane to give the title compounds as a 70:30 mixture of the C and B isomers. mp 119-121C; 84%.

OH
c) ~ c~3 H. ~ SC~3 S\i(CH3)2~ S~i(CH3)2 t-Bu Isomer B

A suspension of Cuprous iodide (4.78 g, 15 mmol) in ether (50 ml) was cooled to 0C and treated under N2, with a 1.9 M

solution of methyl lithium (26 ml, 50 mmol). The brown solution was stirred at O~C for 10 min and then cooled to -60C and treated dropwise with the trans l-l(t-butyl dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (2.43 g, 5.0 mmol) in a mixture of tetra-hydrofuran (10 ml)/ether (40 ml). Stirring was continued for 3 h.
The solution was warmed up to -40C and treated carefully with a lM

solution of ammonium chloride. The mixture was filtered over Celite _l ,yq _ 1~6~,61 and the organic phase was washed with a LM solution of ammonium chloride (3 x 5 ml) and then brine and dried over sodium sulfate. Filtration and evaporation gave alcohol, isomer B, which crystallized from warm pentane to yield 1.6 g (65%), m~ 160-1C; ir (CHC13) V : 1730 cm ;.
Hmr (CDC13) ~: 7.32 (15H, m), .4.05 (lH~ s), 3.4 (lH, d, J=3HZ, 3.25-3.55 (lH, m), 1.6 (lH, s), 0.9 (12H, s) and 0.1 ppm (6H, s).
NOTE: a) tetrahydrofuran and ether were distilled over L.A.H.
~) methyl lithium was titrated with lN hydrochloric acid c) copper (I) iodide was purified by continuous extraction with anhydrous tetrahydrofuran in a Soxhlet extractor for 18 h, then dried under vacuum in a dessicator (P205) for 18 h.

O OH
d) ~ SC~3 ~ CH ~ SC~3 O ~S i (~ ~ S i `tBu ~tBu Methylmagnesium iodide (0.1 ml, 0.1 mmol) was added dropwise to a cooled (0C) and stirred solution of trans l-(t-butyl-dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (25 mg, 0.05 mmol) in THF (2 ml). The solution was stirred 1.5 h at 0C, poured onto an ammonium chloride solution, acidified with a hydrochloric acid solution (lN) and extracted with ether. Drying and concentration of the organic extracts left an oil consisting of starting material and a small amount of a mixture of the two trans title compounds with isomer B predominating.

--~ 5~ -~6~;61 F. PreParation Of (l'S,3S,4R and l'R,3R,4S) l-(t-Butyldimethylsilyl)-3-(1'-trimethyl-silyloxy-l ' -ethyl)-4-tritylthio-2-azetidinone (isomer C) OH OS i -~3 ~ ~ SC~3 O ~ ~ O ~si~

A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldime-thylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (15 mg, 0.3 mmol) and azidotrimethylsilane (35 mg, 0.30 mmol) in dry THF (6 ml) was stirred at room temperature until disappearance of the starting material (15 min). Purification of the reaction mixture by column chromatography (silica gel, CH2C12) gave the desired compound as a white solid (128 mg, 74~) mp 144-46C. IHmr (CDC13) ~:
7.10-7.60 (15H, m, aromatics), 4.30 (lH, d, J=1.5, H-4), 2.25-2.89 (2H, m, H-3, H-l'), 0.82-1.07 (12H, m, t-Bu, H-2'), 0.27 (6H, s, CH3), -0.10 (9H, s, -O-Si(CH3)3; ir (CHC13) V a : 1736 cm (C=O).

G. Preparation Of (l'S,3R,4R and l'R,3S,4S) l'(t-Butyldimethylsilyl)-3-(1'-methoxymethoxy ether-l'-ethyl)-4-tritylthio-2-azetidinone (isomer A).

~3 ~ ~ N ~ ~ (Me)2 N O Si Si(Me)2 ~ t-Bu t-Bu n-Butyllithium (ca 12.5 ml of 1.6M solution in hexane, 20 mmol; just enough to obtain a permanent pink coloration) was added dropwise to a solution of (l'S,3R,4R and l'R,3S,4S) l-(t-Butyl-dimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer A) (10.1 g, 20 mmol) in THF (100 ml) maintained at -78.
~l5l~

~6~;6~

After a 15 min stirring period a solution of bromomethoxymethyl ether (2 ml, 2q mmol) in THF (30 ml) was added dropwise. The mixture was stirred 1 h at -78 and 2 h at room temperature and poured into an ammonium chloride solution (200 ml). Extraction with ethyl acetate (3 x 200 ml), washing with brine, drying with sodium sulfate and concentration gave the crude title compound which was purified by chromatography on silica gel eluting with increasing amounts of ether in benzene (10.4 g 95%). lHmr (CDC13) ~: 7.1-7.5 (15H, m, aromatics), 4.47 (lH, d, H-4), 4.23 (2H, ABq, J=7, 0-CH2-0), 3.1-3.4 (2H, m, H-3 et H-l'), 3.23 (3H, s, 0-CH3), 1.37 (3H, d, J=6.5, CH3), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH3).

. Pre~aration of (1`5,3S,4R and l'R,3R,4S) l-(t-;3utyldimethylsilyl)-3-(1'-formyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) ~H 0,CHO
~3 ~ ~ c~3 \ S 1~ ~ i~

A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer c) (50 mg, 0.1 mmol), p-bromobenzenesulfonylchloride (100 mg, 0.4 mmol) and dimethylaminopyridine (24 mg, 0.2 mmol) in DMF (3 ml) was stirred at room temperature until disappearance of starting material (0.5 h).
Then the reaction mixture was diluted with water and extracted with ether. The organic extracts were washed with brine, dried (MgS04) and evaporated. The title compound was purified by column chromato-graphy. IHmr (CDC13) ~: 7.80 (lH, s, CHO), 7.20-7.66 (15H, m, aromatics), 3.90-4.36 (lH, m, H-l'), 4.07 (lH, d, J=2, H-4), 3.22 (lH, broad s, H-3~, 1.18 (3H, d, J=6.5, H-2'), 1.0 (9H, s, t-Bu), 0.31 (6H, s, di-CH3).

~2866~1 I. Prepar~tion of (l'R,3S,4R and l'S,3R,4S) l'(t-Butyldimethylsilyl)-3-1'-acetoxy-l~-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OH OAc 2 ~

A solution of (l'R,3S,4S and l'S 3R 4S) l-(t-butyldi-methylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (13.85 g, 27.5 mmol) in pyridine (75 ml) acetic anhydride (50 ml) (prepared at 0) was stirred at room temperature for 40 h.
The reagents were evaporated off (the last traces being removed azeotropically with toluene 3 times) leaving a nearly white solid.
Crude derivative was crystallized from an ether-petroleum ether mixture to give pure title compound (97.5%). IHmr (CDC13 ~:
7.64-7.03 (15H, m, H aromatic), 4.60 (lH, m, J=6, H-l'), 3.92 (lH, d, J=2, H-4), 3.55 (lH, dd, J=2, J=6, H-3), 1.79 (3H, s, CH3CO), 0.98 (3H, d, J=6,CH3), 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH3); ir (CHC13) V : 1775, 1740 cm (C=O) J. Pre~aration of l-(t-~utyldimethylsilyl)-3-(l'-Paranitrobenzyldioxvcarhonyl) ethyl)-4-tritylthio-2-azetidinone. (4 isomers) pH QCO PNB
C~3 ~ SC~3 ~Si~ 2 ~ ~ Si~ 2 ~tBu \tBu "Isomer C" n-Butyllithium (8.8 ml of 1.6 M solution in hexane, 14 mmol; just enough to obtain a permanent pink coloration) was -l53~

added dropwise to a solution of "Isomer C" of 1-~t-butyldime-thylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (6.55 g, 13 mmol) in THF (70 ml) maintained at -78C. After a 15 min stirring period a solution of paranitrobenzyl chloro-formate (3.2 g, 14.8 mmol) in THF (30 ml) was added dropwise.
The mixture was stirred 1 h at -78C and poured into ~n a~monium chloride solution (100 ml). Extraction with ethyl acetate (3 x 100 ml) washing with brine, drying and concentration left 11 g of crude material. The pure title compound was obtained by chromatography on silica gel (220 g) eluting with increasing amounts of ether in ben~ene. 93%,mp 118-9C (ether); IHmr (CDC13) ~: 8.35-7 (19H, m, aromatics), 5.12 (2H, s, benzyl), 4.08 (lH, d, J=1.8, H-4), 4-3.5 (lH, dq, J=6.5, J=2, H-l'), 3.10 (lH, dd, J=2, J=1.8, H-3), 1.2 (3H, d, J=6.5, CH3), 1.0 (9H, s, Bu) and 0.30 ppm (6H, 2s, CH3); ir (CHC13) Vmax: 1745 cm (C=O)i Anal. calcd for C38H42N2O6SiS: C 66.83, H 6.20, N 4.10, S 4.69: found: C 66.90, H 6.26, N 4.11, S 4.59.

"Isomer B" The "Isomer B" of l-(t-butyldimethylsilyl)-3-(1'-hydroxy-l'-ethyl(-4-tritylthio-2-azetidinone, treated as described above gave pure "Isomer B" of l-(t-butyldimethylsilyl)-3-(1'-para-nitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone as a foam, 95%. IHmr (CDC13) ~: 8.32-6.90 (19H, m, aromatics), 5.1 (2H, s, benzyl), 4.65-4.20 (lH, m, H-l'), 3.97 (lH, d, J=1.5, H-4), 3.58 (lH, dd, J=1.5, J=5.8, H-3), 1.1 (3H, d, CH3), 0.7 (9H, s; Bu and 0.2 ppm (6H, s, CH ); ir (film) v : 1755, 1740 cm C=O.
3 max "Isomer A" The "Isomer A" of l-(t-butyldimethylsilyl-3-(1'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone, treated as described above gave pure "Isomer A" of l-(t-butyldimethylsilyl-3-(1'-paranitro-benzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone as an oil.
9S~ IHmr (CDC13) ~: 8.3-6.7 (19H,m, aromatics), 4.95 (2H, ABq, benzyl), 4.53 (lH, p, J=7.5, J=7.5, H~ , 4.31 (lH, d, J=6, H-4), 3.32 (lH, dd, J=6, J=7.5, H-3), 1.44 (3H, d, J=6.5), 0.95 (9H, s, tBu) and 0.2 ppm (6H, 2s, CH3).

"Isomer D" Likewise "Isomer D" of l-(t-butyldimethylsilyl-3-(1'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone, gave pure "Isomer D"
of l-(t-butyldimethylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-tritylthio-2-azetidinone, 90%. 1Hmr (CDC13) ~: 8.3-6.7 (19H, m, aromatics), 5.20 (2H, ABq, benzyl), 4.72 (lH, d, J=5, H-4), 3.50 (lH, dq, J=6.5, J=0.5, H-l'), 2.85 (lH, dd, J=0.5, J=5, H-3), 1.03 (3H, d, J=6.5, CH3), 1.0 (9H, s, t-Bu) and 0.35 ppm (6H, s, CH3);
mp 130-2C. Anal. calcd for C 66.83, H 6.20, N 4.10, S 4.70; fou-.d:
C 66.56, H 6.28, N 3.96, S 4.89.

K. Pre~aration of (l'S,3S,4R and l'R,3R,4S) l-(t-ButyldimethYlsilyl)-3-(1'-methane-sulfonyloxy-~-ethyl)-4-tritylthio-2-azetidinone (Isomer C) OH OMs (CH3)2 ~ 3 A solution of ~l'S,3S,4R~andl'R,3R,4S)-l-(t-butyldimethyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.0 g, 4 mmol) in dichloromethane (80 ml) was treated at 5C, with methanesulfonyl chloride (0.99 g, 8.6 mmol) and triethylamine (0.87 g, 8.6 mmol). After stirring at that temperature for 1 h under N2, the solution was washed with brine, dried (MgSO4) and evaporated to dryness. ~fter crystallization from ether-pet-ether, 1.9 g (81.9%) of mesylate was obtained. mp 120-22C; Hmr (CDC13) ~: 7.13-7.61 - I 5~ -1~86~

(15H, m, aromatics), 4.50 (lH, d, J=2, H-4), 3.62 (lH, dq, J=6.5, 2, H-l'), 2.96 (lH, dd, J=2, 2, H-3), 2.84 (3H, s, methanesulfonyl), 1.22 (3H, d, J=6.5, H-2'), 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6H, s, Si (CH3)2); ir Vmax (CHC13): 1746 (C=O), 1343 and 1180 cm 1 (SO

L. Preparation of (l'R,3S,4R and l'S,3R,4S) l-(t-Butyldimethylsilyl)-3-(1'-methane-sulfonyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OH ~sO
SC~3 ~ SC~3 S i ~

A solution of (l'R,3S,4R and l'S,3R,4S) l-(t-butyldimethyl-silyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B?
(5.03 g, 10 mmol), methanesulfonylchloride (2.52 g, 22.0 mmol) and triethylamine (2.23 g, 22.0 mmol) in CH2C12 (200 ml) was stirred at 5C for 1 h. Then the solution was washed with brine, dried (MgSO4) and evaporated to leave a residue which crystallized as a white solid when triturated in ether (5.40 g, 93%) mp 127-31C.
IHmr tCDC13) ~: 7.20-7.63 (15H, m, aromatics), 4.51 (lH, dq, J=5.0-6.2, H-l'), 4.10 ~lH, d, J=2.0, H-4), 3.63 (lH, dd, J=5.0-2.0, H-3), 2.03 (3H, s, -CH3), 1.01 (3H, d, J=6.2, H-2'), 0.90 (9H, s, t-Bu), 0.12 (6H, s, -CH3); ir (CHC13) V ax 1745 cm (C=O).~

1286~61 M. Preparation of (1'5,3S,4R and l'R,3R,4S) 3-(1'-p-Bromobenzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) OH OSO ~Br SC~3 ~ SC~3 S i~

A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethyl-silyl)-3-(1'-hydroxy~ ethyl)-4-tritylthio-2-azetidinone (Isomer C) (2.5 g, 5 mmol) in dry THF (100 ml) was cooled to -78C and treated with 2.52M butyllithium/hexane (2.38 ml, 6 mmol). After 3-4 min p-bromobenzenesulfonylchloride (1.53 g, 6 mmol) dissolved in THF
was added dropwise. The solution was stirred at -78C for 3 h and then allowed to come to room temperature. Then the solvent was evaporated and the desired product purified by column chromatography (silica gel, CH2Cl2) (3.36 g, 94.6%) mp 142-44C; IHmr (CDC13) ~:
7.68 (4H, s, benzenefulsonyl), 7.28-7.60 (15H, m, aromatics), 4.59 (lH, d, J=1.8, H-4), 3.68 (lH, dq, J=6.2, H-l'), 2.99 (lH, dd, J=1.8, 2.0, H-3), 1.18 (3H, d, J=6.2, H-2'), 1.08 (9H, s, t-Bu), 0.40 and 0.38 (6H, 25, -CH3); ir (CHC13) Vmax: 1749 cm (C=O)-1~.86~;6~

N. Preparation o~
(l'S,3R,4R and l'R,35,45) 3~ Methoxymethyl-l'-ethyl)-9-tritylthio-2-azetidinone (isomer A).

C~3 ~ c~3 ~ ~ S ' 2 N ~H
t-Bu A cold (0C) HMPA-H2O (116 ml-13 ml) solution of Isomer A of l-(t-butyldimethylsilyl)-3-(1'-methoxymethyl-1'-ethyl)-4-tritylthio-2-azetidinone (11 g, 20 mmol) was treated with sodium azide (2.7 g, 42 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into cold water (1.3 ~) and dried. The title compound recrystallized from ethyl acetate-hexanes (7.2 g, 83%) as a white solid mp 173-174C. IHmr (CDC13) ~: 7.10-7.
(lSH, m, aromatics), 4.85 (2H, ABq, J=7.4, O-CH2-O), 4.53 (lH, d, J=5.2, H-4), 4.42 (lH, s, N-H), 4.15 (lH, m, H-l'), 3.5 (lH, m, H-3), 3.47 (3H, s, O-CH3), 1.5 (3H, d, J=6, CH3). ir (KBr) V : 3400-3500 (N-H) and 1760 cm (C=O).

O. Preparation of (l'S,3S,4R and l'R,3R,4S) 3-(1'~ ethoxymethyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) J.,,~ ~ ' .~N/H

A cold (dry ice-acetone bath) solution of (l'S,3S,4R
and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (5.03 q, 10 mmol) in THF (50 ml, distilled over LAH) was treated dropwise with a 1.6M solution of n-butyl lithium in hexane (13.0 ml) until a pink coloration persisted.
A THF (20 ml) solution of bromomethyl methylether (1.49 g, 0.97 ml, 1.19 mmol) was added dropwise. The mixture was stirred at -78C
for 30 min and for a 3 h period at 0C. It was poured in an ice cold ammonium chloride solution and extracted with ether. The ether extracts were combined, washed with water, dried (MgS04) and concentrated to give crude (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(1'-methoxy-methyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (5.83 g, 100%) which was deprotected as described below:
A cold (ice bath) solution of the above derivative (5.83 g, 10 mmol) in HMPA-H20 (90 ml-10 ml) was treated with sodium azide (1.365 g, 21 mmol). The cooling bath was removed and the mixture was stirred at room temperature for a 2 h period. It was then poured slowly into ice cold water (900 ml) and stirred for 30 min. The precipi-tate was collected by filtration and redissolved in methylene chloride.
The solution was washed with water and brine and dried (MgS04) to give the title compound (3.0 g, 69.3%), mp 172-2.5 (ethyl acetate-hexane); ir (CHC13) v : 3400 (N-H) and 1760 cm (C=O);lHmr (CDC13~ ~: 7.67-7.12 (15H, m, H aromatics), 4.63 (2H, center of ABq, J=6, 0-CH2-0), 4.49 (lH, s, N-H), 4.40 (lH, d, J=3, H-4~,4.25-3.80 (lH, m, H-l'), 3.35-3.15 and 3.26 (4H, s + m, CH3 and H-3) and 1.30 ppm (3H, d, J=6, CH3) ~ I !;q-~2~6~

P, Preparat ion of (l'R,3S,4R and l'S,3R,4S) 3-tl'-Formyloxy-l~-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OSO2~Br OCHO
3 ~ ~ SC~3 ~ ~Si/~ ~ H

A solution of (l'S,3S,4R and l'R,3R,4S) 3-~1'-p-bromo-benzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone ~Isomer C) in DMF (3 ml) was heated at 50C for 48 h and then at 100C for 4 h. The reaction mixture was then diluted with H2O and extracted with ether. The ethereal extracts were washed with ~rine, dried (MgSO4) and evaporated. The title compound was obtained as white crystals after purification by column chro-matography (silica gel, 5~ CH3CN-CH2C12) (2 mg, 4.8%) mp 131-32C
IHmr (CDC13) ~: 8.07 tlH, s, CHO), 7.24-7.56 (15H, m, aromatics), 5.23 (lH, dq, J=6.4, 7, H-l'), 4.38 (lH, dm J=2.4, H-4), 4.25 (lH, s, NH), 3.20 (lH, dd, J=7, 2.4, H-3), 1.43 (3H, d, J=6.4, H-2'); ir (CHC13) Vma : 3400 (NH), 1765 (C=O), 1725 cm (C=O).

Q. Preparation of (l'R,3S,4R and l'S,3R,4S) 3-(1'-Acetoxy-l'-ethyl)-4-tritylthio-2-azetidinone (isomer B) OAc OAc J STr NaN3 J- ~ STr HMPT O ~ NH
tBDMS
Pure derivative (l'R,3S,4R and 1'5,3R,45) l-(t-~utyl-dimethylsilyl)-3-(1'-acetoxy-1'-ethyl)-4-tritylthio-2-azetidinone (5.77 g, 10.57 mmol) was dissolved in warm HMPT-water (60 ml, 10 ml).

The solution was cooled down at room temperature and NaN3 (1.2 g was added in. It was stirred for 45 min (reaction progression was followed by tlC) and poured slowly in stirred cold water (800 ml).
The mixture was stirred for 20 more min. The crystalline material was collected and washed with water. It was redissolved in CH2C12, washed with water (twice) and brine and dried over MgSO4. Solvent evaporation left a foam which crystallized out from ether-petroleum ether (4.90 g, 96.5%, mp 143-44.5C).

ir (CH2C12)~m~x: 3395 (N-E3), 1772, 1738 cm (C=0). IHmr (CDC13) : 7.9-6.8 (15H, m, H aromatic), 5.12 (lH, center of dq, J=6.5, 7.5, H-l'), 4.33 (lH, d, J=2.8, H-4), 4.20 (lH, bs, N-H), 3.17 (lH, ddd, J3-1' 7 5~ J3_4=2.8~ J3_NH=l, H-3)~ 2-1 (3H, s, CH3Co), 1.35 (3H, d, J-6.5, CH3).

R. Preparation o~
3-(1'-Hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone. Mixture of four isomers) OH OAc O ~ ~Si(CH~ ~ 3 2 ~ 3 i-Cl ~ c~3 3MF-N(Et)3 ~ Si~

A solution of lithium diisopropyl amidel(0.74 mmol) was prepared at -78C in dry tetrahydrofuran (5 ml) from diisopropyl amine (0.103 ml, 0.74 mmol) and BuLi (0.29 ml of a 2.52 M in hexane).
After 30 min at -78C, a solution of the (R and S) l-trimethylsilyl-4-tritylthio-2-azetidinone (0.292 g, 6.99 mmol) in dry tetrahydrofurane (2 ml) was added dropwise. After 5 min, excess of freshly distilled acetaldehyde (0.2 ml) was added all at once. After 20 min at -78C, tlc indicated complete disapp~arance of starting materials and the reaction -l6/-mixture was quenched by adding to a saturated solution of ammonium chloride. Extraction with ethyl acetate (2 x 25 ml) followed by washing of the combined organic phases with saturated NH4Cl, brine and drying on anhydrous magnesium sulfate gave, after evaporation of the solvent, a yellow oil. Filtration of this oil on silica gel (10 g, elution C6H6:E~oAc~ 6:4) gave a mixture of alcoho~ (0.215 g, 80%). This mixture (IHmr) cannot be separated either by hplc or by tlc.
a: Acetylation Acetylation of an aliquot of the mixture (0.065 g) with excess acetic anhydride (1.0 ml) and pyridine (1.4 ml) gave a mixture of acetates. hplc Analysis indicated four components2: a) 34:6%; b) 17.4%;
c) 30.1%; d) 17.9%. Compound a) was identical to the isomer B by direct comparison (hplc). 4 b: t-Butyldimetyl silyl derivatives The mixture of alcohols (0.121 g, 0.34 mmol) was treated with t-butyl dimethylchlorosilane (0.117 g, 0.776 mmol) and triethyl amine (0.10 ml, 7.14 mmol) in dry dimethylformamide (1 ml) for 36 h at room temperature. After dilution with ethyl acetate, the solution was washed with saturated ammonium chloride and dried over anhydrous magnesium sulfate. Evaporation gave an oil (0.716 g) which contains 4 components by HPLC. a = 3.7~; b = 60.6~i c = 31.1%i d = 4.6%
(the identity of each one has not been established)4 NOTE:
IButyl lithium and lithium hexamethyl disilazane were ineffective 2Order of increasing polarity 3Acetylation of the product derived from l-t-butyldimethylsilyl-4-tritylthio-2-azetidinone gave the following ratio:

_ = 29.5%; c = 24.1%; b = 33.8%; a = 12.5%_ 4Reaction of a mixture of alcohols derived from (R and S) l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone gave the following proportions: a = 5.2g; b = 41.3%; c = 48~; d = 4.6%

1~86~

S . Preparat ion of (l'R,3S,4R and l'S,3R,45) 3~ Benzoxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) MsO OCO~
5C~3 ~ sc~3 A solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-methanesulfo-nyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (035 mq, 2 mmol) and sodium benzoate (432 mg, 3 mmol) in 10% H20-DMF (10 ml) was heated at 90C for 7.5 h. Then the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated.
The residue, purified by column chromatography (silica gel, 5% CH3 CN-CH2C12) gave the title compound as a white solid (108 mg, 23.2%) mp 158C~ lHmr (CDC13) ~: 7.03-8.25 (20H, m, aromatics), 5.32 (lH, dq, J=6.1, 9, H-l'), 4.40 (lH, d, J=2.5, H-4), 4.30 (lH, s, N-H), 3.40 (lH, dd, J=9, 2.5, H-3), 1.50 (3H, d, J=6.1, H-2');ir (CHC13) V : 3400 (N-H), 1765 (C-O), 1715 cm (C=O).

T. Preparation of 3-(1'-Paranitrobenzyldioxycarbonyl-l~-ethyl)-4-tritylthio-2-azetidinone (4 isomers).

~CO PNB
SCb3 Si N ~ H
\tBu "Isomer C"
a) A solution of "Isomer C" of l-(t-butyldimethyl-silyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-4-trityl-thio-2-azetidinone (1.3 g) in a mixture of TFA (5 ml), water -l63-~28666~L

(5 ml), dichloromethane (20 ml) and methanol (30 ml) was stirred for 2 days at room temperature. The solution was diluted with water and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with sodium bicarbonate and water, dried and concentrated to leave an oil. Crystallization from ether gave the pure title compound (902 mg), mp 78-80C;
'Hmr (CDCl3) : 8.25-6.75 (19H, m, aromatics), 5.21 (2H, s, benzyl), 5.05 (lH, m, H-l'), 4.40 (lH, s, N-H), 4.27 (lH, d, J=2.8, H-4), 3.37 (lH, dd, J=5.3, 2.8, H-3) and 1.37 ppm (3H, d, J=6.5, CH3);
ir (CHCl3) vm : 3390 (N-H), 1765 and 1745 (shoulder) (C=O, and 1525 cm (NO2).

b) A cold (0C) HMPT-H20 (90 ml - 19 ml) solution of "Isomer C" of l-(t-butyldimethylsilyl)-~-(l'-paranitrobenzyldioxy-carboxyl-l'-ethyl)-4-tritylthio-2-azetidinone (9.11 g, 13.3 mmol) was treated with sodium azide (1.82 g, 27.9 mmol). The cold bath was removed and the mixture was stirred for 30 min. It was then poured into water (1 R) and extracted with ether (5 x 200 ml).
The ether fractions were combined and washed with water (5 x 200 ml), brine and dried over MgSO4. ~lternatively since the title compound precipitated out on water dilution, it was filtered off and recrystallized from ether; 7.22 g, 89~, mp 78-80C.

"Isomer B"
__ "Isomer B" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the "Isomer C"; 92~; mp 155.5-6C (ether); IHmr (CDC13) ~: 8.25-6.80 (19H, m, aromatics), 5.20 (2H, s, benzyl), 4.95 (lH, m, H-l'), 4.35 (lH, d, J=2.9, H-4), 4.17 (lH, s, N-H), 3.20 (lH, dd, J=10.8, J=2.9, H-3) and 1.40 ppm (3H, d, J=7.5, CH3);

ir (CHC13) V : 3480, 3390 (N-H), 1772, 1750 (C=O), and 1525 cm (NO2). Anal. calcd for C32H28N2O6S: C 67.59, H 4.96, N 4.93, S 5.64; found: C 67.48, H 4.98, N 4.92, S 5.67.

~86~

"Isomer A"
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for the "Isomer C"; mp 205-6C. IHmr (CDC13) ~: 8.2-6.7 (19H, m, aromatics), 5.22 (2H, ABq, benzyl), 5.57-4.85 (lH, m, H-1'), 4.65 (lH, N-H), 4.50 (lH, d, J=6.5, H-4), 3.65 (lH, dd, J=6.5, 12, JN H=l~ H-3) and 1.52 ppm (3H, d, J=7.5).
"Isomer D"
"Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone was prepared as described above for "Isomer C"; IHmr (CDC13) ~: 8.15-6.70 (19H, m, aromatics), 5.23 (2H, ABq, benzyl), 5.20 (lH, m, H-l'?, 4.75 (lH, NH), 4.52 (lH, d, J=5.5, H-4), 3.42 (lH, J=5.5, 3, H-3 and 1.5 ppm (3H, d, J=6.5, CH3). (J value for H-3 taken after D20- exchange).
U. Pre~aration of .
(l'R,3S,4R and l'S,3R,4S) 3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer .3) MsO MsO
~3 ~Si ~ ~ N ~

A solution of (l'R,3S,4R and l'S,3R,4S) l-(t-butyldimethyl-silyl) -3-(1'-methanesulfonyloxy-1'-ethyl)-4-trithylthio-2-azetidinone.
(Isomer B) (4.95 g, 8.5 mmol) and sodium azide (1.11 g, 17.0 mmol) in 10~ H20-HMPA (50 ml) was stirred at room temperature for 30 min.

Then the solution was diluted with water (250 ml) and extracted with ether. The organic extracts were washed with brine, dried (MgS04) and evaporated. Crystallization of the residue (ether-pet-ether) gave the title compound (3.33 g, 83.8~). mp 130-31C. lHmr (CDC13) ~: 7.20-7.62 (15H, m, aromatics), 4.97 (lH, dq, J=6.4, 6.1, H-l'), 4.56 (lH. d, J=2.8, H-4), 4.22 (lH, m, N-H), 3.27 (lH, dd, J=6.1, 2.8, H-3), 3.0 (3H, s, -CH3), 1.63 (3H, d, J-6.4, H-2');

ir (nujol) Vmax: 3195 (n-H), 1768 cm (C=0).
~ 6 ~-1286~i61 V. Preparation of (l'S,3S,4R and l'R,3R,4S?3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone. (Isomer C) . .
OMs ~Ms SC~3 ~ c~3 ~i(CH3)2 N ~ H

t-Bu A solution of (l'S,3S,4R and l'R,3R,4S)l-(t-butyldimethyl-silyl)-3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (isomer C) (2.85 g; 4.9 mmol) in 10% aqueous HMPA (25 ml) was treated with sodium azide (0.65 g, 10 mmol) and stirred at 25C for 0.5 h. By diluting the solution with water (250 ml), the reaction product was forced to crystallize out. The crude mesylate was redissolved in dichloromethane, washed with brine, dried (MgSO4) and evaporated.
Trituration in ether gave the title compound as white crystals mp 155-60C;
1.80 g; 78.6~; lHmr(CDC13) ~: 7.43 (15H, m, aromatic), 5.02 (lH, dq, J=6.9, 4.9, H-l'), 4.55 (lH, s, N-H), 4.95 (lH, d, J=3, H-4), 3.33 (lH, dd, J=4.9, 3, H-3), 1.51 (3H, d, J=6.9, H-2'); ir V : 3395 (N-H), 1768 cm (C=O);
Anal. calcd for C2~H25NO4S. C 64.22, H 5.39, N 3.00; found: C 63-93~ H 5.39, N 3.24%.

W. Preparation Of (l'S,3S,4R and l'R,3R,4S) 3-(1'-p-Bromobenzenesulfonyloxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) 2~ 2~
SC~3 ~C~3 \ N ~H

A solution of (l'S,3S,4R and 1' R, 3R, 45) 3-(1'-p-bromoben-zenesulfoxyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-tritylthio-2-azetidinone (Isomer C) (1.42 9, 2 mmol) and sodium benzoate (0.865 g, 1~8~

6 mmol) in 10% H20-HMPA (40 ml) was stirred at room temperature for 1 h. Then the solution was diluted with H2O (100 ml) and extracted with ether. The ether ext:racts were washed with brine, dried (MgSO4) and evaporated. The c.rude crystalline title compound was triturated in a small volume of ether and collected by filtration (0.92 g, 77%) mp 125-26C. IHmr (CDC13) ~: 7.80 (4H, s, benzenesulfonyl), 7.30-7.65 (15H, m, aromatics), 5.13 (lH, dq, J=6.5, 4.0, H-l'), 4.50 (lH, d, J=2.9, H-4), 4.40 (lH, s, N-H), 3.40 (lH, dd, J=4.0, 2.9, H-3), 1.50 (3H, d, J=6.5, H-2');ir (CHC13) V : 3400 cm (N^H), 1770 cm (C=O) .

X. Pre~aration Of (l'R,3S,4R and l'S,3R,4S) 3-(1'-Hydroxy-l~-ethyl)-4-tritylthio-2-azetidinone (Isomer B) OSO ~Br OH
~3 ~ c~3 ~ S i--t O ~
\

To a warm solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-p-bromobenzenesulfonyloxy-l'-ethyl)-l-(t-butyldimethylsilyl)-4-trityl-thio-2-azetidinone (Isomer C) in HMPA (5 ml) was added dropwise l~ml of H20. The reaction mixture was kept at 90C for 20 h, then diluted with ether and washed 4 times with brine. The organic solution was dried (MgSO4), evaporated and the crude title compound purified by column chromatography (silica gel, 15% CH3CN-CH2C12).
A white solid was obtained (122 mg, 44.5%) mp 187-189C which was found to be identical to a sample of the title compound prepared by another method.

-/6 ~~

~2~6~

Y. Preparation Of 3-(l'-HydroxY-ll-ethyl)-4-tritylthio-2-azetidinone pH qH
SC~3 _ ~ SC~3 N ~ ~ O ~

Both isomers, (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) and (l'R,3S,4R and l'S,3R,4S) 3-(1'-hydroxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer D) were prepared by the same method. For example, a solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldimethylsilyl)-3-(l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (1.0 g, 2 mmol) and sodium benzoate (0.865 g, 6 mmol) in 10% H20 - DMF (40 ml) was stirred at room temperature for 18 h. Then the reaction mixture was diluted with H2O and extracted with ether. The organic extracts were washed with brine, dried (MgSO4) and evaporated. The crude title compound was crystallized from cold ether (0.47 g, 61%) mp 134-35C. IHmr (CDC13) ~: 7.12-7.56 (lSH, m, aromatics), 4.48 (lH, s, N-H), 4.28 (lH, d, J=2.8, H-4), 2.94 (lH, dq, J=6.5, 6.2, H-l'), 3.06 (lH, dd, J=6.2, 2.8, H-3), 2.18 (lH, s, -OH), 1.30 (3H, d, J=6.5, H-2');ir (CHC13) V : 3400 ~n-H), 1760 cm (C=O).

