LU81998A1 - ANTIBACTERIAL AGENTS - Google Patents

Description

SA Λ Λ Λ GRAND'DUCHÉ DE LUXEMBOURG ° * 5ο * ^ 45 ^ ...... I ..... y ...... y ο - / / ϊ du l? ---- 46ceg> bre ..... 1979 $ 300¾ Minister -JJÊ.

....... m 4 t) ni · rgjjn ^ of the National Economy and the Middle Classes "t! Title issued: .............. IJUIL.I980 g "Serves" the toduetridle Property, ,, Æ, J LUXEMBOURG _ ·,. , / f 1 '^ i ï. I fit *** I Patent Application | V: »----------------------------------------------- ---------------------------------------------------------- ---------------------------------------------------------- -------, /he

? leew “e umi'PMD & I

I The company known as: BRISTOL-MYERS COMPANY, 345 Park Avflfojfép H {y i NEW YORK. New York loo22, United States of America, represented ______ by Mr. Jacques de Muyser acting as ___________________ Φ agent ....... ..................... .................................................. .................................................. ..................................

drop off ........ this ........ di.Xr.S.ept .... ^ écem33r.e ..... 19.QQ ..... S.Qi. xmt.Srâi.X-ae.lôf .................. (3) to ............. 1.? ... ......... hours, at the Ministry of National Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent for an invention concerning: "Antibacterial agents". i4) i ............................................... .................................................. ................................................:. .................................................. .................................................. ................................. (5) 2. the delegation of power, dated ----- ---------------------- the '3. description in language ________ ™? .® ............... ..................... of the invention in two copies; 4 ........... LL · ...... .. drawing boards, in two copies; 5. the receipt of the taxes paid to the Luxembourg Registration Office, December 17, 1979 ^ _ _________________________________________________________________ 4 ...... .................... .................................................

X claims for the above patent application the priority of one (s) application (s) of ^ 1 (6) ........................ ..Patent __________________________________________ registered® e / (7) * mfr ~ Sfeafe8 'üiits d * Amégjbgee ie ......... i8- “d <eombi? E 1970 (Net 9G9t & G &) __________________________________________________________________________________________________________________ ®) ^ ·.

i [on behalf of ....? ...... ί!:. ™ .Υ®. ^. ί · .®.Ηϊ!.? _______________________________________________________________________________________________________________________________________________________________., {B) take up residence for him and her , if appointed, for its representative, in Luxembourg ..........................,. Z: i 35, bd. ______________________________________________________________________ „m is requesting the grant of a patent for the invention for the subject described and represented in the aforementioned annex, —.with postponement of this grant to ........._______________________________ months.

The agent \ f \ _______ 1 \ ...........

\ II. Minute report ’The aforementioned patent application has been filed with the Ministry of National Economy? and Middle Classes, Industrial Property Service in Luxembourg, dated: December 17, 1979 I - i ----------- Pr. The Minister ·; at _________________ ... hours * / Λ of the National Economy and the Middle Classes, / ’\’ 'p. d.

V; : A 68007 * ’* D. 5ο.945

Patent application for ... 17 .... decemb.re ... lâ7 i Designation of the inventor 0 The undersigned ..mQnMe ^ ... Jaçgues „.de„ Muyser3.5 ... Md ”.. . .. Royal., .. ..I ......................

.......................................... Luxembourg (Luxembourg) .... .................................................. ............................................

acting as édhàddskfol - as agent for the depositor - (2) ......... BRISTOL-MYERS COMPANY, 345 Park Avenue, in NEW-YORK, NY loo22, ........... .......United States of America..................................... .................................................. .......................................

(3) of the invention relating to: ................ "Antibacterial agents" ..................... .................................................. .................................................

designated as inventor (s): 1. Name and forenames .... Mar.cel .... ^ NARD ......................... .................................................. ............................................

Address ... 18. „Abe: Meen., .... Ç_andi. ^ ............................... .........................................

2. Name and first names ..... Alain MARTEL ...................................... .................................................. .................................

Address 13 Monette, Delson, PQ, Canada ......................................... ..................................

3. Surname and first names ............................................. .................................................. .................................................. ...................

Address ................................................. .................................................. .................................................. .....................................

He affirms the sincerity of the aforementioned indications and declares to assume full responsibility for them.

\ ...... Lnxerobourg ............................., the - ~ ill April ....... ........................ 1sS.Q .......

SBïlCE LUXEMBOOkOSÎS DE U PSOPHitlÉ ϋίϊϋΐϊηΙίίίΕ.

ÜEgi ------- \ 1 I ft P \ A t \

The prepress, \ U

.......... Λ —... ’(signature) A 68026 (1) Last name, first names, company, address.

CLAIM OF PRIORITY

of the bib / dji request

In UNITED STATES OF AMERICA From December 18, 1978 1 Description Brief filed in support of a request for

PATENT

at

Luxembourg

in the name of: BRISTOL-MYERS COMPANY

for: "Antibacterial agents".

The present invention relates to new penem derivatives substituted in position 2 and disubstituted% in positions 2 and 6 which have a powerful antibiotic activity. It also relates to various new intermediate compounds useful for the preparation of biologically active penem derivatives and various methods of producing its intermediates and active compounds.

The cyclic system of the penem is of formula:

CD.XD.PG.6 ‘SY-1599 A

1.5 / 12/17 / \ 44λ3 iw "f the penem being therefore called in systematic nomenclature 7-oxo- ^ · -thia-1-azabicyclo [3» 2.0] hept-2-ene. For simplicity, this compound is called here "2-penemeM and the number-rotation adopted for the cyclic system is: 6 5 ~ \ l jÿ-N .___ Ÿ O 4 \ 3 The invention therefore relates to new penem derivatives of formula: yrv i-" W 1 o \ co2z where Z represents a hydrogen atom or an easy-to-remove esterifying protective radical, X represents (a) a radical of formula: (i) -OR, where R represents a hydrogen atom, SL cl ( ii) -COR ^, where R ^ represents a hydrogen atom or a hydroxyl, optionally substituted (lower) alkyl or phenyl or heterocyclic radical optionally substituted on the ring, the substituents po-rted by the alkyl radical 1 in number or more and preferably 1 or 2 being chosen from the halo, hydroxyl, oxo, carboxyl, carbalkoxy (lower), carbamoyl, alkoxy (lower), amino, (lower) amino radicals , dialkyl (lower) -amino, alkanoyl (lower) amino or phenyl or heterocyclic optionally substituted and the substituents carried by the phenyl or heterocyclic radicals numbering at most 1 and preferably 1 or 2 being chosen from hydroxyl, alkoxy radicals (lower), halo, alkyl (lower), halo-alkyl (lower), methanesulfonyl, oxo, alkyl (lower) -thio, amino, alkyl (lower) amino, dialkyl (lower) amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), or (iii) -0C0R, where R represents an amino radical,

O O

alkyl (lower) amino, dialkyl (lower) amino or alkyl (lower) optionally substituted, the substituents of which are as defined under (ii), or (b) an aliphatic (lower), cycloalipha-1 tick (lower) or cycloaliphatic radical substituted (lower) -aliphatic (lower) or phenyl, phenylalkyl (lower), heterocyclic, heterocycloalkyl (lower) or heterocyclothioalkyl (lower) substituted on the ring, the substituents of the aliphatic, cycloalrohatic, nhenyl or heterocyclic radicals ci- above being .. R, (i) radicals -G -or “N = C-- NR2R ^, where R ^ represents a hydrogen atom or a (lower) or phenyl alkyl radical and R2 and R ^ each independently represent a hydrogen atom or an alkyl (lower), phenyl or benzyl radical, (ii) radicals -0Rd, where Rd represents an amino, alkyl (lower) amino, dialkyl (lower) amino, alkyl (lower) radical substituted, alkenyl (lower) or phenyl, - phenylalkyl (lower), heterocyclic or heterocycloalkyl (lower) optionally substituted on the '. * '. . · * -. ·· Γ ring, the substituents carried by the alkyl, phenyl and heterocyclic radicals being as defined in (a) (ii), (iii) of the radicals -0 (GH2) rL0Er, where n represents an integer of 1 to 6 and Rr represents an optionally substituted (lower) alkyl or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the alkyl, phenyl or heterocyclic radicals being as defined under (a) (ii), (iv) radicals -OCOR ^ ', where R * represents an amino, lower alkyl) amino, dialkyl (lower) amino or Rr radical, with the restriction that Rr' cannot represent an unsubstituted (lower) alkyl radical, (v) the radical -OSO ^ H, (vi) the radical - & P (OH) 2 (vii) des. radicals -0S02Kr, where Rr is as defined under (b) (iii), 0 i (viii) of the radicals —OP (ORe) (0Rr), where R0 represents an (lower) alkyl radical and Rr is as defined under (b) (iii), (ix) radicals "^ (O ^ R ^, where 11 represents O, 1 or 2 and R ^ is as defined in (b) (ii) or represents, in case n = 0, a radical R ^ ÎT = C-HR ^ Rg, where R ^ represents a hydrogen atom or an alkyl radical (lower) and R ^ and Rg each independently represent a hydrogen atom or an alkyl radical (lower ), with the restriction that R ^ cannot represent an unsubstituted phenyl radical, (x) of the radicals -C01f, where Rf represents a -radical aminoalkyl (lower), alkyl (lower) aminoalkyl-. (lower), dialkyl (lower ) aminoalkyl (lower) ', -NSHïïg, -M17îffi18, -M0Rig, -S-R17, -Q (CH9) nA-Re or -NReRCT, where Rl7, R1S and Rg each represent an alkyl radical (lower) and Rl9 represents a hydrogen atom or an (lower) alkyl radical, A represents O, S, ïïïï or NCËL and n and E so nt as defined under Cb) (iii) and (b) (viii) "

0 S

(xi) radicals -P0 (0Rw) 2, where R ^ represents a hydrogen atom or an (lower) alkyl radical, (xii) radicals -RHR ^, where R ^ represents an optionally substituted, heterocyclic phenyl radical optionally substituted, -CH = Rïï, -SO ^ H, -OH, alkoxy (lower), amino, alkyl (lower) amino, dialkyl (lower) - amino, -HHCOGH ,, -OSpCS ,, -SOpCHp, -SOp- ^ _y, -SOpHH?,.

1 I · * J ά '“Λ S = GM2, S = CHHGH3, S = Gm - ^ _ y, ïffl ^ G-NE ^ Eg, where Ey and Eg each independently represent an alkyl radical i (lower), phenyl or phenylalkyl (lower), NH = C-Rg, where Eg represents an alkyl radical (lower), phenyl or phenylalkyl (lower), or 0 = CR ^, where R ^ represents an aminoalkyl radical (lower), -ÎŒL, alkyl (lower ) amino, dialkyl (lower) amino,, -HH-C ^ —R ^ q, ®io i. represents an optionally substituted (lower) or phenyl or heterocyclic alkyl radical, the substituents carried by the phenyl and heterocyclic radicals being as defined under (a) (ii), -KH-C ^ - MH2, (lower) alkoxy, -0GH2 - ^^>, -0CH2 - ^^ - N02 or -0 (CH2) 2Si (CH3) 3, (xiii) radicals -SC R- ^, where R- ^ represents an (lower) alkyl radical bearing a radical; amino, amino (lower) amino or dialkyl (lower) amino, 1 (xiv) of the radicals -NR.R,., where R. represents a radical i J &J; alkyl (lower) and R ^. represents an alkyl (lower), alkoxy (lower, heterocyclic, amino or 0 = CR ^, 'radical where R ^ is as defined under (b) (xii), or taken together with the nitrogen atom, R ^ and R ^ represent a radical ji Λγ ^ ι i

-yU

Ο ί ί. ί with the restriction 'only when R ^ represents an radical amino radical or 5 represents a methyl radical and also the restriction that R. and R cannot represent, J ^ i both (lower) alkyl, ij (xv) radicals radicals -ITR.'R, where R. ' represented

ϋ · “<J

an alkoxy radical (lower) and Rv 'represents a: & i dical alkyl (lower), heterocyclic, aminoalkyl (lower), alkyl (lower) aminoalkyl (lower), i dialkyl (lower) aminoalkyl (lower) or 0 = C-Ri} where Rj_ is as defined under (b). (Xii), or taken together with the nitrogen atom, R. ' and R. 'represent one! 3 'k radical

- / I

i 0; j Θ j (xvi) of the radicals -RR-.R R. where R-,, Il and R ^ v '1 m n ’mn j each independently represent an alkyl radical j (lower) or taken together with the nitrogen atom,! © f ~ \ represent a radical -R, y »(xvii) of the radicals -R = CÏÏ-R, where R represents

-λ. X

an (lower) or phenyl or heterocyclic alkyl radical optionally substituted on the ring, the substituents carried by the phenyl or heterocyclic radicals being as defined under (a) (ii), (xviii) of the radicals -R = CRxRy, where R ^ represents an alkyl (lower) or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the phenyl and heterocyclic radicals being as defined under (a) (ii), and Εχ is as defined under (b) (xvii ), (xix) of the radicals = RR ^, where represents a hydroxyl, alkoxy (lower), amino, dialkyl- (lower) amino or -KI--, radical.

^ NOH

(xx) radicals -C —- ^^ 2 ^ n ^ Rl5% 6 'n represents an integer from 1 to 6 and each independently represents a hydrogen atom or an (lower) alkyl radical, and Ί represents a hydrogen atom or a radical chosen from (a) aliphatic (lower), cycloalipha-! . optionally substituted (lower) or cycloaliphatic (lower) -aliphatic (lower) ticks, the substituents being 1 or more being chosen from hydroxyl, alkoxy (lower), phenyloxy, optionally substituted, optionally substituted heterocycloxy, alkyl (lower) optionally substituted thio, optionally substituted phenylthio, optionally substituted hetero-rocyclothio, mercapto, amino, alky1 (lower) amino, dialky1 (lower) amino ,. alkanoyl- (lower) oxy, alkanoyl (lower) amino, optionally substituted phenyl, optionally substituted heterocyclics, carboxyl, carbalkoxy (lower), carbamoyl, N-alkyl- (lower) carbamoyl, R, N-dialkyl (lower) carbamoyl, halogeno , cyano, oxo, thioxo, -SO ^ H, -OSO ^ H, -SOg-alkyl (lower), lower alkyl suifinyl, nitro, phosphono and ^ 0R (0Re) (OR), where R and R are such as defined above, J_ © J? the substituents carried by the lower alkyX radical) thio-in number 1 or more being chosen from the halogeno, hydroxyl, alkoxy (lower), amino, .alkanoyl- (lower) amino and phenyl or heterocyclic radicals optionally substituted, the substituents carried by the above phenyl or heterocyclic radicals 1 in number or more being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), haloalkyl (lower), methanesulfonyl, (lower) thio, amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), (b) radicals -0Rg, where Rg represents an optionally substituted (lower) or lower (alkanoyl) radical or an optionally substituted phenyl or heterocyclic radical, the substituents carried by the alkyl and alkanoyl radicals 1 in number or more being chosen from the halo, hydroxyl and alkoxy radicals (lower eurs), alkyl (lower) amino, dialkyl (lower) -amino, amino, oxo, alkanoyl (lower) amino and phenyl or heterocyclic optionally substituted and the substituents carried by the phenyl or heterocyclic radicals 1 in number or more being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), haloalkyl (lower), methanesulfonyl, alkyl (lower) thio, alkyl (lower) amino, dialkyl (lower) amino, amino, alkanoyl (lower) amino, alkanoyl radicals (lower) oxy, carboxy, carboxyalkyle (lower), sulfo and sulfoalkyle (lower), (c) the radicals -S (0) nRs, where n represents 0, 1 or 2 - and R is as defined above, s (d) halo radicals, and t (e) optionally substituted phenyl or heterocyclic radicals, the substituents of which are 1 or more, are chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), haloalkyl ( lower), methanesulfonyl, (lower) alkyl thio, friend no, amino (lower) amino, dialkyl (lower) amino, alkanoyl- (lower) amino, alkanoyl (lower) oxy, carboxyl, carboxy-alkyl (lower), sulfo and sulfoalkyl (lower), and their pharmaceutically acceptable salts, with the restriction that when Y represents a hydrogen atom, X cannot represent a radical -CHgOCILjCHgOCH ^.