Similarly (l'R,35,4R and 1'5,3R,45) 1-(t-butyldimethylsilyl)-3-(l'-hydroxy-l'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) mp 190-92C. lHmr (CDC13) ~: 7.10-7.55 (lSH, m, aromatics), 4.45 (lH, d, J=2.5, H-4), 4.28 (lH, s, NH), 4.10 (lH, dq, J=6.4, 5.3, H-l'), 3.08 (lH, dd, J=5.3, 2.5, H-3), 1.50 (lH, s, -OH), 1.30 (3H, d, J=6.4, H-2');ir (CHC13) Vmax: 3400 (N-H), 1760 cm (C=O ) -l6 ~-lX86~6~

Z. Preparation o~
(l'S,3R,4R and l'R,3S,45) 3~ MethoxyTnethyl-l~-ethyl)-l-(paranitr benzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones tIsomer A) C~

H ~ ~ OH

A mixture of Isomer A of 3-(1'-methoxymethyl-1'-ethyl)-4-tritylthio-2-azetidinone (7.5 g, 17.3 mmol), paranitrobenzyl glyoxylate hydrate (4.7 g, 20.8 mmol) and toluene (300 ml) was heated under reflux for 1 h in a Dean and Stark apparatus filled with 3A molecular sieves.
The solution was cooled in ice and triethylamine (0.24 ml, 1.7 mmol) was added dropwise. The mixture was stirred for 1 h, washed with diluted hydrochloric acid, sodium bicarbonate and brine, dried and concentrated to give the title compound as a foam (10.5 g, 94%). lHmr (CDC13) ~: 8.25-6.84 (19H, m, aromatics), 5.24 (2H, s, benzyls), 4.67-4.83 (3H, m, O-CH2 and H-4), 4.34-4.55 (lH, m, H-2"), 4.02 (lH, m, H-l'), 3.54 (lH, m, H-3), 3.40 (3H, s, O-CH3), 1.38 (3H, d, J=6.5, CH3);ir tKBr) V : 3360 (OH), 1770 (C=O of ~-lactam), 1735 (C=O of ester) and 1605 cm max (aromatics).

AA. Pre~aration of (l'S,35,4R and l'R,3R,4S) 3-(1'~ ethoxymethoxy l'-ethyl)-l-(paranitro-benzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) J..~ C02PNB ~

A solution of hydrated paranitrobenzyl glyoxylate (1.73 9, 7.11 mmol) was refluxed in toluene (90 ml) using a Dean Stark condenser filled with 3A molecular sieves for a 2 h period. To the boiling solution was added (1'5,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-;6~;1 ethyl)-4-tritylthio-2-azetidinone (3.0 g, 6.93 mmol) and the mixture was refluxed for 2 h more. The mixture was cooled to room temperature, triethyl amine (70 mg, 97 ~1, 0.69 mmol) was added and it w ~ stirred for 2 h. The reaction mixture was diluted with ether, washed with 1% aqueous HC1, water,1% aqueous NaHCO3 water and brine, dried (MgSo4 and concentrated to give the title compound (4.60 g, 100%); ir (CHC13) vmax: 3530-3100 (0-H), 1765, 1750 (C=0) and 1525 cm 1 (NO2); 1Hmr (CDC13) ~: 8.22, 8.18 (2H, 2d, J=8, Hm aromatics), 7.67-7.0 (17H, m, H-aromatics), 5.3 (2H, bs, CH2-PNB), 5.30-5.02 (m, ~-2'~), 4.89-4.52 (m, H-l' and O-H), 4.63, 4.59 (lH, 2d, J=2, H-4), 4.33, 4.30 (2H, 2 center of 2 ABq, J=7, J=7, O-CH2-O), 4.1-3.67 (lH, m, H-l'), 3.2 (lH, H-3), 3.1, 3.6 (3H, 2s, CH3-O), and 1.15 ppm (3H, d, J=6.5, CH3).

BB. Prepara~ion of (1'R.3S.4R and 1S.3R.4S) 3-ll'Acetoxy-1'-ethyl)-1-(Daranitrobenzyl-2"-hydroxy - 2"-acetate) 4 - tritylthi~-2-azeti~dinone pAc J" ~STr ~0 PNa ,~

"Isome B"
A solution of hydrated p-nitrobenzyl glyoxylate (triturated with ether) (1.82 (g, 30 mol) was refluxed in benzene o through a Dean Stark condenser filled with 3A molecular sieves for 2 h . To that was added azetidinone (1'R,3S,4R and l'S,3R,4S) 3-(l'-acetoxy-1'-4-tritylthio- 2-azetidinone (10-88 g, 25.2 mmol) and the mixture was refluxed for 1 h more. The solution was cooled at room temperature and triethyl amine (0.35 ml, 2.5 mmol was added. It was then stirred for 2 h; the reaction progression being followed by tlc. *Solvent evaporation afforded a white ~2~666~L

foam in quantitative yield (100~., mixtl~re of epimers) *A1 .erllatively the sol~tion can be acid and base s:zshed. ir (CH3C12) v : 3520 (OH), 1775, 1/q5 -m (C=O); 1Hmr (CDC13) ~: 8.2, 8.18 (2H, 2d, J=~, Ho aromatic), 7.8C-6.~0 (l~H, m, I~-aro:natic), 5 28, 5.17 (2H, 24, CH2-PNB, 4.89 (0.67H, à, J=7 2, CHO), ~ 80 (center or m, H-l'), 4 38 (0 33 1~, 2d, J=8 8, CHO), 4.22 (D 33H, d, J4 3=2.5, H-4), ~.09 (0.67H, d, J4 3=

2 1 ~1-4) 3.65 (D.67H, dd, J3 1,=5 8, J3_4 2 1~ ?
dd, J3 1~=5-5 J3 4=2.5, l3-3), 3.33 (0 3311, d, J=8 8, 0~3), 3.23 (0.67H, d, J=7.5, OH), 1.38, 1 86 (3H, 2s, CH3CD), 1.10, 1 06 (3H, 2d, J=5.8, ~.3, C~33) CC Preparation of 3~ paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)4-tritylthio-2-azetidinone (4 isomers).

OCO PNB OCO PNB
~S ~3 ~S_~

"Isomer C"
A mixture of "Isomer C" of 3-(l'-paranitrobenzyl-dioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (1.70 g, 0.3 mmol), paranitrobenzyl glyoxylate hydrate (815 mg, 3.6 mmol) and toluene (50 ml) was heated under reflux 7 days in a Dean and Stark apparatus filled with 3A molecular sieves. The cooled solution was washed with dilute hydrochloric acid, sodium bicar-bonate and brine, dried and concentrated to give the title compound (2.l g) as an epimeric mixture at carbon-2". Purification was effected by chromatography over silica gel. Alternatively the title compound could be prepared by using a catalytic amount of triethyl _~q / _ ;6~

amine. Less polar epimer at 2": IHmr (CDC13) ~: 8.25-6.80 (23H, m, aromatics), 5.30 and 3.12 (4H, 2s, benzyls), 4.65 (lH, d, J=9, H-2"), 4.45 (lH, d, J=2.5, H-4), 4.45-4.10 (lH, m, H-l'), 3.50 (lH, d, J=9, 2"-OH), 3.28 (lH, dd, J=2.5, J=2.5, H-3) and 1.23 ppm (3H, d, J=6.5, CH3); ir (CHC13) Vmax: 3530 to 3200 (D-H), 1765, 1750 (C=O) and 1525 cm (NO ). More polar isomer at C-2": Hmr (CDCl ) ~: 8.25-6.85 (23H, m, aromatics), 5.25 and 5.08 (4H, 2s, benzyls), 5.05 (lH, d, J=7, H-2"), 4.35 (lH, d, J=2.5, H-4), 4.40-4.05 (lH, m, H-l'), 3.42 (lH, J=7, 2"-OH), 3.33 (lH, dd, J=2.5, 2.5, H-3), 1.23 (3H, d, J=6.5, CH3); ir (CHC13) Vmax: 3520 to 3200 (O-H), 1755 (C=O) and 1525 cm (NO2).

"Isomer B"
A mixture of hydrated paranitrobenzylglyoxylate (1;74 g, 7.66 mmol) and (l'R,3S,4R and 1'5,3R,45) 3-(1'-paranitrobenæyldioxy-carbonyl-l'-ethyl)-4-tritylthio-2-azetidinone (3.63 g, 6.38 mmol) was refluxed in toluene (70 ml) on a Dean Stark condenser filled with 3A molecular sieves for 3h. The solution was cooled down to room temperature and triethyl amine (64.5 mg, 89 ml, 0.639 mmol) was added. It was then stirred for 4 h, diluted with ether and washed with 2% aqueous HCl, water, 2% aqueous NaHCO3, water and brine. It was dried and concentrated to give pure title compound (5.02 g, 100%).
Separation of the 2 epimers was ef~ected on preparative silica gel plate. Less polar epimer at 2": ir (CHC13) V : 3500 (O-H), 1772, 1750 (C=O) 1525 cm (NO2); lHmr (CDC13) ~:8.30-8.0 and 7.65-6.80, (23H, m, aromatics), 5.27 and 5.13 (4H, 2s, benzyls), 4.71 (lH, m, J=6.5, 6.5, H-l'), 4.28 (lH, d, J=2.2, H-4), 4.23 (lH, d, J=8.7, H-2"), 3.50 (lH, dd, J=2.2, 6.5, H-3), 3.28 (lH, d, J=8.7, O-H) and 1.18 ppm (3H, d, J=6.5, CH3). More polar epimer: ir (CHC13) V 3480 (O-H) 1772, 1750 (C=O) and 1525 cm (NO2); IHmr (CDC13) ~: 8.35-6.90 (23H, m, aromatics), 5.15 (4H, benzyls), 4.72 (lH, d, J=7.5, H-2"0),4.90-~Z~3666~

4.50 (lH, m, J=6.5, 6.5, H-l'), 4.10 (lH, d, J=2, H-4), 3.68 (lH, dd, J=2, 6.5, H-3), 3.28 (lH, d, J=6.5, O-H) and 1.15 ppm (3H, d, J=6.5, 3) "Isomer A"

The "Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of "Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones.

IHmr (CDC13) ~: 8.3-6.7 (23H, m, aromatics), 5.17 (2H, benzyls), 5.0 (lH, m, H-l'), 4.9 and 4.8 (lH, 2d, J=6, H-4, two epimers), 4.32 and 3.96 (lH, 2s, H-2", two epimers), 3.68 (lH, dd, J=6, 6, H-3( and 1.47 ppm (3H, 2d, J=6.5, CH3, two epimers).

"Isomer D"

The "Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-azetidinone likewise gave a mixture of "Isomer D" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinones.

IHmr (CDC13) ~: 8.30-6.60 (23H, m, aromatics), 5.20 (4H, m, benzyls), 4.83 (lH, 2d, J=5, H=4), 5.50-4.30 (2H, m, H-l' and H-2"), 3.48 (lH, m, H-3), 3.15 (lH, m, O-H), 1.37 and 1.30 ppm (3H, 2d, CH3).

DD. Preparation of (l'S,3S,4R and l'R,3R,45)3-(l'~lethanesulfonyloxY-l'-ethyl)-l-(parani-trobenzyl 2"-hydroxy-2"-acetate)~-tritylthio-2-azetidinone (isomer C) (epimers at C2"~.

OMs OMs 5C~3 ~N OH

A solution of paranitrobenzylglyoxylate hydrate (9.72 g;
42.6 mmol) in benzene (350 ml) was refluxed for 2 h, removing the water azeotropically in a Dean-Stark trap. To that solution was added the ~ / 7 3 ~'~8~
(1~S,35,4R and 1~R,3R,4S)3~ methanesulfonyloxy-l'-ethyl) -4-tritylthio-2-azetidinone (16.62 g, 35.5 mmol) and the reflux maintained for an additional 0.5 h. Then the reaction mixture was cooled to-~room temperature, treated with triethylamine (0.5 ml;
3.5 mmol) and stirred for 3 h in order to complete the reaction.
Evaporation of the solvent left a white foam which was used as such in the next step. 1Hmr (CDCl3) ~: 8.12 (2H, d, J=9, Hm aromatic), 7.28 (17H, part of d,Ho aromatic, trityl), 5.28 (2H, s, -CH2-PNB), 4.88 (0.5 H, s, H-l"), 4.62 (1.5H, m, H-2" and H-4), 4.00 (2H, m, H-l~, -OH), 3.15 (lH, m, H-3), 2.73 (3H, s, mesylate and 1.30 ppm (3H, d, J=6 Hz, H-2~);ir max:3520 (O-H), 1775 (C=o) and 1765 cm 1 (C=O).

EE. Preparation of (1'S.3R.4R and 1'_R.3S 4~l 3-(l-Methoxymethyl-l'-ethyl)-l-rparanitrobenzyl 2"-chloro-2"-acetate)-4-trit~lthio-2-a~et;d;nonP (Isomer A~

20 ~SC;~3 ~SC~3 OH a~ ~C 1 2 C 2 D N~3 Pyridine (1.1 ml, 14.2 mmol) was added dropwise to a solution of Isomer A of 3-(l'-methoxymethyl-1'-ethyl) -l-(paranitrobenzyl-2"-hydroxy-2"-acetate) -4-tritylthio-2-azetidinone (7 g, 10.9 mmol) in THF (350 ml) cooled to -15C. Immediately after thionyl chloride (1.0 ml, 14.0 mmol) was added dropwise and the mixture was stirred at -150 for 0.5 h. The precipitate was removed by filtration and washed with benzene. The combined filtrates were concentrated , the residue dissolved in fresh benzene and the solution treated with activated charcoal, filtered and concentrated to leave to title compound as an oil (6.5 g, 90%), 1 Hmr (CDC13) ~ : 6.65-8.35 (19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, OCH3) and 1.42 ppm (3H, d, J=6, CH3).

iÇi~

FF. Preparation of (1'5,3S,4R and l'R,3R,45) 3~ ethoxymethyloxy-l'-ethyl)-l-(paranitro-benzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) STr SOC12 J ~ STr N ~ OH ~ ~ Cl A cold (ice-MeOH bath) THF (60 ml, distilled over LAH) solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-ethyl)-l-paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (4 25 g, 6.62 mmol) was treated dropwise with pyridine (0.696 ml, 8.61 mmol) and thionyl chloride (0.530 ml, 8.61 mmol). The mixture was stirred for 30 min at -15~C. The precipitate was collected by fil-tration and washed with benzene. The THF-benzene solution was concentrated and the residue was dissolved again in benzene. The resulting solution was treated with charcoal. Removal of charcoal on a Ce~ite pad and subsequent benzene evaporation afforded the title compound (4.86 g, 100%); ir (CHC13) Vmax: 1770 (C=O) and 1525 cm (NO2); Hmr tCDC13) ~: 8.15, 8.12 (2H, 2d, H-aromatics), 7.70-7.00 (17H, m, H-aromatics), 5.62, 5.02 (lH, 2s, H-2"), 5.27 (2H, s, CH2-PNB), 4.7 (lH, d, H-4), 4.7-3.7 (m, O-CH2-O, H-l'), 3.5-2.8 (m, H-3), 3.12, 3.08 (3H, 2s, O-CH3), and 1.30-0.96 ppm (3H, m, CH3).

~J7 ~ ~

~6~

GG. Preparation of (l'R, 35,4R and l'S,3R,45) 3-(1'-Acetoxv-l'-ethYl~-l-(paranitrobenzYl 2"-chloro-2"acetate)-4-tritylthio-2-azetidinone OAc pAc STr SOCl J ~ STr OH Pyridine O ~ ~ I C1 "Isomer B"
A THF (distilled over LAH) solution of (l'R,35,4R and l'S, 3R,4S) 3-(1'-acetoxy-1'-ethyl)-1-(paranitrobenzyl-2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (from 10.88 g of N-H) was treated at -15C
(ice-methanol bath) under nitrogen atmosphere with pyridine (2.19 g, 2.24 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol) and thionyl chloride (3.3 g, 2.02 ml, 27.7 mmol). The mixture was stirred for 20 min at -15. The salt was filtered off and washed with benzene. Solvent (THF + benzene) evaporation afforded a residue which was taken up in benzene (warm) and treated with charcoal. The suspension was filtered through a celite pad and solvent evaporation left a foam; ir (CH2C12) V : 1780, 1740 cm (C=O) lHmr (CDC13 ~:
8.17, 8.21 (2H, 2d, J=8, Ho aromatic) 7.76-6.88 (17H, m, H-aromatic), 5.31, 5~16, 5.12, 4.73 (3H, 4s, CH2-PN~3, CHCl), 5.12-4.55 (lH, m, H-1'), 4.35-4.25 (lH, m, H-4), 3.80-3.45 (lH, m, H-3) 1.90 (3H, s, CH3CO), 1.12 1.07 (3H, J=6.5, CH3).

-I 7~-12~6~61 HH. 3~ Paranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinones (mixture of epimers at C2").

SC~3 N ~ OH O ~ N ~ Cl "Isomer C"
Pyridine (58 ms, 0.73 mmol) was added dropwise to a solution of "Isomer C" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate)-3-tritylthio-2-azetidinones (470 mg, 0.6 mmol; mixture of epimers at C-2") in THF (15 ml) cooled to -15"C. Immediately after thionyl chloride (86.5 mg, 0.73 mmol) was added dropwise and the mixture was stirred at -15C for 0.5 h.
The precipitate was removed by filtration and washed with benzene.
The combined filtrates were concentrated, the residue dissolved in fresh benzene and the solution treated with acti~ated charcoal, ~iltered and concentrated to leave the title compound as an oil. 530 mg; 100%.
Hmr (CDC13) ~: 8.7-6.8 (23H, m, aromatic), 5.53 (lH, s, H-2"), 5.30 and 5.17 (4H, 2s, benzyls), 4.52 (lH, d, J=2, H-4), 4.20-3.70 (lH, m, H-l'), 3.31 (lH, dd, H-3), 1.27 and 1.21 ppm (3H, 2d, J=6.5); ir (CHC13) V : 1780, 1750 (C=O) and 1525 cm (NO2).

"Isomer B"
"Isomer B" of 3-(1-paranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-~tritylthio-2-azetidinones (mixture of C-2" epimers) was prepared as described above for the "Isomer C" in quantitative yield. lHmr (CDC13) ~: 8.25-6.90 (23H, m, aromatics), 5.40-5.0 (4H, m, benzyls), 5.40-4.45 (lH, m, H-l'), 4.82 and 4.57 (lH, 2s, H-2"), 4.36 and 4.31 (lH, 2d, J=2.5, H-4), 3.63 (lH, m, J=2.5, J=6.5, H-3), 1.25 and 1.18 ppm (3H, 2d, J=6.5, CH3)i ir (CHCl ) : 1780, 1750 (C=O), and 1525 cm (NO2).
3 max ~l77 ~.2~366~1 "Isomer A"
"Isomer A" of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-l'-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinones (mixture of C-2" epimers). IHmr (CDC13) ~: 8.30-6.80 (23H, m, aromatics), 5.45-4.80 (lH, m, H-l'), 5.18 and 5.21 (4H, 2s, benzyls), 4.87 (lH, 2d, H-4), 4.22 and 3.87 (lH, 2s, H-2"), 4.05-3.40 (lH, m, H-3), 1.57 and 1.50 ppm (3H, 2d, CH3).

"Isomer D"
"Isomer D" of 3-(1"-paranitrobenzyldioxycarbonyl-1'-ethyl-l'-(paranitrobenzyl 2"-chloro-2"-acetate~-4-tritylthio-2-azetidinones (mixture of C-2" epimers). IHmr (CDC13) ~: 8.30-6.70 (23H, m, aromatics), 5.32-5.10 (4H, m, benzyls), 5.48 and 5.30 (lH, 2s, H-2"), 4.82 (lH, d, J=5, H-4), 5.30-5.20 (lH, m, H-1'), 3.15 (lH, m, H-3), 1.40 and 1.30 ppm (3H, 2d, J=6.5, CH3); ir CHC13) V : 1780, 1750 (C=O) and 1525 cm (N02 ) II. Pre~aration of (l'S,35,4R and l'R,3R,4S)3-(1'-M~thanesulfonyloxy-l'-ethyl)-l-(paranitro-benzyl 2"-chloro-2"-acetate(-4-tritylthio-2-azetidinone (isomer C) (epimers at C2").

OMs OMs SC~3 ~ SC~3 NOH ~ N ~Cl To a cold solution (5~C) of ~l'S,3S,4R and l'R,3R,4S)3-(l'-methanesulfonyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (24.0 g, 35.5 mmol) in dry tetrahydrofuran (350 ml) was bdded pyridine (3.65 g, 46.2 mmol) and thionyl chloride (5.5 g, 46.2 mmol) dropwise. After stirring for 45 min, ether (100 ml) was added to precipitate the hydrochloride salt which was filtered off.

~ ~ '7 8' ~

~6663 The filtrate was evaporated and the residue redissolved in benzene (2C0 m and treated with charcoal. Evaporation of the solvent left a nearly white foam which was used as such in the next step. IHmr (CDC13) ~:
8.18 (2H, d, J=9, Hm aromatic), 7.72 (17H, m, part of d.Ho aromatic, trityl), 5.57 and 5.12 (lH, s, H-2"), 5.28 (2H, s, -CH2PNB), 4.73 (lH, 2d, H-4), 3. 21 (lH, 2dq, H-3), 2.78 (3H, 2s, mesylate and 1.21 ppm (3H, 2d, H-6H2; H-2'); ir Vmax 1779 cm (C=O) JJ. Preparation Of (l'S,3R,4R and l'R,3S,4S) 3-(1'-MethoxY~ethoxy-l'-ethYl)-l-(~aranitro-benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (Isomer A) OCH2OCH3 OCH2OcH 3 SC~3 ~C~3 O ~ ~ Cl N ~ p~

A mixture of Isomer A of 3-(1'-methoxymethoxY-l'-ethyl)-l-(paranitrobenzyl-2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (6.6 g, 10 mmol), triphenylphosphine (3.3 g, 12.5 mmol), 2,6-luti-dine (1.3 ml, 11 mmol) and dioxane (140 ml) was heated under reflux for 2 days. The solution was diluted with ether, washed with dilute acid (5% HCl), water, dilute sodium bicarbonate solution and brine, dried and concentrated. The residue was purified by chromatography on silica gel eluting with 10% ether in benzene. Concentration of the pertinent fractions left the title compound as a foam (1.4 g, 13.7~) ir (KBr) V : 1750 (C=O) and 1660-1650 cm (C=C, aromatics).

_/~q_ ~.X~36~6~

KK. PreParation o~
(l'S,3S,4R and l'R,3R,45) 3~ Methoxymethyloxy-l'-ethyl)-l-(paranitro-benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C).

OCH2OCH3 I STr J STr P~3 ~ ~

O PNB

A dioxane (100 ml, distilled over LAH) solution of (l'S, 3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-l'-ethyl)-l-(paranitrobenzyl-2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (4.86 g, 6.62 mmol), triphenylphosphine (2.60 g, 9.93 mmol) and 2,6-lutidine (770 mg, 0.837 ml, 7.20 mmol) was heated under reflux for 4 h and kept in a hot bath (100C) for 16 h. The mixture was diluted with ether, washed with l~ aqueous HCl, water, 10% aqueous NaHCO3, water and brine and dried (MgSO4). The solution was concentrated and the residue filtered through a silica gel (65 g) column (5%, 10% and 20% ether-benzene) to give the title compound (2.8 g, 48%). ir (CHCl3) Vmax: 1795 (C=O), 1620 and 1605 (phosphorane) and 1515 cm (NO2).

LL. (l'R,3S,4R and l'S,3R,4S) 3-(1'-Acetoxy-l'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azeditinone (Isomer B) OAc OAc J""" ~ STr ~3P J ~ STr ~ 2,6-lutidine O L N ~ ~3 02~NB C02~?NB

A dioxane (100 ml, freshly distilled over LAH) solution of crude (l'R,3S,4R and l'S,3R,4S) 3-(l'-acetoxy-l'-ethyl)-l-(paranitro--/~0 -lX~6~6~

benzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone was treated with 2,6-lutidine (2.97 g, 3.23 ml, 27.72 mmol) and triphenyl phosphine (9.91 g, 37.8 mmol). The mixture was refluxed (oil bath 130) for 18 h. The solvent was evaporated and the residue was redissolved in methylene chloride. The resulting solution was successively washed with diluted HCl, H20, diluted aqueous NaHC03,H20 and brine.
Drying and solvent evaporation left the title compound as a solid which was triturated with ether and collected by filtration (14.6 g, 65-9~); ir (CH2C12) Vmax: 1750 (C=0) and 1620, 1610 cm (phosphorane).

MM. 3~ Paranitrobenzyldioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone.

C~3 ~ SC~3 ~L_ ~ Cl 0 ~ ~3 ISOMER B
A mixture of (l'R,3S,4R and l'S,3R,4S) 3-(1'-paranitro-benzyl-dioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl-2"-chloro-2"-acetate) -4-tritylthioazetidinone (isomer B) (4.96 g, 6.22 mmol, mixture of epimers at C-2"), triphenyl phosphine (2.47 g, 9.42 mmol) and 2,6-lutidine (740 mg, 0.80 ml, 6.91 mmol) was refluxed in dioxane (freshly distilled over LAH) for 30 h. The solution was diluted with ether and ethyl acetate, washed with 5% aqueous HCl, water, 10% aqueous NaHC03, water and brine and dried (MgS04). Solvent evaporation afforded a ~1 8~( ~

~.286~

residue which was passed through a silica gel (10 times its weight) column (10% ether-benzene, ether, and ethyl acetate). The title compound was obtained as a crystalline solid (3.1 g, 49%), mp 189-190 (ether);
ir (CHC13~ v : 1750 (C=O), 1620, 1605 (phosphorane) and 1522 cm 2) ISOMER C
Isomer C of 3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone was prepared as described above for isomer B. ir (CHC13) v : 1750 (C=O), 1610, 1620 (phosphorane) and 1520 cm (N02); IHmr tCDC13) ~: 8.6=6.7 (H, aromatics), 5.22 and 4.95 (benzyls), 4.70 (H-4), 2.6 (H-3), 1.19 and 1.07 ppm (CH3).

ISOMER D

A mixture of Isomer D of 3-(1'-p-nitrobenzyldioxycarbonyl-l'-ethyl)-l-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azeti-dinone (4.598 g, 4.45 mmol; purity 77%, mixture of epimers at C-2"), triphenylphosphine (1.425 g, 5.44 mmol; Aldrich) and 2,6-lutidine (0.63 ml, 580 mg, 5.40 mmol; Anachemia) in dioxane (65 ml; distilled from LAH) was heated at gentle reflux under N2 for 41 h, monitoring the reaction by tlc (benzene:ether=3:1). The dark reaction mixture was cooled, diluted with EtOAc and washed successively with 0.1 NHCl, water, 2% NaHC03 and then brine. Drying (Na2S04) and evaporation of the solvents gave 4.18 y of a dark coloured oil which was purified by column chromatography (SiO2, 88 g; eluent 10-25~ ether in benzene)~
yielding 1.108 g (1.08 mmole, yield 24.3%) of the title compound as a yellowish foam: IHmr (CDC13) ~: 1.08 (d, J=6Hz, l'-CH3); ir (neat) max 1745 cm 1 (s, C=O) -/ '81-~ ~36G~

NN. Preparation of (l'S,3S,4R and l'R,3R,4S)3~ Methanesulfonvloxv-1'-ethvl)-1-(pananitro-benzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidi-none (isomer C) OMs - OMs SC~3 ~ sc~3 N P~3 A solution of (l'S,35,4R and l'R,3R,45)3-(1'-methanesul-fonyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (24.7 g, 35.5 mmol), triphenylphosphine (11.2 g, 42.7 mmol) and 2.6-lutidine (4.2 g, 39.1 mmol) in dry dioxane (350 ml) was refluxed under nitrogen for 19 h. The solvent was evaporated and the crude ~roduct redissolved in ethyl acetate and washed successively with dilute HCl, NaHC03 and brine. Purification was completed by chromatography on a silica gel column (8.5 x 12 cm). Elution with 10% ether-dichloromethane (1.5 ~J and then ether (1.5 ~) gave the purified phosphorane; 12.36 g (40~).
Hmr (CDC13) ~: 2.53 and 2.93 ppm (3H, 2s, mesylate)i ir v : 1749 and 1620 cm (C=O) 00. Pre~aration of (l'R,3S,4R and l'S,3R!4S) 3-(1'-Hydroxv-l'-ethyl)-l-(Paranitrobenzvl-2"-triphen~flphosphoranvlidene-2"-acetate) 4-tritylthio-2-azetidinone (Isomer B).

OAc OH
~STr J........ Tr I NaOH ~ ~
0~ _ N ~ p~ ~ - N P~3 A solution of phosphorane (l'R,3S,4R and l'S,3R,4S) 3-(1'-acetoxy-1'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranyl-idene-2~-acetate)-4-tritylthio-2-azetidinone (4.43 g, 5.00 mmol) 1~36~;6~

in methanol (10 ml) THF (60 ml~was treated at room temperature with 1% aqueous NaOH (1 eq, 200 mg in 20 ml H2O). The reaction progression was followed by tlc*. The mixture was diluted with ether-ethyl acetate and washed with HCl, H2O, aqueous NaHCO3, H2O and brine. Solvent evaporation afforded a residue which was crystallized fro~ benzene-ether (3.7 g, 87.7%) mp 169.5-170.5C.
ir (CH2C12) Vmax: 1745 (C=O) and 1620 cm (phosphorane) *Heating the mixture increased the reaction rate.

PP. Preparation o~
(1'5,3R,4R and l'R,3S,4S) Silver 3-(1'-methoxymethyl-1'-ethyl)-1-(para-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (Isomer A) C~i20C~3 OCH20CH3 SAg ~ P~3 O ~ p~3 Silver 3-(1'-methoxymethyl-1'-ethyl)-1-(paranitrobenzyl -2"-triphenylphosphoranylidene-2"-acetate)-3-tritylthio-2-azetidinone (isomer A), was prepared as described elsewhere for the isomer C of the paranitrobenzyldioxy carbonyl derivative. Yield 50%. ir (neat V x 1745 cm (C=O), _/ g~LJ _ 36~61 QQ, Preparation of l'S,3S,4R and l'R,3R,4S) Silver 2-(l' methoxymethyloxy~ ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (Isomer C).

.

0 ~ ~ P~3 AgNO3 o ~N ~ ~3 (1'5,3S,4R and l'R,3R,4S) 3-(1'-methoxymethyloxy-1'-ethyl)-1-(para-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (887 mg, l.0 mmol) was first dissolved in hot ( 40C) methanol (30 ml), treated with pyridine (103 mg, 0.105 ml, 1.3 mmol) and, after cooling, was -treated with a 0.15 l~ methanol solution of silver nitrate (8.7 ml, 1.3 mmol). The mixture was stirred for 1 h at 23C, cooled (ice bath) and stirred for 20 min. The salt was filtered and washed successively with cold methanol and ether (3 times, 671 mg, 87~). ir (CHC13) Vmax: 1745 (C=O), 1605 (phosphorane) and 1520 cm (NO2).

RR. Preparation of Silver 3-(l'-paranitrobenzyldioxycarbonyl-1'-ethYl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate.

SAg N ~ p~3 O N~G~P~

"Isomer B"
(l'R,3S,4R and l'S,3R,45) 3-(l'-paranitrobenzylcarbonyl-dioxy-l'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-trithio-2-azetidinone (1.02 g, 1 mmol) was first dissolved in 1~3666~

CH2C12 (3 ml) and diluted with hot (55C) MeOH (20 ml). The hot solution was treated first wlth pyridine (120 ml, 117 mg, 1.48 mmol) and a hot (55C) 0.15M methanolic solution of silver nitrate (8 ml, 1.2~mmol). The mixture was stirred at room temperature for 15 min, then at 0C for 2 h. It was then concentrated to a 10%
solution on the rotary evaporator (no bath). The mercaptide was filtered and washed twice with cold (-15C) methanol and three times with ether. (917 mg, 100%), :Lr ("NUJOL MULL")* vmax: 1745 (C=O), 1600 (phosphorane) and 1517 cm~1 (N02).
"Isomer C"

Silver 3-(l'-Paranitrobenzyldioxycarbonyl-l'-ethyl) -1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-triphenylphosphora-nylidene-2~-acetate3-2-azetidinone-4-thiolate, "Isomer C", was prepared as described above for the ~Isomer B"; ir(llNUJOL")* ,Vmax:
1745 (C=O) and 1600 cm~1 (phosphorane).

"Isomer D"

A solution of Isomer D of 3-(l'-p-nitrobenzylcarbonyl-dioxy-l'-ethyl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (145 mg, 0.142 mmol) was prepared by first dissolving it in CH2C12 (5 ml), removing the CH2Cl2 at 55- 60 and adding hot MeOH (4 ml). To the above solution was added a hot solution of AgN03 in MeOH (0.15 M, 1.14 ml, 0.17 mmol, 1.2 eq), followed by pyridine (14 ~l, 0.17 mmol, 1.2 eq). The silver mercaptide started to precipitate immediately.
The mixture was stirred 2 h at room temperature and 1 h at 0. The mercantide was collected by filtration and washed with ice-cold MeOH and ether, yielding 99 mg (O. 11 mmol, 78%) of the title compound as a brownish solid: ir ("NUJOL") vmax: 1750 cm 1 (s, c=o) -*Trade Mark ',.

SS. Preparation of (l'R,3S,4R and l'S,3R,4S) Silver 3-(1'-hydroxy-1'-ethyl)-1-)paranitro-benzyl-2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (Isomer B) OH OH
J ~ STr g 3 ~ ~ SAg N ~ P~3 C5H5N ~ P~3 A solution* of (l'R,3S,4R and l'S,3R,45) 3-(1'-hydroxy-l'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (lg, 1.19 mmol) in MeOH (10 ml), was treated with pyridine (124 ~1, 121.3 mg, 1,53 mmol) and at 10C
with a 0.15M solution of silver nitrate in MeOH (15 ml, 2.25 mmol -or until no more precipitation of the silver mercaptide occurred). The mixture was stirred for 1 h and concentrated on the rotary evaporator (no bath) to approximatively 10% concentration. The solvent was filtered off. The cake was washed once with MeOH and 3 times with ether, and pumped under high vacuum (954 mg, 100~). ir (Nujol mull) V : 3500-3400 (O-H), 1752 (C=O) 1595 (phosphorane) and 1525 cm (NO2) max *The crystalline material was first dissolved in CH2C12.

T~, Preparation o~
(l'R,3R,4R and l'S,3S,45) 4-Acetylthio-3-(1'-p-nitrobenzyldioxycarbonyl-l'-ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (Isomer D) SAg CH3cocl-pyr ~SAc ~ CH 2C 12 N ~P ~ 3 CO PNB

To a stirred solution of silver 3-(1'-paranitrohenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate - ! ~7 -~6~i61 (isomer D) (85 mg, 0.095 mmol) in CH2C12 (5 ml) containing pyridine (30 ~ 0.37 mmol; Fisher) was added at 0-5C CH3COCl (20 ~1, 0.28 mmol) and the mixture was stirred at 0-5~C for 30 min. The precipitate ~hich formed was filtered and washed with CH2C12. The filtrate and washings were combined, washed successively with brine, diluted HCl, saturated NaHCO3 and then brine, dried (Na2SO4) and evaporated yielding 75 mg (0.091 mmol, crude yield 95%) of the title compound as a syrup: lHmr (CDC13) ~: 2.33 (s, -SOCOCH3); ir (neat) Vmax: 1750 (~-lactam, ester), 1695 (thioester), 1520 and 1350 cm (-NO2).

W . Preparation of (l'R,5R,6R and l'S,SS,6S) cis p-Nitroben~yl 2-methyl-6-(1'-p-nitrobenzvl-diox carbonylmeth 1- enem-3-carboxylate (Isomer D) Y Y P

toluene ~ ~ ro PNB

A solution of the above acetylthioazetidinone ~74 mg, 0.09 mmol) in toluene (30 ml) was heated at reflux under N2 atmosphere for 7 h. After evaporation of the solvent, the residue was purified by hplc (SiO2; eluent, benzene:ether=3:1) yielding 24 mg (0.044 mmol, yield 49%) of the penem ester as a syrup. (Note: this oil could be crystallized from THF-ether or CH2C12-ether: lHmr (CDC13) ~: 1.40 (3H, d, J=6.5 Hz, l'-CH3), 2.38 (3H, s, 2-CH3), 4.07 (lH, dd, J5 6=4Hz, J6 1=9Hz, 6-H), 5.05-5.30-5.34-5.59 (2H, AB type, 3-CO2CH2-Ar), 5.30 (2H, s, l'-OC02-CH2-Ar), 5.1-5.6 (lH, m, l'-H), 5.68 (lH, d, J5 6=4Hz, 5-H), 7.49-7.64-8.18-8.33 (4H, A2'B2', l'-aromatic Hs), 7.53-7.68-8.18-8.33 (4H, A2lB2', 3-aromatic Hs); ir (neat) v a : 1780 (~-lactam), 1750 (-OCO2-), 1710 (ester), 1520 and 1350 cm (-NO2).

~36~

W , Preparation of - (l'R,SR,6R and l'S,5S,6S) Potassium and sodium 6~ hydroxyethyl)-2-methylpenem-3-carboxylate (isomer D).

OCO PNB OH
S H2/Pd-Celite ~
2 TN~-eth9r-N2o ~ I ~ 33 A solution of the above penem ester (24 mg, 0.044 mmol) in THF (5 ml) was mixed with ether(l0 ml), H20 t5 ml), phosphate buffer (1.00 ml, 0.05 molar pH 7.00: Fisher) and 30~ Pd-Celite (50 mq, Engelhard).
This mixture was hydrogenated at 35 psi for 21.5 h at room temperature.

After removal of the catalyst (over Celite), the aqueous layer was separated, washed with ether and lyophilized yielding 12 mg of the title mixture o~ sodium and potassium salts as a white powder: lHmr (D20) ~: 1.23 (3H, d, J=6Hz, l'-CH3), 2.27 (3H, s, 2-CH3), 3.85 (lH, dd, J5 6=4HZ~ J6 1=9Hz, 6-H), 4.3 (lH, m, l'-H) and 5-65 ppm (lH, d, J5 6=4Hz, S-H); ir (Nujol) vmax: 1755 ( -lactam) and 1570 cm (-C02~ i uv (H20)~ : 297 (~ 2300, calcd as K-salt), 258 (~ 1900, calcd as K-salt). This material was identical to a sample of title compound prepared by an aldol condensation of acetal-dehyde with the dianion of 2-methylpenem-3-carboxylic acid.(IHmr, ir,uv) /~ -~X8~

Example ~
(l'S,5R,6S and l'R,5S,6R) 6~ Hydroxy-l'-ethyl)-2-methylpenem-3-carboxylic Acid (isomer C) OH

~`

Method A:
OC02PNB 2 1 2 O~l SAc ~ S ~ ~ S ~ H
N ~ p~3 ~ N ~ P~3 O N ~ O N ~

Method B:

2 ~ 2 2 2 SAc ~SAC

~Si~-~ 0 ~ ~Sl~ O ~ Si~+ ~ N

SAc ~ Ac l l ~ ~
O - N ~ P~3 _ /qo -~.2~36~;61 METHOD A

1) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(1'-paranitrobenzyldioxy-carbonyl-l'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (isomer C).

J 2 N3SAg J 2 ., ~ CH3COCl ' ~
~ C5H5N ~ N ~ P~3.

A cold (ice-MeOH bath) solution of l'S,3S,4R and l'R,3R,4S) silver 3-(1'-paranitrobenzyl-dioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate ~isomer C) (1.14 g, 1.30 mmol) in CH2C12 (60 ml) was treated with pyridine (0.6 ml, 0.74 mmol) and dropwise with acetyl chloride (236 mg, 0.213 ml, 3.00 mmol). The reaction mixture was stirred for 1 h at -15C. The precipitate was filtered and washed with ether. The filtrate was washed with 2% aqueous HCl, water, 2~ aqueous NaHC03, water and brine and dried (MgSO4). The residue upon solvent evaporation was triturated in ether (895 mg, 83.7~, mp 184-5C dec); ir (CHC13) v : 1755, 1695 (C=O), 1620 and 1605 cm (phosphorane). Anal. calcd max for C42H36N3011SSi: C 61.38, H 4.42, N 5.11, 5 3.90; found: C 61.26, H 4.49, N 4.8B, S 4.26.

_l 9l--~X~

2) (l'S,5R,6S and l'R,5S,6R) Paranitrobenzyl 2-methYl-6-(l'-Paranitr benzyldioxycarbonyl-l'-ethyl)-penem-3-carboxylate (isomer C?

P~3 O ~`_ A solution of (l'S,3S,4R and l'R,3R,4S) 4-acetylthio-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (isomer C) (855 mg, 1.04 mmol) in toluene (60 ml) was heated under reflux for 4.5 h. The residue upon concentration of the solution was passed through a silica gel (10 g) column (1% ether in benzene) to give the pure title compound (393 mg, 69.6%), mp 157-158C (CHC13-ether);
ir (CHC13) V : 1785, 1745, 1710 (C=O) and 1525 cm (NO2); IHmr (CDC13) ~: 8.30-7.2 (8H, m, H-aromatics) 5.46 (lH, d, J=1.8, H-5), 5.40-5.0 (5H, m, z CH2-PNB and H-l'), 3.95 (lH, dd, J=1.8, J=5.4, H-6), 2.35 (3H, s, CH3) and 1.43 ppm (3H, d, J=5.4, CH3); Anal. calcd for C24H21N3OloS: C 53.04, H 3.89, N 7.73i found C 52.76, H 3.86, N 7.69.

3) (l'S,5R,6S and l'R,5S,6R) 6-(1'-Hydroxy-l'-ethyl)-2-methyl penem-3-carboxylic acid (isomer C) A mixture made of (l'S,5R,6S and l'R,5S,6R) parani-trobenzyl 2-methyl-6-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-penem-3-carboxylate (206 mg, 0.379 mmol), TXF-ether-H20 (30 ml, 40 ml, 20 ml), a 0.05 M pH 7 buffer solution (7.64 ml, 0.382 mmol) and 30%
Pd on Celite (500 mg) was hydrogenated at 42 psi H2 on a Parr shaker 12~36661 for 16 h. The catalyst was filtered and washed with water. The aqueous phase was washed with ether (3 times), acidified portionwise with cold 1% aqueous HC1 to pH 2.5 and extracted with ethyl acetate (15 x 20 ml) between each HCl addition. The ethyl acetate extracts were combined and washed with brine (3 x 30 ml). Evaporation of the solvent and trituration of the residue with ether gave the title compound (57 mg, 65.6%), ir (KBr) V : 3580-3300 (O-H), 1755 and 1660 cm (C=O); uv (EtOH) ~ 311 (~ 6538), 262 (~ 3672); IHmr (DMSO-d6) ~: 5.57 (lH, d, J=1.7, H-5), 4.02 (lH, m, H-l'), 3.75 (lH, dd, J=1.7, J=3.5, H-6), 2.23 (3H, s, CH3) and 1.23 ppm (3H, d, CH3).

METHOD B

1) Silver (1'5,3S,4R and l'R,3R,45) 1-(t-Butyldimethylsilyl)-3-(1'-para-nitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone-4-thiolate (isomer C) ~3 ~ S~g o~LN~S~Me2 '' O ~s ~tBu ~ Bu Isomer C of l'-(t-butyldimethylsil~ 3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-4-tritylthio-2-aze-tidinone (1 g, 143 mmol) was dissolved by stirring in hot (40C) methanol (12 ml). A solution of silver nitrate (0.59 g) in methanol (12 ml) was added followed by pyridine (0.13 ml). The mixture was stirred vigorously 1 h at room temperature and 2 h at 0. The solid silver mercaptide was collected by filtration and washed with ether, 352 mg (46%). ir V : 1735 cm ~C=O).

-/~3~

6~

2) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-l-(t-but~ldimethylsilyl-3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-2-azetidinone (isomer C) SAg ~ SAc ~si `si tBu ~ tBu To a solution of isomer C of silver l-(t-butyldi-methylsilyl)-3-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-2-azeti-dinone-4-thiolate (880 mg) in dichloromethane (40 ml) stirred at 0C was added pyridine (0.57 ml) followed, dropwise, by acetyl chloride (0.49 ml). The mixture was stirred 0.5 h at 0, the solids removed by filtration and the filtrates diluted with ether, washed with aqueous hydrochloric acid (2%), water, sodium bicarbonate (2~) and brine, dried and concentrated to leave the title material as an oil. (610 mg). IHmr (CDC13) ~: 8.2 and 7.48 (4H, 2d, aromatics), 5.40 (lH, d, J=2.2, H-4), 5.2 (2H, s, benzyl), 5.3-4.9 (lH, m, H-l'), 3.42 (lH, dd, J=2, H-3), 2.32 (3H, s, CH3), 1.40 (3H, d, J=6.5, CH3), 0.95 (9H, s, t-Bu) and 0.2 ppm (6H, CH3).

3) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(l'-paranitrobenzyldioxy-carbonyl-l'-ethyl)-2-azetidinone. (isomer C) OCO PNB ~OC02PNB
SAc ~ S~c Si ~ N
tBu Isomer C of the above S-acetyl N-t-butyl-methyl-silyl-azetidinone derivative (1.4 g) was dissolved in a mixture of TFA (0.5 ml), water (0.5 ml), methanol (3 ml) and dichloromethane (2 ml) and stirred at room temperature for 48 h.
The solution was diluted with water (lO0 ml) and extracted with dichloromethane (4 x 20 ml). The combined organic extracts were -/qY-~36~61 washed with sodium bicarbonate t2%) and brine, dried and concen-trated to leave the crude title compound as an oil. Purification was done by chromatography over silica gel (30 g) eluting with 5 ether in benzene; (650 mg). Crystallization from benzene gave a white solid. ~Hmr (CDC13) ~: 8.15 and 7.45 (4H, 2d, aromatics), 6.18 (lH, N-H), 5.19 (2H, s, benzyl), 5.05 (2H, m, H-4 and H-l'), 3.35 (lH, dd, J=2.5, 4.5, H-3), 2.34 (3H, s, CH3) and 1.42 ppm (3H~ d~ J=6.5~ CH3); ir vmax 1780~ 1750~ 1695 cm (C=O).

4) (l'S,3S,4R and l'R,3R,4S) 4-Acetylthio-3-(1'-paranitrobenzyldioxycar-bonyl-l'-ethyl)-1-(paranitrobenzyl 2"-hydroxy-2"-acetate)-2-azetidinones (epimers at C-2"). (isomer C) ~SAC J~SAC
O ~ N~ H O N ~ H

A mixture of isomer C of 4-acetylthio-3-(1'-paranitro-benzyldioxycarbonyl-l'-ethyl)-2-azetidinone (750 mg), paranitrobenzyl-glyoxylate hydrate (525 mg) and benzene (50 ml) was heated under reflux for 3 days over a Dean and Stark apparatus filled with 3A
molecular sieves. A second portion of glyoxylate (52 mg) was added and reflux was continued for 2 more days. The mixture was diluted with ether, washed with hydrochloric acid (2%), water, sodium bicarbonate (2~) and water, dried and concentrated to leave an oily residue (975 mg). Chromatography on silica gel, eluting with benzene-ether (85=15) gave the pure title compounds. IHmr (CDC13) ~: 8.25-6.75 (8H, m, aromatics), 5.30 and 5.12 (4H, 2s, benzyls), 5.05-4.70 (lH, H-2"), 4.45-4.35 (lH, 2d, H-4), 4.50-4.10 (lH, m, H-l'), 3.30 (lH, m, H-2 and 1.25 ppm (3H, 2d, CH3).

1~666~L
5) (1'S 3S 4R ~and 1'~.3R,4Sl 4-aoetylthio-3~ paranitrobenzyl~ioxy-carbonvl-l'-ethy~L=l-~Paranitrobenzyl 2"-triphen~l~hosphoranylidene-2"-aaetate)2-azetidinone (i~s~o Qr C~

2 B 2 j)C 2 P ME~

10~ SC12 ~/ 3 ~ 3 ~2PN8 02PN8 CO,P`JB

Isomer C of 4-acetylthio-3-(l'-paranitrobenzyl-dioxycarbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-hydroxy-2"-acetate) -2-azetidinone (577 mg, 1 mmol) was dissolved in anhydrous THF
(10 ml) and Pyridine (95 mg, 1.2 mmol) was added to the solution.
The solution was cooled to 0' and thionyl chloride (143 mg, 1.2 mmol) was added slowly. The mixture was stirred 30 min at O, diluted with a little ether and the insoluble salts removed by filtration and washed with ether. The comblned filtrates were concentrated to give the crude mixture of epimers of the C-2"
chloro compound. It was dissolved in THF (20 ml), triphenylphosphine (314 mg, 1.2 mmol) and 2,6-lutidine (129 mg, 1.2 mmol) were added and the solution was stlrred at 45C for 4 days. The solids were removed by filtration, washed with benzene and the combined filtrates were concentrated to leave an oil whose spectral characteristics and tlc behaviour were identical to a sample of the title compound prepared by acylation of the corresponding silver thiolate.
The desired penem product may be produced by reacting the the title compound according to the method of steps 2 and 3 of Example 35 (Method A).

36~
Example 36 (i'R,5R,6C and 1'5,~5,6R) 6~ Hydroxy-l'-ethyl)-~-methylPcnem-3-c~rbox/llc Acl~

(iso~er B~
OH

METHOD A

~SAg ~Ac 11 ~ `~CH ~ S~--CH

~02PNB C02PNB CO 2P NB CO 2 H

METHOD B

OH OH pH OH
~SAg 1 ) TMS/TEA ~SAc ~ ~CH3 ~ 5 ~ CH3 ~ 3 pyr d ne ~ ~ 3 CO2PNB ~ C02H

METHOD A

1) (l'R,35,4R and 1'5,3R,45) 4-Acethylthio-3-(1'-paranitrobenzyl-dioxv-carbonyl-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone, (isomer B) OCO2PNB ~CO2PNB
O ~ ~ 3 AcCl J ~ ~ cp~3 A solution of ~l'R,35,4R and 1'5,3R,45) silver 3-~1'-paranitrobenzyldioxycarbonyl-l'-ethyl) l'-paranitrobenzyl 2"-triphenyl-phosphoranylidene-2"-acetate)-2-azetidinone-4-thiolste (isomer B) (917 mg, 1.03 mmol) in CH2C12 (20 ml) was treated at -15C (ice-MeOH
bath) with pyridine ~242 ~1, 247 mg, 3.13 mmol) and dropwise with acetyl chloride (142 ~1, 157 mg, 2.0 mmol). ~e mixture uas stirred lZ~661 for 15 min at -15C and the solid was filtered and washed with ether.
The organic solution was washed with 2% aqueous HCl, water, 2% aqueous NaHC03, water and brine and dried over MgS04. The residue upon solvent evaporation crystallized from ether (710 mg, 80%, mp 183-185C; ir (CHC13) V : 1755, 1695 (C=0), 1620, 1605 ~phosphorane) and 1625 cm (N2~;

2) (l'R,5R,6S and 1'5,5R,6R) Paranitrobenzyl 2-methyl-6-(1'-paranitro-benzyld:oxycarbonyl-l'-ethyl)-enem-3-carboxylate. (isomer B) J 2 SA ~,. S
~ ~ ~ ~ CH3 o~__N ~ p~3 ~ ~ N ~

A solution of (l'R,3S,4R and l'S,3R,4S) 4-acetylthio-3-(l'-paranitrobenzyldioxycarbonyl-l'-ethyl)-ltparanitrobenzyl 2"-triphe-nylphosphoranylidene-2"-acetate)-2-azetidinone (650 mg, 0.791 mmol) was refluxed in toluene for 7 h. The concentrated solution upon solvent evaporation was passed through a silica gel column (10 times its weight) and the title compound (0.5% ether-benzene to 2~ ether-benzene) was obtained as a white solid; 329 mg, 77%, mp 134-135C, (CH2C12-ether); ir (CHC13) V : 1785, 1745, 1705 (C=0) and 1525 cm (N02); IHmr (CDC13) ~:
8.20 (2H, d, Ho aromatic), 7.60 (2H, d, Hm aromatic), 5.55 (lH, d, J=1.5, H-s), 5.5-4.75 (5H, m, 2CH2-PNB, H-l'), 3.86 (lH, dd, J=7.8, J=1.5, H-6), 2.38 (3H, s, CH3) and 1.50 ppm (3H, d, J=6.3, CH3); Anal. calcd for C24H21W301oS: C 53.04, H 3.89, N 7.73, S 5.90i found: C 53.05, H 3.98, N 7.63, S 6.02.

--J98~ -6~i1 3) (l'R,5R,6S and 1'5,5S,6R) 6~ Hydroxy~ ethyl)-2-methyl penem -3-carboxylic acid (isomer B) C2PNB ~ H

3 H2 ~N ~ 3 A mixture of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 2-methyl-6-(1'-paranitrobenzyldioxycarbonyl-1'-ethyl)-penem-3-carboxy-late (isomer B) (65 mg, 0.12 mmol), 0.05 M pH 7 buffer solution (1.06 eq), H2O-~HF-ether (10 ml, 10 ml, 25 ml) was shaken on a Parr hydrogenator using 30% Pd on Celite (200 mg) for 16 h at 50 psi H2.
The catalyst was filtered and washed with small volumes of water. The aqueous layer was washed with ether (3 times), acidiied portionwise with 1% cold aqueous HCl, extracted with ethyl acetate between each addition of HCl, and saturated with brine and extracted throughly with ethyl acetate. The ethyl acetate extracts were combined, washed with brine (5 times) and dried (MgSO4). Solvent evaporation afforded a solid residue which was triturated with methylene chloride (19.4 mg, 71~). ir (nujol) Vmax: 3500 (O-H), 1785, 1672 cm (C=O)i uv (EtOH) ~ a : 260 ( 3450), 309 ( 6400); ~Hmr (DMSO d6) ~: 5.54 (lH, d, J=1.5, H-5), 3.88 (lH, m, H-l'), 4.2-3.5 (2H, bs, O-H), 3.65 (lH, dd, J=6.5, J=1.5, H-6), 2.28 (3H, s, CH3) and 1.15 ppm (3H, d, J=6, CH3).

-19q -666~

METHOD B

1) (l'R 35.4R and l'S.3R.4S) 4-Acet~lthio~3-(l'-trimethylsilyloxy-l'-ethyl)-l-~pa~anitrobenzyl 2"-triphenvlphosphoranylidene-2"-ace~Aa~e~
-2-azetidinone tlsomer Bl ~)H OTMS
J.", ~f Ag TMSCl AcCl J ~SAc o~ ~p~ 3 TEA j 5 O'~-- ~P~ 3 C02PNB C02?~n3 A suspen6ion of (l'R,3S,4R and l'S,3R,4S) silver 3-(l'hydroxy-l'-ethyl)-l(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (505 mg, 0.715 mmol) in THF (25 ml) was cooled to -15C (ice-MeOH bath), treated dropwise with triethyl amine (289 mg, 398 ~1, 2.86 mmol), trimethyl chlorosilane (310 mg, 362 ~1, 2.85 mmol) and finally with imidazole (50 mg, 0.734 mmol), stirred for 3 h at -15-C and at room temperature for 16 h. (ir of an aliquot showed absence of hydroxyl group,). The mixture was cooled to -15-C, diluted with CH2C12 (20 ml), treated with pyridine (226 mg, 231 ~1, 2.86 mmol) and acetylchloride (168 mg, 152 ~l, 2.14 mmol), stirred for 0.5 h, diluted with ether, washed with dilute aqueous HCl, water 5% aqueous NaHCO 3 water and brine and dried. The 5 olvent was removed on the rotary evaporator and the residue purified by filtration through a silica gel column (1:10 ratio, 3% to 10% ether in benzene) to give the title compound (360 mg, 84.2%) mixed with a little of the desilylated derivative (30 mg, 7.8%). ir (liquid film) vmax : 1750, 1790 (C=O), 1620 (phosphorane) and 1518 cm 1 (NO2) ., ~

1~86~63 2) (l'R,35,4R and l'S,3R,45) 4-Acetylthio-3-(ll-hydroxy-ll-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azeti-dinone (isomer B) OTMS OH
J SAc H3 ~ ~ SAc ~ Cj61_ N~P~3 A solution of (l'R,35,4R and l'S,3R,45) 4-acetylthio-3-l'-trimethylsilyloxy-l'-ethyl)-l(paranitrobenzyl 2"-triphenylphospho-ranylidene-2"-acetate)-2-azetidinone (360 mg, 0.504 mmol) was treated with TFA (3 drops) and stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate, washed with water, dilute aqueous NaHC03, water and brine and dried (MgSO4). Solvent evaporation afforded the title compound (334 mg, 100~); ir (CHC13) v : 1755, 1690 (C=O), 1620, 1605 (phosphorane and 1520 cm (NO2).
max 3) (l'R,5R,65 and l'S,5S,6R) Paranitrobenzyl 2-methyl-6-(1'-hydroxy-1'-ethyl)-penem-3-carboxylate (isomer B) OH OH
~ ~ SAc a J"'~H3 ~02PNB C02PNB
A solution of (l'R,35,4R and l'S,3R,45) 4-acetylthio-3-(1'-hydroxy-1'-ethyl)-l(paranitrobenzyl 2"-triphenylphosphoranyl-idene-2"-acetate)-2-azetidinone (410 mg, 0.638 mmol) in toluene (40 ml) was refluxed for a 7 h period. Toluene was partially evaporated. The residue was passed through a silica gel (1 to 12 ratio) column (3%, 4% and 5% ether in benzene) to give the title compound (151 mg, 65%) as a white solid mp 161-161.5C;

ir (CDCl ) V : 3600, 3500-3400 (OH), 1780, 1608 (c=O) and 1525 cm 3 max (N02); IHmr ~CDC13) ~: 8.20 (2H, d, J=7, Ho aromatic), 7.60 (2H, d aromatic), 5.57 (lH, d, J=2, H-5), 5.29 (2H, center of A~q, J=15, CH2-PNB), 4.2 (lH, dq, J=7, J=6, H-l'), 3.67 (lH, dd, J=7, J=2, H-6), ~01 ~

2.33 (3H, s, CH3) and 1.33 ppm (3H, d, J=6, CH3); ~n31-calcd for C16H16N265: C 52.74, H 4.43, N 7.69, S 8.80;
found: C 52.67, H 4.41, N 7.71, s 8.96.
4) (1'R.9R.6S and l'S.5S,6R) 6-(1'-Hydroxy~ ethyl)-52-methyl ~enem -3-carboxylic acid lisomer B) o ~N _~C 3 2 .~ ~OH

2 CO2i~
10 A mixture of (1', S~, 6S and l'S,5S,6R) paranitrobenzyl 6-(l'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylate (89 mg, 0.244 mmol), THF-H2O-ether (15 ml, 10 ml, 30 ml), a 0,OS M pH 7 buffer solution (5.06 ml, 0.253 mmol) and 30% Pd on "CELITE"* (250 mg) was shaken on a Parr hydrogenator for 3.5 h at 45 psi H2. A work-up identical to the one previously described gave title compound (32 mg, 57%).
Example 37 (1'S.5R.6R and 1'Rl55.6S) 6-(1'-Hydroxy-1'-ethyl) -2-methyl~enem-3-carboxy~ic Acid (iso~ç~) ~f~s o~

1) (1'S.3R.4R and l'R.3S,~S) 4-Ac~ylthio-~-(l'-methoxymethoxy-l'-ethy~)-l(paranitrobenzyl 2"-t -2"-aç~o~o~LL,L~
(iso~ A) ~Ag p ~35A
N ~ 3 *TradeMark ~ ~36661 Isomer A of 4-acetylthio-3-(1'-methoxymethoxy-1'-ethyl) -l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate)-2-azeti-dinone was prepared as described elsewhere for isomer C of the paranitra-benzyl dioxycarbonyl derivative, yield 85%. ir (neat) V : 1750 and 1690 cm (C=O).

2) (l'S,3R,4S and l'R,3S,4S) 4-AcetYlthio-3-(1'-hYdroxy-l'-ethyl)-l-(para-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone, (isomer A) ~CH20cH3 OH
~AC ~I~AC

O ~ ~3 0 ~ ~3 Isomer A of 4-acetylthio-3-(1'-methoxymethoxy-1'-ethyl)-l-(paranitrobenzyl-2"-triphenylphosphoranylidene-2"-acetate~-2-azetidi-none (500 mg, 0.68 mmol) was added to a cooled solution (0C) of tri-fluoroacetic acid (50 ml) and water (10 ml) and stirred for 15 min in ice and 3 h at room temperature. The reaction mixture was concen-trated, dichloromethane was added and the solution was washed with sodium bicarbonate, water, and brine, dried and concentrated to give the title compound (450 mg, 96%);ir (neat) ~max 3400 (OH), 1745 and 1690 cm (C=O).

12~3666~
3) (l'S.5R.6R and 1'R.5S,~L Pa~anitxobenzyl 6-l1'-hyd~oxy -1'-ethyl)-2-methyl penem-3-carboxyl~te (isom~ A
OH OH

3 /~N--~ 3 Prepared as described fox isomer C of the paranitrobenzyl dioxycarbonyl derivative, yield 45%, 1Hmr (CDC13) ~: 7.93 (4H, ABq, aromatics), 5.68 (lH, d, J=4.0, H-5), 5.33 (2H, Asq, ben~yl), 4.3 (lH, m, H-l~), 3.8 (lH, dd, J=4.0, H-6), 2.41 (3H, s, CH3), 2.31 (lH, s, OH), and 1.42 ppm (3H, d, J=6, CH3 ); ir (CHC13) Vmax: 3100--3600 (OH), 1780 and 1710 cm 1(C=o).
4) (l'S.5R.6R and l'R.5S.6Sl 6-(1'-Hydroxy-1'-ethvl) -2-methyl penem-3-carboxylic acid (isomer A) OH OH

CH , ~;~--CH 3 A mixture of isomer A of paranitrobenzyl 6-(l'-hydroxy- 1'-ethyl)-2-methyl penem-3-carboxylate (82 mg, 0.2 mmol), palladium on Celite t30%, 400 mg), THF (10 ml), ether (25 ml), water (10 ml) and buffer (0.05 M, pH=7, Fisher #SO-B-108) (4 ml) was hydrogenated on a Parr shaker at an initial hydrogen pressure of 45 psi for 4 h. The catalyst was removed by filtration on "CELITE"* and washed with water. The filtrates were washed with ether and the aqueous layer was acidified in the cold hydrochloric acid (0.25 M) and extracted with ethyl acetate (5 x 10 ml). The combined organic extracted were washed with brine, dried and concentrated. The foamy solid was *TradeMark ~Z~6~

triturated in ether to give a white solld (2 mg, 44%). ir (''NUJOL'')*V max: 3500 (OH), 1765 and 1665 cm 1 (C=O) ; uv (EtOH) max: 301 ( ~5922), 260 (~ 4280).
- Exam~le 38 (l'R 5R.6S and 1'5.5~.6R)2-Aminomethy1-6- (l'-hydroxy-l'-ethy -~enem-3-carboxylic Acid (isomeL ~1 Ho~",~ S ~
~ N ,~/ CH 2 NH2 (1'R 3S.4R and l'S.3R.4S) 4-azidoacetylthio-3-(1'-hYdroxy-l'-ethyl)~ aranitrobenzyl 2"-tri~henylphogphoranylidene-2"-acetatel-2-azetidinone (isomer 3) OH
OH SAg TMSCl ClCOCH2~l3 ,~3 JF~cccH2N3 N~P~3 T~ ~3 A cold (ice-MeOH bath) suspension of (1'R,3S,4R and 1'S,3R,4S) silver 3-(1'-hydroxy-1'-ethyl)-1- (paranitrobenzyl 2"-triphenyl phosphoranylidene -2"-acetate) -2-azetidinone-4-thiolate (970 mg, 1.37 mmol, from 1 g of the corresponding trityl) in THF (40 ml) was treated dropwise with trimethylchlorosilane (0.695 ml, 595 mg, 5.48 mmol), trlethyl amine (0.765 ml, 555 mg, 5.49 mmol) and imidazole (50 mg, 0.734 mmol). The mixture was stirred under N2 for 17 h, then cooled to -15C (ice-MeOH bath) and azidoacetyl chloride (406 mg, 3.40 mmol) was added in. It was stirred for 30 min (the reaction progression being followed by tlc). The solid was filtered and washed with ether. The filtrate was diluted with more ether, washed with 1% aqueous HC1, water, 1% aqueous NaHCO3 , water and brine and dried (MgSO4l. The residue *Trade Mark ~ X~36~6~

upon solvent evaporation was taken up ln moist CH2C12 (50 ml) and treated with TFA (3 drops, cleavage of TMS-ether being followed by tlc). The methylene chloride solution was then washed with 1%
aqueous NaHCO3, water and brine and dried (MgSO4). The residue was passed through a silica gel (B times its weight) column (benzeneether 1:1, ether and ethylacetate-ether 1:1) to give the title compound (565 mg, 69.8%); ir tfilm) vmax : 3500-3200 (0-H), 2100 (N3), 1755, 1609 (C=O), 1620-1605 (phosphorane) and 1518 cm 1 (NO2).
(l~R 5R.6S and l~S 5S 6R~ paranitrobenzYl 2-azidomethvl-6-(1'-hydroxy-1'-ethyl)-penem-3-carboxylate (isomer B) OH OH
j ~ ScoC~2N3 ~oluene J
o ~ 1 ~3 ~ 2~3 ~O2PN~3 2 A solution of (l'R,3S,4R and l'S,3R,4S) 4-azido-acetylthio-3-(l'-hydroxy-l'-ethyl)-l-(paranitrobenzyl 2"-triphenyl-phosphoranylidene-2"-acetate)-2-azetidinone (500 mg, 0.731 mmol) in toluene 100 ml was refluxed under N2 for 30 min.
The solution was concentrated under vacuum and the residue was passed through a silica gel (5 g) column (3.5-4% ether-benzene) and yielded the title compound (193 mg, 65.1%) as a yellowish solid 1Hmr (CDCl3) ~ 8.13 (2H, d, Ho aromatic), 7.52 (2H, d, Hm aromatic), 5.59 (lH, d, J=1.8, H-5), 5.27 (2H, center of ABq, J=13.5, CH2-PNB), 4.50 (2H, center of ABq, J=16, CH2-N3), 4.15 (lH, m, H-1'), 3.73 (lH, dd, J=6.3, J=1.8, H-6), 1.92 (lH, d, J=4, O-H) and 1.33 ppm t3H, d, J=6.3 CH3); ir (CHC13) vmax :
2110 (N3), 1785, 1705 (C=O) and 1520 cm 1 (NO2).

~3666~L

(l'R,5R,6S and l'S,5S,6R) 2-aminomethyl-6-(l'-hydroxy-1'-ethyl)-penem-3-carobxylic acid (isomer B) ~ H2 F~

A solution of (l'R,5R,6S and l'S,5S,6R) paranitro-benzyl 2-azidomethyl-6-(l'-hydroxy-l'-ethyl)-penem-3-car~oxylate (25 mg, 0.062 mmol) in THF-ether-water (6 ml, 6 ml, 15 ml) was shaken on a Parr hydrogenator for 2.5 h at ~0 psi H2 using 10% Pd on carbon (100 mg). The catalyst was filtered and washed with small volumes of water. The aqueous layer was washed with ether (3 times) and lyophilized to give the title compound (11 mg, 73%).
IHmr (D20) ~: 5.75 (lH, d, J=2, H-5), 4.30 (lH, center of m, J=6.5, H-l'), 4.02 (lH, dd, J=6.5, J=2, H-6) and 1.37 ppm (3H, d, J=6.5, CH3); ir (nujol mull) ~max 3550-2450 (0-H, N-H), 1765 (C=0) and 1600 cm 1 (C02~ ; uv (H20), ~ : 309 ( 3650), 255 (~ 2815).