The compounds of formula I, where Z represents a hydrogen atom (and their pharmaceutically acceptable salts and physiologically hydrolysed esters are powerful antibacterial agents. The other compounds are useful intermediates for the preparation of biologically active penem derivatives.

The substituents mentioned above for j - positions 2 and 6 of the penem cycle can be defined more precisely as follows: (a) the halo radicals are formed by chlorine, bromine, fluorine and iodine, but preferably with chlorine and fluorine atoms, (b) (lower) alkyl radicals include saturated straight or branched chain aliphatic hydrocarbon radicals of 1 to 6 carbon atoms inclusive, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, etc., the preferred (lower) alkyl radicals containing 1 to h carbon atoms and more advantageously 1 or 2 carbon atoms, (c) aliphatic radicals (lower) include hydrocarbon radicals, saturated or unsaturated, acycli-qp.es in a straight or branched chain of 1 to 6 carbon atoms, the unsaturated radicals being able to contain one or more double bonds or triples liai sounds, but preferably with a double bond or a triple bond; examples of the lower aliphatic radicals are the methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, s-butyl, n-pentyl, isobutyl, vinyl, 1-propenyl radicals.

2-propenyl, isopropenyl, 2-methyl-2-propenyl, ethynyl and 2-propynyl, the especially preferred aliphatic radicals being the alkyl radicals (lower) as defined in (b), (d) the cycloaliphatic radicals (lower ) comprise saturated and unsaturated alicyclic hydrocarbon radicals of 3 to 8 and preferably of 3 to 6 carbon atoms; unsaturated radicals can comprise one or more double bonds but preferably include only one; examples of such radicals are the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclopentenyl radicals, l) 3 “cyclohexadienyl and cyclohexenyl, (e) cycloaliphatic (lower) -aliphatic radicals (lower) cycloaliphatic - aliphatic radicals containing 3 to 8 and preferably 3 to 6 carbon atoms in the cycloaliphatic part and ί 1 to 6, preferably 1 to ^ and especially 1 or 2 carbon atoms in the aliphatic part; examples are! ! cyclopropylmethyl, cyclopropylethyl, cyclopropylpentyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropenylmethyl, cyclopentenylethyl, ί cyclopropylethenyl, cyclopropylethynyl radicals; the radicals i

especially preferred of this kind being the cyclo- I radicals

i alkylalkyl of which the cycloalkyl part has 3 to 6 carbon atoms i and the alkyl part of 1 to 2 carbon atoms, (f) the (lower) alkoxy radicals comprise alkoxy radicals of 1 to 6 carbon atoms, the alkyl part of which is defined as in (b); examples are the methoxy, etboxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s-butoxy, n-pentyloxy, etc radicals; preference being given to C1-alkoxy radicals - and especially in ° 1 - ° 2- (g) (lower) tbio alkyl radicals include alkylthio radicals of 1 to 6 carbon atoms, the alkyl part of which is as defined in (b); examples are the methylthio, ethylthio and n-butylthio radicals, (b) the (lower) amino alkyl radicals include alkylamino radicals of 1 to 6 carbon atoms whose alkyl radical is as defined in (b); examples are the metbylamino, ethylamino, n-propylamino and n-butylamino radicals, i (i) the (lower) amino dialkyl radicals include dialkylamino radicals in which each alkyl radical of 1 to 6 carbon atoms is an alkyl radical such as defined in (b); examples are dimethylamino and diethylamino radicals, (3) alkanoyl (lower) oxy radicals include radicals of formula alkyl (lower) -CO- whose alkyl radical is as defined under (b), (k) the alkanoyl (lower) amino radicals include radicals of formula (lower) alkyl -C -—HH- whose 'alkyl radical is as defined under (b), (l) carbalkoxy (lower) radicals include radicals -C ^ -alkoxy (lower) whose alkoxy radical (lower) is as defined in (f), (m) haloalkyl radicals (lower) include alkyl radicals of which one or more hydrogen atoms are replaced by one or more halogen atoms, (n) sulfoalkyl radicals (lower) include radicals of the formula - (CH ^^ SO ^ H, where n represents a number from 1 to 6, (o) carboxyalkyl radicals (lower) include radicals of formula - (CHg) COOH, where n represents a number from 1 to 6, (p) phenylalkyl radicals (lower) c include radicals of formula - (GHg) ^ - ^^, where n represents an integer from 1 to 6, (a) (lower) aminoalkyl (lower) radicals include radicals of formula - (CH2) nKH-alkyl (lower), where n represents a number from 1 to 6 and the alkyl radical of which is as defined in (b), (r) the dialkyl (lower) aminoalkyl radicals (lower) include radicals of the formula: i alkyl (lower) - <cwC ^ ^ alkyl (lower) where n represents a number from 1 to 6 and of which each alkyl radical is as defined in (b), (s) the (lower) alkanoyl radicals include radicals of formula alkyl (lower) -C = 0, the alkyl radical of which is as defined in (b), (t) the (lower) carbamoyl alkyl radicals include the radicals of formula (lower) alkyl -Iïïï-C = 0, of which the alkyl radical is as defined under (b), (u) the N, ï-dialkyl (lower) carbamoyl radicals include the radicals of formula

CD.YD. PG.9 - 12 - SY-1599 A

alkyl (lower) 0 \ Il NC- alkyl (lower) each alkyl radical of which is as defined under (b), (v) aminoalkyl radicals (lower) include radicals of formula - (Cïïg) Nïïg, where n represents a number from 1 to 6, (w) the hydroxyaminoalkyl radicals (lower) include radicals of formula - (CH ^^ MOH, where n represents a number from 1 to 6, (x) the alkyl radicals (lower) sulfinyl - include ° k.

radicals of formula —S-alkyl (lower) in which the alkyl radical (lower) is as defined in (b), (y) the alkenyl radicals (lower) comprise unsaturated straight or branched chain aliphatic hydrocarbon radicals, including a double bond! and having 2 to 6 carbon atoms inclusive, such as vinyl, allyl, isopropenyl, 2-methallyl or 3-methallyl or 3 ~ butenyl radicals.

The term “heterocyclic radicals” should be understood to mean in particular heteromonocyclic and heterobicyclic radicals of aromatic character, as well as partially or fully saturated radicals as required, these heterocyclic radicals having at least one heteroatom of oxygen, sulfur or d and being united by a ring carbon atom to a carbon atom of the penem cycle. Preferred heterocyclic radicals are pentagonal or hexagonal monocyclic radicals or condensed hexagonal-hexagonal or pentagonal-hexagonal bicyclic radicals. Examples of suitable heterocyclic radicals are:

CD.YD. PG.9 - 13 - SY-1599 A

Γτ Γ1 ΓΤ Ο- ΓΤ 'Η' ·

, Α. ιΑι 'rAr r ^ K> riN

- Ν V-NJ η -C ^ j]

^ Ν \ _, / Ν- ι ^ ν ^ Υ ι — I

υ Ο ^ [^ jLr ^ / V, ^ η2 / γν: U U- U - * - υυ I ΑΑ ^ Ι ^ ΑΑ kAA ΑΆ: ί

^ s ^ n Α ^ ν _ _r- r ^ 0> V

Li Ll CL Q Q

TT

H H

N- = N

'I M_N

0 N-N N — N I, II

Ü Q Li IjJ V

\ S ~ N V = / |

• N H

H

-N N-N N-N ΊΪ Ü || η

O AsJ 'AoJ vO

H

τ il li il 1 il J il

Ά>, / Η “S" M

H H

CD.YD. PG.9 - lh - SY-1599 A

At "C0 -

H

Likewise, by heterocycloalkyl (lower), heterocyclothioalkyl (lower), heterocycloxy and heterocyclothio radicals, we mean radicals - (CHg ^ -hetero-cyclo, - (CH2) nSh.eteroc.yclo, -O- heterocyclo and -S-heterocyclo, respectively, where n represents a number from 1 to 6 and preferably 1 or 2.

As the compounds substituted in position 2 of formula I comprise an asymmetric carbon atom, they can exist in the form of racemic mixtures (form R, S) or in the form of optical isomers dextrorotatory and distinct levorotatory (form. R and form S) . Preferred compounds are those whose configuration at the carbon atom in position 5 corresponds to that of penicillin: natural (JR configuration) · The substituents in positions 5 and 6 of 2,6-disubstituted penemes can occupy the j | cis or trans position relative to each other. When the substituent in position 6 of the penem radical contains an asymmetric carbon atom, the resulting isomers are identified as being the A, B, C and D isomers (reference may be made to Example 3 ^ for stereochemistry).

The preferred isomer of such compounds is the B isomer.

The separation of the different optical and geometric isomers can be carried out according to conventional separation and duplication techniques well known to the specialist.

the subject of the invention is the compounds of formula I in the form of the isomeric mixtures, as well as in the form of the separate and separated isomers.

The pharmaceutically acceptable salts mentioned above include the non-toxic salts formed by the carboxylic acid radical, for example the non-toxic metal salts, such as the sodium, potassium, calcium, aluminum and magnesium salts, the salt of ammonium and salts derived from non-toxic amines such as trialkylamines (triethylamine), procaine, dibenzylamine, N-benzyl-p-phenethyl amine, 1-ephenamine, ΪΓ, Ν'-dibenzyl-ethylenediamine , U-alkylpiperidines and other amines which have already been used to form salts of penicillins and cephalosporins, when the molecule comprises a basic radical, the invention also relates to the addition salts of pharmaceutically acceptable acids ,, for example the salts formed with mineral acids, such as hydrochloric, hydrobromic, hydroiodic, phosphoric or sulfuric acid or with. suitable organic carboxylic or sulfonic acids, such as trifluoroacetic, p-toluenesulfonic, maleic, acetic, citric, oxalic, succinic, benzoic, tartaric, fumaric, mandelic, ascorbic or malic acid. The compounds comprising an acid radical and a basic radical can also exist in the form of internal salts, that is to say of zwitterion. the preparation of the above salts can be carried out according to the usual techniques for forming the salts of β-lactic antibiotics such as penicillins and cephalosporins.

By "easily removable esterifying protective radical" is meant a radical having a conventional definition in the field of β-lactams and peptides. We know dp r> adi ρ.ρπυ dp op οάπτά nui pont ntili rpr 001171 nro— tégéger the carboxyl radical during subsequent chemical reactions and which are subsequently removed according to conventional techniques for the release of free carboxylic acid . Known esterifying protective radicals are in particular 2,2,2-trichloroethyl, t-alkyl of with 6 carbon atoms, t-alkenyl of 5 to 7 carbon atoms, t-alkynyl of 5 to 7 carbon atoms, alkoxy -methyl, alkanoylmethyl of 2 to 7 carbon atoms, N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, benzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, tri-tyle, trimethylsilyl, triethylsilyl, ß-trimethylsilyl-ethyl, etc. The choice of the esterifying protective radical depends on the subsequent reaction conditions which the radical must resist and the conditions desired for its elimination. The choice of an appropriate radical is easy for the specialist. The ester especially preferred as a chemical intermediate is the p-nitrobenzyl ester, the p-nitrobenzyl radical of which is easy to remove by catalytic hydrogenation. For the preparation of compounds containing functional radicals capable of being reduced under the conditions of such elimination, an alternative preferred ester is the β-trimethylsilylethyl ester from which the β-trimethylsilylethyl radical can be eliminated by reaction with fluoride ions . Among the esterifying protective radicals which are easy to remove, mention should also be made of the physiologically hydrolysable ester radicals, that is to say the esters known in the chemistry of penicillins and cephalosporins as being easily hydrolysed in the body with the release of related acid. Examples of these physiologically hydrolysable esters are esters with indanyl, phthalidyl, thienylglycyloxymethyl or acyloxymethyl radicals of formula: 0 il -CHgC-ï 'where T' represents an alkyl radical of 1 to k carbon atoms or phenyl. Particularly preferred esters of this kind are those comprising methoxymethyl, acetoxymethyl, pivaloyloxymethyl, phthalidyl and indanyl radicals.

It should be noted that the compounds of formula I can exist in different states of solvation and that the invention relates to both anhydrous compounds and solvated compounds (especially hydrated).

Among the compounds of formula I, the preferred compounds are those in the formula of which Y represents a hydrogen atom or an (lower) alkyl radical optionally substituted by a hydroxyl radical (preferably on the carbon atom a ). More preferred compounds of this class are those in the formula of which Y represents a hydroxyl, ethyl or o-hydroxyethyl radical. Even more preferred compounds of formula I are those in which Y represents a hydrogen atom or an α-hydroxyethyl radical. The especially preferred compounds are those in which Y represents an α-hydroxyethyl radical.