.:Lo~ -1~36661 Example 39 (1'R SR 6S and l'S 55.6R)-2-(4-Amlnobuty~)-6-(l'-hydrPXY-ethyl~--pçnem-~ rboxylic Acid (isomer BL

OH

oj~ ( 2~ 4NH2 COOH

(l'R 3S.5R and l'S,3R 4S) 4-(~-azidobu~anoylthio)-3-(l'-hydroxyethyl)-1-(paranitrobenzyl 2"-triphenyl~hosph~ranylidene -2"-açç~ate)-2azetidinone JOH THSCl N3 (CH2) 4COCl H ~Ç,,,,~f -C (C~2) 4N3 O~C TEA, Im. C5H5N H2 ~C=PPh3 COOPN~ OOPN~

A solution of (l'R,3S,4R and l'S,3R,4S) silver 3-(1'-hydroxyethyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene 2"-acetate)-2-azetidinone -4-thiolate t3.03 g, 4.28 mmol) in dry THF (S5 ml) kept under a nitrogen atmosphere was cooled to -25C and successively treated 30 with triethylamine (2.39 ml, 17.12 mmol) trimethylchlorosilane (2.18 ml, 17.12 mmol) and imidazole (0.10 g, 1.47 mmol). The reaction mixture was stirred at -25C for 0.25 h, the cooling bath was ~366Ç;~L

removed, and the stirring was continued ~or 16 h. The reaction mixture was cooled to 0C and diluted with CH2Cl2 (55 ml); it was then treated successively with pyri.dine (0.73 ml, 9.0 mmol) and with a solution o~ 4-aminobutanoyl chloride (1.36 g, 8.56 mmol) in CH2Cl2(10 ml). The reaction mixture was stirred at 0C for 1 h and filtered through a "CELITE"* pad. The pad was washed with CH2Cl2 (25 ml); the filtrate and washings were combined and diluted with EtOAc (300 ml) . ~he organic solution was washed with lN HCl solution, H2O, saturated NaHCO3 solution and H2O, dried over anhydrous MgSO4 and concentrated on a rotary evaporator to an orange syrup (3.83 g). The syrup was disso~ved in CH2C12 (75 ml) and water (4 ml) and TFA (O. 2 ml) were added;
the reaction mixture was stirred at 23C for 1.5 h, washed with NaHCO3 and H2O, dried over anhydrous Na2SO4 and concentrated to an orange syrup (3.4 g). Purification of the syrup was achieved by a column chromatography (silica gel G 60, 80 g; eluent: EtOAc in CH2Cl2 10% ~ 75%). Evaporation of the appropriate fractions gave an oil; 2.14 g, 67.7%. Anal. calcd for C37H36N5O7SP: C
61.23, H 5.00, N 9.65, S 4.42; found: C 61.17, H 5.10, N 10.02, S
3.71.
(1'R.5R,6S and 1'S.5S 6R) ~aranitrobenzyl 2-(~-azidobutyl)-6 -fl'-hydroxye~hyl~-penem-3-carboxylate OH R o~
J""~ ~ SC (C-~2) 4N3 ~ J" S
oL N \ Toluene o~N ~(CH2) N3 f 3 OOPN3 COOPNB

A solution of (l'R,3S,4R and l'S,3R,4S) 4-( -azido-butanoylthio)-3-(l'-hydroxy-l'-ethyl)-l-(paranitrobenzyl-2"-tri-phenylphosphoranylidene-2~-acetate)-2-azetidinone (2.04 g, 2.81 mmol) in a toluene-CH2Cl2 mixture (30:1, 310 ml) was refluxed for 9 h under a *Trade Mark l~Ç~6661 nitrogen atmosphere (The CH2C12 was removed at the beginnlng of reflux). The reaction mixture was cooled to 23C and the toluene was removed in vacuo leaving an orange residue which was purlfied by colum~ chromatography (silica gel 60, 45 g; eluent, ether in pet. ether, 1:1 9:1). The appropriate fractions were combined and concentrated to a syrup which was crystallized from an ether-pet.ether mixtuxe, 0.443 g, mp 85C, 35.2%. Anal. calcd for C19H21N506S: C 51.00, H 4.73, N 15.65, S 7.17; found: C 51.05, H
4.86, N 15.86, S 7.19. The fractions corresponding to unreacted starting material were cyclized as described above to give an additional quantity (0.276 mg, 21.9%) of title compound. vmax : 2100 (N3), 1770 (C=O, B-lactam,) and 1705cm 1 (C=0, PNB ester); ~v(H20 23C) ~max :268 (~ 13757), 316 (~ 69826). 1Hmr (CDC13):~ 1-36 (d~JH-2''-H-1''= 6-3 Hz~ 3H~
methyl), 1.52-1.77 (m, 4H, H-2', H-3'), 2.57-3.00 (m, 2H, H-4'), 3.00-3.42 (m, 2H, H-l'), 3-72 (dd, JH-6-H-5 = 1-6 Hz~
JH_6_H_1"=6.4 Hz, H-6), 4.02-4.42 (m, lH, H-l"), 5.32 (ABq, J.
a-b= 13.6 Hz, 2H, CH2 of PNB ester), 5-60 (d, JH-5-H-6 = 1-6 Hz~
lH,H-5), 7.61 (d, JHm_HO =8.8 Hz, 2H, Hm of PNB ester) and 8.21 ppm (d~ JHo-Hm= 8-8 Hz, 2H, Ho of PNB ester).

(1'R.5R.6S and l'_L,L5.5~ In~h~ ~-6 -(l'-hydroxyethyl~-penem-3-carboxylic acid OH
OH S 109~ Pd/C S

--~OOPNP DME:: E t 2 ' ~ 2 O~ ( CH 2 ) 4 ~IH

To a solution of (1'R, 5R, 6S and l'S,5S,6R) paranitro-benzyl 2-( -azidobutyl)-6-(1'-hydroxyethyl) -penem-3-carboxylate (0.54 g, 1.21 mmol) in dimethexyethane (50 ml) was added ether (50 ml), water (50 ml) and 10% Pallaaium on charcoal (0.54 g). The reaction mixture was hydrogenated under 45 psi of hydrogen at 23C for 3 h. The reaction , ~ ~, 12~6661 mixture was filtered over a l'CELITE''*pad and the filtrate was diluted with ether. The aqueous phase was separated, washed with ether and lyophylized. The crude title compound was purified by hplc. ir (-KBr) vmax: 1760 (C=O, B-lactam) and 1565 cm 1 (C-O, carboxylate); 1Hmr (D2O) ~: 1. 32 (d, JCH3-H-l''=6. 4 Hz, 3H, CH3), 1. 45-1. 85 (m, 4H, H-l', H-3~ ), 2. 50-3. 20 (m, 4H, H-l', H-4~ ), 3. 84 (dd~ JH-6-H-l"= 6- 1 Hz, J H-6-H-s =1. 4 Hz, 1-H, H-6), 4. 00-4. 45 (m, lH, H-l"- and 5. 62 ppm (d, J H-5-H-6 =1. 4 Hz, lH~ H );
(H20) max: 260 ( 4240), 302 (~: 5480).
Example 40 (l" R.5R.6S and 1' S 5S 6R)-2-(trans-3' -~mino-l~ -çYclobutyl)-6-(l"-hydroxy -l"
ethyl)pe~em-3-çarboxylic Acid (isomer B) OH
~ O""UH2 COOH
(1"R.3S.4R and l"S.3R 4S) 4-ttrans-~' -azidocyclobutanoylthio)-3--hydroxy-l~-ethyl)-l-~E2ara~nltroben~YL
20 2"' -triDhenyl~ho6phoranylidene-2"' -acstate)-2-azetidinone ~C ~ ~ C-~h ~ r ~ 3 A solution of (1' R, 3S, 4R and l' S,3R,4S) silver 3-(l' -hydroxyethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene -2"acetate)-2-azetidinone -4-thiolate (1. 01 g, 1. 43 mmol) in dry THF (25 ml), kept under a 30 nitrogen atmosphere, was cooled to -40C and successively treated with triethylamine (0. 80 ml, 5. 74 mmol) trimethylchlorosilane (0. 726 ml, 5. 72 mmol) and imidazole (0. 10 g, 1. 47 mmol). The reaction mixture was warmed to -15C, stirred for 3 h, the cooling bath was removed and the stirring was continued for 18 h.
35 The reaction mixture was cooled to -15C and diluted with CH2C12 (25 ml); it was *TradeMark 1~3666~
then treated with pyridine (0.15 ml, 1.85 mmol) and trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The cooling bath was removed and the solution was stlrred for 1 h and treated wiIh pyridine (0.15 ml, 1.~5 mmol) and trans-3-azidocyclobutanoylchloride (0.274 g, 1.72 mmol). The reaction mixture was stirred at 23C for 1 h and filtered through a "CELITE"*pad. The filtrate was diluted with EtoAc (100 ml) and washed with lN HCl, H2O, saturated NaHCO3 solution and H2O, dried over anhydrous MgSO4 ancl concentrated on a rotary evaporator to an orange syrup (1.47 g). To a solution of the syrup in CH2C12 (50 ml) was added H2O (2 ml) and TFA (0.2 ml).
The reaction mixture was stirred at 23C for 2 h, washed with saturated NaHCO3 solution and H2O, dried over anhydrous Na2SO4 and concentrated to an orange syrup (1.1 g). Purification of the syrup was achieved by column chromatography (silica gel 60, 20 g;
eluent EtOAc-ether 35% + 70%) . Evaporation of the appropriate fractions gave the title compound as an oil; 0.77 g, 74.4% ir (neat) vmax: 3440 (OH), 2100 (N3), 1755 (C=O B-lactam), 1735 (C=O), 1680 (C=O) and 1625 cm~1 (aromatics).
(l"R.5R.6S and l"S SS 6Rl paranitrobenzyl 2-(trans-3'-azidocyclobutyll-6-(1"-hydroxy-1"-ethyl)penem-3-carboxylate ~ N3 ~oluene ~ ~.............................. , N3 COOPN~ COOPN3 A solution of (1"R,3S,4R and l"S,3R,4S) 4-(trans-3'-azidocyclobutanoylthio)-3-(1"-hydroxy-1"-ethyl)-1-(paran-itrobenzyl-2"'-triphenylphosphoranylidene-2"' -acetate)-2-azetidinone (2.27 g, 3.14 mmol) in CHC13 (40 ml) was diluted with toluene (300 ml) and refluxed under a nitrogen atmosphere for 6 h. The first 60 ml of solution (CHC13 + toluene) were removed with a Dean-Stark trapp. The reaction mixture was cooled to 23C and the solvent was evaporated *Trade Mark ~A . -' under a reduced pressure leaving an orange syrup which was purified by a silica gel column (silica gel 60, 35 g, eluent, ether-benzene, 0 6%). Evaporation of the appropriate fractions gave the title compound, 0.38 g, Mp 134-5C, 27.3%. Anal calcd for C1gH1gN506S: C 51.24, H 4.30, N 15.73, S 7.20; found: C
50.98, H 4.20, N 15.83, S 7.10; ir (KBr) vmax : 2110 (N3), 1765 C=O B-lactam), 1690 (C=O PNB ester), 1510 (NO2 ) and 1355 cm 1 (NO2); Hmr (CDCl3) ~: 1-36 (d, JCH3-H-1=6 3 Hz~ 3H~ CH3 )~
2.0-2.75 (m, 4H, H-2', H-4'), 3.67 (dd, JH_6_H_5"1.5 Hz, JH_6_H_l"= 6.5 Hz, lH, H-6), 3.8-4.55 (m, 3H, H-l', H-3' and ~ 5-30 (ABq~ Ja-b =13-6 Hz, 2H, CH2-Ph-NO2), 5.60 (d, JH 5 H 6=1 5 Hz, lH, H-5), 7-59 (d, JHo-Hm=8 3 Hæ~ 2 ~
PNB) and 8.20 (d,JHm_Ho=8.8 Hz, 2H, H-0 of PNB). uv (CHCl3, 23C) Amax : 266 ( E 13050) and 322 ppm ( 10008). The lS unreacted phosphorane was recovered mixed with Ph3P-0 and cyclized as described before to give an additional quantity of title compound: 0.145 g, 10.4% for a total yield of 37.7%.
t1"R 5R 6S and l"S,5S.6R)-2-(~ans-3'-amino-l'-cYclobutyl(-6-(l"-hydroxyethyl)penem-3-carboxylic acid ~ 3 DME,et~e-, H20 J ~ ~ ~ ""NH2 OOPNs coo~

To a solution of (l"R,5R,6S and 1"S,5S,6R) paranitrobenzyl 2-(trans-3'-azidocyclobutyl)-6- (l"-hydroxyethyl)-penem-3-carboxylate (0. 33 g, 0. 74 mmol) in dimethoxyethane (40 ml) added ether (40 ml and 10% Palladium on charcoal (0.33 g). The reaction mixture was hydrogenated under 45 psi of H2 for 3 h and filtered over a Celite pad. The pad was washed with water and the filtrate and washings were combined and diluted with ether. The aqueous phase was separated, washed with ether and lyophylized, 0.20 g, 95%, uv (H20, 23C) AmaX 258 (E 2725) and 306 ( 3613).
The crude material was triturated 1~6~i6~

with water and the white solid was filtered and dried overP205 under high vacuum for 5 h, 84 mg, 40%; 1Hmr (D20) ~:
1-34 (d~ JH-2"-H-1"=6-3 Hz, 3H, H-2"-, 2.3-2.7 (m, 4H, H-2', H-4'), 3.90 (dd, J H_6_H_5=1.5 Hz, J H-6-H-1" =6-1 Hz, lH, H-6) and 5.68 (d, JH_5_H_6=1.5 Hz, lH, H-5); uv (H2O, 23C) Amax : 258 (E 4738) and 306 (E 6318). The filtrate was purified by hplc, 58 mg; uv (H2O, 23C) Amax:
257 ( E3580) and 306 (E 5033).

,, ~.

~t Example ~
~ ollowing the general procedure of Example ~ , the following 2,6-disubstituted penem compounds may be prepared using the indicated electrophiles.

~lectrophile Product R ~_~S

O

CH3CH20502~CH3 CH3CH2-CH3CH2CH205o2 ~ CH3 3 2 2 CH =CH-CH -Br CH2=CHCH2-HC--C-CH Br HC-CCH2 Br l~r~6G61 Electrophile R =

2 0CH2_ CH

~ Br CH3 0CH2CH2CH2S2 ~ 3 0 0CH=CHCH2Br 0C-CCH2Br 0C_CCH2-Br Br CH CH-CH ~
CH30CH2Cl CH30CH2-CH35CH2Cl CH3SCH2- ~) ~ Cl ~O ~
CH30CH2CH2Cl CH30CH2CH2-O O
may be oxidized to produce CH3SCH2- and CH3SCH2-O O
may be oxidized to produce CH3SCH2CH2- and CH3SO2CH CH -OH protected via -C-OPNB

~ 2~3666~

Electrophile R =
OH

OH
~S CH CH-CH -SH
/ ~/ CH3CH-CH2-~a) 0 ~ O ~ OH

0SCH2C1 0SCH2- q 0CH25CH2CH2C1 0CH25cH2cH2- ~) o OH
0~ 0~ ~
o ~9SH protected -C-O-PNB
may be oxidized to produce HO35CH2CH2-0 may be oxidized to produce CH3CH-CH2-may be oxidized to produce 0 CH2 and 0S02CH2-may be oxidized to produce 0C82SCH2- and 0CH25O2CH2-@) may be oxidized to produce 0SCH2CH - and 0502CH2CH2-0 may be oxidized to produce 0CH2SCH2CH2- and 0CH2SO2CH2CH2-~ ~/ q ~

~2~6~

Electrophile R =
~ . .
~<IS
(~) (~3 SH

0CH2CHO 0 ~ OH
0CH=CH-CHO 0~

s o Il u Cl 0 O

0 ~ ~ `Cl O O
J~/, ~/ O

~ay be oxidized to produce 0 6G6~

Electrophile R
o Cl ~S ~ Cl ~ ~ D

0CH=CHC02CH3 0~\
OH
0C-C-CHO 0C_C-CH-O
0C_C-C02CH3 0C--C-C-SH
0CHS 0 ~
OH
CHO

~C02CH3 Br Br _~, 19 -~r~6G~l Electrophile R =

~3 , Br ~/\

~Br ~

C~\Br CN

~;~Br C~i 3_ ~ Br [~N

\> ~Br C~\Y~

~ Br C2H50C-Cl C 2H 50C-C2H50CCH2Br C2H50C /\

N - C-CH 2 C 1 NC ~\

_~1 ~r3~

Electrt ph i 1 e R =

FCH2CH2C2CH3 F~
02N-CH2Cl HONH
3 OCH 2 c 1 sl ~ o~\

- o (PNB-O) 2P 2 3P~\

C H 3 CHO /~\

OH OMS ~ 3 ~S~

J~ Ct~3 as i 58Example /~

NH2 ~HCH3 N-CO2PNB
Also, J~

or ~ CH3 -- co2~

~36~6~

NH2 N(CH3)2 N(CH3)2 ~C02H

or or NHCONHR

> 3 R = H, CH3, or CH3CO-CO H

~ Z~366~1 Also, OH

o Si~

STr ~ ~ 2HH3 N --N
OH OMS CH3,~s ; SH

G~ ~ 5'/ ~ 5 / ~ N ~

S ~ N ,N

_~ ~3- Co2H

~36661 Electrophile R =
NRR' R, R' = H, CH3 ~)CH 2CHO

`r'~ R, R ' = H, CH 3 RR ' N

CH30Cl ~6~i61 ExamDle 42 (1'S,5R 6S ~nd 1'R.SS,6R) B-Trimethvlsi1yle~hyl-6(1'-açQ~Q~y-1' ethy~ methyl~enem-3-~car~oxylat~ Qmer C) OAc /~ ~Me C02~ 51--3-(1'-hydrQxy-l~-ethy~ -trim~hyl~ilylethyl-2"-t~iphenyl-~hos~horanylidene-2~-acetate!-4-tritylthio-2-azetidinone STr ~OH
~ 1) LDA ~ Me ~Tr 2 2) CH3C~0 ~N PPh3 SiMe3 To a solution of diisopropylamine (185 mg, 1.84 mmol) in tetrahydrofuran (5 ml) at -78 C was added n-butyl lithium (1.3 ml, 2.0 mmol) with stirring. After 5 min, a solution of 1-tB-trimethylsilylethyl 2'- triphenylphosphoranylidene -2'-acetate)--4-tritylthio-2-azetidinone (1.27 g, 1.67 mmol) in 25 tetrahydrofuran (15 ml) wa6 added dropwise over 20 min with stirring. After 2 min, freshly distilled acetaldehyde (1 ml) was added and the solution was stirred for 5 min. Hydrochloric acid (12.6 ml of 0.3M) was added and the mixture was allowed to warm to 23 C. Nater and ethyl acetate (20 ml each) were added, shaken, and separated. The organic phase was washed with water and saturated sodium chloride (20 ml each), dried and the solvent was evaporated in vacuo to give crude product, 1.37 g. The product was absorbed from methylene chloride onto 7 g of silica gel and placed (dry) on a 28 g silica gel column. The column was eluted with ether (100 ml) and then with ether/ethyl acetate 1:1 (50 ml). The first 20 ml of column fractions were discarded. The rest were combined and the solvent was . f l i 12~36661 evaporated in vacuo to give a product, 1.03 g. This product was absorbed from ether onto a 50 g silica gel column (wet). The column was eluted with ether (680 ml) and then with ethyl acetate (200 ml). Later fractions were combined (major low Rf spot on tlc) and the solvent was evaporated in vacuo to give partially purified title compound, 440 mg (33~);
ir V : 3400 ~OH) and 1750 cm ~-lactam and ester); IHmr ~CHC13) ~:
too poorly resolved to make peak assignments other than aromatics and trimethylsilyl.

Silver 3-(1'-hydroxy-1'-ethyl)-1-(~-trimethylsilylethyl 2"-triphenyl-phosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate.

OH OH
Me ~ STr AgNo3/pyridine ~ Me ~ Ag iMe3 C2 SiMe3 A solution of silver nitrate (425 mg, 2.5 mmol).
pyridine ~79 mg, 1.0 mmol) and water ~10 ml) was added to a solution of the above compound ~403 mg, 0.50 mmol) in ether ~10 ml).
The mixture was stirred vigorously for 1 h. The precipitate was collected by filtration and washed with water and ether to give the title mercaptide 267 mg (80~). ir V : 3400 (OH) and 1750 cm (~-lactam and ester).

1~6~61 4-Acetylthio-3-(l'-acetoxy-l'-ethyl)-l-(~-trimethYlsilylet-hyl 2~-tri-p~nYlphosphoranylidene-2l~-acetate ! - 2-azetidinone OH OAc PY ne ~ Me~ ~3 A solution of acetyl chloride (70 mg, 0.88 mmol) in methylene chloride (1 ml) was addecl dropwise to a solution of the above silver mercaptide (267 mg, 0.40 mmol) and pyridine (70 mg, 0.88 mmol) in methylene chloride (5 ml) at 0C. The mixture was stirred at 0C for 1.5 h and then at 23C for 15 min. The precipitate was filtered off and the solution was washed with 0.1 M hydrochloric acid and 0.1 M
sodium bicarbonate (10 ml each). The solvent was evaporated in vacuo to give the title compound, 153 mg (59%); ir vmax:
3450 (OH), 1750 (~-lactam and ester) and 1690 cm~1 (thioester); 1Hmr (CDC13) ~: 7.5-8.2 (m, 15H, Ph), 5.85 (br, lH, H-4), 3.0-5.0 (unresolved, 4H, OCH, OCH2, H-3), 2.0-2.6 (3 singlets; 6H, OAc, SAc), 0.9-1.7 (m, 5H, CH3, CH2Si) and 0.20 ppm (s, 9H, SiMe3).
(l'S 5R 6S and l'R.SS.6R) ~-trimethylsilylethyl 6-~l'-acetoxy-l'-ethyl)_2-methyl~enem-3-carboxylate (isomer C).
OAc OAc ¦ H H
Me~SAc Me~ ~--Me N~PPh3 ~ --~2~ SiMe3 A solution of the above phosphorane (150 mg, 0.23 mmol) in toluene (15 ml) was heated under reflux for 2 h. The solution ., ."
,r.

~J~
was mixed with 1 g of silica gel and the solvent was evaporated in vacuo. The silica was placed on a 4 g silica gel column (dry) and eluted with ether. The first 5 ml fraction tsingle high Rf spot on tlc), on evaporation of the solvent, gave the title compound, 65 mg (76~) as a waxy solid. ir vmax: 1790 (~-lactam), 1740 (ester) and 1700 cm~l (OAc); lHmr (CDC13) ~: (d, J=2Hz, lH, H-5), 5.4 (m, lH, H-l'), 4.3 (m, 2H, OCH2), 3.90 (q, J=2Hz, 4Hz, lH, H-7), 2.37 (s, 3H,2-CH3), 2.11 (s, 3H, OAc), 1.42 (d, J=6.5, Hz, 3H, 2'-CH3), 1.1 (m, 2H,CH2Si) and 0.05 ppm (s, 9H, SiMe3).
The product was found to be a single isomer.
Example 43 (l'R 5R 6S and l'S.5S 6R) 6-1'-Amino-l'-ethyl)-?-methvlpenem-3-carboxyllc Acid Procedure A
~l'R.3S 4R and l'S 3R 4S)3-(1'-azido-1'-ethyl)-1-(paranitrobenzyl 2"-triphonvlphosphoranylidene-2"-acetate)-4-tritylthio -2-azetidinone lisomer B) SC~ ~ c~3 N P~3 N ~ 3 A solution of (l'S,3S,4R and l'R,3R,4S)3-(1-methane-sulfonyloxy-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (isomer C) (12.36 g, 13.4 mmol) in 10~ H2O-HMPA (135 ml) was heated at 85C for 35 7 h in the presence of sodium azide (1.75 g 27.0 mmol). The solution was then poured into lX~il cold water (1 Q ) and the reaction product which crystallized out was collected by filtration. Redissolution in dichloromethane, washing with brine and drying (MgSO4) gave the azido phosphorane as a yellow foam after evaporation of the solvent: 11.5 g (98.9%). It was used as such for the next step. ir Vmax (CHC13): 2100 (N3), 1740 and 1610 cm~1 (C=O).

(l'R 3S 4R and l'S 3R 4S)4-acetylthio-3-(l'-azido-l'-ethyl) -l-(paranitrobenzyl 2"-triphenvlphosphoranylidene -2"-acetate) -2-azetidinone (isomer B) 3 j~S) 2H5 ~ SCOCH3 o N ~1 3 N ~P~ 3 N~P~ 3 C02PNB C022NB C02PN~
A cooled solution (5C) of (l'R,3S,4R and l'S,3R,4S)3-(1'-azido-l'-ethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidine-2"-acetate)-4-tritylthio-2-azetidinone (8.9 g, 10.25 mmol) in dichloromethane (30 ml) was treated with a solution of mercuric acetate (2.12 g, 6.66 mmol) in methanol (30 ml). After stirring at 5C for 0.5 h and room temperature for 1.5 h, the solvent was evaporated and the crude mercuric salt redissolved in dichloromethane and washed with dilute NaHCO3 and brine.
After drying (MgSO4) the solution was cooled to 5C and treated directly with pyridine (1.66 g, 21 mmol) and dropwise with acetyl chloride (1.65 g, 21 mmol). The reaction mixture was stirred at 5C for 1 h. The precipitated mercuric chloride was filtered off and the filtrate washed successively with dilute HC1, NaHC03 and brine. Then the organic solution was saturated at 5C with hydrogen sulfide in order to precipitate the remaining mercuric impurities as mercuric sulfide. The crude thioester obtained after evaporation of the solvent was purified on a silica gel column (8.5 x 9 cm), eluting with dichloromethane (500 ml) ~ .~

~36~
and 15% acetonitrile-dichloromethane: 5.1 g (74.6~ Hmr (CDC13) ~: 3.70 (lH, m, H-l'), 2.98 (lH, m, H-3), 2.33 and 2.20 (3H, 2s, acetyl), 1.28 (3H, d, J=6.2 Ha, H-2'); ir vmax (CHC13): 2115 (N3) 1758, 1693 and 1620 cm 1 (C=0) (1'R.5R.6S and 1~S,5S,6R) paranitrobenzyl 6-(l'azido-1'-ethyl) -2-methylpenem-3-carboxylate (isomer B) D-- ~ 3 ~PNB
C02PN~ 2 A solution of (l'R,5R,6S and l'S,5S,6R)4-aeetylthio-2-(1'-azido-l'-ethyl)-l-paranitrobenzyl 2"-triphenylphosphoranylidene-2~-acetate)-2-azetidinone (5.lg, 13.1 mmol) in toluene (100 ml) was refluxed for 2 h under nitrogen. The solvent was evapoxated and the reaction mixture purified by chromatography on a silica gel column (7 x 5 cm). The azido penem was eluted with dichloromethane (further elution with 10% ether-dichloromethane allowed to recover 1.82 g of unreacted phosphorane):1.21 g (40.6%) mp 132-34C; 1Hmr (CDC13) ~: 8.21 (2H, d, Hm aromatie), 7.60 (2H, d, Ho aromatic), 5.51 (lH, d, J=1.6 Hz, H-5), 5.33 (2H, ABq, H-benzyl), 3.92 (lH, dq, J=8, 6.4 Hz, H-l'), 3.67 (lH, dd, J=1.6, 8 Hz, H-6), 2.37 (3H, s, CH3), 1.46 (3H, d, J=6.4 Hz, H-2'); ir vmax (CDC13): 2123 (N3), 1788 and 1712 em 1 (C=O).

1~36~
(l'R 5R.65 and l'S 5S,6R)6-(l'amino-1'-ethyl)-2-methvl penem-3-c~rboxylic acid ~isomer BL
~ 3 NH2 ~ ~ H3 ~ ~ CH3 C02PNB . C02H
A solution of (l'R,5R,6S and l'S,5S,6R) paranitrobenzyl 6-(l'azido-1'-ethyl)-2-methyl penem-3-carboxylate (440 mg, 1.13 mmol) in THF-ether-water (1:1:1) (120 ml) was hydrogenated at 50 psi for 1 h in the presence of 10% Pd-C
(440 mg). The catalyst was filtered off, the filtrate extracted with ether and the aqueous phase lyophilized. The crude amino acid (100 mg) was purified by hplc: 19.5 mg 1Hmr (D20) ~: 5.69 (lH, d, J=o.s Hz, H-5), 3.94 (2H, m, H-6, H-l'), 2.28 (3H, s, CH3), 1.50 (3H, d, J=6.4 Ha, H-2'); ir v max ("NUJOL")*: 1767, 1576 cm~l (C=O); uv (H20) ~max 300 m~ ( 5326).

Procedure (l'R.3S,4S and l'S 3R 4S) 3-(1'-azido-1'-ethyl)-4-tritylthio-2azetidinone (Isomer B) pMs ~3 ~ C~3 ~ SC~3 S~i~CH3)2 ~ N

t-Bu A solution of (l'S,3S,4R and l'R,3R,4S) l-(t-butyldime-thylsilyl)-3-(1'-methanesulfonyloxy-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer C) (1.75 g, 3 mmol) and sodium azide (0.39 g, 6 mmol) in 10% H20:HMPA (15 ml) was heated under N2 at 75-80C for 3 h. Then the reaction mixture was diluted with ethyl acetate and washed several times with brine. The organic phase was dried (MgS04 ) and evaporated to leave an oil which crystallized spontaneously.

*Trade Mark .,,,,~,~
.,,., ,.~..

36~;6~
5.35 (2H, ABq, benzyl ester), 5.20 (2H, 8, benzyl carbamate), 4.90 (lH, broad N-H), 4.20 (lH, dq, J=6, 8, H-11), 3.80 (lH, dd, J=1.2, 8.0, ~-6), 2.40 (3H, B, (CH3 ), 1.40 (3H, d, J=6, CH3 );
ir vmax : 3435 (n-H), 1777 and 1717 cm 1 (C=O).
The p-nitrobenzyl ester may bs subjected to catalytic hydrogenation as by the procedure of example 43 (Procedure A) to provide the corresponding carboxylic acid.

Exam~le 44 6-Dimethylaminomethyl-2-methylpenem-3-carboxylic Acid ~ N ~ ~ CH

l-(t-~uty1~_methylsilyl)-3-JaLm~h~1lmL~ome~hyl-4-tritylthio-2-aæetidinone tcis ~g~ trans).

C~l 2 ~ c ~ ~ SC~3 O ~ ~ S~ 2 3 ~si \t-8U \ t- BU

To a solution of dlmethylamine (18.5 ml of a 2N solution in methanol, 36.9 mmoles) in methanol (80 ml) was added a solution of hydrochloric acid in methanol (2.5 ml) of a 5N solution in methanol) followed by trans l-(t-butyl-dimethylsilyl)-3-formyl-4-tritylthio-2-azetidinone (3.0 g, 6.16 mmoles) and by sodium cyanoborohydride (0.27 g, 4.31 mmoles) The mixture was stirred at room temperature for 3.5 h, poured onto ice-hydrochloric acid (pH=2) and made basic with sodium ~Z~3666~
hydroxide (lN NaOH, pH =9) The mix~ure was extracted with ether and the ether phrase was washed with brine, dried and evaporated to give the title compound as a crude oil (3.0g).

cis and trans 3-dimethylaminomethyl-4-tritYlthio-2-azetidinone SC~3 NaN3 ~N ~SC~3 1 O O ~ 5 L/ 2 Me ~ N ~H
\t-3u A solution of the above crude compound (3.0 g, 6 mmoles) in hexamethylphosphorous triamide (HMPT, 16 ml) containing water (10%) was cooled (50) and treated with sodium azide (0.78 g, 12 mmol). The mixture was stirred 1.5 h at room temperature, poured onto ice-water and extracted with ether (5 x 30 ml). The organic phases were extracted with hydrochloric acid (lN) and the acidic extracts washed well with ether to remove the HMPT. The acidic phase was made basic (lN, NaOH) and extracted with dichloromethane. The organic layer was washed with brine, dried and concentrated to give the title compounds as an amorphous white solid (1.5 g, 62.5% overall). The mixture of isomers was separated on a Waters Prep 500*, eluting with methanol (5%), ammonia (0.2%), ethyl acetate (95%). Trans isomer: 1.0 g, m.p.
129-131C (Pentane); ~ (ppm, CDC13 ): 6.8-7.8 (lSH, m, aromatics), 4.5 (lH, N-H), 4.28 (lH, d, J=2.5, H-4), 3.35 (lH, m, H-3), 2.75-2.1 (2H, m, H-l'), 2.3 (6H, s, CH3 ).
Cis isomer: 0.5 g, m.p. 132-3 C (ether-pentane); ~ (ppm, CDC13):
7.7-6.7 (15H, m, aromatics), 4.72 (lH, N-H), 4.5 (lH, d, J=5.3, H-4), 3.5 (lH, n:, H-3), 2.85-2.35 (2H, m, H-l'), 2.31 (6H, s, CH3 ). The cis to trans ratio can be varied by changes in conditions.
* Trade Mark 6~61 cis and trans 6-dimethylaminomethvl-2-methylpenem-3-carboxylic acid The title compound was prepared from cis and trans 3-dimethylaminomethyl-4-tritylthio-2-azetidinone by the procedure of Example 58.
(ppm, CDC13): 5.5 (lH, d, J=1.3), 3.7 (lH, dt, J=1.3, J=8), 2.8 (2H, d, J=8), 2.35 (6H, s), 2~3 (3H, s).

Example 45 2-Amininoacetoxymethvl-penem-3-carboxylic-Acid (via mercaptide intermediate ~ H 2 OCCH 2NH 2 4-Azidoacetoxyacetylthio-l-(paranitrobenzyl 2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone S~OH ClCOCH2N3 S~3 d~--N~f~P~3 C6H5N o~--M~P~I13 A cold (ice-MeOH bath) solution of 4-hydroxyacetylthio -l-(paranitrobenzyl 2'-triphenylphosphoranylidene -2'-acetate) -2-azetidinone (586 mg, 0.954 mmol) in methylene chloride (15 ml) was treated successively with azido acetyl chloride 240 mg, 2.01 mmol) and dropwise with ~36~61 Trituration in ether and filtration gave g51 mg (76.5~) of the azido compound as a white solid mp 185-90C, dec. lHMR (CDC13) ~:
7.23-7.78 (15H, m, aromatics), 4.43 (lH, d, J=3, H-4), 4.37 (lH, s, N-H), 3.89 (lH, dq, J=7, 6.5, H-l'), 3.16 (lH, dd, J=7, 3, H-3), 1.50 3H, d, J-6.5, H-2'); ir V (CHCl ): 3410 (n-H), 2123 (N ) and max 3 3 765 cm 1 (C=O).