According to a preferred embodiment, the subject of the invention is the compounds of formula I in which the substituent Z is an aliphatic (lower), cycloaliphatic (lower) or cycloaliphatic (lower) -aliphatic (lower) radical or a phenyl, phenylalkyl ( lower), heterocyclic, heterocycloalkyl (lower) or heterocyclothioalkyl (lower) cycloaliphatic, cycloaliphatic-aliphatic, phenyl, phenylalkyl, heterocyclic, heterocycloalkyl and hetero-rocyclothioalkyl being of formula:

WSL

H

-CEE ^ E ^ or -E ^ C-KE ^ E ^ h where E- ^ represents a hydrogen atom or a (lower) alkyl or phenyl radical and E ^ and E ^ represent each independently, a hydrogen atom or an alkyl - (lower), phenyl or benzyl radical. Among these compounds, preference is given to those in which Y represents a hydrogen atom or an ethyl or α-hydroxyethyl radical, especially in which Y represents a hydrogen atom or an α-hydroxyethyl radical and most especially in which Y represents a α-hydroxyethyl radical, j According to another preferred embodiment, the invention relates to the compounds of formula I, where X represents an aliphatic (lower) radical, cyclo-. substituted aliphatic (lower) or cycloaliphatic (lower) -aliphatic (lower) or substituted phenyl, phenylalkyl (lower), heterocyclic, heterocycloalkyl (lower) or heterocyclothioalkyl (lower), substituents for aliphatic, cycloaliphatic, cycloaliphatic radicals -aliphatic, phenyl, phenylalkyl, heterocyclic, heterocycloalkyl and hetero cyclothioalkyl being of formula: -C0Ef where E_p represents an aminoalkyl (lower), alkyl- (lower) aminoalkyl (lower), dialkyl (lower) amino- -C ^ CH ^ radical ^ -AR ^ or -HRgRg, where R- ^ y, R ^ g? Re and R ^ represent alkyl radicals (lower), R- ^ g represents a hydrogen atom or an alkyl radical (lower), A represents 0, S, SH or HCH ^ and n represents an integer from 1 to 6 Among these compounds, preference is given to those in which Y represents a hydrogen atom or an ethyl or α-hydroxyethyl radical, especially in which Y represents a hydrogen atom or an α-hydroxyethyl radical and most especially in which Y represents an α-hydroxyethyl radical.

According to yet another preferred embodiment, the invention relates to the compounds of formula I, where Σ represents λγ ^ ι

(a) a radical - (CH ^^ - N JJ

where n represents an integer from 1 to 6 and preferably I from 1 to (b) a radical - (CÏÏ2) nÏIHOH, where n represents an integer from 1 to 6, preferably from 1 to (c) a radical - (CH2) rP0 (0-alkyl in - 0 ^) 2, where n represents an integer from 1 to 6 and preferably from 1 to h and whose alkyl radical is preferably a methyl, ethyl or isopropyl radical, (d ) a radical - (CH2) nNH-C -alkyl. in C- ^ - Gg, where n represents an integer from 1 to 6 and preferably in 1 to and in which the alkyl radical is preferably a methyl or ethyl radical, (e) a radical - (CH2) nR = CH, where n represents an integer from 1 to 6 and preferably from 1 to * +, (f) a radical - (CH2) n0C— (CH2) mMARB, where n and i

Δ B

each independently represent 1 or 2 and R4 * and R represent

. .η · * S i. . ...-, -. V

lower alkyl radical, or

JSE

(g) a radical - (GH) NHC —— Rc, where n represents η an integer from 1 to 6 and preferably from 1 έΛ and Rc represents an alkyl radical from 1 to H · carbon atoms, which is preferably a methyl or ethyl radical, or a phenyl radical, or, where m represents 1 or 2.

Among these compounds, preference is given to those in which Y represents a hydrogen atom or an ethyl or α-hydroxyethyl radical, especially in which Y represents a hydrogen atom or an α-hydroxyethyl radical and most especially in which Y represents a a-hydroxy-ethyl radical.

According to other preferred embodiments, the invention relates to the intermediate compounds of the formulas: ..... (A) Γ 1 _y ^ s ~ -

J-N P (Q) 3M

o CO-R "z x

III

where Y represents a hydrogen atom or is as defined above with respect to the compounds of formula I, Q represents a phenyl or (lower) alkyl radical, R "represents an easy-to-remove esterifying protective radical, x represents 1 or '2 and M represents Gu (II), Pb (II) or Hg (II), when x represents 2 or Ag (I) when x represents 1,

(B) Y ^ SHgCOOCH

π J-N P (Q).

O 3 C02R "Ilia where ï, Q and R, r are as defined above under (A), and

(C) ^ ~ T

π C02R "

IV

where Y is as defined above with respect to the compounds of formula I, Q represents a phenyl or (lower) alkyl radical, R, r represents an esterifying protective radical "" ^ c6h5 easy to remove and T represents a radical C ^ H, - “” G * ^ 'C /' ïï I; D 5 or 0 = C-Z, where 1 is as defined above with respect to the compounds of formula I.

In formulas III, III and IV of the intermediates, Q preferably represents a phenyl radical, R, [preferably represents a p-nitrobenzyl radical and X and Y preferably represent the substituents mentioned as preferred with regard to the compounds of formula I. Reactive functional radicals, such as the mercapto, amino and hydroxyl radicals in the X and Y radicals, can be protected by means of conventional protective radicals during the conversion of the intermediate compounds into biologically active desired products.

Compounds of formula I can be prepared

r -.- n-î TT-mif ηνία nll 1 Π C! Ί ΩΠ Y · Q H Ω C! mi OO Η Ω C-σΎΙ 4 * Vl Ω Q Ω Η Ω T> Ί 4τ Ω S

below. These different synthetic routes can be divided into three main processes depending on the stage of incorporation of the substituent in position 6, namely the radical ï. Thus, in method I, the substituent in position 6 is incorporated into the starting compound, in method II, it is incorporated at the end of the synthesis and in method III, it is incorporated during the synthesis itself. Each of these three main processes can differ, in turn, by the mode of incorporation of the desired substituent in position 2, namely the radical X. In general, it is preferable to incorporate the radical I when the synthesis is to be half performed and to incorporate the radical X by acylation of an intermediate mercaptide of formula III or III, because these procedures have proven to be most generally useful.

The stages of process I are illustrated in the diagram! . following.

Method I (variant 1): early incorporation of the substituent in position 2.

• y, O

\ _ ^ OAc II

Y-CH = CH-OAc CSI | XC-SNa i— N PH 7.5 ^

OH

? O

Y «Vv_ · SC-X Y N

- ^ sc-x _ ^ ^ _ ^ sc-x _ ^ j. Ç110 I soci Nî C02r ". 0 ^ ~ Νγ0Η C02R" 0 ο Υ \ _ ^, SC-X K, gp_y —f _î ^ _ * TT Δ o '^ _ K'Y ^' 'C1 baSe 0T — N \ ^ ^ 3 "> C02R” C02R ”

V Y

Π> * ^ vrv N '—- / deprotection \ ^ / T ~ 0 CO R "<Γ ~~ 1 Λ

c C02H

-. -II

Ac = CH3C-. 0 = C6H5-! Method I (variant 2): late incorporation of. substituting in position 2.

v 0 Y T _OAc ^ Y-CH = CH-OAc CSI ^ I T CH3C-SNa ^ * ^ i——. N PH 7.5 -

ο H

Y'VH- ^ SAC _v, Y * U _.SAC ............ S ”ÇHO I SOC1- C02R” ο ^ “Νγ ° Η C02R”

\ - ^ SAc P0 ^ f SAc fiA

I I -> J-N. ~ C1 base Λ-N base o iT ^ 0 C02R "C02R"

O

γ ^ _ o H

- ^ SM x-j! - ® “N — psc'x A

N \ ^ p03 q ^ J-N \ ^ P03 C02R "C02Rw y * -> vr — f'Vx * 9 ~ w ^ y deprotection l_ ^ ff

COR "O

2 C02H

I ·

O

X-C- Θ = acylating agent MA = heavy metal salt

Method I (variant 3): late incorporation of the substituent in position 2. - S-r ^ 0Ac 0 CSNa Y-CH = CH-OAc CSX> J _3_ ^

J— N PH 7.5 V

O

/ '' d — rsc03 -> \ —rsc03--5 I ÇHO I SOC1

^ N __ / · · IsL ·, OH

O XH C02R

co9r "

^ -r ^ SC0 3 P0 ^ MA

I - ^ I r- £ J_N CT base J - ÿ: P0, base

ο 0 ^ Y

C02R "co2r” 0 y >> ov il ^ “V-, -sm H Υ'Λ-ν_ ^ sc-x λ ht * -c- ®> ~ r -> o ^ -N \ ^ P03 q <^ - N \ ^ P03 C02R "co2R” ^ deprotection J __ // ° Λακ ”.

2 C02H

|

In process I, a vinyl ester (in which case X represents a hydrogen atom or a radical as defined with respect to the compounds I) containing the desired substituent in position 6 is converted into the optionally α -etoxy ^ -azetidino-ne 1-substituted by a cycloaddition reaction with chlorosulfonyl isocyanate (symbolized by CSI), then reduction using an inorganic reducing agent such as sodium sulfite. The reaction with chlorosulfonyl isocyanate is advantageously carried out in an inert organic solvent, such as diethyl ether at a temperature of 0 ° C or lower. The reduction can be carried out in an aqueous or aqueous-organic reaction mixture at a temperature of 0 ° C or lower and in a weak alkaline medium.

After the formation of U-acetoxv-P-azé + r-irH-nonp ·.

process I can be divided into three different ways. According to one of the routes (variant 1), the azetidinone is reacted with a thiolic acid X— C-SH, where X has the meaning indicated with respect to the compounds I, or with a salt of such an acid, in a suitable solvent (eg aqueous or aqueous-organic). I <e displacement of the acetoxy radical incorporates at this stage in azetidinone, the desired substituent in position 2. This displacement reaction is preferably carried out at room temperature or at a lower temperature and in a weakly alkaline medium (pH of approximately 7.5) · When Y does not represent a hydrogen atom, the cis and trans isomers of the resulting azetidinone are preferably separated (for example by chromatography) at this stage of the operations. Variants 2 and 3 above are the conversion of 4-acetoxy-2-azetidinone to V-acetylthio-2-azetidinone and to V-trityl-I thio-2-azetidinone, respectively, by the displacement reaction nucleophile with thioacetic acid or tri-phenylmercaptan (possibly in the form of a salt such as the sodium salt), respectively.

The 4-thioazetidinone is then reacted with a glyoxylic ester C-C0oR ", where R" represents a ΙΓ ^ protective radical esterifying which is easy to remove, such as a p-nitrobenzyl or trimethylsilylethyl radical, or else with a corresponding reactive oxo derivative , as a hydrate, in an inert organic solvent (such as benzene, toluene, xylene, etc.), preferably at a high temperature (for example from $ 0 ° 0> up to, preferably, the reflux temperature ). When using an ester hydrate, the water released can be removed by azeotropy or by means of a molecular sieve. The hydroxyester obtained Λ miL “Ml Vt“ M £ * 1 AM MA ^ A Λ AV \ -î ΎΥ1 λ “VA A Π Λ11 · ί T \ ΑΤΓΛΠ Ί rvm -V \ 4— Â4“ * nr \ the process I can be divided into three different ways. According to one of the routes (variant 1), the azetidinone is reacted with a thiolic acid X — C-SH, where X has the meaning indicated with respect to the compounds I, or with a salt of such an acid, in a suitable solvent (eg aqueous or aqueous-organic). The displacement of the acetoxy radical incorporates at this stage in azetidinone, the desired substituent in position 2. This displacement reaction is preferably carried out at room temperature or at a lower temperature and in weakly alkaline medium (pH of about 7 , 5) · When I does not represent a hydrogen atom, the cis and trans isomers of the resulting azetidinone are preferably separated (for example by chromatography) at this stage of the operations. Variants 2 and 3 above are the conversion of V-acetoxy ^ -azetidinone to acetylthio-2-azetidinone and to V-trityl- (thio-2-azetidinone, respectively, by the nucleopnile displacement reaction with l thioacetic acid or tri-phenylmercaptan (possibly in the form of a salt such as the sodium salt), respectively.

The ^ -thioazetidinone is then reacted 0 ^ with a glyoxylic ester ^ .C-C0oE ", where R" represents a

H

easy to remove esterifying protective radical, such as a p-nitrobenzyl or trimethylsilylethyl radical, or else with a corresponding reactive oxo derivative, such as a hydrate, in an inert organic solvent (such as benzene, toluene, xylene, etc.), preferably at a high temperature (for example from 5 ° C to, preferably, the reflux temperature). When using an ester hydrate, the water released can be removed by azeotropy or by means of a molecular sieve. The hydroxyester obtained, S -, -, /. \. * / _____ j ____- i M_____i Λ .___ purified, for example by chromatography, or used directly in the following stage.

The conversion of the hydroxyester into the corresponding chloroester is carried out by reaction with a chlorinating agent (for example SOCl ^, POCl ^, PCI, -, etc.) in an inert organic solvent (for example tetrahydrofuran, diethyl ether, methylene chloride, dioxane, etc.) in the absence or the presence of a base which is preferably a tertiary aliphatic amine (for example triethylamine) or a tertiary heterocyclic amine (for example pyridine or collidine ). The reaction is advantageously carried out between about -10 ° C and room temperature. The resulting chloroester is obtained in the form of a mixture of the epimers which can optionally be purified before being used in the next stage.

The intermediate phosphorane can be obtained by reacting the chloroester with a suitable phosphine (which is preferably triphenylphosphine or a tri (lower) phosphine such as triethylphosphine or tri-n-butylphosphine) in an inert organic solvent, such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dimethoxyethane, dioxane or an aliphatic, cycloaliphatic or aromatic hydrocarbon (such as hexane, cyclohexane, benzene, toluene, etc.) in the presence of a base, which is preferably a tertiary organic amine such as triethylamine, pyridine or 2,6-lutidine. The reaction is advantageously carried out from room temperature to the reflux temperature of the solvent system.

At this stage, the process again diverges in two ways. According to variant 1 (in which case the sub-, ·,, ·, · η /. \ /, / ___ / \ -, -, ___ X. ____.

intermediate is converted to the desired peione by thermal cyclization in an inert organic solvent at a temperature ranging from just above room temperature to the reflux temperature of the solvent system.

Most advantageously, the cyclization is carried out at reflux. Suitable inert organic solvents are in particular aliphatic, cycloaliphatic or aromatic hydrocarbons (such as benzene, toluene, hexane and cyclohexane), halogenated hydrocarbons (such as methylene chloride, chloroform or carbon tetrachloride ), ethers (such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane), amides of carboxylic acids (such as dimethylformamide), dialkylsuifoxides with alkyl radicals in 0 ^ - 0 ^ such as dimethyl sulfoxide or C 1-6 alkanols (such as methanol, ethanol or t-butanol) or a mixture of such solvents.

According to variants 2 and 3, the phosphorane is converted into a heavy metal mercaptide of formula: „J — γ" 0 |> »CCUR” x

III

or ^ SHgCOOCH ^ J-N P (Q) 0 3 L ....... ..III ".

where Q preferably represents a phenyl or (lower) alkyl radical, x represents 1 or 2, M represents Cu (II),

Pb (II) or Hg (II) when x represents 2 or Ag (I) when x represents 1. The formation of mercaptide is carried out by reaction of phosphorane with a salt of Ig (II), Pb (II), Cu (II ) or Ag (I) or with methoxycarbonyl-mercury acetate (III) in a solvent containing methanol and in the presence of an organic or inorganic base, such as aniline, pyridine, hill, 2,6 -lutidine, an alkali metal carbonate, etc. A preferred base is pyridine. the reaction can be carried out at room temperature or, if desired, under slight heating or cooling. The anion (A) of the heavy metal salt may be any anion forming a salt soluble in the solvent chosen, for example an anion NO ^ ”, CH ^ COO“, BP ^ -, CIO ^, GITO, etc. The intermediate mercaptide is [then reacted with an acylating agent capable of introducing the radical of formula 0 = C-X, where X represents the desired substituent in position 2 of the penem. The acylating agent (XC == 0) can be X —C - OH acid 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. The acylation is carried out in an inert solvent (for example a halogenated hydrocarbon, such as methylene chloride, or an ether such as dioxane, tetrahydrofuran or diethyl ether) and when using a derivative of 1 "acid" in the presence of an acid acceptor such as a trialkyl (lower) -amine (such as triethylamine) or a tertiary organic base such as pyridine, collidine or 2,6-lutidine. When using the free acid, the acylation is carried out in the presence of a suitable condensing agent, for example a carbodiimide, such as Ν, ΪΓ'-dicyclo-hexylcarbodiimide. The acylation of the mercaptide can be performed over a wide temperature range, but preferably from about -20 to about + 25 ° C. After acylation, the resulting phosphorane is cyclized as described above to form the desired penem ester.