(l'R,3S,4R and l'S,3R,4S) 3-(1'-amino-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B).

.

~H ~ C~3 A suspension of (l'R,3S,4R and l'S,3R,4S) 3-(1'-azido-l'- thyl)-4-tritylthio-2-azetidinone (Isomer B) (1.0 g, 2.41 mmol) and platinum oxide (100 mg) in ethyl acetate (100 ml) was hydroge-nated for 1 h at a pressure of 50 psi. Since the reaction was incomplete, 200 mg of platinum oxide was added and the mixture hydrogenated for one additional hour. Finally, 200 mg of platinum oxide was again added and the reaction continued for 2.5 h. Total catalyst: 500 mg. Total time: 4.5 h. Then the catalyst was filtered off and the solvent evaporated. The crude amine crystallized from ether: 700 mg (80~).
mp 128-30C. IHmr (CDC13) ~: 7.13-7.63 (lSH, m, aromatics), 4.40 (lH, d, J=2.5, H-4), 4.30 (lH, broad, H-l), 3.30 (lH, dq, J=5.1, 6.3, H-l'), 3.03 (lH, dd, J=5.1, 2.5, H-3), 1.20 (3H, d, J=6.3, H-2') and 1.0-1.80 ppm (2H, broad, NH2).

-~3 666~

(l'R,3S,4R and 1'5,3R,45) 3=(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) ~ . = . . .

SC~3 ~ c~3 N ~ H N ~ H

A solution of (l'R,3S,4R and l'S,3R,4S) 3-(1'-amino-1'-ethyl)-4-tritylthio-2-azetidinone (Isomer B) (1.00 g, 2.57 mmol) in dichloromethane (100 ml) was cooled to 5C and treated with p-nitro-benzylchloroformate (0.61 g, 2.83 mmol) and pyridine (0.22 g, 2.83 mmol). After stirring at 5C for 45 min and at room temperature for 2.25 h, the reaction mixture was washed with dilute HCl, brine, dried (MgS04) and finally evaporated to dryness. The crude carbamate was crystallized from ether: 1.03 g (70.5~). mp 147-50C. IHmr (CDC13) ~:
7.10-8.33 (19H, m, aromatics), 5.23 (2H, s, benzyl), 5.08 (lH, N-H), 4.40 (lH, s, N-H), 4.29 tlH, d, J=2.2, H-4), 4.10 (lH, dq, J=8, 6, H-l'), .18 (lH, dd, J=2.2, 8, H-3) and 1.23 ppm (3H, d, J=6, H-2'); ir V
max CHC13): 3395 (N-H), 1765 and 1724 cm (C=0).

(l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 2-methyl 6-(1'-p-nitrobenzyl-oxycarbonylamino-l'-ethyl) penem-3-carboxylate (Isomer B) 3 ~ ~

The title product was prepared from (l'R,5R,65 and l'S,55,6R) 3-(1'-p-nitrobenzyloxycarbonylamino-1'-ethyl)-4-tritylthio-2-azetidinone (isomer B) by the standard procedure; mp 108-110C. IHmr (CDC13) ~: 7.50-8.40 ~8H, m, aromatics), 5,58 (lH, d, J=1.20, H-5), _L33-1~t3666~

pyridine ~226 mg, 231 ml, 3.0 mmol) in methylene chloride ~10 ml);
At the end of the addition tlc showed disappearance of starting material The mixture was diluted with ether, washed successively with dilute HCl, water, dilute aqueous sodium bicarbonate, water and brine. It was dried over sodium sulfate. Purification of the residue was performed on a silica gel (10 g) column, eluting with 20~ ether in benzene, ether, and 30% ethyl acetate in ether. Concentration of the pertinent fraction gave the title compound as a foam; 533 mg, 80.1%; ir v (CHC13): 1763, 1702 (C=0), 1625 (C=P~3), 1522 (N02) and 2110 cm (N3).

paranitrobenzyl 2-azidoacetoxymethylpenem-3-carboxylate ~ 5 ~ ~ 3 r ~

A solution of phosphorane (533 mg, 0.764 mmol) was heated under reflux in toluene (90 ml) for 0.5 h using a catalytic amount of hydroquinone. The solvent was concentrated on the evaporator and the concentrated solution was passed through a silica gel (10 g) column. (benzene: ether, 48:2). It gave the tltle compound (236 mg, 73.7~) as an oil. This oil was found to be unstable at room temperature. It was kept at -78C until needed. lHmr (CDC13) ~:
8.21 (2H, d, Hm aromatic), 7.57 (2H, d, Ho aromatic), 5.68 (lH, dd, J . =4, J =2, H-5), 5.43 (2H, center of ABq, J=16, CH2-PNB), 5-6 ClS 5-6 trans 5.39 (2H, CH20), 3.93 (2H, s, CH2-N3), 3.72 (part of dd, J6 5 i =4~ H-6), and 3.50 ppm (lH, dd, J =17, J =2, H-6); ir v (CHCl ): 1795, gem 6-5 trans max 3 1755, 1710 (C=0), 1525 (N02), 2110 cm (N3).

-7t~-2-Aminoacetoxymethylpenem-3-carboxvlic acid ,0, o 2 ~ ~ ~ NH2 A mixture of above ester (219 mg, 0.522 mmol) in THF
(16 ml)-ether (30 ml) and water (16 ml) was shaken on a Parr hydrogenator for 2.25 h at 50 psi of H2 using 10% pd/C (240 mg) as catalyst. The catalyst was filtered off and washed with water and ether. The aqueous phase was washed with ether (3 x 30 ml) and lyophilized. The crude powder was purified on a reversed phase hplc column and gave the title compound (8 mg, 6.7~) as a white powder. lHmr (D2O) ~:5.72 (lH, dd, J5-6 cis=3 5~ J5-6trans=2, H-5), 5.37 (2H, center of ABq, J-13.5, CH2-O), 3.96 (2H, s, CH2-NH2), 3.87 (lH, dd, Jgem=16-5, J6-5 cis=3 5~ H 6) and 3-49 Nmr (lH~ dd Jgem=16-5, J6-5 tranS=2, H-6); ir vmax (nujol 1775, 1755 and 1600 cm~l (C=O); uv (H2O) ~max 306 (~4900), 256 (~3000)-~ ~6~.16~

Example 46 Silver l-(B-Trimethylsilylethyl-2'-triphenvl~hosphoranYlidene-2'-acetate)-2-azetidinone-4-thiolate ~ SAg o N ~ P~3 ~CH3 C02CH2CH25i~ CH3 di-~-trimethylsilylethyl fumarate Cl ~ H0~-~-~ 3)3 ~ ~ Si(cH
o pyridine 3 3Si To a cold (-10C) ether (20 ml) solution of 2-trimethyl-silyl ethanol (4.73 g, 0.04 mmol) ~H. Gerlach Helv.

Chim. Acta 60, 3039 t1977)] and pyridine (5.66 ml, 0.07 mol), under nitrogen, was added dropwise (15 min) fumaryl chloride (3.78 ml., 0.035 mol) dissolved in ether (10 ml). The black mixture was stirred five minutes at -10C and ten at room temperature. Charcoal was added and the reaction mixture filtered on a Celite pad. The filtrate was washed with sodium bicarbonate 1% - brine (1:1, 150 ml). The aqueous phase was back extracted with ether (30 ml). The ether solutions were combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give ~3G~i61 a brown solid. This compound was purified on a silica gel pad (30 g, 4 x 5 cm) with benzene (300 ml) as eluent to give an oil (4.855 g, 77%) which solidified on standing: mp 33-34C. Anal. calcd for C14H28O4Si2: C 53.12, H 8.91i found: C 53.35, H 8.91. IHmr (CDC13) ~:
6.78 (2H, s, C=CH), 4.26 (4H, m, CH2-0~, 1.03 (4H, m, CH2-Si) and 3)3Si); ir (CHC13) vmax: 1710 (C=O of ester) 1643 (C=C), 1267, 12S8, 862 and 840 cm (Si-C).

Trimethylsilyle-thyl glyoxylate hydrate (CH3~3Si = 2) (CH3)25 CO2 ~ i(CH3)3 A solution of di-~-trimethylsilylethyl fumarate (37 g, 0.117 mmol) in methylene chloride (1.1 ~) was ozonized at -78C until a blue color persisted. The excess ozone was purged with nitrogen and dimethyl sulfide (2.57 ml, 0.351 mol) was added.
The solution was allowed to gradually warm to 23C. The reaction mixture was diluted with carbon tetrachloride to 2 liters and washed with 1~ aqueous solution of sodium carbonate (500 ml). The organic phase was dried over sodium sulfate, filtered on Celite and evapo-rated (~ 25C) to dryness to give 43.9 g of the titl~e compound (97%)i ir (neat) v : 3450 (-OH), 1740 (ester, 1255, 860 and 840 cm (Si-C).

l-(~-trimethylsilylethyl_2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone o6~ CIH (OH) z ~

Trimethylsilylethyl glyoxylate hydrate (4.000 g, 11.6 mmol) and the 4-tritylthio-2-azetidinone (4.8 g, 24.96 mmol) were refluxed in benzene (25 ml) through a Dean Stark condenser, under nitrogen for 24 h. The solvent was evaporated under a vacuum. The product was chromatographed on a silica gel column (450 g, 8.5 x 14.5 cm) and eluted with ethyl acetate: methylene _2y~-1~36661 chloride (1:19) until the title compound started to come out (- 1.5 ~) and then with ethylacetate: methylene chloride (1:9, 2 ~). The fractions containing the title compound were combined and evaporated to dryness to give 5.415 g (89%) of the title compound. IHmr (CDC13) ~: 7.80 to 6.70 tl5H, m, trityl), 5.23 and 4.90 (lH, 2s, H-C-O), 4.50 to 4.10 (3H, m, H-3 and O-CH2), 2.60 (2H, m, H-2), 0.95 (2H, m, CH2-Si and 0.1 ppm (9H, s, Si-CH3);
ir (CHC13) vmax: 3520 (-OH), 1765 (C=O of ~-lactam), 1740 (C=O of ester), 1595 (C-H, aromatic), 1257, 860 and 840 cm (C-Si) 1-(3-trimethylsilylethyl 2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone STr SOC12 ~ STr N ~ "~= Si(CH3)3 pyridine ~ ~ ~ Si(CH3)3 A solution of thionyl chloride (0.74 ml, 10.37 mmol) in dry THF (9 ml) was added dropwise with stirring to a solution of l-(~-trimethylsilylethyl 2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone (4.9 g, 9.37 mmol), pyridine (0.84 ml, 10.38 mmol) and dry THF (40 ml) at -15C under a nitrogen atmosphere. The mixture was stirred at -15C for 2 h. The precipitate was removed by filtration on a Celite pad and washed with benzene (50 ml). The filtrate was evaporated in vacuo at 30C. The residue was dissolved in benzene (100 ml), treated with charcoal and filtered through a Celite pad. Evaporation of the solvent gave a residue which was purified through a silica gel pad (100 g, 4.7 x 11 cm): hexane-benzene (1:1, 400 ml), ether-benzene (1:19, 1 ~). Evaporation of the pertinent fractions gave 4.64 g of the title compound (92%).
Hmr (CDC13) ~: 7.30 (15H, m, aromatic H), 5.77 and 5.43 (lH, 2s, CH-Cl), 4.7 to 4.2 (3H, m, H-4 and CH2-O), 2.85 to 2.50 (2H, m, H-3), 1.15 (2H, m, CH2-Si) and 0.06 ppm (9H, s, Si-CH3); ir (neat) v : 1760 (C=O), 860 and 840 cm (C-Si).
max _ 2~

l~S36~61 ~ -trimethylsilylethyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone Tr ~ p STr Cl 2~6-lutiaine ~ p~
2 Si(CH3)3 2 Si(CH3)3 A dioxane (20 ml) solution of the above chloroazeti-dinone (4.12 g, 7.568) was treated with triphenylphosphine (2.209 g, 8,424 mmol) and 2,6-lutidine (0.98 ml, 8.424 mmol). The mixture was refluxed for 3.5 h. The cooled solution was filtered and the white solid washed with THF. The filtrate was evaporated to dryness. The residue was purified on a silica gel column (200 g, 4 x 31 cm) using ethylacetate-hexane (3:7, 1 ~; 7:3, 1 ~) to give the title phosphorane (4.836 g, 83~). ir (film) v : 1755 (C=O), max 1615 (phosphorane), 850 and 830 cm (Si-C). Anal. calcd for C47H46NO3PSSi: C 73.89, H 6.07, N 1.81; found: C 72.18, H 6.08, N 1.83 Silver l-(~-trimethylsilylethyl 2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone-4-thiolate STr SAg + AgNo3 + (nBu)3N + CF3C2 ether/H20 ~ P~3 2i(CH3)3 ~ Si(CH3)3 l-(~-trimethylsilylethyl 2'-triphenyl phosphoranylidene-2'-azetate) -2-azetidinone (7.64 g, lO mmol) was dissolved in ether (60 ml).
An aqueous solution of silver nitrate (0.5M, 80 ml, 40 mmol) was added followed by a rapid addition ( 1 min) of a solution of tributylamine (3 ml, 12.58 mmol) and trifluoroacetic acid (0.154 ml, -2~3 ~

36~

successively with cold lN hydrochloric acid, lM sodium bicarbonate and brine, dried (MgS04) and evaporated in vacuo. The residue (mixture of hydroxy and mesylate cpd) was treated a second time as before, to give the mesylate (90 g, 97%) as an amorphous solid. It was used as such in the next step without further purification. The analytical sample was recrystallized from methylene chloride mp 167-168C; ir (neat) v : 1755 cm ; lHmr (CDC13) ~: 7.3 (15H, m), 4.4 (lH, d, J=2Hz), 3.9 (lH, dd, J=8Hz, 4Hz), 3.2 ~2H, bs), 2.8 (3H, s), 0.95 (9H, s) and 0.3 ppm (6H, s).

trans 3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone and trans-3-azidomethyl)-4-tritylthio-2-azetidinone M 0 ~"~ ~ SC~
Si(CH3)2 H 0 H

t-Bu A solution of trans -l-(t-butyldimethylsilyl)-3-methane-sulfonylmethyl-4-tritylthio-2-azetidinone (21.0 g, 37.0 mmol) in H~A
(90 ml) was cooled in an ice bath and treated with sodium azide (2.7 g, 41.2 mmol) in H20 (10 ml). The reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate, washed with H20 (5 x 100 ml), dried (MgS04) and evaporated in vacuo. The trans-3-methanesulfonyloxymethyl-4-tritylthio-2-azetidinone was diluted with HMPA (90 ml), treated at roam temperature with sodium azide (2.7 g, 41.2 mmol) in H20 (10 ml), heated at 60C for 2 h and triturated with cold water. The crude azide was diluted with benzene-ether (5:1) and washed with water (S x 20 ml). Evaporation of the solvent followed by crystallization from ether gave 18.0 g (77%) of azide as a white solid. The analytical sample was recrystallized from CH2C12/
ether mp 174-5C; Anal. calcd for C23H20N405: C 68.97, H 5.03, N 13.99;

' Z~

~36~i61 found C 68.78, H 5.00, N 14.16; ir (nujol) v : 2100, 1765 cm : IHmr (CDC13) ~: 7.35 (15H, m), 4.75 (lH, bs), 4.4 (lH, d J=2Hz), and 3.1-3.7 ppm (3H, m).

trans-3-aminomethyl-4-tritylthio-2-azetidinone H H SC~ H H
H2N~ ~ ~3 H NH
To a solution of trans 3-azidomethyl-4-tritylthio-2-azetidinone (10.0 g, 47.5 mmol) in dry methanol (500 ml) was added ammonium chloride (19.0 g) and zinc powder ~1.0 g) and the suspension was stirred at room temperature for 5 h. The reaction mixture was filtered and evaporated. The residue was partitioned between lN
hydrochloric acid and benzene. The aqueous layer was basified with lM sodium bicarbonate and extracted with methylene chloride.
The extracts were washed with brine, dried (MgSO4) and evaporated in vacuo. The crude amine crystallized from ether, 14.05 g (79~);
mp 139-9Ci Anal. calcd for C23H22N20Cl l/4 CH2C12: C 70.56, H 5.73, N 7.08; Found: C 70.68, H 5.94, N 7.27; ir (CHC13) v : 3400 and 1760 cm ; lHmr (CDC13) ~: 7.35 (15H, m), 5.15 (lH, m), 4.3 (lH, bs), 2.7-3.5 (3H, m) and 1.3 ppm (2H, m).

--2~6 ~

~ ~6~;61 trans 3-phthalimidomethyl-4-tritylthi.o-2-azetidinone H2N ~ 3 ~ N ~ ~ SC~3 A solution of trans 3-aminomethyl-4-tritylthio-2-azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 ml) was heated under reflux for lS h. The solvent was evaporated in vacuo and the residue crystallized from ether to give 17.4 g (93%) of the title compound;
mp 172-3Ci Anal. calcd for C31H24N2035: C 73.78, H 4.79, N 5.55, found: C 73.92, H 4.87, N 5.49; ir (CHCl ) ~ : 1770 and 1715 cm 3 max IHmr ~CDC13) ~: 7.8 (4H, m), 7.3 (15H, m), 4.45 (lH, d, J=2Hz), 3.3-4.1 (3H, m) and 3.3-4~6 ppm (lH, m).

trans 3-phthalimidomethyl-1-~paranitro~enzyl 2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone " ~ C~3 A mixture of trans-3-phthalimidomethyl-4-tritylthio-2-azetidinone (17.4 g, 34.52 mmol), paranitrobenzylglyoxylate hydrate (9.4 g, 41.4 mmol) and triethylamine (4.8 ml, 34.5 mmol) in tetra-hydrofuran (250 ml) was stirred at room temperature for 20 h. The reaction mixture was evaporated in vacuo and the residue was treated with charcoal in benzene. Evaporation of the solvent yielded the crude hydroxyglyoxylate (25 g, quantitative) as an amorphous solid.

~ Z~7~
12~36~

It was used in the next step without further purification. ir ~CHC13) V : 1770 and 1715 cm ; IHmr (CDCl ) ~: 8.1 (2H, d, J=9Hz), 7.55 max 3 (3H, d, J=9Ha), 7.3 (19H, m), 5.0-5.4 (2H, bs), 4.3-5.0 (2H, m) and 2.8-3.8 ppm (4H, m).

trans-3~phthalimidomethyl-1-(paranitrobenzyl-2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone OH ~ ~ ~ Cl To a cooled (ice bath, 0C) solution of trans-3-phthal-imidomethyl-l-(paranitrobenzyl-2'-hydroxy-2'-acetate)-4-tritylthio-2-azetidinone (25 g, 35 mmol) in tetrahydrofuran (150 ml) was added dropwise a lM solution of thionyl chloride in tetrahydrofuran (46 ml, 46 mmol) followed by a lM solution of pyridine in tetrahydrofuran (46 ml, 46 mmol). The reaction mixture was stirred at room tempe-rature for 20 min, diluted with pet-ether (50 ml) and filtered over a Celite/charcoal bed. The solvent was evaporated in vacuo to give the chloro azetidinone (26 g, quantitative) as an amorphous solid.
It was used in the next step without further purification. ir (CHC13) V : 1775 and 1720 cm . ~Hmr (CDC13) ~: 3.12 (2H, d, J=9Hz), 7.60 (2H, d, J=9Hz), 7.3 (19H, m), 5.25 (2H, m), 4.7-5.4 (lH, m), 4.55 (lH, bs) and 3.3-4.0 ppm (3H, m).

-2 ~ ~~

~2~ i6~

trans-3-phthalimidomethyl-1-(paranitrobenzyl-2'-triphenylphosphora-nylidene-2'-acetate)-4-tritylthio-2-azetidinone ~ ~ ~ Cl A mixture of trans-3-phthalimidomethyl-1-(paranitro-benzyl-2'-chloro-2'-acetate)-4-tritylthio-2-azetidinone (26 g, 35.5 mmol), triphenylphosphine (10.25 g, 39.1 mmol) and 2.6 lutidine (4.6 ml, 39.1 mmol) in dioxane (200 ml) was heated at 100C for 20 h.
The reaction mixture was filtered over Celite and evaporated. The residue was chromatographed on a silica gel column (350 g) eluting with benzene to benzene/ether (1:1) to yield the phosphorane (21 g, 62%) as a white solid. ir (CHC13) vmax: 1750 and 1710 cm Hmr (CDC13) ~: 7.4 (38H, m), 4.8-5.4 (3H, m), 4.6 (2H, m) and 3.7 ppm (lH bs).

trans-3-phthalamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphora-nylidene-2'-acetate)-4-tritylthio-2-azetidinone N ~ p~3 C2H ~ 3 CO~PNB C02PNB

A cooled (ice bath) suspension of trans-3-phthalimido-methyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (18.02 g, 18.83 mmol) in tetrahydrofuran (30 ml), water (30 ml) and acetone (30 ml) was treated dropwise with sodium sulfide (4.97 g, 20.7 mmol) in acetone/water 1:1 (30 ml) and heated to reflux for 8 h. The reaction mixture was diluted with water, acidified with lN hydrochloric acid and extracted with dichlo-~666~1 romethane. The organic extracts were washed with brine and evaporated in vacuo to give 17.1 g (88%) of the title compound as an amorphous light yellow solid. It was used in the next step without further purification. ir (neat) V : 3150-3600, 1750 and 1700 cm i ~mr (CDC13) ~: 7.4 (38H, m) and 3.3-5.5 ppm (8H, m).

trans-3-phthalisoimidomethyl-1-(paranitrobenzyl-2'-triphenylphos-phoranylidene-2'-acetate)-4-tritylthio-2-azetidinone ~N~""~ 3 ~ H H SC~
C2H N ~ ~3 N P~3 A solution of trans-3-phthalimidomethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (17.1 g, 17.54 mmol) in dichloromethane (125 ml) was treated dropwise at room temperature with N,N'-dicyclohexylcarbodiimide (3.62 g, 17.54 mmol) in dichloromethane (30 ml). The solution was filtered over Celite and evaporated to give the title compound (18.23 g, quantitative) as an oil. It was used in the next step without further purification. ir (neat) V : 2110, 1755 and 1710 cm i IHmr (CDCl ) ~:
max 3 7.5 (38H, m), 4.6-5.3 (4H, m) and 3.9 ppm (2H, bs).

6~

trans-3-aminomethyl-1-(paranitrobenzyl-2'-triphenyl~hosphoranylidene-2'-acetate)-4-tritylthio-2-azetidino _ o~N ~ _ H2N~ 'P3 N ~ P~3 N ~ p~

A solution of trans-3-phthalisoimidomethyl)-1-(parani-trobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (5.9 g, 6.16 mmol) in tetrahydrofuran (40 ml), cooled to -20C, was treated dropwise under N2 with hydrazine (0.2 ml, 6.16 mmol) and stirring was maintained for 30 min. The reaction mixture was acidified with lN hydrochloric acid and washed with ether; the aqueous phase was basified with lM sodium bicarbonate and extracted with methylene chloride. The organic extracts were washed with brine, dried (MgS04) and evaporated. The residue was purified on a silica gel column (60 g) eluting with ether to ethyl acetate to give 3.38 g (66~) of the amino phosphorane as an amorphous solid.
ir (CHC13) v : 1730, 1710 cm ; IHmr (CDC13) ~: 6.5-8.1 (34H, m), 3.8-5.3 (6H, m) and 0.9-1.9 ppm (2H, m).

trans 3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphora-nylidene-2'-acetate)-4-tritylthio-2-azetidinone SC~ ~ H ~ SC~3 N ~ P~3 N ~ ~3 To a cooled (ice bath) solution of trans 3-(aminomethyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (5.0 g, 6.04 mmol) in dichloromethane (S0 ml) was added dropwise under N2 a solution of acetic formic anhydride (600 mg, 6.8 mmol) in dichloromethane (5 ml) followed by 2 ~-~f~

a solution of triethylamine (1 ml, 7 ~mol) in dichloromethane (2 ml).Stirring was continued for 30 min. The solution was washed successively with lN hydrochloric acid, water, lM sodium bicar~onate and brine. The organic layer was dried (MgSO4), evaporated and the residue was chromatographed on a silica gel column (50 g). ~lution with ether to ethyl acetate yielded 2.0 g (39~) of the formamide as an amorphous solid. ir (CHC13) v : 1740, 1685 and 1620 cm ; IHmr (CDC13) ~: 6.6-8.2 (35H, m), and 2.5-5.3 ppm (7H, m).

trans silver 3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphos-phoranylidene-2'-acetate)-2-azetidinone-4-thiolate H~N ~-~SC~3 o~
N ~ p~3 N ~ p~3 A solution of trans 3-formamidomethyl-1-(paranitro-benzyl-2'-triphenylphosphoranylidene-2'-acetate)-4-tritylthio-2-azetidinone (550 mg, 0.64 mmol) in dichloromethane (10 ml) was evaporated to dryness and diluted with hot methanol (20 ml). The solution was stirred at 60C and treated with a pre-heated (60C) solution of 0.15 M silver nitrate in methanol (5.7 ml, 0.86 mmol) followed by a solution of 1.5 M pyridine in methanol (0.57 ml, 0.86 mmol). The creamy solution was stirred at room temperature for 30 min, then in an ice bath for 2 h. The solid was filtered washed with cold methanol and ether, and dried to give 300 mg (65%) of the silver salt as a beige solid. It was used in the next step without further purification.

_~ ~ z _ ~L~,S~6~

trans 4-acetylthio-3-formamidomethyl 1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone HCRN / L j--~` R

To a cooled (ice bath) solution of trans silver 3-formamidomethyl-l-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone-4-thiolate (800 mg, 1 11 mmol) in dichloromethane (10 ml) was added dropwise under N2 a solution of lM acetylchloride in dichloromethane (1.33 ml, 1.33 mmol) followed by a solution of lM pyridine in dichloromethane (1.33 ml, 1.33 mmol). The solution was stirred in a cold bath for 1 h, and was then ~iltered over Celite. The filtrate was washed successively with lN hydrochloric acid, water, lM sodium bicarbonate and brine and the organic layer was dried (MgS04) and evaporated.
The residue was purified on a silica gel column (5.0 g) and eluted with ethyl acetate to 10% methanol in ethyl acetate to give 450 mg (62~) of the title compound: ir (CHC13) Vmax: 1755, 1685 and 1620 cm Hmr (CDC13) ~: 8.18 (2H, d, J=9Hz), 7.0-8.0 (20H, m), 6.75 (2H, d, J=9 Hz), 6.3 (lH, m), 5.5 (lH, m), 5.2 (2H, bs), 4.9 (lH, bs), 3.6 (lH, m), 3.0 (lH, m) and 2.2 ppm (3H, two s).

' ~3-L

paranitrobenæyl 6-formamidomethyl-2-methylpenem-3-carboxylate & ~- ~ P~3 ~ H ~ ~ CH3 A solution of trans 4-acetylthio-3-formamidomethyl-1-(paranitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate)-2-azetidinone (450 mg, 0.686 mmol) in toluene (10 ml) was heated under reflux for 12 h. Concentration and purification on a silica gel column eluting with ether to 10~ methanol in ether gave 100 mg (39%) of the penem as an amorphous solid. ir (CHC13) Vma : 1780 and 1690 cm ; IHmr (C~C13) ~: 8.2 (2H, d, J=9Hz), 8.2 (lH, s), 7.6 (2H, d, J=9Hz), 6.9 (lH, m), 5.55 (lH, s), 5.35 (2H, 2s), 3.3-4.1 (3H, m) and 2.33 ppm (3H, s).
6-formamidomethyl-2-methylpenem-3-carboxylic acid sodium and potassium salts ~.""~H ,o, ~""~ s a~
C02PNB 2~ and A mixture of paranitrobenzyl 6-formidomethyl-2-methyl-penem-3-carboxylate (80 mg, 0.21 mmol), palladium on Celite (30~, 100 mg), tetrahydrofuran (10 ml), ether (25 ml) and 0.05 M buffer solution pH 7 (4.46 ml, 0.223 mmol) was hydrogenated on a Parr shaker at an initial hydrogen pressure of 45 psi for 3 h. The catalyst was removed by filtration on Celite and washed with water.
The filtrate and washings were combined and the phases separated.
The aqueous phase was washed with ether (3 x 15 ml) and lyophylized.

--~S~ ~

~6~
0.2 mmol) in ether (20 ml). The mlxture was meohaniaally stlrred for 19 min. The precipitate waa flltered, rinaed with ether (200 ml), triturated in water (70 ml), fi.ltered again and rinsed with ether (100 ml). The light brown solid waa dried under vacuum (water aspirator 10 min and pump 65 min) to give the title compound (6.52 g). IR (CHC13 ) v max :1862 (C=0),1630 (phosphorane), 860 and 840 cm~1 (Si-C).

- 243a -1~6661 Example 47 6-Formamidomethyl-2-methylpenem-3-carboxylic acid, sodium and potassium salts lD ~ ~"' ~ c ~ a~ a~d :~

trans 1-(t-butyldimethylsilyl) -3-methanesulfonyloxymethyl-4-tritylthio -2-azetidlnone OH H H
HJ~ 3 ~' ~ C~3 C~ ~5~ (CH3) 2 Si (CH3) 2 t-au A solution of trans-l-(t-butyldimethylsilyl)-3-hydroxy-methyl.-4-tritylthio-2-azetidinone (8.0 g, 16.36 mmol) in dichloromethane (50 ml) was treated at 5C with methanesulfonyl chloride (1.4 ml, 18 mmol) in dichloromethane (10 ml) and triethylamine (2.5 ml, 18 mmol).
Stirring was maintained for 1 h under N2. Then the solution was washed ~.~ ,- ~

The crude solid was purified by hplc to glve 18 mg of a mixture of the sodium and potassium salts.
uv (H2O) max: 299 (~ 4933), 259 (~ 4094) ; ir ("NUJOL")*
max: 3100-3650 and 1755 cm 1; 1Hmr (D2O)~ : 8.15 (lH, s), 5.53 (lH, d, J=1.4H~), 4.0 (lH, m), 3.74 (2H, d, J=5Hz), 3.25-4.25 (lH, m) and 2.27 ppm (3H, 8).
Exam~le 48 (1'S 5R.6S. and 1'R.5S.6R) 6-_(l'-Hx~roxy-1'-propyl)-2-methyl~enem-3-carboxylic acid. sodi~um salt ~isomer C) Et ,~
>5.~ ~

co2Na trans_1-t-Bu~yldimethylsilyl-3-pro~ionyl-4-tritylthio -2-a~Q~idinones + 2 ~ \SlMe2 PROCE~URE:
n-BuLi (37.50 ml, 1. 6M/hexane, 60 =mmol) was added dropwise under N2 to a cooled (dry ice-acetone bath) and stirred solution of diisopropylamine (8.50 ml, 60 mmol) in dry THF (200 ml). The mixture was stirred in the cold and 1-t-butyldimethyl-silyl-4-tritylthio-2-azetidinone (22.9 g, 50 mmol) in dry THF
30 (100 ml) was added. After 15 min, methyl propionate (40 ml, excess) was added and the reaction mixture was kept at -78 for 4 h. Then the cooling bath was removed and the internal temperature was allowed to come to OC (-40 min). It was poured over ice-HCl (pH - 6) and extracted with ether. The layers were separated and the aqueous layer was extracted with ether. The combined ether solution was washed with water and brine and dried *Trade Mark ~'3~;~;63l (Na2SO4). It was evaporated in vacuo to give an oil in quantitative yield. This contained a mixture of starting material and title compound. It was used as such and 1l purified in the next step. ir (Neat) vmax : 1710 (-C-), 1750 cm 1 (B-lactam).
1-t-Buty~dim~hylsilyl-3-(l'-hydro~xy-l'-p~,g~ syl~hio-2-az~idi nonçs OH
O ~ 5~Me ~ ~ 5 r PROCEDURE:
A solution of 1-t-butyldimethylsilyl-3-propionyl-4-tritylthio-2-azetidinone (26 g, 50 mmol) and sodium borohydride (7.6 g, 200 mmol) in THF (400 ml) was stirred at, room temperature for 18 h. It was poured onto ice-HCl (lN) (pH 6) and extracted with ether. The acidic phase was extracted several times with ether and the combined ether solution was washed with brine, dried (Na2SO4) and evaporated to give an amorphous solid, 25.0 g. This crude product was chromatographed on SiO2 (ACT. 1, 400 g) and eluted first with CH2C12 to give 10.8 g of 1-t-butyldimethylsilyl-4-tritylthio-2-azetidinone. Elution with 20% ether in CH2Cl2 gave 10.3 g of the title compound as a mixture of two isomeric trans alcohols. This was separated by hplc (Water Associates, System 500*), and using 10% EtoAc in CH2C12 as eluent. Isomer C, white solid, 3.8 g; mp (pet. ether) 134-36C. 1Hmr (CDC13)~ : 7.1-7.8 (15H, m, STr), 4.35 (H, d), 3.1 (H, dd), 2.5 (H, m), 0.7-1.7 (5H, m), 0.97 (9H, s) and 0.25 ppm (6H, s). Anal. calcd for C31H39NO2SSi: C 71.91, H 7.59, N 2.71;
found: C 71.51, H 7.60, N 2.96. isomer B, white solid, 5.4 g; mp (pentane-pet. ether) 97-99C. 1Hmr (CDC13) ~ : 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6H, s).
*Trade Mark 97-99C. 1Hmr (CDC13 ) ~: 7.1-7.8 (15H, m, STr), 4.15 (H, d), 3.4 (H, dd), 3.2 (H, m), 0.7-1.7 (5,H, m), 0.85 (9H, s) and 0.1 ppm (6H, s). Total yield of these two alcohols (based on recovered starting material was 67.5%.

(l'S 3S,~R and l'R~3R!4S~
l-t-butvldimethylsilyl-3-rl'-paranitrobenzyldioxycarbonyl-l'-propyl)-4-tritylthio-2-azetidinone (isomer C).