The preparation of phosphorane via mercaptide (variants 2 and 3) has been found to give a product "much purer than that obtained by variant 1 which is the more conventional route.

After the formation of the penem from which the carboxyl radical is protected, the protective radical can be removed according to conventional techniques for removing the protective radicals (for example by hydrolysis, hydrogenation or photolysis) for the release of the deprotected penem I. The elimination of the p-nitro-benzyl esterifying radical, for example, can be carried out by catalytic hydrogenation in the presence of a catalytic noble metal, such as palladium or rhodium, or of a corresponding derivative such as an oxide, hydroxide or halide. , the catalyst being optionally deposited on a conventional support, such as carbon or diatomaceous earth. The operation is carried out in an inert aqueous or non-aqueous non-reducible solvent, such as water, ethanol, methanol, ethyl acetate, tetrahydrofuran, diethyl ether or dioxane · Hydrogenation can be carried out under atmospheric pressure or under higher pressure, advantageously at room temperature for approximately 1 to 5 hours depending on the nature of the solvent and that of the catalyst. When the hydrogenation is carried out in the presence of an equivalent weight of a base, such as an alkali or alkaline earth metal hydroxide or an amine, the product can be isolated in the form of the carboxylic acid salt. The elimination of the esterifying radical β-trimethyl-silylethyl, which is another useful protective radical, is advantageously carried out by treatment with a source of fluoride ions. Other protective esterifying radicals can also be removed according to known link processes.

The sequence of reactions in a second important process (process II) is as follows.

Method II (variant 1): early incorporation of the substituent in position 2.

O

_ ^. OAc 11 CK0 = CH-OAc CSX v Γ XC-SNa ^ * J_ N PH 7,5> O '' h! i? o

11 a.m.

^ .sc-x ^ sr — x ^ Γ -> —r -> I çho I socx cT% C02R '· 0 <^ Ν-γ-0Η C02R "0 0

He II

r-rsc “x P0, r- ^ sc“ x Δ I. I »0 ^ N \ ^ C1 base C02R" C02R "CO R" ο \ C02E, r

77: ΓΤ> \ \ -X

deprotecuion 1 // J-

O

co2h

Method II (variant 2): late incorporation of the substituent in position 2.

_ ^> OAc CH '-, = CH-OAc CSI. Γ AcSNa c.

* J_ N PH 7.5 '

i 0 X H

- ^ ^ SAc _ ^ I ÇH0 I soci- q ^ —Ke co2r · '0 ^ -n γ0Η C02R "I — rSAc P03 I- {SAC icv IV, 11 -> I Γ-> λ-N. _C1 base J -, N. ^ P0, base ο ck 3 co2r "co2r" Ο Ο I Γ X ~ C- θ - <S ”_X Δ 0J ~ * γ» 3 ^ oJ _] ^ P03 * CO_R "„ „2 C02R" xx ^ · * ". Χχν * C ° 2R" Ο Λ C02Rm \ -> Γ \ x deprotection J, // J — n ^ 7 o \

C02H

II

PjÇqc.édé II (variant 3): late incorporation of the substituent in position 2.

CH0 = CH — OAc CSI. Γ 03CSNa ^ —ν '1 -——

J- N pH 7.5 X

0 VH

I rsc03 -—I — r-sc ^ 3 -_ * y_l îH ° i socix

θ '"C02R" q <? - N \ ^ 0H

C02R "[~ TSC03 P03 ^ rrsc03" ο ^ Ύ ^ 1 base 0Λ,! Γρ ^ tase C02R "C02Rm o î ——— / SM II ολ · _ v XC- 0 -r ^ bt- Ä Δ <À ~ ' ^ 0J — N \ / pi33 '? C02R "CO /" / r> CO / ”O ^ CO /"! Y% —r ^ \ -> Γ Vx deviation 1 // ^ —N- ^ y ο Λ

C02H

As can be observed, method II is substantially the same as method I (except that Y must represent a hydrogen atom) up to the thermal cyclization stage giving the penem substituted in position 2. However, one. substituent in position 6, if desired, is now introduced at this stage by reaction of the 2-penem with an appropriate electrophilic reagent in an inert solvent (eg tetrahydrofuran, diethyl ether, dimethoxyethane, etc.) in the presence of a strong base.

Su T is worth this urocédo. Ίο? —Uônèmo pst set to cool in the form of free acid (obtained by deprotection as described above) in the presence of approximately 2 equivalents of a base or, alternatively, a suitable 2-penem ester can be reacted in the presence of about 1 equivalent of a base. Any ester inert with respect to anion chemistry (the reaction involves anion formation with the base, then the reaction of the electrophilic reagent with the penile anion) is suitable, for example an ester comprising an (lower) alkyl radical , such as methyl, ethyl, n-propyl or t-butyl, or a phenyl, trichloroethyl, methoxymethyl, silyl radical, such as trimethylsilyl or t-butyldimethylsilyl, etc. Penem esters comprising activated methylene radicals, such as the p-nitrobenzyl ester, are unsuitable and in case the 2-penem ester is of this kind, it must first be deprotected and the compound must therefore be used as a free acid or converted to a suitable ester. t The base used in particular is not critical and common strong bases such as sodium hydride, phenyl lithium or butyllithium are suitable. More advantageously, however, a lithium disilylamide or dialkyl lithium amide, such as lithium dicyclohexylamide (LDCA), lithium diethylamide, lithium dimethylamide or lithium diisopropylamide (LDA), is used. The electrophilic reagent is chosen so as to give the radical Y by reaction with the anion and can be, for example, a halogen, (such as Br2 or I2) an alkyl halide (such as C10) a similar halogenide such than an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, phenylalkyl (lower), heterocyclic, heterocyclothio, heterocyclo-thioalkyl (lower) or heterocycloalkyl (lower) halide, a tosylate or mesylate ^ C by example CH ^ CÏ ^ C ^ ^, CEL CHo0S0oCEL, L J-0S0o S0o, 0CIhCHoCHoOSOoCHo, ο etc.), an epoxide (for example / \), an episulfide (for example Δ), an aldehyde (for example CïLCHO, C ^ H ^ H-CHO) αο j ^) or an ester (for example CH ^ CH ^ COOCH ^ or C ^ ïïyUOOCH ^). Representative examples of other electrophilic reagents are given below: CH2 = CH-CH2Br ï> ^ · î

Br CH3CCH = CH2 CH3CH-CH3

Ci '\ Q ^ C1 0CH2Br HCHO 0C = CCH2Br ΔΥ ° \ _ (CH2SCH2C1 CH3SS02CH3 0OCH2C1 0CH = CHCHO 0

O

ch.cch7ci Π ks> -C-CH2Cl.

O

An especially preferred electrophilic reagent is acetaldehyde which provides the hydroxyethyl radical in position 6. The introduction of a substituent in position 6 in this way is preferably carried out under cooling (for example from -80 to 0 ° C) depending on the general technique described in Canadian Journal of Chemistry, JyO (19), 3196-3201 (1972).

After the formation of the desired 2,6-penem, all ra- rH r.al -n-nn-hp.Ci-tp.nr "fi * nnt npnt itrp. Eliminated η.ητητηρ γ) αρ.τη · ϊ: ci above for the formation of the deprotected product.

The third important process (process III) is illustrated by the following diagram.

Method III (variants 1 and 2).

_ ^ sc03 _ Sc03

Y <N_SSCH

base ._N

<y nb deprotect ^ n ^ \> ^ MVbase

Y, Y

% _, ^ SC0, V_JSÜL

I. I

<p HO O

CO R "X-C- <$) Ψ Ψ ï '^ j — j ^ sc03 psl-x

J-N OH i-N

0 <f XB

co2r "SOCl_ V ^ \ / protection N ~ TSC03 YX- J-r sO '- v. r-Cl".

0 n \ h CO, R "P03 base

ψ CHO

Y_N-Y »I N-rsc-x

• J -— 'I

0 T o ^ ~ N \ ^ OH

CO, R "CO, R" MA / base V V ° ch

1 Y'-N · O

^ -V — T ^ SM \ H

f \ _ ^ sc-x

J-N. . * P0 I

Çy Y 3 J-N Cl

O

CO-R "I

2 co2r »O 'v x-c- © ** 3 ο Φbase ^, sS-X *?

-’Ç N - SC-X

Çy N \ ^ ~ 03 o <J, N \ ^ 03

CO — R ** I

2 co2r ", Δ Δ '' ^ Ψ rA_ ïV-r '\

Ai Ai C ° 2R 'CC ^ R "deprotection deprotection' AA 'Ai- CO H 0'

2 C02H

B = protective radical for nitrogen in the cycle.

The ^ -triethylthio-2-azetidinone of method III \ is formed as described in method II (variant 3).

The nitrogen of the azetidinone ring is then protected by a conventional easily removable protective radical, for example a triorganosilyl radical (such as trimethylsilyl or t-butyldimethylsilyl), methoxymethyl, methoxyethoxymethyl, tetrahydropyrannyl, etc. The introduction of the desired radical Y in position 1 of the azetidinone is then carried out by reaction of a suitable electrophilic reagent with the N-protected azetidinone in the presence of a strong base (under reaction conditions as described above in About process II). At this stage, the process diverges in two ways according to the moment of deprotection of azetidinone.

According to one of the synthetic routes, the N-protected intermediate is deprotected according to conventional techniques (for example acid hydrolysis), then converted rvv »T r \ O r \ An Àwi Λ rv r» v> · Ρλ "Wm a4- * Î Λν" λ TIA av "λΤλΤ λ · ηη 4-4 mim J ^ hydroxyester, conversion of chloroester to phosphorane, conversion of phosphorane to heavy metal mercaptide, acylation of mercaptide using the reagent XC = O, thermal cyclization of the phosphorane resulting in 2,6-penem ester and elimination of the protective radical of the carboxyl function. The reaction conditions for these stages are those indicated in connection with process II (variant 3). The other synthetic route comprises the stages of conversion of the protected azetidinone to the heavy metal mercaptide, the acylation of the mercaptide by means of the reagent i Θ XC = 0, elimination of the protective radical of nitrogen, reaction of deprotected azetidinone with glyoxylic ester, chlorination, reaction of chloroester with phosphine forming phosphorane, cyclization of phosphorane to penem ester and elimination of the protective radical of the carboxyl function for the formation of 2,6-penem. The reaction conditions for these stages are those which have already been indicated.

During the preparation of the 2-penemes and 2,6-penins according to the above methods, the free functional radicals of the substituents X or Y which do not participate in the reaction can be temporarily protected in a conventional manner, by for example the amino radicals. free by acylation, tritylation or silylation, free hydroxyl radicals by esterification or etherification, mercapto radicals by esterification, and free sulfo or carboxyl radicals by esterification, in particular silylation. After the reaction, these radicals can, if desired, be released individually or jointly in a conventional manner.

ment in the compounds of formula I, the substituents in positions 2 and / or 2 and 6 during the reactions or at the end of these following conventional procedures for the supply of other substituents coming within the scope of the invention - For example, carbonyl radicals can be converted to alcohol radicals, unsaturated aliphatic radicals can be halogenated, amino radicals can be alkylated or acylated, nitro radicals can be converted to hydroxyamino or amino radicals, hydroxyl radicals can be etherified or esterified, etc.

Penemes in the form of free acids can be converted into their pharmaceutically acceptable salts or into esters which are easy to hydrolyze (in particular into esters which can be hydrolysed physiologically). The salts can be formed by reacting the free acid with a stoichiometric amount of a suitable non-toxic acid or base I in an inert solvent, then isolating the desired salt, for example by lyophilization or precipitation. The esters, and in particular the esters which can be hydrolysed physiologically, can be prepared like the corresponding esters of penicillins and cephalosporins. The mixtures of isomers thus obtained can be fractionated into their constituent isomers according to the usual techniques. Mixtures of diastereoisomers, for example, can be separated by fractional crystallization, adsorption chromatography (on a column or in a thin layer) or by other suitable separation techniques. The racemates obtained can be split into their antipodes in the usual manner, for example by forming a mixture of diastereoisomeric salts with optically active salifying reagents, separation of the salts rln a o + -à η ό ^ -î a + - rlôiTGCPÛTnprit fipB f " ΓΥΠΤη O Q Q <3 T T "h TA Q to TlOTtï T> of the salts or else by fractional crystallization in optically active solvents.

The invention further relates to a process for preparing the compounds of formula I according to which a compound of formula is cyclized:?.

oi_tl p (q) 3 C02R "where Q represents" a phenyl or alkyl radical (lower), R11 represents an ester radical easy to remove and I and ï have the meanings given to them above, in an organic solvent inert at a temperature ranging from just above room temperature to temperature? ' rature of reflux of the solvent, the easily removable ester radical and possibly other protective radicals are eliminated in a known manner and in the case where Y represents a hydrogen atom, the product is converted, if desired, to another product of which Y does not represent a hydrogen atom, by reaction of this product with a corresponding electrophilic reagent in an inert solvent, in the presence of a strong base.

Another subject of the invention is embodiments in which compounds intervening as intermediate products are used as starting compounds and the other operating stages are carried out on these latter compounds, or else the process is interrupted at any stage. In addition, starting compounds can be used in the form of derivatives or can be formed. . ni * i ♦

The penemes in the form of the free acids which are the subject of the invention, as well as their pharmaceutically acceptable salts and physiologically hydrolysable esters have been found to be powerful broad-spectrum antibacterial agents useful for the treatment of infectious diseases caused in humans and animals by both Gram-negative and Gram-positive organisms. These compounds are also useful as dietary supplements for animal feed and as agents for the treatment of mastitis in cattle.

The penem-2-carboxylic acids and their physiologically hydrolysable esters and pharmaceutically acceptable salts which are the subject of the invention, that is to say the compounds of general formula I, where Y represents an atom of hydrogen have, by themselves, an antibacterial activity and are also useful intermediates (preferably in the form where the carboxyl radical is protected) for the preparation of 2,6-disubstituted penemes of formula I by formation of an anion and reaction with an electrophilic reagent.