OH ST ~Co22~B

n~ 2 ~ ~STr d--~ S i.`~!e 2 O ~ S iMe 2 PROCEDURE:
To a cooled (dry ice-acetone bath) solution of (l'S,3S, 4R and l'R,3R,4S) 1-t-butyldimethylsilyl-3-(1'-hydroxy-1'-propyl)-4-tritylthio-2-azetidinone (isomer C) (3.1 g, 6 mmol) in dry THF (20 ml) was added dropwise under N2 a solution of 1.6M
n-BuLi/hexane (4.88 ml, 7.8 mmol) stirred at -78C for 25 min Paranitrobenzyl chloroformate (1.56 g, 7.2 mmol) in dry THF (10 ml) was then added dropwise and the resulting mixture was stirred at -78C for 4 h. It was diluted with ether and washed with NH4C1 solution brine. The organic phase was dried (Na2SO4 ) and evaporated to dryness to give 4.2 g of title compound (Quantative yield). 1Hmr (CDC13) ~:
8.2 (2H, d), 7.0-7.7 (17H, m), 5.13 (2H, s), 4.05 (H, d), 3.75 (H, dt), 3.25 (dd), 0.55-1.8 (5H, m), 0.9 (9H, s) and 0.25 ppm (6H, d).

~, ~ 2~36~i61 ~1'S 3S.4R and l'R 3R 4S) 3~
~aranitrobenzyldioxycarbonyl-l'-propyl) -4-tritylthio-2-azetidinone (isomer C) OC02PNB OCO2P~,3 ,_~ S Tr ~J,. STr oL~ ` + ~MPT + NaN3 SiMe2 (10% ~120) o~N~

PROCEDURE:
To a cooled (ice bath) solution of (l'S,3S,4R and l'R,3R,4S) 1-t-butyldimethylsilyl-3-(1'-paranitrobenzyldioxy-carbonyl-l'propyl)-4-tritylthio -2-azetidinone (isomer C) (4.2 g, 6 mmol) in HMPT (40 ml) containing 10% H2O was added sodium azide (0.78 g, 12 mmol). The mixture was stirred at room temperature for 1 h.
It was diluted with water (100 ml) and extracted with benzene: pet. ether (1:1) (4 x 15 ml). The organic phase was washed several times with water (6 x 30 ml) and brine It was dried (Na2SO4 ) and evaporated to dryness to give 3.5 g of a solid (quantitative yield). It was treated with pentane and filtered to give 3.4 g of a pale yellow solid.
mp 84-86C; lHmr (CDC13) ~: 8.2 (2H, d), 7-7.7 (17H, n), 5.2 (2H, s), 4.95 (H, dt), 4.4 (NH), 4.25 (H, d), 3.4 (H, dd), 1.7 (2H, m) and 0.95 ppm (3H, t).

~ ¢
,,1, ,._ ~2~fi661 (1'5,3S,4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-1'-propyl)-l-(paranltrobenzyl 2"-hydroxy-2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (isomer C).

QC02PNB PC2P~JB
. ~ STr THF ~ " ~ STr O ~ N PNB glyoxalate TEA ~ N ~ H

PROCEDURE:
To a solution of (l'S,3S,4R and l'R,3R,4S) 3-(1'-paranitro-benzyldioxycar~onyl-l'-propyl)-4-tritylthio-2-azetidinone (isomer C) (3.2 g, 5.5 mmol) and paranitrobenzyl glyoxylate hydrate (1.362 g, 6 mmol) in dry THF (50 ml) was added a catalytic amount of TEA
(4 drops) and Na2504 (to absorb H20 formed). The resulting mixture was stirred at room temperature for 6 h. It was filtered and evaporated to dryness to give 4.35 g of an amorphous solid (quan-titative yield). lHmr (CDC13) ~: 8.25 (4H, dd), 7-7.g (19H, m), 5.28 (2H, s), 5.1 (2H, s), 4.8 (H, d), 4.4 (H, dd), 4.1 (H, dt), 3.4 (H, m), 1.1-1.8 (2H, m) and 0.8 ppm (3H, t), (l'S,3S!4R and l'R,3R,4S) 3-(1'-paranitrobenzyldioxycarbonyl-1'-propyl)-l-(paranitrob~;L_____ hloro-2"-acetate(-4-tritylthio-2-azetidinone (isomer C) ~OC02PaB Py/THF J 2 N ~ H SOC12/THF O N ~ Cl PROCEDURE:
To a cooled (ice salt bath) solution of the above glyoxylate (4.35 g, 5.5 mmol) in dry THF (30 ml) was added lM py/THF (7 ml, 7 mmol) followed by dropwise addition of lM SOC12/THF (7 ml, 7 mmol). The re-~Z~36~

sulting mixture was stirred at the above-indicated temperature for 1 h.
It was diluted with benzene (30 ml), stirred in the cold (ice water bath) for 30 m-n and filtered over Celite-charcoal. The filtrate was evaporated to dryness to give 3.8 g of an amorphous solid (85.3~); IHmr (CDC13) ~: 8.15 (4H, d), 6.75-7.7 (19H, m), 5.65 (H, s), 5.2 (2H, s), 5.1 (2H, s), 4.5 (H, m), 3.85 (H, m), 3.4 (H, m), 1.25~2.0 (2H, m) and O.g ppm (3H, t).

(l'S,35,4R and l'R,3R,45) 3-(1'-paranitrobenzvldioxycarbonyl-1'-propyl)-l-~paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate) -4-tritylthio-2-azetidinone (isomer C) 2 STr ~ ." ~ STr N Cl lutidine O ~ ~ ~3 PROCEDURE:
To a solution of the above chloro compound ~3.7 g, 4.568 mmol) in dioxane (35 ml) was added ~3P (1.197 g, 5 mmol) and lutidine (0.54 g, 5 mmol). The mixture was heated in an oil bath at 100 C for 3 days. It was cooled, diluted with ether and washed successively with lN HCl, IM NaHC03 and brine.
It was dried (Na25O4) and filtered over Celite-charcoal. The filtrate was evaporated to dryness to give 3.6 g of an oil.
This was chromatographed on SiO2 (120 g) and eluted with benzene, benzene-ether to give 1.45 g of title compound as an amorphous solid (31~); ir (neat) vmax: 1750 cm (broad).

- L~

(l'S 3S.4R and l'R.3R.4S) 4-acetYlthio-3-(l'Paranitrobenzvldioxycarbonyl-l'-propyl)-l-(Paranitrobenzyl 2"-triphenylphosphoranylidene -2"-acetate)-2-azetidinone (isomer C) 2 ~C022Ng 2 ~J ~ STr AgN03~J" ~ SAg C~i3~Cl ~J ~ SAc o~N~P~3 Py/MeOH O ~P~3 Py/MeOH ~ o~N~P~3 PROCEDURE:
To a hot solution (60C) of the above phosphorane (1.4 g, 1.35 mmol) in MeOH (40 ml) was added with stirring a hot solution of AgNO3 (0.3 g, 1.76 mmol) in MeOH (10 ml) followed by pyridine (0.107 g, 0.11 ml, 1.76 mmol). The silver mercaptide began to precipitate immediately. The mixture was stirred at room temperature for 15 min and at OC for 2 h. It was filtered, and the solid washed well with cold MeOH and ether, 1.2 g (quantitative yield); mp 113-115C (d); ir("NUJOL")*. vmax : 1740-1760 cm~l (broad).
This solid was used as such. To a cooled (ice bath) solution of the above mercaptide (1.2 g, 1.35 mmol) in CH2C12 (15 ml) was added acetyl chloride (0.118 g, 0.107 ml, 1.5 mmol) in CH2C12 (2 ml) followed by pyridine (0.119 g, 0.122 ml, 1.5 mmol) in CH2Cl2 (2 ml). The mixture was stirred at 0C for 30 min. It was filtered over "CELITE"* to remove silver salt and the filtrate was washed successively with HCl (0.5N), H2O, NaHCO3 (0.5 M) and brine.
The CH2Cl2 solution was dried (MgSO4) and evaporated to dryness to give 0.94 g of title compound as an amorphous solid. (83.4%) ir (neat) vmax: 1750 cm~l (broad).

*Trade Mark ....-.

~ 2r36~

(l'S,5R,6S and l'R,5S,6R) paranitrobenzyl 6~ paranitrobenzyldioxy-carbonyl-l'-propyl)-2-methylpenem-3-carboxylate (isomer C) J~ ~sTr ~f ~

PROCEDVRE:
A solution of the above phosphorane (0.4 g, 1.077 mmol) in toluene (35 ml) was heated to reflux and 5 ml of toluene was distilled off. The yellow solution was refluxed for 7.5 h. It was evaporated to dryness to give 0.76 q of a thick oil. This was chromatographed on SiO2 (ACT 1.30 g) and eluted wlth benzene and benzene-ether to give the title compound as a solid, 0.32 g (53.4%);
mp (pentane) 160-162C; Hmr (CDC13) ~: 7.3-8.4 (8H, m, aromatic), 5.4 (H,d), 5.3 (4H, benzyls, m), 5.0 (H, dt), 4.0 (H, dd), 2.35 (6H, s), 0.8 (2H, dq) and 1.0 ppm (3H, t).

(l'S,5R,6S and l'R,5S,6R) 6-(1'-hydroxy-1'-propyl)-2-methylpenem-3-carboxylic acid (isomer C), sodium salt.

CH3 H2/Pd-Celite HO ~ ~ CH3 N ~ phosphate O N ~
PROCEDURE: \CH3 buffer \ - +

A mixture of the above ester (48 mg, 0.086 mmol) and 30% Pd-Celite (100 mg) in TH~ (10 ml), Et2O (20 ml), H2O (10 ml) and phosphate buffer (pH7, 2 ml) was hydrogenated at an initial pressure of 50 psi for 23 h It was filtered over Celite and the layers separated. The organic layer was washed with H2O (2 x 5 ml) and the combined water layer was washed with EtOAc (2 x 10 ml). The aqueous layer was then lyophilized to give the title campound as a white salt, 30 mg; ir (KBr) v : 1750 (~-lactam), and 1600 -1650 cm (broad, -CO2 ); uv ~ : 258 (~ 1105) and 305 (~ 1244).
~ C ~--Example 49 (l'R 5R.6S and l'S 5S 6R) 6-(l'-HydLQ~y-1'-~opyl ~2-methylpenem -3-carboxylic acid sodium and pQ~a~ium s~lts_(isomer B~
H~ ,H
~R ,,~ ~ CH 3 (l'R.3S.4R apd l'S.3Rl4Sl 1-t'-Butyldi~thY19~1~1:3b~ 9~-YlXY
-1'-propyl)-4-tritylthio2-azetidinone ~isomer B) OH HCO ~ t N OCHO
~J. ~ ~ STr 2 3 ~J ~STr ~SiMe2 C~2C12 o Si.~e2 4-Dimethylaminopyridine (DMAP) was prepared according to a) H.C. Brown et al. Org. Synth. Collect Vol. 5, 977 (1973) and b) Helmet Vorbruggen et al. Angew. Chem. Int. Ed., 17, 569, (1978).
PROCEDURE:
To a cooled (OC) solution of (1'R,3S,4R and l'S,3R,4S) 1-t-butyldimethylsilyl-3(1'-hydroxy-1'-propyl)-4-trityl-thio-2-azetidinone (isomer B) (3.612 g, 7 mmol) in CH2C12 (50 ml) was added Et3N ( 4.48 ml, 35 mmol) HCO2H (0.63 ml, 16 8 mmol) and DMAP (0.854 g, 7 mmol) followed by dropwise addition of acetic anhydride (7.14 g, 7 mmol) The yellow solution was stirred at -40C and milky mixture. It was poured onto ice-lN
HCl (pH 6) and the layers were separated. The CH2C12 solution was washed with lM NaHCO3 and brine. It was dried (Na2SO4 ) and evaporated to dryness to give 3.8 g of a solid residue. This was treated with pentane and filtered to glve 3.7 g of a white solid O
(96.8%); mp 125-27C; ir (neat) vmax: 1720 (H-C) and 1750 cm~

(B-lactam); 1Hmr (CDC13) ~: 7.1 (H, s, H -C-) 6.8-7.7 (15H, m), 4.8 (H, m), 4.05 (H, d, J=1.5), 3.7 (H, m, J=1.5, J=7), 1.4 (2H, 35 m), 0.95 (9H, s), 0.8 (3H, t) and 0.1 ppm (6H, s); Anal. calcd for C32H39NO3SSi:C 70.42; H 7.20; N 2.57; found: C 70.20; H
7.33, N 2.73.

~2~6~;61 (l'R,3S,4R and l'S,3R,4S) 3-(1'-formyloxy-1'-propyl)-4-tritylthio-2-azetidlnone (isomer B) OCHO OCHO
S~r ~ NaN HMPT ~ ~ Tr ~ SiMe2 10% H2O N~H

PROCEDURE:
To a cooled tice bath) solution of t3.7 g, 6.77 mmol) in HMPT t40 ml) Containing 10~ H20 was added NaN3 tO.91 g, 14 mmol).
The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (200 ml) and extracted with ether (4 x 40 ml). The ether solution was diluted with pet-ether and washed extensively with water and brine to remove HMPT. It was dried (Na2S04) and evaporated to dryness to give 2.92 g of a thick colorless oil. (quan-titative yield). IHmr (CDC13) ~: 8.1 (H, H-C-,S), 7.1-7.7 (15H~ m, -STr), 5.23 (H, m, J=7), 4.38 (H, d, J=2.5), 4.3 tH, -NH), 3.35 tH, dd, J=2.5, J=7), 1.75 t2H, m) and 1.0 ppm t3H, t).

tl'R,3S,4R and l'S,3R,4S) 3-tl'-formyloxy-1'-ethyl)-1-tparanitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone tisomer B) OCHO ~ STr OCHO STr -- PNB GLYOXYLATE ~
H Et3N/THF

PROCEDURE:
A mixture of 3-~1'-formyloxy-1'-propyl)-4-tritylthio-2-azetidinone tisomer B), t2.9 g, 6.77 mmol), PNB glyoxylate tl-59 g, 7 mmol), Et3N t5 drops) and Na2S04 tanhydrous, 5.0 g) in T8F t50 ml) was stirred at room temperature for 18 h. It was filtered and evaporated to dryness to give an amorphous solid in quantitative yield (4.33 g); IHmr tCDC13) ~: 8.2 t2H, d), 7.1-7.8 tl8H, m), 5.2 --26 1~-l~r~6~;61 (2H, d), 4.9 (H, m), 4.65 and 4.3 [H, 4.65 (1/2 H,s) 4.3 (1/2 H, s)], 4.2-4.3 (H, d, 1/2 H at 4.2, 1/2 H at 4.3), 3.65 (H, m), 1.4 (2H, m) and 0.8 ppm (3H, t).

tl'R 3S 4R and l'S 3R 4S) 3-fl'-formyloxy-1'-propyl)-1-(paranitrobenzyl 2"-chloro-2"-aceta~e)-4-tritylthio-2-azetidinone (isomer B) oc~o oc~o J~ "~sTr ~J,., ~ STr a~ N y OH SOC 1 2/THF O~ N ~f C 1 C32PNB co2~s PROCEDURE:
To a cooled (ice salt bath) solution of the above glyoxylate (4.3 g, 6.77 mmol) and lM Py/THF (8 ml, 8 mmol) in dry THF (30 ml) was added dropwise lM SOC12 /py (8 ml, 8 mmol). The resulting solid mixture was stirred at the above temperature for 1 h. It was diluted with benzene (30 ml) and stirring was continued for 20 min. It was filtered over "CELITE"*- charcoal and the filtrate was evaporated to dryness to give 4.1 g of an amorphous solid (92%). ir (neat) O o max : 1720 (H-C-), 1750 (-C-OPNB) and 1780 cm~1 (~-lactam); lHmr (CDC12 ~: 8.25 (2H, d), 7.8 (H, s, H-C-), 7-7.75 (17H, m), 5.25 (2H, d), 5.0 (H, m), 4.6 -(H, s), 4.4 (H, d), 3.7 (H, m), 1.6 (2H, m) and 0.9 ppm (3H, t).

*Trade Mark lZ~36~;61 (l'R,3S,4R and l'S,3R,4S) 3~ formyloxY-l~-prop~l)-l-(paranitrobenæ

2"-triphenylphosphoranylidene-2"-acetate~-4-tritylthio-2-azetidinone (isomer B) OCHO OCHO
STr ~ ......... STr l 03P dioxane ' ~
O ~ ~ Cl lutidineo ~ ~ ~3 PROCEDURE:
A mixture of the above chloro compound (4.0 g, 6.07 mmol) ~3P (1.834 g, 7 mmol) and lutidine (0.749 g, 7 mmol) in dioxane (40 ml) was heated at 100C (oil bath) for 2 days. It was cooled, diluted with ether and washed successively with cold solution of lN HCl, lM NaHCO3 and brine. The organic solution was dried (Na25O4) and filtered over Celite-charcoal. It was evaporated to dryness to give an oil which was chromatographed on SiO2 (Act. 1, 200 g) and eluted with benzene and benzene-ether to give 2.60 g of the title compound as an amorphous solid (48.45~); ir (neat) V : 1720 (H-C-O-), and 1750-1760 cm (-CO2PNB and ~-lactam).

(l'R,35,4R and 1'5,3R,4S) 4-acetylthio-3-(1'-formyloxy-1'-propyl)-1-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (isomer B).

OCHO OCHO OCHO
" ~ STr O ~ ~ ~3~N ~ P~3 PROCEDURE:
A warm solution (60C) of 0.15 M AgNo3-cH3o~ (8.7 ml, 1.3 mmol) was added to a mixture of the above phosphorane (0.88 g, 1 mmol) and pyridine (0.103 g, 1.3 mmol) in MeOH (5 ml) warmed -~ ~6-6~
to 60C. The mixture was stirred at room temperature for 15 min and at OC for 2 h. It was filtered and washed with cold MeOH to give 0.53 g of the silver mercaptide as a yellow solid (71%) which was used as such. To a cooled (ice bath) mixture of the above mercaptide (0.53 g, 0.71 mmol) and pyridine (0.079 g, 1 mmol) in CH2Cl2 (10 ml) was added dropwise CH3COC1 (0.079 g, 1 mmol) in CH2Cl2 (5 ml). After stirring at 0C for 1 h, it was filtered. The filtrate was washed well with a cold solution of 0.5M HC1, 0.5M NaHCO3 and brine. It was dried (Na2SO4) and evaporated to dryness to give 0.43 g of an oil. (63%); ir (neat) max:
1700-1760 cm 1 (broad -C and B-lactam).
(l~R,3S.4R and l'S.3R.4S) and acetylthio-3-(1'-hydrox~ -l'-propyl-l-(~aranitrobenzyl 2"-tr1~henvl~hoa~horanylide -2"-acetate)-2-azetidinone ~isQme~-~3) oc~o pH
n~SAC ~3Cl/MeOH , ~ SAc od--N~ P~3 ~

PROCEDURE:
The above formate (1 0 g, 1 45 mmol) in THF (10 ml) was treated at room temperature with HC1/MeOH (10 ml, prepared from 2 ml concentrated HCl and diluted with MeOH to a volume of 24 ml) The mixture was kept at room temperature for 0.5 h. It was basified with lM NaHCO3, extracted with EtOAc solution, washed with brine and dried (Na2SO4 ) It was evaporated to give 0.9 g of crude title compound. This was chromatographed on SiO2 and eluted with ether and ether: EtOAc (1:1) to give 0.6 g of pure title compound as an amorphous solid (62.5%); 1Hmr (CDC13)~ :
8 25 (2H, d), 7 3-8.1 (17H, m, aromatic), 5.6 (H, m), 5.2 (2H), 4 9 (H), 4 4 (H, m), 2 3 (3H, SAc), 1.5 (2H, m) and 0.9 ppm (3H, t).

-~ ~6~6~

(l'R,5R,6S and l'S,SS,6R) paranitrobenzyl 6-(1'-hydroxy-1'-~ropyl)-2-methylpenem-3-carboxylate (isomer B).

OH

~ ~ 3 ~H3 PROCEDURE:
The above phosphorane (0.2 g, 0.3 mmol) in toluene (45 ml) was heated to reflux and 5 ml of toluene was distilled off.
The resulting solution was refluxed for 6 h. It was cooled and evaporated to dryness to give 0.2 g of an oil. This was chroma-tographed on SiO2 and eluted with ether to give 0.1 g of title compound as a white solid. (87%); mp (pentane) 133-135C; IHmr (CDC13) ~: 8.3 (2H, d), 7.6 (2H, d), 5.6 (H, d), 5.35 (2H, d), 4.15 (H, m), 3.8 (H, m), 2.4 (3H, s, CH3), 2.2 (H, OH), 1.7 (2H, m) and 1.05 ppm (3H, t).

(l'R,5R,6S and l'S,5S,6R) 6-1'-hydroxy-1'-propyl)-2-methylpenem-3-carboxylic ac id (isomer B), mixed K and Na salts OH OH
F~ 3 CO2PNB 2 (lla+K) PROC~DURE:
A mixture of the above ester (0.07 g, 0.185 mmol), 30 Pd-Celite (150 mg) and buffer solution (pH 7, 4 ml) in THF (15 ml, Et2O (25 ml) and deionized water (15 ml was hydrogenated at an initial pressure of 48 psi for 4 h. It was filtered over Celite and the layers were separated. The aqueous layer was washed with ethylacetate and then lyophilized to give 91 mg of a solidi r (KBr) v : 1780 (~-lactam) and 1650 cm (broad, -CO ); uv max 2 H O ~ : 255 (~ 983) and 300 (~ 1092).
2 max lX~6~

Exam~le ~
(l'R,5R,6S ~nd l'S,5S,6R) 6-(1'-Hydroxy-2'-~henylethyl)-2-methylpenem-3-carboxylic acid (isomer B) H, .~H

trans l-(t-butyldimethylsilyl)-3-phenylacetyl-4-tritylthio-2-azetidinone ~Tr + LDA + ~CH CO Et ~ ~STr N -SiMe2 2 2 N -~lMe2 l-t-Butyldimethylsilyl-4-tritylthio-2-azetidinone tl8.32 g, 40 mmol) in dry THF (100 ml) was added dropwise under N2 to a cooled (-78C) LDA solution [prepared under N2, at -78C from dropwise addition of 1.6 M n-8uLi (101.25 ml, 162 mmol) to diisopropyl amine (22.95 ml, 162 mmol) in dry THF (150 ml) and stirred at -78C for 30 min]. The mixture was stirred at -78"C for 30 min and ethyl phenylacetate (15.66 g, 15.12 ml 15.12 ml, 93.6 mmol) in dry TH~ (50 ml) was added and the reaction mixture was stirred at -78C for 2 h. It was poured onto ice-lN HCl (pH S-6) and extracted with ether several times. The ether solution was washed with brine and dried (Na2SO4). It was evaporated to dryness to give 33.7 g of a crude solid. This was dissolved in ether (10 ml) and triturated with pentane (200 ml).
The solid was filtered and washed several times with pentane to give 18.3 g of a white solid (79.6~) mp 141-143. IHmr (CDC13 ~:
7.0 - 7.6 (20H, m), 4.8 (H, d), 3.7 (H, d), 3.53 (H, s), 3.43 (H, s) 1.5 (9H, s) and 0.3 ppm (6H, s).

--L6q_ 6~
l-~t-butyldimethylsilyl-3-(1'-hydroxy-?'-phen~lethyl) OH
5 ~ STr (P ~J~f Tr O N ~iMe2 N ~~iMe2 trans 1-~t-butyldimethylsilyl)-3-phenylacetyl -4-tritylthio2-azetidinone (28.8 g, 50 mmol) and NaBH4 (0.5 g, 0.25 mole) in THF (200 ml) were stirred at room temperature for 18 h. The mixture was poured onto ice-lN HCl and extracted with CH2C12. The CH2C12 solution was washed with brine and dried (Na2S04 ). It was evaporated to give an amorphous solid (27.7 g). A portion of the solid (23.0 g) was chromatographed on sio2 and eluted with hexane: ether to give off-white solid (14.4 g) which was found to be a mixture of (l'R,3S,4R and l'S,3R,4S) and (l'S,3S,4R and l'R,3R,4S) isomers in the ratio o~ 1:1 (60~). lHmr (CDC13) ~: 7-7.7 (20H, m), 4.37 (1/2H, d), 4.18 (1/2H, d), 3.3-3.8 (H, m), 3.45 (1/2H, dd), 3.1 (1/2H, dd), 2.7 (2H, m), 0.87 (9H, d) and 0.25 ppm (6H, s).

l-(t-butyldimethylsily~L-3-(~ o~mylQ~y-2~--p-hen-ylethylL
-~its~L~;hiQ-2-a~

¢`~", Tr ~p H, ~C STr ~ ST-09C~ 2 o~1--+i.~1e 2 o~N--,~LMe isomer B i somer C

To a cooled (-40C) solution of the above mixture of alcohols (14.4 g, 24.9 mmol) in CH2C12 (250 ml) was added Et3N (15.93 ml, 125 mmol), HC02H (2.24 ml, 59.76 mmol) and DMAP (3.04 g, 24.9 mmol) . After stirring for 5 min acetic anhydride (2.
35 ml, 249 mmol) was added dropwise. The clear solution was stirred at -40C for 15 min whereby it turned into a white cloudy mixture. It was kept at -40C for another 45 min (total time 1 h). It was poured onto ice-lN HCl, and the layers separated. The CH2Cl2 solution was washed well with cold lN HCl,H2O, lM NaHCO3 and brine. It was dried (MgSO4 ) and evaporated to give 14.0 g of an amorphous solid. This was separated by hplc (Water Associates, System 500*) to lo give: "Isomer B" 6.0 g, mp 172-73C and "Isomer C" 6.0 g mp 188-89C. Total yield of pure compound 12.0 g (73.2~).
Isomer C: lHmr (CDC13) ~: 6.8-7.7 (21H, m), 5.05 (H, dt), 4.05 (CH, d) 3.65 and 3.75 tH, two doublets), 2.7-2.9 (2H, d), 0.88 (9H, s) and 0.2 ppm (6H, s). Isomer B: 1Hmr (CDCI3) ~: 7.75 (H, s), 6.9-7.5 (20H, m), 4.3 (H, dt), 3.95 (H, d), 3.37 (H, dd), 2.95 (H, s), 2.85 (H, s), 0.9 (9H, s) and 0.2 ppm (6H, s).

3-(l'-formyloxy-2'-phenylethyl)-4-tritylthio-2-azetidinone tl'Rr3S,4R and l'S,3R,4S enantiomers) ~OC'10 S~R ~ STr N--S i,Ye 2 N
I somer B
To a cooled (ice bath) solution of the above formate (5.9 g, 9.375 mmol) in HMPT containing 10~ water (50 ml) was 30 added NaN3 (1.3 g, 20 mmol). The mixture was stirred at room temperature for 1.5 h. It was poured onto ice water (300 ml) and extracted with ether (3 x 100 ml). The ether solution was washed well with water and brine. It was dried (Na2S04 ) and evaporated to give a solid residue. This was treated with *Trade Mark . .. .

petroleum ether and filtered to give 4.4 g of a white solid (92%) mp 169-71C. Anal. calcd for C31H27NO3S: C 75.
N 2.84; found: C 7504, H 5.64 N 2.78. 1Hmr(CDC13)~ : 7.9 (H, 8), 7.1-7.6 (20H, m), 5.4 (H, m), 4.6 (H, NH), 4.2 (H, d), 3.3 (H, dd), 3.15 (H, s) and 3.0 (H, 5).

3-(1'-formyloxy-2'-phenylethyl)-l-(par.anitrobenzyl 2"-hYdroxy-2"acetate)4-tritylthio-2-azetidinone (1'R.3S,4R and l'S.3R.4S enantiomers) o,~STr '~ ~,F~STr o ~H N ~OH
C02P~3 A suspension of PNB glyoxylate (2.37 g, 10.16 mmol) in dry benzene (100 ml) was refluxed under a Dean Stark apparatus (packed with moleoular sieve 3~) for 2 h. Then the above N-H compound (4.2 g, 8.537 mmol) was added and refluxing continued for 1 more h. It was cooled to room temperature Et3N
(0.12 ml, 0.85 mmol) was added and the mixture was stirred at room temperature for 1.5 h. It was evaporated to dryness to give the title compound in quantitative yield as a mixture of two isomeric alcohols. 1Hmr (CDC13)6 : 8.0-8.3 (2H, two doublets), 7.5 and 7.6 (H, two singlets), 7.0-7.4 (20H, m), 5.25 (2H, d), 4.9 (H, OH), 4.25 and 4.35 (H, two doublets), 3.5-4.5 (H, m, broad), 3.1- 3. 3 (H, m) and 2.9 ppm (2H, m).

. . .

~36~61 3-(l'-formyloxy-2~-phenYlethyll-1-(~aranitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (l~R 3S.4R and l'S.3R 4S
enantiomers) ~!~9T~ ¢Oc~

To a cold (ice salt bath) solution of the above glyoxylate (6.0 g, 8.537 mmol) in dry THF (30 ml) was added a lM solution of pyridine in THF (10 ml, 10 mmol) followed by the dropwise addition of a lM solution of thionyl chloride in THF (10 ml, 10 mmol). After 1 h at the above temperature was diluted with benzene (30 ml) and stirring was continued in the cold for 30 min. It was filtered over "CELITE"*-charcoal and evaporated to dryness to give 6.0 g of an amorphous solid (98%): 1Hmr (CDC13) : 8.2 (2H, m), 7-7.7 (23H, m), 5.8 (H, s), 5.25 (2H, s), 4.35 (H, d), 3.5-4.0 (H, m), 3.3 (H, m) and 2.9 ppm (2H, d).
3-(l'-f~ormYloxy-2'-phenylethyl)-1-(Daranitrobenzyl 2"-triphenylphosphoranylidene-2"-acet~a~e~ -tritylthio -2-azetidinone (l'R 3S.4R and lS.3R 4S enantiomers).

H OCHO ST--N~f.Cl N ~ ~

A mixture of the above chloro compound (6.0 g 8.333 mmol), ~3P
(2.489 g, 0.5 mmol) and lutidine (1.0165 g, 1.1 ml, 9.5 mmol) *Trade Mark ~, ~666~

in dioxane (50 ml) was heated at 110C (bath temp) for 18 h.
It was cooled and filtered over Celite. The filtrate was diluted with ethyl acetate and washed with cold lN HCl, H2O, lM
NaHCO3 and brine. It was dried (Na2SO4) and evaporated to give 8.0 g of a crude product. This was chromatographed on SiO2 and eluted with ether: hexane (1:1) and ether to give 4.0 g of the title compound. mp (needless from ether) 235-37C (d). (51~);
ir (film) V a : 1720, 1750 cm 4-acetYlthio-3-(l~-formyloxy-2~-phenylethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone (l'R,3S,4R
and l'S,3R,4S enantiomers) . ~ OCHO ~ OCHO SA

O ~ ~ ~3 o~N ~ ~3 ~ N ~ P~3 To a refluxing solution of the above phosphorane (3.6 g, 3.8 mmol) and pyridine (0.33 g, 4.2 mmol) in CH2C12 (30 ml) and MeOH
(30 ml) was added dropwise a 0.15M AgNO3/MeOH solution (28 ml, 4.2 mmol).
The mixture was stirred at room temperature for 2.15 h. It was concentrated to a small volume ( 10 ml), cooled and filtered to give the silver mercaptide as a yellow solid (2.3 g, 77%). This mercaptide and pyridine (0.277 g, 3.5 mmol) in ice-cold (CH2Cl2 (20 ml) was treated dropwise with CH3COCl (0.27 g, 3.5 mmol) in CH2C12 (5 ml).
The mixture was stirred at room temperature for 3 h. It was filtered over Celite and the filtrate was washed with cold lN HCl, H20, IM
NaHCO3 and brine. It was dried (MgSO4) and evaporated to dryness to give 1.0 g of an amorphous solid (89.8~ Hmr (CDC13) ~: 8.2 (2H, d), 7.0-8.0 (23H, m), 4.5-5.7 (4H, m), 2.6-3.3 (3H, m), and 2.3 ppm (2H, d, SAc).

_ Z 7V-S~66~1 4-acetylthio-3-(l'-hydroxy-2'-phenylethyl)-l-(paranitrobenzyl 2"-triphenylphosphoranylidene 2"-acetate)-2-azetidinone tl'R,3S,4R
and 1'5,3R,45 enantiomers).

OCHO 5 H ~

~N ~ P~3 ~ N ~ P~3 O PNB

A solution of the above phosphorane (1.8 g, 2.416 mmol) in THF (10 ml) was treated with lN HCl/MeOH (l0 ml) and the mixture was stirred at room temperature for 4h. It was concentrated to remove methanol, diluted with cold water, basified with lM NaHCO3 and extracted with CHCl3. The CHC13 solution was dried (MgSO4) and evaporated to give 1.65 g of an amorphous solid. This was chro-matographed on SiO2 and eluted with ether: ethyl acetate to give 1.30 g of the title compound (75~ Hmr (CDC13) ~: 8.2 (2H, d), 6.7-8.0 (22H, m), 4.0-6.0 (5H, m), 2.5-3.5 (3H, m) and 2.2 ppm (3H, SAc).

paranitrobenzyl 6-(l'-hydroxy-2'-phenylethyl)-2-methylpenem-3-carboxylate (l'R,SR,6S and 1'5,5S,6R enantiomers) H OH

A solution of the above phosphorane (1,2 g, 1.67 mmol) in toluene (80 ml) was heated to reflux (10 ml was distilled off to remove moisture and low boiling point solvent present) for 6 h.
It was evaporated to dryness and the crude product was chromato-graphed on SiO2. The title compound was obtained by eluting the column with ether to give 0.65 g of amorphous solid (89%). IHmr --2 ?5-~2.r~6G61.

(CDC13) ~: 8.2 (2H, d), 7.6 (2H, d), 5.4 (H, d), 5.2-5.4 (2H, d), 4.0-4.5 (H, m), 3.7-4.0 (H, dd), 3.0 (2H, d) and 2.3 ppm (3H, S).