Active compounds which are the subject of the invention can be presented in the form of pharmaceutical compositions comprising, in addition to the active constituent, a pharmaceutically acceptable diluent or vehicle. These compounds can be administered both orally and parenterally. The pharmaceutical compositions can be presented in solid form, for example in the form of capsules, tablets or dragees, or in liquid form, for example in the form of solutions, suspensions or emulsions. For the treatment of bacterial infections in humans, the active compounds of the invention can be administered by the oral or general route in the dark from about 5 to 200 mg per kg per day and preferably from about 5 to 20 mg per kg per day in several doses, for example in three or four doses per day.

They can be administered in the form of unit doses containing, for example, 125-250 or 500 mg of active ingredient with physiologically acceptable vehicles or diluents.

The subject of the invention is also a method for combating bacterial infections in animals, in particular homeotherms, according to which an acid of formula I or an ester hydrolysable by physiological route or corresponding pharmaceutically acceptable salt or a pharmaceutical composition comprising it is administered. to the infected host, the amount administered is sufficient to fight the infection.

You will find below examples of preparation! starting compounds and end products forming the object of the invention. All temperatures are given in ° G. For convenience, the examples are written using abbreviations, some of which are specified below.

ICS or GSI chlorosulfonyl isocyanate ether pet. petroleum ether P.Eb. boiling point R. M. IJ. nuclear magnetic resonance h time ether diethyl ether (unless indicated otherwise)

Diatomaceous earth gelite sold by the Company

Johns-Manville Products Corporation t.a. room temperature PHB p-nitrobenzyle * Π TP * r \ λ τ w 4- Λ * f * n o -î rvn HLA. or LAH lithium aluminum hydride n-BuLi n-hutyllithium.

MIBC or MIBK methyl isobutyl ketone

And C2H? -

Tr -C (C6V3

Me CE, - IHF tetrahydrofuran

Pix or 0 phenyl DMF dimethylfozraamide TEA triethylamine GPNB or PNB G p-nitrohenzyl glyoxylate PEH tetrahydropyrannyl ATF or TFA trifluoroacetic acid SEPT or HMPA hexamethylpho sphorotriamide

EtOAc ethyl acetate DMSO dimethyl sulfoxide j Ac GH ^ CO-

Ms CÏÏ3S02- DMAP 4-dimethylaminopyridine,

Py pyridine DAL or LDA lithium diisopropylamide DBu diazabicy clorundecene TD or DE diatom resistance TMS trimethylsilyl EXAMPLE 1.-

Aoide 2 '- (2' -diethylphosohono-11 -ethyl) penem-3 ~ carboxylic.

r ^ \ _ (CH2) 2 # - (OEt) 2

Yo2h

(EtO) 2-P- (CH2) 2C02CH3 -). (Et0) 2L {CH2) 2C02H -V

i 2

(EtO) 2P- (CH2) 2COCl - * (Eto) 2 ~ ^ ~ CH2) 2COSH

3 1 l A mixture of compound 1 (11.2 g, 50 millimoles) and 5 N sodium hydroxide (10 ml) is stirred under cooling in an ice bath for 15 minutes and at room temperature for 15 minutes. The mixture is extracted with ether and the extract is discarded. The aqueous solution is acidified with 5N hydrochloric acid, then it is extracted with methylene chloride to obtain, after drying and evaporation of the solvent, 10 g (95%) of compound 2 which is an oil whose EMET spectrum (CDCl ^) includes the following signals: 4-, 1 (4-ïï, m), 1,8 - 2,9 (4Ή, m) and 1,2 (6H, t).

Oxalyl chloride (2.7 ^ g or 1.88 ml, 21.5 mmol) is added dropwise to an ice-cold solution of compound 2 (2.26 g, 10.76 mmol ). The mixture is stored at room temperature for 6 hours, then evaporated to dryness. The traces of oxalyl chloride are removed by azeotropy with benzene to obtain 2.4 g (quantitative yield) of crude compound 3, the IR spectrum of which reveals the radical at 0 'OR.

1800 and 173? cm 1 and whose RM spectrum includes the following signals <$: 4-, 3 (4-H, m), 3.0 ~ 3.7 (2H, m), 2.0 - 3.0 (2H, m ) ,. l, 4- (6H, m). This compound is reacted with hydrogen sulfide and triethylamine in a conventional manner to obtain 1.9 g (80%) of compound 4- which is one. oil with an estimated purity of 80%. The RM spectrum of this latter compound comprises the following signals 6: 4-, 1 (4-ïï, q), 2,7 - 3 ,? (2H, m), 1.7 - 2 ,? (2H, m) and 1.33 (6ïï, t).

_ ° Ac? 9 - c ^ (CH,) _î (OEt).

| J '(EtO) 2l4- (CH2) 2 (!! s _ | ^ SvY ^ 3 2 2

0 ^ ~ NH 4 0J-N

1 6

It ,.

f

A 1 M solution of EaHCO 4 (10 ml) is added to compound 4- (1.9 g, 8.4-millimoles) while operating in a nitrogen atmosphere, then the compound is added? (0.813 g, 6.3 millimoles) in water (3 ml). The pH of the mixture is adjusted to 7-8 by the addition of a supplement of sodium bicarbonate. After allowing the mixture to stand for 4- hours, it is extracted with chloroform to obtain, after drying and concentration, 1.05 g (56.4 ·% based on compound 5) of solid compound 6, the PR of which is 64- - 67 ° and whose EM spectrum includes the following signals 5: 7.7 (ΓΓΗ), 5.3 (1H, q), 4-, 2 (4-H), 3.8 (1H, q) , 3.5 (1, H, q), 2.6 - 3.2 (2H, m), 1.7 - 2.4- (2H, m), 1.3 (6H).

S JCH î J (OEt) (CH) X (OEt)

rfY _. fYY

J— NH qJ— Ν-γβΗ

C02PNB

6 7

The mixture is heated to reflux in "benzene (6 ml), a mixture of compound 6 (260 mg., · 0.88 millimole) and p-nitrobenzyl glyoxylate (198 mg, 0.88 millimole) for 16 hours using a Dean & Stark apparatus for obtaining, after evaporation of the benzene, 14 * 53 mg of compound 7 which is a thick oil, the EM spectrum of which comprises the following signals 6: 8.3 (2Ï, d), 7.6 (2H , d), 5.3 - 5.7 ", * f, 9 (OH), if, 2 (IfH), 3.55 (1H, 'q), 3Λ (lïï, q), 2.5 - 3 , 2 (2H, m), 1.7 - 2.5 (2H, m), 1.3. (6h).

\ / pu, S / OFM 'e (CH) 1 * - (OEt).

πΎ Λ ’^ γ =,.

o ^ 'y1

L2PNB COpPNB

• day 8

Compound 7 is dissolved (50 mg, 0.88 millimole) in a 1 M solution of pyridine in tetrahydrofuran (0.9 ml). To the solution is added dropwise and with stirring with cooling in an ice bath, a 1 M solution of thionyl chloride in tetrahydrofuran (0.9 ml) and the mixture is stirred in the cold for 15 minutes and at temperature. ambient for * + 0 minutes. Benzene (10 ml) is added thereto, then the solid is filtered off. The filtrate is concentrated in vacuo to obtain ^ -63 mg (quantitative yield) of the crude compound 8, the EMU spectrum of which comprises the following signals 6: 8.3 (2H, d), 7.6 (211, d), 6, 1 (1H, s), 5.7 (1H, m), 5.3 (2H, d), \, 2 (> fH), 1.8 - 3.6 (6H, m), 1.3 ( 6h).

, (CH) i (OEt) S.. (CH) X (OEt)

rTY - rfY

C0 ^ -ΝγΦ3

CC ^ PNB C02PNB

8 9 To a solution of the crude compound 8 (M33 mg, 0.88 millimole) in tetrahydrofuran (h ml), triphenylphosphine (236 mg, 0.9 millimole) and 2,6-luti are added -dine (96 mg, 0.9 millimole), then the mixture is left to stand at room temperature for 65 hours. The mixture is filtered, then the filtrate is concentrated and the residual oil is chromatographed on a column of silica gel which is eluted with a mixture of ethyl acetate and 2% ethanol to obtain 203 mg (30.6%) of compound 9 which is an oil which, on standing, forms a solid whose P * 3? · Is • 126 - 128 °.

_. (CH_) J (OEt)

Ff Y -►) ï (oet)

3 d ^ -NY

1 CO GNP

C02PNB, 2 9 10

Is heated under reflux for 5 hours, a solution of compound 9 (V70 mg, 0.635 millimole) in. toluene (30 ml), then the mixture is concentrated and the residue is chromatographed on silica in ethyl acetate, to obtain 167 mg (56%) of compound 10 in the form of an oil whose spectrum IR includes signals for '0 = 1795, 171Ο cm 1 and whose RM spectrum includes the following signals 6: 8.3 (2H, d), 7.7 (2H, d), 5.7 (1H, m) , 5.38 (2H, d), H, 1 (H-ïï), 1.8 - 3.8 (6η), 1.35 (6H).

mt) 2 - ^ ojiq ^ i0Ec’2

C02PNB c02H

10 he

Sodium bicarbonate (9 mg, 0.107 millimole), water (1 ml) and 10% palladium on celite (60 mg) are added to a solution of compound 10 (59 mg, 0.126 millimole) in tetrahydrofurarme (3 ml) and ether (1 ml), f then the mixture is hydrogenated for 2 hours under 2, Hkg p pan cm. The product is isolated as usual to obtain 36 mg (86%) of compound 11 in the form of an oil, the IR spectrum of which (CHCl 3) includes signals for V = 1798, 173Ο, 1710 cm "1, and whose RM spectrum includes the following 6 signals: 9.0 (CQ2H), 5.6 (lïï, m), 4, * + (½), 3.6 (lïï, q), 3.15 (1H, q ), 1.7 - 3.0 (Η-H, m), 1.3 (6ïï).

EXAMPLE 2.-

6-acetoxymethyl-2-methylpenem-3-carboxylic acid.

AcO // "L'v | - \

C02H

Preparation of 1jl-diacetoxypropene.

(See R.W. McTeer, U.S. Patent _> 0Ac y ^ r— / hc

ics Acor ^ '1 i ^ Ac0 I I

Ac0CH2CH = CH-0hc -—> J dJH 4 I NH

cr cr 1 2a 2b

Procedure.

Chlorosulfonyl isocyanate (16.92 g, 0.12 mole) is added dropwise under cooling to -15 ° to the salt and ice bath of compound 1 (18.96 g, 0.12 mole The pale yellow mixture is kept at 5 ° PeD- ”for 5 hours during which it turns dark yellow.

The mixture is diluted with ethyl acetate (20 ml) and cooled to -30 °, then it is gradually added to a mixture of water (3, ** ml), ice ( 17.0 g), sodium bicarbonate (0.3 g) and sodium sulfite (3Λ g) cooled in a salt and ice bath. At the end of the addition, the resulting mixture is stirred vigorously for 20 minutes by adding small supplements of sodium bicarbonate to maintain the pH at 7 - 8. The layers are separated, then the aqueous layer is extracted with acetate ethyl (2 x OJ ml). The combined organic phase is dried (ïïa2S0 ^: EaHC0 ^ 1: 1).

The whole is filtered and the filtrate is evaporated to obtain 17.1 g of an oil. This is distilled under high vacuum (0.01 - 0.0J mm Hg) in a hot air bath (temperature 55 to 85 °) to separate the compound 1. The light brown oil is not distilled, it is taken up in ether and the solution is filtered through a mixture of Celite and charcoal to obtain, after evaporation to dryness, 5.28 g (22%) of an M-: l mixture of compounds 2a and 2b (as indicates the EMU spectrum) as a colorless oil. The EMU spectrum includes the following 6 signals: 7.25 (h, HH), 6.0 j = 6.5), 4.4- (1.5a, a, J - 4-, 5), 3.8 (0.25H, m), 3.5 (0.75H, m), 2.13 (3H, s), 2.1 (3H, s). The IR spectrum includes signals ^ C-0 = 1 ^ 80 and 174-0 cm ^ ·

. .OAC

Acc / N-f CH3COSNa ^ J ~ m * SAc .SAc a 2 AcO-'N_ / Αοο'Λ-f ^ -j '0Ac

_NH i-NH J- ~ NH

3a 3b 3c '

Procedure.

Sodium thioacetate is prepared by adding thioacetic acid (2.22 ml or 2.363 g) to a 1 M solution of "sodium bicarbonate (31.0 ml) in a nitrogen atmosphere. Sodium thioacetate is added to a solution r cooled in an ice bath and formed of compound 2 (5.2 g, 25.9 millimoles) and water (20 ml), then the mixture is stirred for 4 hours at room temperature. A little acetone (about 20 ml) is added to make the reaction mixture homogeneous. The acetone is removed from the mixture by concentration in vacuo, then the mixture is extracted with methylene chloride. The extract is dried and evaporated to collect 5.6 g (83.14%) of a mixture of the isomers 3a and 3b. The RiST spectrum of the crude oil reveals that the mixture comprises a trans compound and two cis compounds. A sample (550 mg) is chromatographed on silica gel (30 g at 10% water) which is eluted with the benzene-ether-methanol system in order to collect 200 mg of a mixture of the compounds 3a © t 3b in the ratio 7: 1, then 150 mg of a cis compound

Ί „__J ___ ΏίνΓΛΤ _____, ___ J___„ 4___n f 1? rftf J

J = 4.3) to which the structure 3c is provisionally assigned. The RM spectrum includes the following signals <5: 6.78 (H, HH), 5.52 (0.17H, d, J => e), 5.18 (0.83H, d, J "1.5 ), ^, 37 (2ÏÏ, d, J - 4,5), 3,45 (H, m), 2,35 (3H, s), 2,05 (3H, s) and the IR spectrum includes signals for ^ q_q = 1765, 1740, 1600 cnT ^.

ACO ^ V- / · “'V ~ {O ^ H2C02a' (0H) 2 ^ s NH - —V c

0 ^ N - <| H-OH

° CO PNB

2 2 ’i

Procedure.

The mixture is refluxed for 20 hours, collecting the water in a Dean & Stark trap, a mixture of the crude compound 3 (2.17 g, 10 millimoles) and * p-nitrobenzyl glyoxylate (2.5 g, 11 millimoles) in 200 ml of benzene, after which the mixture is concentrated in vacuo to collect 3.4 g of the crude compound 1+ in the form of an oil. This is used without further purification. The RM spectrum includes the following 6 signals: 7.5 - 8.5 (te), 5.2 - 5.8 (te), 3.4 - 5.1 (te), 2 - 2.4 (6H) and the IR spectrum includes signals for x? C_Q = 1665, 17 ^ 0, 1730, 1700 ouf1.

.—, N-CH — OH ^ N — CH — Cl co2pnb 0 co2pnb 4 5

Procedure.