6- (1'-hYdroxy-2'-Phenylethyl)-2-methylpenem-3-carboxylic acid (l'R,5R,6S and l'S,5S, 6R enantiomers) 3 ~ ~ CH3 A mixture of the paranitrobenzyl ester (0.33 g, 0.75 mmol), 0.05 M Buffer solution (pH 7, 17.4 ml), THF (30 ml), Et2O (30 ml), distilled H20 (60 ml), and 30~ Pd/Celite (0.69 g) was hydrogenated at an initial pressure of 50 psi for 24 h. It was filtered over Celite and the organic layer washed with water, The combined water layer was washed several times with EtOAc and it was lyophilized for 18 h to give the title compound as a yellow solid salt. This was treated with a small amount of water, acidified with cold lN HCl and extracted well with CHC13. The CHC13 solution was dried (MgSO4) and evaporated to give a solid residue. This was treated with ether and filtered to give 30 mg of a white solid (13.2%), mp 165-167C; ir (nujol) V : 3580 (OH, Sharp), 1660 and 1760 cm ; uv ~MeOH) ~ x 310 (~ 5490) and 254 (~ 4880).

-27~-Exam~le 51 4'R 5R.6S and 4'S.5S.6R) 6-(2',2'-Dim~thyl-1', 3'-dioxolan -4~-v1)-2 methvl~enem-3-carboxvlic Acid (isomer C) ~ Q
~."~s o~L N ~ 3 A. PREPARATION OF

~
/ ~ ~ ST.

(4'R,3S,4R and 4'S,3R,4S) and (4'S,3S,4R and 4'R,3R,4S) 1-(t-Butyldimethylsilyl)-3-(2',2'-dimethyl-1'-,3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone ("Isomer C" and "Isomer B") Ethyl _-(2-methoxy-2-propyl)glycolate ) POC13 ~ Et To a solution of ethyl glycolate (15.6 g, 0.150 mol;
freshly distilled) and 2-methoxypropene (16.4 g, 0.216 mol; 95~
pure) ) in CH2C12 (150 ml) was added at 0-5 phosphorus oxychloride (3 drops, 35 mg, 0.23 mmol) and the mixture was stirred at 0-5 for 15 min and at room temperature for 1.5 h. This was then quenched with pyridine (30 drops), stirred 45 min and the solvent evaporated. The residue diluted with pentane (150 ml) was dried over K2CO3. After filtration, the solvent was evaporated yielding 27.89 g (0.158 mol, 100%; 94.9~ pure) of the title compound as a colourless oil:
lHmr (CC14) ~: 1.25 (3H, t, J=7Hz -CH2CH3), 1.28 (6H, s, Me2), 3.12 (3H, s, -OCH3), 3.88 (2H, s, -OCH2CO-), 4.10 (2H, q, J=7Hz, -CH2CH3);
ir (neat) Vm x 1760 and 1735 cm (ester).
1) J. Meinwald Q* o~., Tet. Lett., 4327 (1978) 2) M.S. Newman and M.C. Vander Zwan, J. Org. Chem.,38, 2910 (1973).

(3S,4R and 3R,4S) l-(t-8utyldimethylsilyl)-3-(1'-keto-2'-(2"-methoxy-2"-isopropyloxy)-1'-ethyl)-4-tritylthio-2-azetidinone STr 1) LDA/THF ~ X ~ ~ STr Si 2) ~ Et OCH3 ~Si OMe To a stirred solution of diisopropylamine (18.5 ml, 0.134 mol) in THF (400 ml; freshly distilled from LAH1 at -78C
was added n-butyllithium (1.6M in hexane, 90 ml, 0.144 mol) under --11 9"--6~;61 N2 atmosphere. After 30 min, a solution of l-(t-butyldimethylsilyl) 4-tritylthio-2-azetidinone (50.0 g, 0.109 mol) in THF (100 ml) was added dropwise over 10 min and the mixture was stirred for 5 min.
To this pink solution was added ethyl 0-(2-methoxy-2-propyl)glycolate (23.94 g, 0.136 mol) and the mixture was stirred for 1 h. After removing the dry-ice bath saturated NH4Cl solution (200 ml) was added followed by brine (100 ml). The aqueous phase was extracted with Et2O (3 x 100 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated yielding 60.95 g (0.103 mol, crude yield 94.6%) of the title compound as a crude orange oil. This crude material was used in the next reaction. A pure sample was obtained by column chromatography (SiO2, eluent: 2% St2O in benzene);
IHmr (CDC13) ~: 0.30 (6H, s, Si-CH3), 0.95 (9H, s, t-Bu), 1.12 (3H, s, CH3), l.lS (3H, s, CH3), 3.15 (3H, s, OCH3), 3.57 (lH, A of AB, J

17Hz), 3.77 (lH, d, J=1.6Hz, H-3), 3.97 (lH, B of AB, J =17Hz), 4.83 lH, d, J=1.6Hz, H-4), 7.1-7.6 (lSH, m, aromatic Hs); ir (neat) v max 1750, 1725, 1710 cm (C=O); tlc, Rf 0.53 (benzene; Et2O=4:1), Rf 0.61 (hexane: EtOAc = 2sl).

(3S,4R and 3R,4S) l-(t-Butyldimethylsilyl)-3-(1'-hydroxy-2'-methoxy-isopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of epimers at C-l') O QH
STr NaBH ~ Sl ~

A solution of crude l-(t-butyldimethylsilyl)-3-(1'-keto-2' (2"-methoxy-2"-isopropyloxy)-1'-ethyl)-4-tritylthio-2-azetidinone (60.95 g, 0.103 mol) in THF (100 ml) was diluted with abs.EtOH
(350 ml) and to this solution was added at 0C NaBH4 (4.88 g, 0.156 mol). The mixture was stirred at room temperature for 2 h and _? tq~

~3~

quenched by slow addition of brine (280 ml). The mixture was extracted with Et2O (3 x 150 ml) and the extracts were washed with brine, dried (Na2SO4) and evaporated to yield a yellow residue which was redissolved in CH2C12 (500 ml). This was dried (Na2SO4) again and evaporated yielding 57.1 g (0.0966 mol, crude yield 93.8%) of the title compound as a crude yellow foam: Hmr (CDC14) ~: 0.17 (s, SiCH3), 0.80, 0.87 (2s, Si-tBu), 1.22, 1.25 (2s, CH3), 3.03 (s, OCH3), 4.32 (d, J=2Hz, H-4), 7.0-7.7 (m, aromatic Hs); ir (neat) V 3460 (OH), 1745 (C=O), 1595 (aromatics): Rf 0.47 and 0.42 (hexanes: EtOAc=2:1).
This crude material was used in the next step without purification.

(4'R,3S,4R and 4'S,3R,4S) and (4'S,3S,4R and 4'R,3R,45) l-(t-Butyldimethyl-silyl)-3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone.
(Isomer C and Isomer B) QH _L_~
STr p-TsOH H2o ~ ~ ~ Tr ~ ~ Si/ X OMe / ~

A solution of (3S,4R and 4R,4S) l-(t-butyldimethylsilyl)-3-(1'-hydroxy-2'-methoxyisopropyloxyethyl)-4-tritylthio-2-azetidinone (mixture of diastereomers at C-l' (57.1 g, 0.0966 mol; crude) in CH2C12 (500 ml) was treated at room temperature with p-toluenesulfonic acid monohydrate (200 mg) and 2,2-dimethoxypropane (20 ml) and then stirred for 1 h. It was washed with sat. NaHCO3 and then brine, dried (Na2SO4) and evaporated yielding 49.64 g (0.0888 mol, crude yield 91.9%) of a mixture of the title compounds (Isomer B and Isomer C) as yellowish foam. This was purified by H~LC (Waters 500 Silicagel; eluent, hexane:
EtOAc=9:1) and by crystallization yielding 14.28 g (25.5 mmol, 26.4~) of the title compound (Isomer C) as white crystalsi mp 146-7C (pentane);
Hmr (CC14) ~: 0.27 (6H, s, Si-CH3), 0.95 (9H, s, Si-tBu), 1.15 (6H, s, --ZS?o--i6~

di-Me), 2.5-2.9 (lH, m, H-4'), 2.97 (lH, t, J=1.8 Hz, H-3), 3.25-3.9 (2H, m, H-5'), 4.27 (lH, d, J=1.8Hz, H-4), 7.1-7.6 (15H, m, aromatic Hs);
ir (nujol) V : 1750 (C=O) and 1595 cm (aromatics); Rf 0.45 (hexanes:
EtOAc-4:1) and 14.50 g (25.9 mmol, yield 25.9~) of the title compound (Isomer B) as white crystals: mp lg4-5C (Et20-pentane); IHmr (CC14) ~:
0.02 (6H, s, SiMe), 0.833 (9H, s, Si-tBu), 1.13, 1.18 (6H, 2s, diMe), 2.5-2.8 (lH, m, H-4'), 3.3-4.1 (2H, m, H-5'), 3.48 (lH, dd, J3 4=1.5Hz, J3 4,=5.0Hz, H-3), 3.93 (lH, d, J4_3=1.5Hz, H-4), 7.1-7.7 (15H, m, aromatic Hs); ir (nujol) v : 1650 (C=O) and 1595 cm (aromatics);
Rf 0.37 (hexanes: EtOAc=4:1). Anal calcd for C33H41N0355i: C 70.80, H 7.38, N 2.50, 5 5.73; found: (Isomer C) C 70.23, H 7.30, H 7.3-;
N 2.41, S 5.53 and (Isomer B) C 70.52, H 7.31, N 2.40, S 5.05.

_ Z~ _ ~2~36~61 B. Preparation of the Penem Product (Isomer C) (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer C) ~STr NaN3 ~ ~ STr Si ~ HMPT-H O N ~H

To a stirred solution of (4'R,3S,4R and 4's,3R,4S) l-(t-butyl-dimethylsilyl)-3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-4-trityl-thio-2-azetidinone (Isomer C) )14.3 g, 25.6 mmol) in hexamethylphos-phoric triamide(230,4 ml) was added slowly ( in 20 min) at 0-5C a solution of sodium azide (2.50 g, 38.4 mmoli 1.5 eq) in H2O (25.6 ml).
The mixture was stirred at room temperature for 2 h and poured into cold water (2.5 2). The white precipitate formed was collected, washed with H2O and dried yielding 11.26 g (25.3 mmol, crude yield 98.8%) of the title compound as a white solid. A pure material was obtained by crystallization from CH2C12-Et2O: mp 192-3C (dec.)i IHmr (CDC13)~:1.33, 1.37 (6H, 2s, di-Me), 3.27 (lH, t, J=3Hz, H-3), 3.8-4.4 (3H, m, H-4' and H-S'), 4.40 (lH, d, J=3Hz, H-4), 4.47 (lH, br, NH, D2O exchanged) and 7.1-7.7 ppm (15H, m, aromatic Hs); ir (nujol) V
3220 (NH), 1760 (C=O) and 1950 cm (aromatics); Rf 0.31 (hexanes:
EtOAc = 3:2).

6ti~il (4'R,35,4R and 4'S,3R,4S) 3-t2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(~-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (mixture of epimers_ at_C-2") (Isomer C) STr ~O2PNB ~ ~ Tr N~ Et3N/THF N ~ OH

A suspension of p-nitrobenzyl glyoxylate hydrate (6.57 g, 28.95 mmol; 1.15 eq) in benzene (500 ml) was heated at reflux with Dean-Stark trap for 2 h. Evaporation of the solvent gave p-nitrobenzyl glyoxylate as an oil. A mixture of thls oil and (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1'-3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer C) (11.2 g, 25.2 mmol) in THF (350 ml, distilled from LAH) was treated with triethylamine (289 mg, 2.86 mmol) at room temperature under N2 for 18 h (overnight).
After evaporation of the solvent, the residue diluted with CH2C12 (200 ml) was washed successively with brine containing lN HCl (2.9 ml) sat. NaHCO3 and brine, dried (Na2SO4) and evaporated after addition of Et2O (30 ml) to give 17.2 g (26.3 mmol, crude yield 100%i purity 95.8~) of the title compound as a white foam: Rf 0.40 and 0.30 (benzene: Et2O=3:2).
Each isomer was separated by hplc (SiO2, eluent, benzene: Et2O=3:2) and purified by crystallization from CH2C12-Et2O. Isomer I: Rf 0.40 (benzene:
Et20=3:2); mp 153-4C; lHmr (CDC13) ~: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and OH), 3.5-4.2 (3H, m, H-4' and H-5'), 4.55 (lH, d, J=2Hz, H-4), 5.12 (lH, br, H-2"), 5.30 (2H, s, OCH2Ar) and 7.1-8.3 ppm (19H, m, -2.~'3 ~

6~i6~L

aromatic Hs); ir (nujol) Vmax: 3370 (OH), 1775 (3-lactam) and 1745 cm (ester); Anal. calcd for C36H34N2O8S: C 66.04, H 5.23, N 4.28, found:
C 65.85, H 5.64, N 4.11. Isomer II: Rf 0.30 (benzene: Et2O=3:2);
mp 164-5C; 1Hmr (CDC13) ~: 1.17 (6H, s, di-Me), ~3.2 (2H, m, H-3 and OH), 3.4-4.0 (3H, m, H-4' and H-5'), 4.57 (lH, d, J=2Hz, H-4), 5.23 (lH, br, -2"), 5.27 (2H, s, -OCH2Ar), and 7.1-8.3 ppm (19H, m, aromatic Hs);
ir (nujol) V : 3340 (OH), 1765 (~-lactam) and 1740 cm (ester);

Anal- calcd for C36H34N2O8S: C 66.04, H 5.23, N 4.28, S 4.90, found:
C 66.01, H 5.34, N 4.28, S 4.75.

(a'R ~C,aR 3 L~l ~',C,~,R,,4,C.) 3-(2'.2'-DimethY1-1',3~-dioxolan-4'-Yl)-l-(P-nitrobenzvl 2"-chloro-2"-acetate)-4-tritvlthio-2-azetidinone (mixture of epimers at C-2") (Isomer C) Tr SOC12-Pyr ~ ~ STr y H THF O N ~ C1 To a stirred solution of (3'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) (17.13 g, 25.07 mmol;
mixture of epimers at C-2") in THF (250 ml) was added at -15C under N2 pyridine (2.84 ml, 35.1 mmol) and then immediately afterwards thionyl chloride (2.20 ml, 30.1 mmol; Anachemia). The mixture was stirred for 20 min at -15 and then the white precipitate was filtered off. After washing with benzene, the filtrates and washings were combined and concentrated. The residue dissolved in benzene (250 ml) was treated with activated charcoal, filtered and evaporated, yielding 17.94 g (26.65 mmol, crude yield 100%; purity 94.1%) of the crude title compound as white foam: Rf 0.76 .(benzene: Et2O=3:2); 1Hmr (CDC13) ~:

~ 2 ~ ~

1.20 (6H, s, diMe), 3.17 tlH, m, H-3), 3.4-3.9 (3H, m, H-4' and H-5'), 4.67, 4.72 (lH, 2d, J=2.5 Hz, H-4), 5.30 (2H, s, OCH2Ar), 5.83 (s, H-2") and 7.1-8.3 ppm (19 H, m, aromatic Hs)i i:r (neat) Vmax: 1770 cm (~-lactam and ester). This material was used in the next step without purification.

(4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) .. STr 3 ~ STr ~N ~ Cl diox. ~ ~ P~3 A mixture of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) (17.87 g, 25.0 mmol; purity 94.1~ mixture of epimers at C-2"), triphenylphosphine (7.27 g, 27.5 mmol) and 2,6-lutidine (3.19 ml, 27.5 mmol) in dioxane (350 ml; distilled from LAH) was heated at reflux under N2 for 40 h. Evaporation of the solvent in vacuo gave 29.5 g of dark oil which was purified by column chromatography (SiO2 330 g; eluent 20-50% Et2O in benzene), yielding 10.5 g of yellowish solid. This solid was rinsed with Et20 to give 7.49 g (8.33 mmol, yield 33.3~) of the title compound as slightly yellow crystals: lHmr(CDC13) ~: 1.07 (s, di-Me) and 7.1-8.2 ppm (m, aromatic Hs); ir (nujol) V : 1760 cm (C=O). An analytical sample was obtained by crystallization from CH2C12-Et2O:
mp 231-2C; Anal. calcd for C54H47N2O7PS: C 72.14, H 5.27, N 3.12, S 3.57i found: C 72.18, H 5.43, N 2.98, S 3.41; Rf 0.17 (benzene: Et20=1:1).

- 2 ~ 5 -12S~6~

(4'R,35,4R and 4'S,3R,4S) Silver_3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone-4-thiolate (Isomer C) . STr ~ SAg , ~ AgNO3-Pyr N ~ P~3 MeOH C~ ~

CO PNB

A solution of (4'R,35,4R and 4'5,3R,45) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene--2"-acetate)-4-tritylthio-2-azetidinone (Isomer C) (319 mg, 0.355 mmol) in CH2C12 (10 ml) was evaporated to yield an oily residue which was redissolved in hot methanol (~3 ml; 60). To this solution was added at 60 a hot solution of AgNO3 in MeOH (0.lSM, 4.0 ml, 0.60 mmol) and then pyridine (29 ~1, 0.36 mmol). The mixture was stirred at room temperature for 5 h and at 0C for 1 h. The precipitate was collected and washed with ice-cold methanol and then cold Et2O, yielding 255 mg (0.334 mmol, yield 94.1~) of the title compound as a brownish solid: ir (nujol) v : 1750 cm (s, C=O).

(4'R,35,4R and 4'5,3R/4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetyl-thio-2-azetidinone (Isomer C) O~ "~ SAg cH3cocl/pyr ~ ~ SAc ~N ~ P~3 CH2C12 O ~ ~3 To a solution of (4'R,35,4R and 4'5,3R,45) silver 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate-2-azetidinone-4-thiolate (Isomer C) (254 mg, 0.333 mmol) in CH2C12 (15 ml) containing ~~ ~6 -~L~J3~

pyridine (100 ~1, 1.24 mmol; 3.72 eq) was added at 0-5C acetyl chloride (71 ~1, 1.0 mmol; 3.0 eq). The mixture was stirred at 0-5C for 40 min. After filtration of the precipitate over Celite the filtrate was washed successively with brine containing lN HCl (1.25 ml), sat. NaHCO3 and then brine, dried (Na2504) and evaporated, yielding 200 mg of an oil which was crystallized from Et20 to give 155 mg (0.222 mmol, yield 66.7%) of the title compound as white crystals: lHmr (CDC13) ~: 1.23 (s, di-Me), 2.20, 2.33 (2s,-SAc) and .2-8.3 ppm (m, aromatic Hs): ir (nujol) V : 1750 (3-lactam and max ester) and 1690 cm (thioester). An analytical sample was obtained by crystallization from CH2C12-Et20: mp 177-8C; Anal. calcd for C37H35N2O8PS: C 63.60, H 5.05, N 4.01, S 4.59; found: C 63.34, H 5.32, N 3.83, S 4.31; Rf 0.62 OEtOAc) (4'R,5R,65 and 4'S,4S,6R) p-Nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer C) 7'g ~
\~; ~ SAc toluene ~ ~ ' ~ ~ H3 ~02PNB 02PNB

A suspension of (4'R,3S,4R and 4'S,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphospho-ranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (443 mg, 0.634 mmol) in toluene (70 ml) was heated at reflux under N2 for 6 h.
Evaporation of the solvent gave white solid which was purified by column chromatography (SiO2 10 g; eluent 10% Et20 in benzene) yielding 247 mg (0.587 mmol, yield 92.7%) of the title compound as white solid: lHmr (CDC13) ~: 1.42 (6H, s, di-Me), 2.38 (3H, s, ?-CH3), 3.8-4.5 (4H, m, H-6, H-4' and H-5'), 5.02-5.25-5.33-5 57 (2H, AB type, _~ ~7~

12~3666~

-OCH2Ar), 5.57 (lH, d, J=1.8 Hz, H-5) and 7.52-7.67-8.12-8.27 ppm (4H, A2'B2', aromatic Hs); ir (nujol) v x 1760 (3-lactam) and 1700 cm (ester). An analytical sample was obtained by crystallization from CH2Cl2-Et2O: mp 167-8C; uv (EtOH) ~ a : 265 ( 14,000) and 314 m~
(~ 10,000); Anal. calcd for C19H20N2O75: C 54.28, H 4.79, N 6.66, 5 7.63;
found: C 54.15, H 4.78, N 6.54, S 7.64; Rf 0.62 (benzene-Et2O=l:l).

(4'R,5R,6S and 4'5,5S,6R) 6-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl) -2-methylpenem-3-carboxylic acid (Isomer C) ~ CH3 2/ C
C 0 2PNB o 2H

A solution of (4'R,5R,6S and 4'S,5S,6R) p-nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4-yl)-2-methylpenem-3-carboxylate (Isomer C) (195 mg, 0.464 mmol) in THF (20 ml) was mixed with Et2O
(20 ml), H2O (20 ml), NaHCO3 (39 mg, 0.46 mmol) and 10% Pd-C (200 mg, Engelhard). This mixture was hydrogenated at 35 psi for 4 h at room temperature. After removal of the catalyst (over Celite), the aqueous layer was washed with EtOAc (x2), saturated with NaCl, acidified with lN HCl (0.47 ml) and immediately extracted with EtOAc (20 ml x 3).
The extracts washed with brine were dried (Na2SO4) and evaporated yielding 94 mg of yellowish solid which was rinsed with pentane to give 89 mg (0.31 mmol, yield 67%) of the title compound as yellowish solid: mp 132-3C; Rf 0.60 (Acetone: HOAc=5: 0.7); IHmr (CDCl3) ~:
1.37, 1.43 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH3), 3.9-4.6 (4H, m, H-6, H-4' and H-5') and 5.59 ppm (lH, d, J=1.7 Hz, H-5); ir (nujol) V : _ 1760 (~-lactam) and 1660 cm (CO2H); uv (EtOH) ~ : 309 (E 6300) and 263 m~ (~ 3800).
- 2 9'~-6~i6'1 Example ~
(4'S,5R,6S and 4'R,5S,6R) 6-(2'~2'-Dimethyl-1',3'-dioxolan-4'-yl)-2-methyl~enem-3-carboxylic Acid (Isomer B) 7~
~""~S\

(4'5,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer B) o ~N ~ / NaN~ O ~ Tr / ~<

~( The title compound was prepared as described in Example~t~5 for the "Iso~er C" from t4ls~3s~4R and 4'R,3R,4S) l-(t-butyl-dimethylsilyl)-3-(2',2'-dimethyl-1',3'-dioxolan-3'-yl)-4-trityl-thio-2-azetidinone tIsomer B) (14.4 g, 25.8 mmol): yield 10.8 g, 24-3 mmol, 94.1%; mp 15SC (CH2C12-Et2O); Rf 0.24 (hexanes:
EtOAc=2:1); Hmr (CDC13) : 1.37, 1.40 (6H, 2s, di-Me), 3.23 (lH, dd, J3-4=2.5 Hz, J3 4,=5Hz, H-3), 3.7-4.5 (4H, m, H-4',H-5',N-H), 4.50 (lH, d, J=2.5Hz, H-4) and 7.1-7.6 ppm (lSH, m, aromatic Hs);
ir (nujol) 3170 (NH) and 1745 cm (C=O); Anal. calcd for C27H27NO3S:
C 72.78, H 6.11, N 3.14, S 7.20; found: C 72.16, H 6.11, N 3.14, S 7.17.

-2~9 -~36~

(4'S,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2") (Isomer B) CIHO O

N ~H Et3N/THF

The title compound was prepared as described in Example 103 for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-4-tritylthio-2-azetidinone (Isomer B) (10.8 g, 24.3 mmol): yield 15.8 g, 24.1 mmol, 99.3%); yellowish foam; Rf 0.29 and 0.22 (benzene: Et2O+l:l); IHmr (CDC13) ~: 1.28, 1.34 (2s, di-Me), 3.4-4.4 (m, H-3, H-4',H-5', H-2",0H), 4.39, 4.53 (2d, J=2Hz, H-4), 5.15, 5.25 (2s, OCH2Ar) and 7.1-8.3 ppm (m, aromatic Hs); ir (neat) V : 3440 (br, OH), 1760 (C=O), 1520, 1350 cm (NO2).

(4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (mixture of epimers at C-2") (Isomer B) ~ STr SOC12-pyr ~ ~ STr ~ THF

The title compound was prepared as described in Example 103 for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-1',3'-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-hydroxy-2"-acetate)-4-tritylthio-2-azetidinone (Isomer B) ~14.9 g, 22.8 mmol; mixture of qO ~

~ 2~6~i6~l epimers at C-2"); yield 14.1 g, 20.9 mmol, 91.9%; yellowish foam;
Rf 0.52 (benzene: Et20=3:2); IHmr (CDC13) ~: 1.30, 1.38 (6H, 2s, di-Me), 3.4-4.5 (4H, m, H-3, H-4',H-5'), 4.57 (lH, d, J=3Hz, H-4), 5.13 (s, H-2"), 5.27 (s, OCH2Ar) and 7.1-8.3 ppm (19H, m, aromatic Hs);
ir (neat) v x 1780 cm (3-lactam, ester).

(4'S,3S,4R and 4'R,3R,45) 3-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-triphenylphosphoranilidene-2"-acetate)-4-tritylthio-2-azetidinone (Isomer B) ST~ dlox. ~N ~Sf~3 The title compound was prepared as described in Example 103 for the "Isomer C" from (4'5,35,4R and 3'R,3R,45) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-chloro-2"-acetate)-4-tritylthio-2-azetidinone (Isomer ~) (14.0 g, 20.8 mmol; mixture of epimers at C-2"): yield 4.64 g, 5.16 mmol, 24.89s; mp 190-95C (dec., CH2C12-Et20); IHmr (CDC13) 0: 1.12, 1.20, 1.27, 1.35 (4s, di-Me) and 7.0-8.1 ppm (m, aromatic Hs); ir (CH2C12) vmax: 1750 cm (~-lactam ester); Anal. calcd for C54H47N2O7PS: C 72.14, H 5.27, N 3.12, S 3.57 found: C 71.90, H 5.57, N 3.07, S 3.56; Rf 0.21 (benzene: Et2O=l:l).

_2,ql ~

i~36~;61 l4' S 3S 4R and 4'_R.3S.4R) Silver 3-~2' 2' -dimethyl~ ' -dioxol~n -4' -yl)-l-(p-nitrobenzyl 2"-triDhenyl~hosl~hQranyli~,ene -2"-acetate)2-azetidinone-4-thiolate (Isomer B) STr AgNOl-pyr 7~g ~Ag O N ~P~3 MeOH o ~ 3 Co2PNE3 2 The title compound was prepared a6 de6cribed in Example 51 15 for the "Isomer C" from (4' S, 3S,4R and 4' R, 3S,4R) 3-(2', 2' -dimethyl-1',3' -dioxolan-4' -yl)-l-(p-nitrobenzyl 2"-triphenyl-phosphoranylidene-2"-acetate) -4-tritylthio-2-azetidinone (Isomer B) (1. 00 g, 1. 12 mmol):
yield 580 mg, O. 760 mmol, 67. 8%; mp 129-135C (dec); ir (nujol) 20 Vmax: 1745 cm~1 (B-lactam, ester).

(4' S.3S.4R and~ R.3R.4S) 3-~2'.2' -Dimç~hyl-1' 3' -dioxolan -4' -yll-1-(p-nitrobenzyl 2"-tri~henyl;~hQ~pht ranylidene-2"
-aceta~)-4-acetylthio-2-azetidinone (Isome~

0~ ~3 3 ~ ~
C02PNB 02P~8 The title compound was prepared as described in Example 51 for the "Isomer C" from (4' S, 3S, 4R and 4' R, 3R, 4S) silver 3-(2', 2' -dimethyl-l', 3' -dioxolan-4~ -yl)-1-(p-nitrobenzyl 35 2"-triphenylphosphoranylidene-2"-acetate)-2-azetidinone -4-thiolate (Isomer B) (2. 46 g, 3 22 mmol): yield after purification by column chromatography (SiO2 '~

~.2~6~i6~

32 g, eluent lO~-50~ EtOAc in CH2Cl2=l:l); IHmr (CDC13) ~: 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 (2s, SAc) and 7.3-8.3 ppm (m, aromatic Hs);
ir (neat) V a 1755 (~-lactam, ester) and 1695 cm (thioester).

(4'S,5R,65 and 4'R,55,6R) p-Nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer B) 3 0 ~ ~
O PNB

The title compound was prepared as described in Example 103 for the "Isomer C" from (4'S,35,4R and 4'R,3R,45) 3-(2',2'-dimethyl-1', 3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (200 mg, 0.286 mmol):
yield 64 mg, 0.15 mmol, 53~; mp 151-2C (CH2C12/Et20); Rf 0.67 (benzene:
Et20=1:1); IHmr (CDC13) ~: 1.29, 1.38 (6H, 2s, di-Me), 2.30 (3H, s, 2-CH3), 3.6-4.4 (4H, m, H-6, H-4',H-5'), 5.00-5.18-5.28-5.46 (4H, ABq, -OCH2Ar), 5.47 (lH, d, J=l.SHz, H-5) and 7.42-7.55-8.05-8.15 ppm (4H, A2'B2', aromatic Hs); ir (neat) V : 1785 cm (~-lactam) and 1710 cm (ester); uv (EtOH) ~ a : 266 (~ 13,300) and 314 m~ (~ 9,700); Anal. calcd ClgH20N2075: C 54.28, H 4.79, N 6.66, S 7.63; found: C 54.00, H 4.75, N 6.68, S 7.61.

~ ~ ~ 3 ~

6~i6~

(4'5,5R,6S and 4'R,5S,6R) 6-(2',2'-Dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-carboxylic acid (Isomer B) ~ ~ ~ H2/Pd-C ~ ~ H3 The title compound was prepared as described in Example 103 for the "Isomer C: from (4'S,5R,65 and 4'R,55,6R) p-nitrobenzyl 6-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-2-methylpenem-3-carboxylate (Isomer B) (79 mg, 0.19 mmol): yield a~ter recrystallization from CH2C12-pentane 9 mg, 0.032 mmol, 17~; Rf 0.54 (Acetone: HCAc=5:0.5);
lHmr (CDC13) o: 1.35, 1.44 (6H, 2s, di-Me), 2.37 (3H, s, 2-CH3), 3.6-4.5 (4H, m, H-6, H-4',H-5') and 5.56 ppm (lH, brs, H-5); ir (neat) V
1785 cm (3-lactam); uv (EtOH) ~ a : 307 (~ 4300) and 262 m~ (~ 3700).

~3 Example ~

(l'R,5R,6S and l'S,5S~6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2-ethyl)-2-methylpenem-3-carboxylic acid (Isomer C) OH

0 ""~ 5 N ~ 3 (l'R,35,4R and 1'5,3R,4S) 3-(1',2'-dihydroxyethyl)-1-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) Ac H ~ ' SAc \~ - ~ TFA-H2O ~

O ~ ~

A solution of (4'R,3S,4R and 4'S,3R,45) 3-(2',2'-dimethyl-1',3'-dioxolan-4'-yl)-1-(p-nitrobenzyl 2"-triphenylphos--2 9~`

~X~36~61~

phoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (472 mg, 0.676 mmol) in trifluoroacetic acid (1.0 ml) and H2O (0.1 ml) was left at room temperature for 30 min. The mixture was added dropwise to a cold solution of NaHCO3 (2.5 g) in H2O (50 ml) and extracted with CH2C12 (20 ml x 3). The extracts washed with sat.
NaHCO3 and then brine were dried (Na2SO4) and evaporated yielding 458 mg (0.695 mmol, crude yield 100%; purity 97.3%) of the crude title compound as yellowish foam: IHmr (CDC13) ~: 2.20, 2.32 (2s, SAc) and 7.2-8.3 ppm (m, aromatic Hs); ir (neat) v : 3420 (OH), 1745 (~-lactam, ester) and 1690 cm 1 (thioester); Rf 0.16 OEtOAc).

(l'R,35,4R and l'S,3R,4S) 3-(1'-Hydroxy-2'-methoxymethoxy-1'-ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetyl-thio-2-azetidinone (Isomer C) OH
OH
HO J ~", ~ SAc BrCH20CH3-dimethylaniline ~ ~"--~ SAc N ~ P~3 CH2C12 o N ~ P~3 To a solution of (l'R,3S,4R and l'S,3R,4S) 3-(1',2'-dihydroxyethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (291 mg, 0.430 mmol;
purity 97.3%) and bromomethylmethylether (55.2 mg, 0.442 mmol; 4 drops) in CH2C12 (8 ml) was added at 0C, N,N'-dimethylaniline (58.8 mg, 0.483 mmol;
5 drops) and the mixture was stirred at room temperature for 20 h. Addi-tional bromomethylmethylether (2 drops) and N,N'-dimethylaniline (2 drops) were added and it was stirred for another 4 h. The mixture diluted with CH2C12 was washed successively with lN HCl, sat. NaHCO3 and brine, dried (Na2SO4) and evaporated. The crude residue was purified by hplC (SiO2, eluent EtOAc) collecting (31 mg, 0.186 mmol, yield 42.2%) of the title compound as an oil: Rf 0.24 (EtOAc); IHmr (CDC13) ~: 2.20, 2.32 (2s, SAc), 3.30 (s, OCH3), 4.52 (s,-OCH2O-) and 7.4-8.3 ppm (m, aromatic Hs); ir (neat) v : 3420 (OH), 1755 (br, ~-lactam and ester) and 1690 cm (thioester).