Thionyl chloride (1.01 g, 8.5 millimoles) in benzene (10 ml) is added dropwise to an ice-cold solution of the crude 5 "compound (3.3 g, 7, 75 millimoles) and pyridine (0.67 g, 8.5 millimoles) in benzene (20 ml), then the mixture is stirred at the above temperature for 15 minutes and at room temperature for 15 minutes. the benzene solution and the residual semi-solid is washed three times with 15 ml aliquots of benzene. The combined benzene solution is evaporated to collect 1.90 g (55%) of compound 5-crude. The EMU spectrum includes the following S signals: 7.5-8.5 (W, 6.12 and 6.2 (lïï), 5.66 (1H, m), 5Λ (2H, d, J = 6), 3 - 7 (2H , m), 3.63 (H, m), 2, if (3H, d), 2.1 (3H, s) and the IR spectrum includes signals for

Vc = o = 1765, 17lt0 ’1730’ 1700 f ......

AcO ^^ j- ^ KC (Φ) 3P Anc / N- ^ J— n-Chci dioxane ’J — n - <ρ = ρ (φ) ^

0 ‘ŒLPNB

CO GNP 2 2 5 6

Procedure.

The mixture is heated at 55 ° for 18 hours, a mixture of the crude compound 5 (1.90 g, if, 27 millimoles), triphenylphosphine (1.572 g, 6 millimoles) and 2,6-lutidine (0.6if2 g, 6 millimoles) in dioxane (20 ml). The mixture is cooled, filtered and the filtrate is evaporated to collect 3.8 g of a dark crude oil. This is chromatographed on silica gel to obtain 1.2 g (if2%) of compound 6.

acct ^ N — f Ac aco '^ N — r ^ s \

I -V λ — CH

/ - «- ΓΡ (Φ) 3 3

C02PNB Vo2PNB

^. 7

Procedure.

A solution of the compound 6 hrut (1.20 g, 1.79 millimole) in toluene (15 ml) is heated at reflux for 5 hours. The solution is cooled and evaporated to obtain an oil which is chromatographed on silica (30 g) which is eluted with benzene to obtain 0.5 g (57%) of compound 7 ·

Analysis for ° 17ïï16W:

Calculated: C, 52.0M-; H, h-, 11; H, 7.1½%.

Found: C, 51.77; H, ^ 08; N, 7.30%.

The cis and trans isomers are separated by careful chromatography on silica gel (60 g) which is eluted with benzene. The cis isomer gives an EMET spectrum (ppm, CDCl · ^) comprising the following signals S: 7.5-8.5 (½ ^ aromatic), 5, ^ 7 (1H, d, J = 5, H-5 ), 5.28 (21, quadruplet AB, benzyl), ^ 33 (2H, d, AcOOHg), ^ 20 (1H, dt, H-6), 2.31 (3H, s, CH ^), 2.0 ( 3H, s, CH-, CO) and an infrared spectrum comprising signals for Ν? · Α = £) = 1770, 17 ^, 1730 cm "*. The trans isomer gives an EMET spectrum (ppm, CDGl ^) comprising the following δ signals: 7.5 “8.5 (½ ^ aromatic), 5.53 (1H, d, J = 2, H-5), 5.30 (2H, quadruplet AB, benzyl), ^ 32 ( 2H, d, Ac0CH2), ½, 27 (ÎH, dt, J = 5, J = 2, H-6), 2.31 (3H, s, CH-,), 2.0 (3H, s, CH-, C0) and an infrared spectrum including signals for vc-0 = 1 ^ 70, 17 ^, 1730 cm

Acd'- "''] H Pd / C Acl / Vv <Ç CH

o ^ _I / - “3 Hagc03— ^ 3 CO ^ NB CO ^ Na 2 J.

Procedure.

Sodium bicarbonate (25.2 mg, 0.3 millimole) and palladium on carbon (110 mg) are added to a solution of trans isomer 7 (119 mg, 0.3 millimole) in acetate. ethyl (15 ml) and water (7 ml) and the hydrogenation is carried out for 4 hours and 30 minutes at 2.11 kg per cm. The mixture is then filtered and the layers are separated. The aqueous layer is washed with ether, then lyophilized to obtain 40 mg (48%) of the solid compound 8. The IR spectrum includes signals for O q_q = 1765} 1740, \ 1600 cm '"' 1 'and the NMR spectrum (ppm, D ^ 0) includes the following signals: 5jÎ? 2 (1H, H-5), * +, 85 (2H, AcOCELQ, 4.0 (lïï, H-6), 2.65 (3H, CH3), 2.40 (3H, CH300).

C02Na 'co H

£ ‘'n

Procedure.

Using cold hydrochloric acid 1 R, a solution of the crude trans isomer 8 (100 mg) is acidified in cold water (2 ml) and then extracted with chloroform. The extract is dried (la ^ SO ^) and evaporated to obtain 30 mg of a pale yellow solid having a PP of 111 - 1 Ί 20 ανοΛ riAAnrrmAci -hï nn _ Τ, ο ση »Λ +: τ > ρ TR ρ.ητητνρρη ri γΙαη ri οτιοπυ for V = 1780, 17!? 0, 1680 cm (pure) while the IR spec (tre) includes signals for Ό G = 0 “^ 775 (strong), 17 * + !? and 1670 cm 1.

The treatment of p-nitrobenzyl 6-acetoxymethyl-2-methylpenem-3-carboxylate carried out as above gives the cis isomer of the sodium salt and of the free acid. EXAMPLE 3 - 6- (2 '-hjdroxyisopropyl) -2-methylpenem-3-carboxylate, potassium (process with anion).

/

Seen

0 t02K

/TV".

CO H ^ + CO K

2 K Λ 1 4a

A solution of acid 1 (116 mg, 0.627 millimole) in anhydrous tetrahydrofuran (½ ml, freshly distilled on lithium aluminum hydride) is added dropwise at -78 ° to a solution of lithium diisopropylamide ( prepared from 7 °, 7 mg or 98 microliters or 0.699 millimole of diisopropylamine and 0, hh0 ml of 1.6 M n-butyllithium or 0.70½ millimole per 30 minutes of stirring at -78 °) in tetrahydrofuran (2 ml). The mixture is stirred for 5 minutes, then diisopropylamine (70.7 mg or 98 microliters, 0.699 millimole) and 1.6 H n-butyllithium (0.1 + 1 + 0 ml, 0.70½) are successively added thereto. millimole) at -78 °. The mixture is then stirred for 10 minutes at 78 ° and acetone (5 ml) is quickly added to it. The mixture is allowed to react with acetone for 10 minutes. It is acidified to 2% with 1% hydrochloric acid, then diluted with ethyl acetate (4-0 ml) and washed with brine (3 x 20 ml) . The organic phase is dried over sodium sulfate. By evaporation of the solvent, 90 mg of crude or compound residue (3a) is obtained which is taken up in methylene chloride.

The crude acid is dissolved in methyl isobutyl ketone (2 ml) and a solution of potassium 2-ethylhexanoate is added dropwise to the solution. Two lots of the potassium salt (36.5 mg, 26%) are thus obtained in the form of a mixture of cis and trans isomers, in which the trans isomer is predominant. The EMU spectrum (ppm, hexadeutero-dimethyl sulfoxide) includes the following signals 6: 5d60 (1H, d, J? _6 ois -> *, h-5), 5.55 (1H, a, J5_6 trans - 2, I h -5), 3.93 (1H, d, σ6_5 ois = Μ-, H-6), 3.62 (1H, d, J6-5 trans = 2 'H_6>' 3.50 (si, OH), 2.3M- (3H, s, CHj), 1Λ7, ΙΗΟ (6H, 2s, 2CH3), 1.35, 1.32 (6H, 2s, 2CH,), the IR spectrum (nu.jol) includes signals for \? r, _, = 1765,

1582 cm ^ and for = ^ 600 - 3100 cm ^ and the UV spectrum

(EtOÏÏ) includes λ max at 257 nm (ε = 3920) and 300 nm (ε = 4-020).

EXAMPLE h.- 6-Hydroxybenzyl-2-methylpenem-3-potassium carboxylate, (process with anion).

V

HoXrrVcH3 CO K 2 rö — 3 Tct? -— w> xq ^^ \ or ß \ o, k 2 2 1 4b

A solution of acid 1 (100 mg, 0.5 ^ 0 millimole) in anhydrous tetrahydrofuran (6 ml ', distilled over aluminum hydride bed) is added dropwise to a cold solution (-78 °) of lithium diisopropylamide (prepared from 84 microliters, ie 60.6 mg or 0.599 millimole of diisopropylamine and 0.380 ml or 0.608 millimole of 1.6 M n-butyllithium) in tetrahydrofuran (2 ml). The mixture is stirred for 5 minutes, then diisopropylamine (successively 8½ microliters or 60.6 mg or 0.599 millimole) and 1.6 H n-butyllithium (0.380 ml, 0.608 millimole) are successively added thereto. The mixture is then stirred for 7 minutes at -78 ° and 300 microliters of benzaldehyde are quickly added thereto. The mixture is left to react at -78 ° for 20 minutes. It is acidified to a pH of about 2 with 1% hydrochloric acid, then diluted with ethyl acetate (^ 0 ml) and washed with a 1: 1 mixture. water and brine (3 x 20 ml) and with brine (1 x 20 ml). The organic mixture is dried over sodium sulfate. By evaporation of the solvent, a residue is obtained which is dissolved in methyl isobutyl ketone (2 ml). A solution of potassium 2-ethylhexanoate is added dropwise to this solution. 35 mg (20%) of compound 4b are thus obtained in the form of a diastereoisomeric mixture. The EM spectrum (ppm, hexadeuterodimethyl sulfoxide) includes the following signals S: 7? 95 (5 ^ 5 s, aromatic H), 5.57 (d, J ^ _6 trans = 1.5, H-5), 5 , 1 + 5

Cd 'J5-6 trans = ^ H ""'? .35 (d, Jj_6 cis = ^ H-?), 5.0 (m, GH hydroxÿbenzyle), 4-, 25 (dd, cig = 4-, J6 ~ CH hydroxybenzyle = 10 '5 3.90 (m, ïï-6), 3.65 (si, OH), 2.35 (3H, 2s, OH ^), the spectrum IE (nujol) includes signals for " 0 C = Q = 1760, 1590 cm-1 and for Vqjj = 3600 - 3100 cm "1 and the UV spectrum (H ^ O) includes at 252 nm (ε = 5100) and 296 nm (£ = 3300).

EXAMPLE 5.- 6 ^ -Ίlhiomβthyl · -2-methyl · penem-3-oar'boxylate potassium.

Çprocedure with anion).

SMe

CO K

__2_______

> rf> CH3 -—- * LT V-CH

ch3sso2ch3

W + CO K

2 K 2 1 4c

A solution of acid 1 (100 mg, 0.54-0 millimole) in anhydrous tetrahydrofuran (5 ml, distilled on lithium aluminum hydride) is added dropwise to a cold solution (-78 °) of lithium diisopropylamide. (prepared from 84 microliters, ie 60.6 mg or 0.599 millimole of diisopropylamine and 0.380 ml or 0.608 millimole of 1.6 H n-hutyllithium) in tetrahydrofuran (2 ml). The mixture is stirred for 7 to 8 minutes, then diisopropylamine (84 microliters or 60.6 mg or 0.599 millimole) and 1.6 M n-butyllithium are successively added thereto.

(0.380 ml, 0.608 millimole). The mixture is stirred for 7 minutes at -78 ° and an excess of methyl thiomethylsulfonate (300 microliters) is rapidly added thereto. The mixture is allowed to react at -78 ° for 5 minutes. It is acidified to about 2% with 1% hydrochloric acid, then diluted with ethyl acetate (4-0 ml) and washed with a 1: 1 mixture of water and brine (3 x 20 ml) and with brine (20 ml). The organic solution is dried over sodium sulfate. By evaporation of the solvent, a residue is obtained which is dissolved in cold methyl isobutyl ketone (2 ml). A solution of potassium 2-ethylhexanoate is added dropwise to the cold solution. 4-0 mg (28%) of compound 4-c are thus obtained in the form of an 8: 3 mixture of the cis and trans isomers having a P.P. (decomposition) of 115 ~ 120 °. The EMT spectrum (ppm, hexadeu-terodimethylsulfoxide) includes the following signals 6:, 5.85 (1H, 4, J5_6 is = 4, H-5), 5.57 CXH), d, J? _6 trans = 1, 5, H-5), 4.87 (1H, d, J6_? Ois = 4, H-6), 4.72 (1H, d, J6-5 trans = 1> 5> H_6) '3, ^ 2 . (si, OH), 2.37 (s, SCH ^, 2.33 (s, CH,), 2.25 (s, SCHj). the IR spectrum (nujol) includes signals for V, 0 = 1770 and 1600 cm ^ and the ITV spectrum includes "X at 252 nm (g = 4200), 297 (£ = 3700) ·

fflctX

EXEMPIÆ 6, - 1- (p-Hitrobenzyloxycarbonylmethyltriphenylphosphoranyl) -4— (argentomercaptidyl) -2-azetidinone.

.SAg ο ^ ΪγΦ3 co2pnb STr. OAc / _ / TrSH 1

NaOMe * J— N „i. -

A suspension of triplienylmetliylmercaptan (13.8 g, 0.05 mole) in methanol (90 ml) is degassed for 30 minutes using a stream of nitrogen. The mixture is cooled to 0 ° and little by little sodium hydride is added thereto (2.5 g, ie 0.05 mol, 50% dispersion in oil).

The resulting solution was stirred for 5 minutes, then β-acetoxyazetidinone (7.7 g, 0.059 mole) in water (55 ml) was quickly added thereto. ^ Triphenylmethyl-mercaptoazetidinone 2 precipitates immediately. The mixture is stirred for ^ hours at room temperature. The solid is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate to isolate with yield 89.8% the compound having a PE of 1 ^ 6.5 - 1V7.5 °.

Analysis for ¢ ^ 22 ^ 19 ^ 0 ^:

Calculated: C, 76, ^ - 9; H, 5.5 ^ 5 E, 05; S, 9.28%.

Found: 0.76.5 ^; H, 5.60; .H, M-, 00; S, 9.36%.