36~6~

l'R,5R,6S and l'S,5S,6R) p-Nitrobenzyl 6-(1'-hydroxy-2'-methoxy-methoxy-2'-ethyl)-2-methylpenem-3-carboxylate OH
PH SAc /o~o~ ~ S
toluene ~ 2 A solution of (l'R,3S,4R and l'S,3R,45) 3-(1'-hydroxy-2'-methoxymethoxy-1'-ethyl)-1-(p-nitrobenzyl 2"-triphenylphosphora-nylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer C) (167 mg, 0.238 mmol) in toluene (30 ml) was heated at reflux under N2 for 8 h.
Evaporation of the solvent in vacuo gave oily residue which was purified by hplc (SiO2, eluent EtOAc) to give 68 mg (0.16 mmol, yield 67~) of the title compound as an oil: Rf 0.61 OEtOAc), 0.15 (benzene: Et2O=l:l);
lHmr (CDC13) ~: 2.38 (3H, s, 2-CH3), 3.35 (lH, br, OH), 3.40 (3H, s, OCH3), 3 6-3.8 (2H, m, H-2'), 3.90 (lH, dd, J6_5=2Hz, J6-1' 4Hz, H 6), (lH, m, H-l'), 4.67 (2H, s, -OCH20-), 5.03-5.27-5.38-5.62 (ZH, ABq, OCH2Ar), 5.65 (lH, d, J=2Hz, H-5) and 7.55-7.70-8.15-8.30 ppm (4H, A2'B2', aromatic Hs)i ir (neat) V : 3450 (OH), 1785 (~-lactam), 1710 (ester) and 1520 cm (NO2); uv (EtOH) ~ : 266 (~ 13000) and 313 m~ (~ 9100)i Anal. calcd for C18H20N2O8S: C 50.94, H 4.75, N 6.60; found: C 51.13, H 4.77, N 6.36.

_2.96, ~

~ ~r:3~:i66~

(l'R,5R,6S and l'S,5S,6R) 6-(1'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2-meth 1 enem-3-carbox lic acid (Isomer C) Y P Y

OH OH
~ CH3 A solution of (l'R,5R,6S and l'S,5S,6R) p-nitrobenzyl 6-(1'-hydroxy-2'-methoxymethoxy-2'-ethyl)-2-methylpenem-3-carboxylate (Isomer C) (51 mg, 0.12 mmol) in THF (10 ml) was mixed with Et2O
(10 ml), H2O (10 ml), NaHCO3 (10 mg, 0.12 mmol) and 10% Pd-C (50 mg;
Engelhard). It was hydrogenated at room temperature at 32 psi for 3 h. After filtration of the catalyst over Celite, the aqueous layer separated was washed with Et2O (x 3) and saturated with NaCl.
The aqueous phase acidified at 0C with 0.lN HC1 (1.2 ml) was immediately extracted with EtOAc (15ml x 3). The extracts were washed with brine, dried (Na2SO4) and evaporated yielding 22 mg of yellowish solid which was rinsed with a small amount of Et2O to give 20 mg (0.069 mmol, yield 58%) of the title compound as slightly yellow solid:
1Hmr (DMSO-d6) ~: 2.28 (3H, s, 2-CH3), 3.27 (3H, s, OCH3), 3.49(2H, d, J=6 2HZ, 2~-H), 3.87 (lH, dd~ J6-5 1-7Hz~ 6-1~
(2H, s, -OCH2O-) and 5.55 ppm (lH, d, J=1.7 Hz, 5-H); ir (KBr) ~ :
3410 (OH), 1755 (~-lactam) and 1655 cm (CO2H); uv (EtOH) ~ :
308 (~ 6800) and 262 m~ (~ 4200), mp 137-8C (dec.).

--2q7-36~
Exam~le 54 1'S 5R 6S and l'R.5S~6R) 6-(l'-Hydr~ 2'-methoxymQthQxY
-2'-ethyl)-2-methylpenem-3-carboxylic acid (Isomer B!

,OH
~O~ .,~S~

1 0 ~

(l'S 3S.4R and l'R.3R.4S) 3-(l'.2'-dihydroxyethyl) -l-(p-nitrobenzyl 2"-triphenyl~ho6~hQra~ylidene-2"-acetate)-4-acetylthio-2-azetidinone _(ISQmer Bl OH
(V r_fAc HF-H;~O ~J~SAC

o~ N ~p~3 N ~p~3 The title compound was prepared as described in Example 53 for the "Isomer C" from (4'S,3S,4R and 4'R,3R,4S) 3-(2',2'-dimethyl-l',3'-dioxolan-4'-yl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylldene-2"acetate)-4-acetylthio -2-azetidinone (Isomer B) (1.03 g, 1.47 mmol): yield 970 mg, 1.47 mmol, 100%; yellowish foam: 1Hmr (CDC13) ~: 2.20, 2.32 (2s, -SAc) and 7.3-8.2 ppm (m, aromatic Hs); ir (neat) v max: 3410 (OH), 1750 (B-lactam, ester) and 1690 cm~1 (thioester): Rf 0.16 (EtOAc).

... ...
~....~
, , ~

~!36~

(l'S,35,4R and l'R,3R,45) 3~ HvdroxY-2~-methoxymethoxy-l~-ethyl)-1-(p-nitrobenzYl 2"-triPhenylphosphoranylidene-2"-acetate)-4-acetYl-thio-2-azetidinone (Isomer,B) OH OH
~ ~........ SAc ~ O ~ "" J SAc " ~ BrCH2OCH3/dimethylaniline l l O~ - N ~ P~3 CH2C12 ~ N ~ p~3 The title compound was prepared as described la Exa~.~d~
for the "Isomer C" from (1's,3S,4R and l'R,3R,4S) 3-(1',2'-dihydroxy-ethyl)-l-(p-nitrobenzyl 2"-triphenylphosphoranylidene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (485 mg, 0.736 mmol): yield 205 mg, 0.292 mmol, 39.6~; oil: IHmr (CDC13) ~: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH3), 4.57 (s,-OCH2O-) and 7.2-8.3 ppm (m, aromatic H~

ir (neat) ~ : 3420 (OH), 1755 (~-lactam, ester) and 1690 (thioester) Rf 0.32 (EtO~c ) .

(l'S,5R,6S and l'R,5S,6R) p-Nitrobenzyl 6-(l'-hydroxY-l~-meth methoxy-2'-ethyl)-2-methylpenem-3-carboxylate OH QH
O ~ ." ~ SAC ~O ~
toluene-HR ~ ~ ~ CH3 ~02PNB O2PNB
The title compound was prepared as described in Ex~3p`c for the "Isomer C" from (l'S,3S,4R and l'R,3R,4S) 3-(1'-hydroxy-2'-methoxymethoxy-l'-ethyl~-l-(p-nitrobenzyl 2"-triphenylphosphoranyl-idene-2"-acetate)-4-acetylthio-2-azetidinone (Isomer B) (205 ms, 0.292 mmol) and hydroquinone (10 mg, 0.09 mmol): yield 38 mg, 0.090 mmol, 31~; 152-4C; Rf 0.23 (benzene: Et20=1:1); ~Hmr (C~C13) ~:

2.37 (3H, s, 2-CH3), 3.40 (3H, s, OCH3), 3.4-3.9 (3H, m, H-6, H-2"), 1~36~6~L
~.15 (lH, M, H-l'), 4.67 (2H, 8, -OCH20-), 5. 10-5. 27-5.39-5.56 (2H, ABq, -OCH2Ar), 5.67 (lH, d, J=l.S Hz, H-S) and 5.55-5.16-8.15-8.27 ppm (4H, A2'B2', aromatic H3); ir (CH2C12 mull) vmax : 3370 (OH), 1785 (B-lactam) and 1700 cm~1 (ester);
uv (THF-EtOH=1:1) Amax: 265 (~ 10400) and 314 m~ (~ 7800).

(l'S.SR,6S and 1'R.5S.6R) 6-(l'-Hydroxy-2'-methoxymethoxy-2'-ethyl)-2-methylpenem-3-carboxylic acid (Isomer B) OH OH

J'C~ CH H 2/Pd-C ~ ~J=

02P~B co2 The title compound was prepared as described in Example 53 for the "Isomer C" from (1'S,5R,6S and l'R,5S,6R) p-nitrobenzyl 6-(1'-hydroxy-2'-methoxymethoxy-2'-ethyl) -2-methylpenem -3-carboxylate (Isomer B) (36 mg, 0.085 mmol): yield 7.5 mg, 0.026 mmol, 30%; yellowish crystals; lHmr (CDC13) ~ : 2.36 (3H, s, 2-CH3), 3.39 (3H, 3, OCH3), 3.6-3.9 (3H, m, H-6, H-2'), 4.15 (lH, m, H-l'), 4.66 (2H, s, OCH20) and 5.67 ppm (lH, d, J=1.4 Hz, H-5); ir tCH2C12)VmaX: 1785 (B-lactam) and 1675 cm 1 (CO2H); uv (EtOH) max: 308 (~ 2900) and 263 m~ (F 2900) ~,~

~t~6 5~
Example ~
2-Benzimidoylaminomethylpenem-3-carboxylic ACid COOH

A. ~ 2 ~ H2C02Na + (COC1)2 2 2 > ~ 2 ~ H2COC-(I) (II) To a suspension of 0.38 g (0.0015 mole) of sodium 3-benzyl-1,2,~-oxadiazol-5-one-4-aCetate (I)l in 10 ml of methyl chloride, containing 2 drops of DMF~ was addedat room temperature 0.13 ml (0.0015 mole) of oxalyl chloride, causing the mixture to effervesce. The reaction mixture was stirred at room temperature for 1 hour.The NaCl that had formed was removed by filtration and the filter cake was washed with several small portions Of methylene chloride. The solution of acid chloride (II), was used directly.
1. K. Takacs and K. Harsanyi, Ber. 103~ 2330 (1970).

B. (II) ~ ~ 03 pyridine 0~ ~ ~ ~ ~ 2 (III) (IV) A solution of 1.0 g ~0.0015 mole) of (III) and 0.12 ml (0.015 mole) of pyridine in 10 ml of methylene chloride under a nitrogen atmosphere was cooled to ~. The acid chloride (II) solution was added all at once to the solution of (III) and the reaCtion mixture was stirred at ~ for 5 minutes~ then at room temperature for 1.5 hrs. A thick precipitate formed in the reaction mixture. The mixture was filtered and the filtrate diluted with methylene chloride to a volume to 70-90 ml . The organic phase was then washed successively with 70 ml of O.lN hydro-chloric acid, 80 ml of 1% sodium bicarbonate and 80 ml of water. The methylene chloride phase was dried over magnesium sulfate. The solvent was removed at ~ Xr~6~

reduced pressure and the residual oil chromatographed on Mallinckrodt "SILIC AR CC-7"*silica gel using chloroform as the eluant, giving 0.4 g (30.5%) of (IV) as an oil. The infrared and nuclear magnetic resonance spectra were consistent for (IV).
toluene ~ ~ ~ ~ CH

2~
(V) A solution of 0.4 g (0.00045 mole) of IV in 50 ml of toluene was lQ heated at reflux for 4 hrs. The solvent was removed at reduced pressure and the residue chromatographed on Mallinckrodt~SILICAR
CC-7'~* silica gel, using 5% ethyl acetate in methylene chloride as eluant, affording 0.15 g (66.6%) of V as an oil which solidified. The infrared and nuclear magnetic resonance spectra were consistent for V.
Anal. Calcd for C23 H 18N407S: C, 55-86; H, 3.67; N, 11.33.
Found: C, 56.17; H, 3.76; N, 11.23.

loZ Pd/C ~ ~ 2 2~
A solution of 0.135 g (0.00027 mole) of V in 40 ml of tetrahydrofuran and 40 ml of anhydrous diethyl ether was added to a slurry of 10% palladium on carbon catalyst in 40 ml of water under a nitrogen atmosphere. The resultant mixture was hydrogenated in a Parr hydrogenation apparatus at room temperature at an initial hydrogen pressure of 52 psi for 3.5 hrs. Hydrogen uptake was 4.5 psi. The catalyst was removed by filtration, washing the filter pad well with water. Additional diethyl ether was added to the filtrate and the phases were separated. The aqueous phase was extracted 3x with diethyl ether.
The aqueous phase was then concentrated to dryness at reduced pressure. The residue was chromatographed, using the high pressure liquid chromatography technique, to afford 0.050 g (58%) of the title penem acid; decomp 156-173. The infrared and nuclear *Trade Mark ~f~
magnetic resonance spectra were consistent for the desired product.
Anal. Calcd for C15H15N303S~1.5H20: C, 52.31; H, 5.27; N, 12.20.
Found: C, 51-64; H, 4.95; N, 12.31.
Example 56 2-Phenylimidoylaminomethylpenem-3-carboxylic Acid ~ CH2-NH-C

COOH

Following the procedure of Example 55 but using an equimolar amount of sodium 3-phenyl-1,2,4-oxadiazol-5--one-4-acetate as the starting material in place of the sodium 3-benzyl-1,2,4-oxadiazol-5-one-4-acetate used therein, there was produced the title product.
Bioloaical Data Representative compounds of the present invention were subjected to in vitro antibiotic screening against a variety of microorganisms. Samples of the indicated compounds after solution in water and dilution with Nutrient Broth were found to exhibit the following Minimum Inhibitory Concentration (MIC) in mcg./ml. versus the indicated microorganisms as determined by overnight incubation at 37C. by the tube dilution method.

6~61 M.I.C. in mcg/ml Compoun~d L~x~m~lQ N~-L
Orqanism Streptococcus pneumoniae 125 Streptococcus pyogenes >125 Staphylococcus aureus 10 Staph aureus +50% 8 Serum A9537 Staphylococcus aureus 32 Staphylococcus aureus 4 Streptococcus faecalis 125 Escherichia coli 8 20 Escherichia coli 2 Klebsiella pneumoniae 125 Klebsiella species 4 Proteus mirabilis 8 Proteus mirabilis 63 30 Proteus morganii 63 Proteus rettgeri 32 Serratia marcescens 63 Enterobacter cloacae 16 Enterobacter cloacae 16 40 Pseudomonas aeruginosa 125 Pseudomonas aeruginosa >125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis . . .

~ ~r~6~61 M.I.C. in mcg/m1 ComDound (ExamDle No.
5Organism 2 3 Streptococcus pneumoniae Streptococcus pyogenes 2 4 10 Staphylococcus aureus 8 2 Stapn aureus +50% >63 >63 Serum A9537 Staphylococcus aureus 4 4 Staphylococcus aureus 8 32 Streptococcus faecalis 63 125 20 Escherichia coli 32 63 Bscherichia coli 32 63 Klebsiella pneumoniae 63 125 Klebsiella species >125 >125 Proteus mirabilis 63 63 30 Proteus vulgaris 63 32 Proteus morganii 63 125 Providencia stuartii 32 63 Serratia marcescens 125 63 Enterobacter cloacae 125 125 40 Enterobacter cloacae >125 125 Pseudomonas aeruginosa >125 >125 Pseudomonas aeruginosa >125 >125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis ~! r ~36~1 M.I.C. in mcq/ml Com~ound (Exam~le No.) 5Organism 4 5 Streptococcus pneumoniae 1 .5 Streptococcus pyogenes 4 4 10 Staphylococcus aureus 8 4 Staph aureus +50% >63 >63 Serum A9537 Staphylococcus aureus 4 9 Staphylococcus aureus 125 63 Streptococcus faecalis 125 125 20Escherichia coli >126 63 Escherichia coli >125 125 Klebsiella pneumoniae >125 63 Xlebsiella species >125 >125 Proteus mirabilis 63 63 30 Proteus vulgaris 63 32 Proteus morganii 125 125 Providencia stuartii 125 32 Serratia marcescens >125 63 Enterobacter cloacae >125 125 40 Enterobacter cloacae >125 125 Pseudomonas aeruginosa - >125 Pseudomonas aeruginosa - >125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis M l.C. in mc~/ml ComPound (Example No.) Or~anism 11(5) 11(6) Streptococcus pneumoniae Streptococcus pyogenes P~9604 2 4 Staphylococcus aureus Staph aureus +50~
Serum A9537 32 63 Staphylococcus aureus Staphylococcus aureus StreptococCus faecalis A20688 >63 125 Escherichia coli AlSll9 16 16 Escherichia coli A20341 - 1 >63 125 Klebsiella pneumoniae Xle~siella species A20468 > 63 > 125 Proteus mirabilis Proteus vulgaris Proteus morganii Proteus rettgeri Serratia marcescens Enterobacter cloacae A965g 63 63 Enterobacter cloacae Pseuaomonas aeruginosa ~21213 32 > ~2 5 Hemophilus influenzae Haemop~ilus influenzae ~21522 Bacteroides fragilis Bacteroides fragilis ^37~

lXJ~6~61 M.I.C. in mcg/ml CompQund (Example No.) Organism 12 Streptococcus pneumoniae .016 Sreptococcus pyogenes .06 10 Staphylococcus aureus .13 Staph aureus +50% 4 Serum A9537 Staphylococcus aureus 8 Staphylococcus aureus 125 Streptococcus faecalis 63 20 Escherichia coli .5 Escherichia coli 63 Klebsiella pneumoniae 8 Klebsiella species >125 Proteus mirabilis Proteus vulgaris Proteus morganii Proteus rettgeri 2 Serratia marcescens Enterobacter cloacae 2 Enterobacter cloacae Pseudomonas aeruginosa Pseudomonas aeruginosa 125 Haemophilus influenzae 125 Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis 6~1 M.I.C, in rncq/ml Compound (Example No.) Orqanism 32 18 24 Streptococcus pneumoniae .25 .25 .016 Streptococcus pyogenes 8 2 .25 Staphylococcus aureus 8 4 .03 Staph aureus +50~ 32 63 63 Serum A9537 Staphylococcus aureus 16 4 16 Staphylococcus aureus 63 16 >125 Streptococcus faecalis~i25 125 16 Escherichia coli 63 4 63 Escherichia coli >125 16 >125 ~lebsiella pneumoniae125 32 >125 Klebsiella species >125 125 >125 Proteus mirabilis 63 16 32 Proteus vulgaris 125 16 Proteus morganii 125 32 32 Proteus rettgeri 63 32 Serratia marcescens 63 32 16 Enterobacter cloacae 125 32 >125 Enterobacter cloacae 125 63 125 Pseudomonas aeruginosa125 125 ~125 Pseudomonas aeruginosa125 125 >125 Hemophilus influenzae - - -Haemophilus influenzae Bacteroides fragi lis - - -Bacteroides fragilis _3O~ -M I.C. in mcg/ml Compound ~Examole No.) Organism Pseudomonas aeruginosa - - _ Pseudomonas aeruginosa - _ _ Pseudomonas aeruginosa Proteus species Proteus mirabilis - _ 16 Providencia stuartii - - 63 lX~6~61 M.I.C. in meg/ml Compou~d (Exam~
5Organism 25 Streptocoeeus pnsumoniae 2 Streptocoeeus pyogenes 16 10 Staphylococcus aureus 32 Staph aureus +50% >63 Serum A9537 Staphyloeoccus aureus >125 Staphylococcus aureus >125 Streptococcus faecalis 125 20 Escherichia coli 63 Escheriehia coli >125 Klebsiella pneumoniae >125 Klebsiella species >125 Proteus mirabilis 63 Proteus vulgaris Proteus morganii 125 Proteus rettgeri 125 Serratia mareeseens >125 Enterobaeter eloaeae >125 40 Enterobaeter eloaeae >125 Pseudomonas aeruginosa 125 Pseudomonas aeruginosa 125 Hemophilus influenzae Haemophilus influenzae Baeteroides fragilis Baeteroides fragilis M.I.C. in mca/ml Compound (Example No.) organism 25 Pseudomonas aeruginosa PseudoNonas aeruginosa Pseudomonas aeruginosa Proteus species Proteus mirabilis 63 Proteus mirabilis M.I.C. in m~s~ml Compound (Example No.) 5Organism 31 Sreptococcus pneumoniae 63 Streptococcus pyogenes 125 10 Staphylococcus aureus 32 Staph aureus +50% 32 Serum A9537 Staphylococcus aureus >125 Staphylococcus aureus 63 Streptococcus faecalis 63 20 Escherichia coli 63 Escherichia coli 32 Klebsiella pneumoniae >125 Klebsiella species 63 Proteus mirabilis 125 30 Proteus vulgaris >125 Proteus morganii 125 Proteus rettgeri 125 Serratia marcescens 125 Enterobacter cloacae 125 40 Enterobacter cloacae 32 Pseudomonas aeruginosa 125 Pseudomonas aeruginosa 125 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis :

6~

M.I.C. in mcq/ml Compound (Example No.) 5Organism 33 34 Streptococcus pneumoniae .06 .25 Streptococcus pyogenes .13 2 10 Staphylococcus aureus 1 4 Staph aureus +50~ 16 63 Serum A9537 Staphylococcus aureus 125 4 Staphylococcus aureus >125 16 Streptococcus faecalis 125 125 20 Escherichia coli 16 4 Escherichia coli >125 16 Klebsiella pneumoniae 125 32 Klebsiella species >125 125 Proteus mirabilis 8 16 30 Proteus vulgaris 63 16 Proteus morganii 32 32 Proteus rettgeri 16 32 Serratia marcescens 63 32 Enterobacter cloacae 125 32 40 Enterobacter cloacae 63 63 Pseudomonas aeruginosa 125 125 Pseudomonas aeruginosa 125 125 Hemophilus influenzae - -Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis 6~

M.I.C. in mcg/ml Compound (Example No.) 5 ~ Organi 5 m _35_ 36. 40 Streptococcus pneumoniae 32 .25 .004 A9585 32 .25 .008 Streptococcus pyogenes125 1 .004 A9604 125 1 .004 10 Staphylococcus aureus - - .008 A9537 >125 2 .008 Staph aureus +50% - - .06 Serum A9537 >63 8 .06 Staphylococcus aureus - - .06 A9606 >125 4 .06 Staphylococcus aureus - - .06 A15097 >125 8 .25 Streptococcus faecalis>125 63 .5 A20688 >125 63 .5 20 Escherichia coli >125 16 .13 A15119 >125 16 .25 Escherichia coli >125 16 <.25 A20341-1 >125 16 .13 Klebsiella pneumoniae>125 16 <.25 A15130 >125 16 .5 Klebsiella species >125 16 .5 A20468 >125 16 .5 Proteus mirabilis >125 32 <.25 A9900 >125 16 .25 30 Proteus vulgaris >125 16 <.25 A21559 >125 16 .25 Proteus morganii >125 32 A15153 >125 16 Proteus rettgeri >125 16 <.25 A21203 >125 16 .5 Serratia marcescens >125 16 .5 A20019 >125 16 .5 Enterobacter cloacae>125 32 4 A9659 >125 - 2 40 Enterobacter cloacae>125 16 .5 A9656 >125 - .5 Pseudomonas aeruginosa>125 >125 16 A9843A >125 - 16 Pseudomonas aeruginosa>125 >125 125 A21213 >125 - 63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis P,~

~36~

M.I.C. in mcg/ml ComPound lExample No.) Orqanism 37 38 39 Streptococcus pneumoniae A9585 03 03 .016 Streptococcus pyogenes .06 .5 .03 Staphylococcus aureus A9537 .5 .03 .06 Staph aureus +50%
Serum A9537 4 .25 .13 A9606 1 .25 .13 Staphylococcus aureus 2 .5 .25 Streptococcus faecalis 2 32 4 Escherichia coli AlSll9 2 8 Klebsiella pneumoniae 8 16 4 Xlebsiella species Proteus mirabilis Proteus vulgaris 4 2 2 Prote~s morganii Serratia marcescens 8 16 4 Enterobacter cloacae Pseudomonas aeruginosa He~ophilus influenzae ~833 ~ae~ophilus influenzae Bacteroides fragilis ~20931 Bacteroiacs fragilis A20929 _3~L-~ ~6'~6~L
M.I.C. in mcq/ml Compound (Example No.) 5organi6m 43 Sreptococcus pneumoniae >63 Streptococcus pyogenes >63 10 Staphylococcus aureus >63 Staph aureus +50% >32 Serum A9537 Staphylococcus aureus >63 Staphylococcus aureus >63 Streptococcus faecalis >63 20 Escherichia coli >63 Escherichia coli >63 Klebsiella pneumoniae >63 Klebsiella species >63 Proteus mirabilis >63 30 Proteus vulgaris >63 Proteus morganii >63 Proteus rettgeri >63 Serratia marcescens >63 Enterobacter cloacae >63 40 Enterobacter cloacae >63 Pseuaomonas aeruginosa >63 Pseudomonas aeruginosa >63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis :: $

~6~i61 M.I.C. in mcq~ml Compound ~Example No.
5Oraanism 45 Streptococcus pneumoniae 2 Streptococcus pyogenes 16 10 Staphylococcus aureus 32 Staph aureus +50% >32 Serum A9537 Staphylococcus aureus 2 Staphylococcus aureus 8 Streptococcus faecalis 63 20 Escherichia coli 2 Escherichia coli 32 Klebsiella pneumoniae 8 Klebsiella species >63 Proteus mirabilis 4 30 Proteus vulgaris 16 Proteus morganii 8 Proteus rettgeri 8 Serratia marcescens 8 Enterobacter cloacae 8 40 Enterobacter cloacae 8 Pseuaomonas aeruginosa 63 Pseudomonas aeruginosa >63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis ,~., ~.

~

M.I.C. in mcg/m~
Compound ~Example No~L
5Orq~nism 47 Streptococcus pneumoniae .S

Streptococcus pyogenes .5 10 Staphylococcus aureus 8 Staph aureus +50% 32 Serum A9537 Staphylococcus aureus 16 Staphylococcus aureus 32 Streptococcus faecalis >63 20 Escherichia coli 32 Escherichia coli 32 Klebsiella pneumoniae 63 Klebsiella species 63 Proteus mirabilis 32 30 Proteus vulgaris 32 Proteus morganii 63 Proteus rettgeri 32 Serratia marcescens 63 Enterobacter cloacae 63 40 Enterobacter cloacae 63 Pseuaomonas aeruginosa >63 Pseudomonas aeruginosa >63 Hemophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis .~

~ ,~r;~6661 M.I.C. in mc~/ml ComPound ~Example No.) Organism 4.8 49 50 streptocc~ccus pneumoniae>125 1 32 Strept cc~ccus pyogenes>125 16 32 Staphyloc~ccus aureus >125 32 125 Staph aureus +509c. >63 >63 >63 Serum A9537 Staphyl coccus aureus >125 32 >125 A 1509 7 > 125 > 125 > 125 A 206 88 > 125 > 125 > 125 A 15 119 > 125 > 125 > 125 A 20 341 - 1 > 125 > 125 > 125 A 15 130 > 125 > 125 > 125 A 2046 8 > 125 > 125 > 125 A9900 > 125 > 125 > 125 Proteus vulgaris >125 >125 >125 A15 15 3 > 125 > 125 > 125 Proteus rettgeri >125 >125 >125 Serratia marcescens >125 >125 >125 Enterobacter cloacae >125 ~125 >125 Enterobacter cloacae ~125 >125 >125 Pseudomonas aeruginosa>125 >125 >125 Pse domonas aeruginosa>125 >125 >125 He~ophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroi~cs fragilis A20929 _ 3,~o_ 1~6661 ComPound (Example No.) Orqanism 51 52 53 ~_ Streptococcus pneumonlae 63 16 4 32 Streptococcus pyogenes 63 32 4 32 Staphylococcus aureus >63 63 >8 - 63 staph aureus +50~ >32 >32 >32 >32 Staphylococcus aureus >63 63 63 >63 StaphylocoCcus aureus >63 63 >63 >63 Streptococcus faecalis >63 63 >63 >63 A15119 >63 >63 63 63 A20341-1 ~63 >63 63 63 A15130 >63 >63 63 >63 Klebsiella species >63 >63 >63 >63 A9900 63 >63 ~63 63 ProteUs vulgaris >63 >63 >63 >63 A15153 >63 >63 >63 >63 A21203 >63 63 32 63 Serratia marcescens >63 . >63 >63 63 A9659 >63 >63 63 >63 Enterobacter cloacae >63 >63 63 63 Pseudomonas aeruginosa 63 63 63 63 Pse domonas aeruginosa 63 63 63 63 Hemophilus influen~ae Haemophilus influenzae Bacteroides fragilis Bacteroi~es fragilis A20929 -32l-12~36661 M I.C. in mc~/ml Compound ~Exa~ple No.) Orqanism 55 56 Streptococcus pneumoniae A9585 .5 . 2 5 Streptococcus pyogenes A9604 .5 .25 Staphylococcus aureus A9537 .5 .25 Staph aureus ~509u Serum A9537 16 16 Staphylococcus aureus Staphylococcus aureus A15097 >63 >125 Streptococcus faecalis A20688 >63 125 Escherichia coli AlSll9 63 63 Escheri chia coli A20341-1 >63 >125 Klebsiella pneumoniae A15130 >63 125 Klebsiella species A20468 >63 >125 Proteus mirabilis Proteus vulaaris Proteus morganii Proteus rettgeri Serrati a marcescens Enterobacter cloacae A9659 >63 125 Enterobacter cloacae Pseudomonas aeruginosa Pseudomonas aeruginosa He3nophilus influenzae Haemophilus influenzae Bacteroides fragilis Bacteroides fragilis ~3Z~^

1~36~1 Representative compounds of the present invention were also tested in vivo in mice and their PD50 (dose of compound in mg/kg required to protect 50% of the treated mice against an otherwise lethal infection of a microorganism) values determined with respect to the test organisms shown below.

'i.,~

6~
S. aureus A9537 # of infecting organisms of S. aureus # of Treatment PD50 Compoun_ a 9537 _ _ treatments route (m ~kg/treatment Compound of Ex.65 7.8 x 105 2 IM 0.12 Compound of Ex.36 6.6 x 105 2 IM 7.7 1~.36~

S. aureus A9537 # of infecting organisms of S. aureus # of Treatment PD50 Compound a 9537 treatments route (maJka/treatment Compound 10 of Ex.62 8.6 x 105 2 IM 1.0 Compound of Ex.56 8 x 105 2 IM >5 Compound of Ex.39 8 x 105 2 IM 0.04 12r`3~i6~

Mouse blood levels after intramuscular administration of representative compounds of the present invention were determined and are reported in the table below.

*Mouse Blood Levels in mcg/ml After intramuscular Administration of 40 mq/kq Body Weiqht Compound Minutes After Administration _ Compound of Ex. 4044.7 34.4 23.7 17.6 9.8 3.6 *Average of 6 mice , .~,~
. .

Claims (6)

1. A process for the preparation of a compound having the formula I

wherein Z is hydrogen or an easily removable ester protecting group; X is (a) in which n is an integer from 1 to 6;
(b) -(CH2)nNHOH in which n is an integer from 1 to 6;
(c) -(CH2)nPO(O-C1-C6 alkyl)2 in which n is an integer from 1 to 6;
(d) -(CH2)nNH-?-C1-C6 alkyl in which n is an integer from 1 to 6;
(e) in which n is an integer from 1 to 6;

(f) -(CH2)nO?(CH2)mNRARB in which n and m are each independently 1 or 2 and RA and RB are each independently hydrogen or (lower)alkyl; or (g) -(CH2)nNH?-RC in which n is an integer from 1 to 6 and RC is C1-C4 alkyl, phenyl or in which m is 1 or 2 , or (h) O(CH2)nORr in which n is an integer from 1 to 6 and Rr is a (lower) alkyl;
Y is hydrogen, ethyl or hydroxyethyl; or a pharmaceutically acceptable salt thereof, with the proviso that when Y is hydrogen, X may not be -CH2OCH2CH2OCH3;
which process comprises cyclizing a compound of the formula wherein Q is phenyl or (lower) alkyl, R" is an easily removable ester group and X and Y are as defined above in an inert organic solvent at a temperature of from just above room temperature to the reflux temperature of the solvent; removing the removable ester group and optionally, other protecting groups; and, if Y is hydrogen and when desired, converting the product to any other desired product where Y is not hydrogen by treating said product with a corresponding electrophile in an inert solvent in the presence of a strong base.
2. A process according to claim 1 wherein Y is hydrogen.
3. A process of claim 1 wherein Y is .alpha.-hydroxyethyl.
4. A compound having the formula I

wherein Z is hydrogen or an easily removable ester protecting group and wherein X is:

(a) in which n is an integer from 1 to 6;

(b) -(CH2)nNHOH in which n is an integer from 1 to 6;
(c) -(CH2)nPO(O-C1-C6 alkyl)2 in which n is an integer from 1 to 6;

(d) -(CH2)nNH-?-C1-C6 alkyl in which n is an integer from 1 to 6;

(e) in which n is an integer from 1 to 6;

(f) -(CH2)nO?(CH2)mNRARB in which n and m are each independently 1 or 2 and RA and RB are each independently hydrogen or (lower) alkyl; or (g) -(CH2)nNH?-RC in which n is an integer from 1 to 6 and RC is C1-C4 alkyl, phenyl or in which m is 1 or 2, or (h) O(CH2)nORr in which n is an integer from 1 to 6 and Rr is a (lower) alkyl;
Y is hydrogen, ethyl or hydroxyethyl; or a pharmaceutically acceptable salt thereof, with the proviso that when Y is hydrogen, X may not be -CH2OCH2CH2OCH3.
5. A compound according to formula I as defined by claim 4 wherein Y is hydrogen.
6. A compound according to formula I as defined by claim 4 wherein Y is .alpha.-hydroxyethyl.
CA000342069A 1978-12-18 1979-12-17 2,6-disubstituted penem compounds Expired - Fee Related CA1286661C (en)

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SE7910390L (en) 1981-06-18
SE8405813L (en) 1984-11-19
IE851853L (en) 1980-06-18
FI793903A (en) 1980-06-19
GR81420B (en) 1984-12-11
IL58804A0 (en) 1980-02-29
JPS60222486A (en) 1985-11-07
IE50597B1 (en) 1986-05-28
DK161520C (en) 1991-12-23
DK135291A (en) 1991-07-15
SE461395B (en) 1990-02-12
ZA796813B (en) 1981-05-27
DK161520B (en) 1991-07-15
YU276079A (en) 1983-02-28
IL58804A (en) 1986-03-31
CH643846A5 (en) 1984-06-29
CH643265A5 (en) 1984-05-30
YU43280B (en) 1989-06-30
FI69845C (en) 1986-05-26
DK135291D0 (en) 1991-07-15
SE8405719L (en) 1984-11-14
CA1268183A (en) 1990-04-24
AU557545B2 (en) 1986-12-24
AU541717B2 (en) 1985-01-17
ES487034A0 (en) 1980-12-16
SE454779B (en) 1988-05-30
DK237690D0 (en) 1990-10-01
SE448995B (en) 1987-03-30
DK236590D0 (en) 1990-10-01
IE49877B1 (en) 1986-01-08
FI69845B (en) 1985-12-31
IE852246L (en) 1980-06-18
SE8405812L (en) 1984-11-19
AU5378779A (en) 1980-08-28
SE8405719D0 (en) 1984-11-14
DK533779A (en) 1980-06-19

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