The EM spectrum (ppm, CDCl ^) includes the following δ signals: 7.60 - 7.10 (15H, m, H-trityle), 4.62 (1H, si, NH), (1H, dd, Jlt_3 trans = 3.0, J ^ 3 oi6 = i, H-Jf), 3.24- (1H, ddd 'Jgem = J3-1 + ois ”J3-HH” 1'8 ”2.81 (1H, ddd, Jge.m - -15, J3Jt trans ”3'0 'J3-HH = H-3) and the spectrum IE (CHC1-.) Includes signals for V = 1760 cm ^ and = 335-0 cm __ ÇHO ßTr ^ STr _ / tt ÎO PNB r —f r- <

D 2, ► OH + J_1 OH

J—] ννη ο ^ ~ νΎ c / -

CO PNB CO PNB

2 · * 3. 2

Heated p-nitro-benzyl glyoxylate hydrate (5-, 55- g, 0.02 mole) and azetidinone 2 (6.90 g, 0.02 mole) in benzene are heated to reflux for 2 hours. using a Dean & Stark trap containing 3A molar sieve. Glyoxylate supplements (2 x k ^ k mg, 2 millimoles) are added while maintaining reflux for 18 hours after each addition. The mixture is diluted with ether, washed with 5% aqueous hydrochloric acid, water, 5% aqueous sodium bicarbonate, water and brine. The organic phase is dried over magnesium sulfate (12 g, quantitative yield). A small fraction of the spinal mixture is separated on a plate of silica gel (methylene chloride-ether 6: 5 ·). Isomer A:

Rf = 0.87, P.E. 170.5 - 171.5 °.

the NMR spectrum (ppm, CDCl 4) includes the following signals: 8.07 (2H, d, J = 9, aromatic im), 7.5-5 (part of d, aromatic Ho), 7.5-0 - 7.00 (15e1, m, trityle), 5r 25 (2H, s, · CH2-PHB), 4-, 75 (1H, s, HC-0), 5-, 37 (1H, dd, ^ trans = 3, J3 ^ ois * · H = 3)> 2'83 (1H> dd> Jgem = l6 · V3 ois - ^ H-ll ·), 2.10 (1H, dd, Jgem = 16, trang. 3 , H-4), 1, ^ 2 ('si, OH) and the IR spectrum (CHGl ^) includes signals for ^ q_q = 1770 and 176Ο cm- "' '(shoulder),

Oj, 0 = 1525 cm-1 Bt -J0H = 3W c "" 1.

Isomer B:

The NMR spectrum (ppm, CDCl 4) comprises the following signals 6: 8.13 (2ÏÏ, d, J = 9, aromatic Hm), 7, k7 (2H, d, J = 9,

Aromatic Ho), 7, k0 “7.00 (15H, m, trityle), 5.30 (3H, s, ch2-pnb, H-C-0) ,. M5 (1H, t, J = 3.5, Ξ-4), 2.90 - 2.70 (2ÏÏ, AB part of ABX, HM ·), 1.55 (if »OH) and the IR spectrum (GHGl ^) includes signals for ''? c_Q = 1767, 1755 cm “1 (shoulder), n? N02 = 1525 cm ^ and ^ 0H = 3500 cm“ 1.

.STr ^ STr r-f <S0C12 r ~ [OH Uridin. / -Ηγ “

L CO PNB

CC ^ GNP 2 3 4

Pyridine (1.9 g, 2 ^ -, 1 millimoles or 1.94 ml) is added to a cold solution (-15 °) of azetidinone 3 ^ (12 g, 21.7 millimoles) in 150 ml of tetrahydrofuran dried on molecular sieve and operating in a nitrogen atmosphere, thionyl chloride (2.86 g, 2k millimoles, 1.88 ml) is added dropwise. The mixture is stirred for 4-5 minutes at -15 ° · The precipitate is separated by filtration and washed with Benzene. By evaporation of the solvent, a residue is obtained which is taken up in benzene and to which activated carbon is added to finally isolate 11.7 S (9k%) of the desired compound after crystallization from chloroform. The NMR spectrum (ppm, 0DCl ^) includes the following δ signals: 8.17 (2H, d, J = 8, aromatic Hm), 7.67 - 7.00 (17H, m, aromatic Ho, Ir-ïï) , 5.80 (s, HC-Cl), 5.37, 5.33 (2s, HC-Cl, CH2-PEB), Ml (1Ξ, m, H-4-), 3.27 -2, kO (2H, m, ïï-3) and the IR spectrum (film. KBr) includes signals for \? C_0 = 1785, 1770 cm “1 and = 1-525 cm 1.

_ ^ STr p _ ^ STr J 2,6-lutidine QJ—

CO ^ NB _ CQ2PNB

1 5

Triphenylphosphine (7.86 g, 30.0 millimoles) and 2,6-lutidine (2.36 g or 2.56 ml, 22.0 millimoles) are added to a solution of chloroazetidinone b (11, 6 g, 20.2 millimoles) in tetrahydrofuran (100 ml, distilled on lithium aluminum hydride). The mixture is heated at reflux for 72 hours. The precipitate is collected by filtration and washed with ether. The organic solution is washed with 2% aqueous hydrochloric acid and 5% aqueous sodium bicarbonate, then dried over magnesium sulfate. By evaporation of the solvent, a residue is obtained which is purified by passage over silica gel (200 g). The desired phosphorane is eluted with mixtures of 30, U-0 and JQfo of ether in benzene to collect 11, if g (70, ½%) of the desired compound having a pH of 201-202 °.

'Analysis for

Calculated: C, 73.57 *, H, 5, OR ·; N, 3.50; S, U, 01%.

Found ·: C, 73.58; H, U, 91; H, 3, UU ·; S, 3.87% · the IR spectrum (CHCl ^) includes signals for = 17M-0 cm'1, v? PhosphoraM = 1620 and 1610 cm'1 and = 1525 cm “1.

._i AgN03 _ ^ SAg J- Ν ^ ΡΦ3 Pyridine J ^ N Ρφ3

CO PNB I

2 CO.PNB

2 5 6

4 ™ tritylmercaptoazetidinone 5 (1.6 g, 2 millimoles) is dissolved in methylene chloride (20 ml) and the solvent is removed at 55-60 °. The phospho-rane 5 is dissolved at 55-60 ° in methanol (32 ml) preheated to 55-60 °. Immediately after the formation of a methanolic solution of compound 6, a mixture preheated to 55 "" 60 ° of methanolic 0.15 M silver nitrate solution (16 ml, 1.2 equivalents) and py ~ ridine (17 * + mg, 178 microliters, 2.2 millimoles, 1.1 equivalent) The hain marie is immediately removed and the mixture is stirred at room temperature for 2 hours and at 0 ° for 1 hour. The silver mercaptide 6 is filtered off, which is washed twice with methanol at 0 ° and three times with ether to obtain the desired compound (1.12 g, 84-, 5%) having a PE of 130 - 35 (decomposition).

The IR spectrum (CHGl ^) includes signals for V C_Q = 1795 "Y 1725 cm-1 (shoulder), \ 3 phosphorane = 1620> 1660 cm" 1 and VMo2 = 1530 O "-1.

EXAMPLE 7. 1- (p-iritrobenzyloxycarbonylmethyltriphenylphosphoranyl) -1t— (argentomercaptidyl) -2-azetidinone.

I-S 3 K, COv * 9K03 r — S

MeOH J-N

0 ^ fFph3

COOPNB

7 i

A solution of phosphorane 7 (1.796 g, 3.0 millimoles) in chloroform (3 ml) is diluted with methanol (90 ml) and cooled to 0 ° in an atmosphere.

'of nitrogen, then successively adding ar- σοηΊ- (C \ Cl cr \. O nri 1 Ί i πιηΊ pr'1 (=> +: dn f'.aThnnatfl de. nn-ha aoinm) (0.33 g, 2.4 millimoles) The reaction mixture is stirred, protected from light, at 0 ° for 15 minutes, then the cooling bath is removed and stirring is continued for 3 hours. the reaction mixture is cooled to -10 ° and stirred for 1 hour, then filtered, after which the silver mercaptide is washed successively with cold methanol and ether to give 1.91 g ( 96%) of the compound having a PF of 138-145 ° and whose IR spectrum (nujol) comprises signals at 174-8, 1620 and 1605 cm-1. By preparative thin layer chromatography (ethyl acetate), obtains the analytically pure compound having a PP of 14-0 - 145 ° (decomposition).

Analysis for C ^ Hp ^ NpO ^ SPAg:

Calculated: C, 54.31; H, 3.65; U, 4 ·, 22; S, 4-, 83%.

Found: C, 54.11; H, 3.48; N, 3.92; S, 4-, 62%.

EXAMPLE 8, i 1- (p-Uitrobenzyloxycarbonylmethyltriphenylpho sphoranyl) -4- (argentomercaptidyl) -2-azetidinone.

A. Use of aniline as a base.

SCOCH, .SAg

j f J aniline / AgNO ^ p — J

J — N MiÔH * / —N

0 ^ ^ = PPh ^ 0 ^ “C = PPh3

COOPNB COOPNB

1 6

A solution of phosphorane 7 (1.8 g, 3.0 millimoles) in chloroform (4 ml) is diluted with methanol (90 ml) and the solution is cooled to -15 ° in a nitrogen atmosphere, then there is successively add silver nitrate (0.56 g, 3.3 millimoles) and aniline (1.5 ml, 16.5 millimoles). The reaction mixture is stirred in the dark at -15 ° for 30 minutes, then the cooling bath is removed and stirring is continued for 2+ hours. The reaction mixture is cooled to -10 ° and stirred for 1 hour before filtering, then the silver mercaptide is washed successively with cold methanol and ether to obtain 1.55 g (77.9 %) of the compound having a P.] ?, of 11 * + - 115 °, whose spectrum IE (nujol) reveals the identity with the compound of example 7 · 1- (p-Hitrobenzyl-2'-triphenylphosphoranylidene -2'-acetate) - 2- silver azetidinone-4-thiolate.

B. Use of 4 - dimethylaminopyridine as a hase.

0SCOCH SAg

3 _AgNOyDMAP | -S

νγ ^ Φ3 CH2C12 / CH3OH <y N '^ ί> Ρφ3

CO.PNB CO PNB

6 *

A solution of the above S-acetylphosphorane (17.96 g, 30 millimoles) in a 1: 2 mixture of methanol and dichloromethane (* + 50 ml) is purged with nitrogen for 5 to 10 minutes. cooled to 5 ° and silver nitrate (5.35 g, 31.5 millimoles) and 4-dimethylaminopyridine (3.85 g, 31.5 millimoles) were successively added thereto. The ice bath is removed and the solution is heated at high reflux for 2 hours, then stirred at room temperature for 1 hour. Charcoal is added to the colored reaction mixture, filtered and the filtrate is evaporated The residue is redissolved in the minimum amount of dichloromethane and the solution is added dropwise and with stirring to cold methanol (300 ml). The precipitated silver salt is collected by filtration and washed with ether. and dried to obtain it in the amount of 18.1 g (91%); its IE spectrum (CHCl 4) includes signals for = 174-5 (0 = 0 of ß-lactam and 1β07 cm ™ 1 (0 = 0 ester).

1- (silver p-nitrobenzyl-2 1 -triphenylphosphoranylidene-2 “-acetate ') -2-azetidinone-4-thiolate.

C. Use of diazabicycloundecene as a base.

ä9Bo3 J- iy *, ~ 555Γδϊ55> oJ_> 1 Ρφ3

C02PNB CC ^ PNB

The above S-acetylphosphorane (36.0 g, 0.60 millimole) is dissolved in methylene chloride (120 ml). The solvent is evaporated to obtain an oil. The residual oil is dissolved in 24-0 ml of hot methanol (35 °) and a methanblipue solution (420 ml) of silver nitrate (10.68 g, 62.8 millimoles) is quickly added. The resulting solution or suspension is stirred for 5 minutes at room temperature, cooled in an ice bath and added to J? minutes, a solution of diazabicycloundecene (8.96 ml, 60 millimoles) in methanol (20 ml). The mixture is stirred for 5 minutes. The solid is collected by filtration, washed once with 0 ° methanol and ether, then dried under vacuum to obtain 37.0 g (93%) of the compound including the IR spectrum (nujol) includes signals Ό_β__ (C = 0) and at 1600 cm ^ (phosphorane).

R · Use of pyrrolidine as a base.

1- (p-Nitrobenzyl-2 / -triphenylpho sphoranylidene-2 n-acetate e) - 2- azetidinone-4-thiolate silver.

SCOCH _sShq j —- j pyrrolidine_ J j J — N A9N03 0 ^ ~~ N ^ C = PPh, 0 ^ C = PPh. J | 3 I 3 COOPNB -

COOPNB

To a 0 ° solution of ^ -acetylthio-1-ip-hi ^ 0 “benzyl-2 ,, - triphenylphosphoranylidene-2 ,, - acetate) -2-'azetidinone (0.60 g, 1.0 millimole) in methylene chloride (2 ml) add methanol (½ ml), a solution of silver nitrate in methanol (0.1½ ΪΓ, 7.86 ml, 1.1 millimole) and a pyrrolidine solution (0 , 92 ml, 1.1 millimole) in methanol (2 ml). The cooling bath is removed and the reaction mixture is stirred for 105 minutes, then cooled to -10 ° and stirred for 15 minutes before filtering. The solid is washed with cold methanol and dried under vacuum to give 0.5 ^ 8 g (82.5%) of the compound having a P.3 ?. of 115 ° and whose IR spectrum (nujol) includes signals for V = 1755 (0 = 0) and 1600 cm ^ (aromatic radicals).

EXAMPLE 9 - l-ln-Nitrobenzvl 2 ’-Trit) hénvlr) hosphoranylidene-2" -acetate) -2-azetidinone - ^ - mercury (II) thiolate.

S7x.

rf. rf "1’ ’J-N J_M PPÏ1- ® Ns'C = PPh CT ν '3 I 3 il

CO ^ pNB j CO ^ PNB

! "

Do we cool to 5 °? a solution of compound I (2½ g, 3 millimoles) in dichloromethane (15 ml) and a solution of mercuric acetate (0.525 S> 1.65 millimole) in methanol (15 ml) is added thereto. After 2 hours of stirring at 5 °, the solvent is evaporated and the residue is redissolved in dichloromethane, then the solution is washed with cold water. After drying over magnesium sulfate, carbon is added to the organic solution and filtered, then the filtrate is evaporated to obtain a foam which is crystallized by trituration from ether. 1.73 S (91%) of the compound thus having a P.E. of 123 ° 127 ° and (V ^ q of β-lactam) and 1608 cm 1 (phenyl radical) are thus obtained.

EXAMPLE 10 2-Metii7 / -pénème-3-O-nitrobenzylcarboxylate (from the intermediate mercaptide).

| -S 2 g 2CH3C0C1 2 | - ^ SC0CH3 or — N ^ Y ^ PPh3 Pyridine </ ^ Ν \ ^ * ΡΚ3

C02PNB C02PNB

- 11 III

Stirred for 1 hour, a solution of compound II (262 mg, 0.2 millimole), acetyl chloride (35 mg, 0, ½½ millimole) and 2 drops of pyridine in 10 ml of dichloromethane. The precipitated mercuric chloride is filtered off and the filtrate is washed successively with cold dilute hydrochloric acid, with sodium hydroxide and finally with brine. The organic solution is exposed for 2 minutes to a stream of hydrogen sulfide at 5 ° and the solution is stirred at this temperature for another 10 minutes to precipitate the last traces of mercuric salt. We add a little thistle to the black mixture which we filter on Oelite. By evaporation of the clear filtrate, 193 mg (80.7%) of compound III are obtained in the form of a frothy material. The IR spectrum (CiCl) comprises signals at 1755 cm 1 (V c_0 of β-lactam), 1692 cm "" 1 (gQ0Qg;) e_b 1620 (phenyl radical).

PU - .iCb

I “„ „„ CO_PNB

C02PNB 2

The phosphorane III (75 mg, 0.126 millimole) in toluene (10 ml) is heated at reflux in a nitrogen atmosphere for 150 minutes. By evaporation of the solvent, then purification of the residue, a crystalline derivative (25 mg, 63%) is obtained, the physical and spectroscopic properties of which are in perfect agreement with those of the desired compound.

If desired, the compound IY can be subjected to hydrogenation (Celite palladium 30%) to obtain the corresponding 3-carboxylic acid.

EXAMPLE 11.-

2-aminomethylpenem-3-carboxylic acid (from the intermediate mercaptide).

\: ooh

F

JSCOCH N

r — r ^ A9 C1C0CH> NT fl LL ° λ

O ^ C = PPh_ I

1 J COOPNB

COOPNB

2 1 -

A solution of silver mercaptide 1 (1.25 g, 1.99 millimole) in dichloromethane (15 ml) is cooled to 0 ° under a nitrogen atmosphere and a 2 M solution is added dropwise. azido-acetyl chloride in dichloromethane (1.13 ml, 2.26 millimoles). The reaction mixture is stirred at 0 ° for 1 hour, then the cooling bath is removed and stirring is continued for 5 hours. The reaction mixture is filtered through Celite. the solids are washed with dichloromethane (35 ml). The filtrate and the washing liquors are combined and washed with a sodium bicarbonate solution, then water, after which they are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an orange syrup than purified by chromatography on a column of silica gel No. 60 (30 g) which is eluted with ether. 2% ethyl acetate (200 ml), 6% ethyl acetate ether (200 ml) and 20% ethyl acetate ether (500 ml), volume of the fractions being 10 ml.

By recombination and evaporation of fractions k9 to 80, 0.73 g (60.8%) of a yellow powder is obtained having a P.P. of 61 - 70 °.

SCOCH.N, ^ .s rf —â — ► À — N. toluene

O | = pp-h3 COOPNB

COOPNB

2 3

A solution of phosphorane 2 (0.593 g, 0.93 millimole) in toluene (20 ml) is heated at 105 ° for 1 hour, then cooled to 23 ° and concentrated to obtain a semi-crystalline compound which purified by chromatography on a column of silica gel No. 60 (12 g) which is eluted with benzene (100 ml) of benzene with 2% ether (100 ml) and benzene with ether, the volume of the fractions being 10 ml. By combining and evaporating fractions 18 to 26, a yellow syrup is obtained which crystallizes at rest by depositing 0.18 g (53.7%) of the compound melting at 127 - 128 ° and whose EMET spectrum (CDCl 4) comprises, the following signals δ: 8.22 (2ÏÏ, d, <T-go πτη = 8.8 Hz, Ho of p-nitrobenzyl), 7.60 (2ÏÏ, d, Ho = 8.8 ________ „„ T „\ rr "Γ7Ί / HT ^ JT £ XJr-r T - 2.1 Hz, H-5), 5.33 (2H, center of qAB, J = 14.0 Hz, p-nitrobenzyl CH2), 4.58 (2H, center of qAB, J, = 15> 0 Hz, CH2 in C-2), 3.88 (1H, dd, J6)? Ois = 3.6 Hz, Jgem = 16 ,? Hz, H-6 ois) and 3, ?? (1H, dd, fcraJ13 = 2.1 Hz, Jgea = 16 ,? Hz, ïï-6 trans), while the IR spectrum (nujol) includes signals at 2115 and 2090 cm * " (H ^), 1780 cm ** "(C = 0 of ß-lactam) and 1685 cm" · * · (G = 0 of p-nitrobenzyl ester).

By preparative thin layer chromatography, an analytical sample is obtained, melting at 127 ° 128 °.

Analysis for C] _ 4 ^ 1 ^ 0 ^ 3:

Calculated: C, 46.54; H, 307; -H, 19.37; S, 8.87%.

Found: C, 46.43; H, 3.08; H, 19.37; S, 8.90%.

1 f V-CH N ... »CHJiH

2 3. THF, ether, H20 2 2

tOOPNB \ 00H

1 4 l '' 'To a solution of peenE3 (0.18 g, 0.5 millimole) in tetrahydrofuran (6 ml), successively add ether (6 ml), water (6 ml) and 30% palladium celite (0.18 g). The reaction mixture is subjected to hydrogenation at 2.11 kg per cm at 23 ° for 150 minutes, then filtered through Celite, after which it is washed with water and the filtrate is combined with the washing water and all washed with a mixture of ether and tetrahydrofuran before lyophilization giving 30 mg (30%) of compound 4. [The insoluble compound is dissolved in water and ether in chloroform and the organic solution is washed with water, then dried over anhydrous sodium sulfate. By evaporation of the solvent under reduced pressure, 77 mg (42.8%) of _ ______ * d -, ✓, -1 ~ r 1 txtvttvt / »n are obtained. * j · _ *, -i__ sulfoxide includes the following signals 6: 5.7 (dd, J5-6 cis = 3.5 Hz, J ^ _6 trans = 1.5 Hz, H-5), the spectrum IE ( nujol) includes signals at 1775 cm-1 (C = 0 of ß-lactam) and l6l5 and 1585 cm, while the UV spectrum includes λ ^ Ιχ to 300 ψ (ε = 2320) and 307 y (ε = 2685 ).

The title compound H · is also obtained from intermediate 3 as follows:. I r'S H .Pd / D.E. —R ^ s \

I λ-CH M -2 -.- Ù— ~ CR _ NH

J — 2 3 THF, ether, -N 2 2

'COOPNB 2 COOH

2!

30% palladium on diatomaceous earth (b, 8 g) is added to a solution of the penem 3 (2, H.g, 6.89 millimoles) in a 1: 1: 1 mixture of tetrahydrofuran, ether and of water (165 ml). The reaction mixture is hydrogenated at 23 ° for 150 minutes under a pressure of 3.16 fcg per cm, then the whole is filtered through Celite.

The filtrate and the washing liquors are combined and the whole is washed twice with ether, then centrifuged. new mixture and filtered several times to obtain a clear solution which is lyophilized in order to isolate 0.622 g W%) of the compound. The crystallization of this compound is induced by addition of water (0.8 ml), then the suspension is centrifuged and the water is separated to collect an orange solid. This is washed twice with water to obtain, after drying, 0.273 mg (19.8%) of a light yellow solid whose spectrum W comprises at 307 mp. (£ = * + 318) and 257 τψ- (8. = 2650). A certain quantity of starting compound is collected (1.2 g, 5%) · ° n can also purify the compound (50 mg) by chromatography on a column of m Λ A /. S 1 * -, «« Jl _ Ί / - \ __- I _____1_______ which is eluted with distilled water, the volume of the fractions being 1.5 ml and the quantity observed being the index

H O

refraction) - The UV spectrum includes X ^ at 307 mu max / (£ = 3597) and 255 mpa (e = 24-24 ·).

The stability of the compound is checked in an aqueous medium: by measuring the spectrum IV, the results being collected below: UV = 6 h 307 (ε = 354-5) and 255 (ε = 2773) 21 b 307 (ε = 3 ^ 67) and 255 (É = 24-11) 28 h 307 (ε = 3337) and 254 -. (S = 2398) 4-6 h. 307 (g = 3259) and 25½ (ε = 2398) 70 h 307 (e = 3076) 9b h 307 (ε = 284-2) 170 h 307 (ε = 1900)

A sample of compound 4- is stored at 23 ° for 3 days and the U? Spectrum is raised again. which 0 * includes at 307 mp. (£ = 3055) and 255 mp- (ε = 2008).

The compound 4- is converted as described below into two other 2-penem derivatives.

1.

-r "S \ © NaHCO, H O, - / H

οίΧ / - ° ΗΛ "0XX> Wch 0 - CH3J-0And ΛΑ® 1 5 To a suspension of compound 4: (50 mg, 0.25 millimole) in distilled water (0.5 ml), add 1 equivalent of sodium bicarbonate (21 mg) followed by ethyl acetimidate (21.8 mg, 0.024 ml) The reaction mixture is stirred at 23 ° for 20 minutes and lyophilized to re-- > -! · "I · 1 · 1. TMIITÏ-I · / -P »Λ \ includes the following signals S: 5 ^ 7 (m, H-5) and 2.23 (si, CH ^ of amidine), whose IR spectrum (KBr) includes a signal at 1772 cm ^ (C = 0 of ß-lactam) and whose spec- Λ D2 ° tre UT comprises Amax at 305 Μμ (a = 3116) and 253 ψ.

(S = 2525) * Compound 5 is applied to a Sephadex G10 column (1.6 cm × 100 cm column which is eluted with water, the detection being carried out by observation of the IR spectrum while the volume of fractions is 1.6 ml), then the suitable fractions are lyophilized to collect 23 mg (^ 5%) of a slightly yellow powder whose _ ïï20 UT spectrum comprises Amax at 303 ip (£ = 2960) and 2 ^ -8 ip (S - 2885).

° ^ Λ “Ρ nir ° \ ofta ©! i - To a suspension of compound b (50 mg, 0.25 milli mole) in distilled water (0.5 ml), sodium bicarbonate (21 mg, 0.25 millimole) is added and the mixture is stirred all for 90 seconds before adding in 2 minutes, a mixture of sodium bicarbonate (126 mg, 1.5 millimole) and ethyl formimidate hydrochloride (16½ mg, 1.5 millimole). The reaction mixture is stirred for 10 minutes at 23 ° and then lyophilized to obtain an orange powder whose UT spectrum comprises one at 30 ^ np (ζ = 2300).

EXAMPLE 12 Sodium 2-Hyaroxyaminopropyiperene-3-carboxylate.

rTV '-' X ', _ C02Na___ 1) NaOH 5%

° 2N ° 2And 2) HCl conc H

Δ 22 - · "2

Ester 1 (21.6 g, 0.13½ mole) is added to a cold 5% aqueous sodium hydroxide solution (320 ml). The resulting mixture is stirred for 2 hours at room temperature, then concentrated to 250 ml and acidified with concentrated hydrochloric acid. The mixture is extracted * with ethyl acetate (½ x 200 ml), then the organic extracts are dried over sodium sulfate. By concentration on a rotary evaporator, we obtain 13.2 g (75%) of an oil ° 2n '^ Nv' / ^ co2h + soci2 -► o2tf '/ Vs'XSscoci 1 3

A solution of acid 2 (13.2 g, 0.1 mole) in thionyl chloride (25 ml) is stirred for 2 hours at 30 °. After evaporation of the thionyl chloride, the residue is distilled under vacuum at 76-78 ° / 0.2 mm ïg to obtain 8.8 g (58.3%) of a colorless liquid with the NMR spectrum (GDCl ^) includes the following signals S: 2, HO

whose IE spectrum (pure) includes signals at 1550 cm- * 1 (^ jjo) 1790 cm "" 1 (Ό of acid chloride).

/ v 1) H2S / Et3N I 1 fl 2

° r cocl-J-iH

2) NaHC03 / J ^ I -

A solution of compound 3 (19, * + 6 g, 0.128 mole) in methylene chloride (200 ml) is rapidly added to a solution stirred at 0-10 ° of triethylamine (36 ml, 0.256 mole) in methylene chloride (500 ml) saturated with hydrogen sulfide at 0 - 5 ° ·

The mixture is stirred at -10 ° for 1 hour, then nitrogen is bubbled through it to remove excess hydrogen sulfide. The mixture is washed with 10% hydrochloric acid, then the organic extract is concentrated to about 150 ml, after which sodium bicarbonate (10.9 g) and water ( 500 ml). The pH is adjusted to about 7> 5 using sodium bicarbonate or hydrochloric acid. The resulting mixture is cooled to 0 ° and V-acetoxy-2-azetidinone (16.8 g, 0.13 mole) in water (20 ml) is added thereto with vigorous stirring. After hours, the mixture is extracted with ethyl acetate. The extracts are washed with 10% hydrochloric acid, saturated sodium bicarbonate and brine, then dried over sodium sulfate and evaporated. The residue is purified by chromatography on a column of silica which is eluted with ether, then ether with 5% ethyl acetate to obtain an oil which is crystallized from acetate. ethyl and hexane to collect 3> 5 g (12.5%) of the compound hc / · ”.-, n 1„ -Ρπ-ητγ, π kl ^ -kl „„ „„ J- "□ TP kl ~ ll C "_) 1/70 - ÇH (OH) ^ ° 2pmb,

° 0 ^ H — OH

co2pnb 4 i

A mixture of azetidinone * + (1.09 g, 5 millimoles) and p-nitrohenzyl glyoxylate hydrate (1.2 g, 5.25 millimoles) in benzene (100 ml) is heated to reflux. 6 p.m. using a Dean & trap

O

Stark containing molecular sieve ^ A. By evaporation of the solvent, 2.1 g of the addition product of glyoxylate 5 · socl7 is obtained in the form of an oil. rY'SN | / Vs' / ^ NO: * 0 xJN2pnb Pï 0 f'Y "ci

C02PNB

5 6

Azetidinone glyoxylate 5 (2.1 g) is dissolved in tetrahydrofuran (50 ml) and pyri-dine (0.57 ml, 7 millimoles) is added to the solution. The mixture is cooled to 0 ° and slowly added thionyl chloride (0.5 ml, 7 millimoles). The mixture is stirred for 1 hour at 0 °, then filtered before evaporating to dryness. By filtration through silica gel with methylene chloride, 1.9 g (85%) of a foaming material X 2,6-lutidine are obtained.

pH — Cl.

I - c = p <i CO PNB | 3

2 CO PNB

We. add triphenylphosphine (555 0.02 mole) 2,6-lutidine (2.5- ml, 0.02 mole) to a solution of chloroazetidinone (6.2 g, 1½ millimoles) in tetrahydro-furan ( 300 ml). The mixture is heated to 5-5 ° for 20 hours. The lutidine hydrochloride is filtered off and washed with ether. The filtrate is then evaporated. The residue is purified by chromatography on a column of silica gel which is eluted with dichloromethane and with a 1: 1 mixture of dichloromethane and ethyl acetate. By evaporation of the eluted fractions, 2.9 g (30%) of a white solid are obtained.

rTsrTV ^^ J_N toluene

V CO PNB

C02PNB 1 {· *

The phosphorane 7 (2.0 g, 3 millimoles) in toluene (150 ml) is heated at reflux for 150 minutes. By evaporation of the solvent, an oil is obtained which is purified by chromatography on a column of silica gel which is eluted with dichloromethane and with a 9: 1 mixture of dichloromethane and ethyl acetate. By evaporation of the solvent, a syrup is obtained which is crystallized from ethyl acetate and hexane to obtain 0.82 g (5-0.7%) of a white solid.

30% Pd / DE

J ί THF-ETHER-H ^ O-N aHCO>

° \ θ GNP

- rr'y ^^ oH

Q <? NOT

C02Na 9

Water (10 ml), sodium bicarbonate (10 mg, 0.127 millimole) and 30% palladium on diatomaceous earth (50 mg) are added to a solution of ester 8 (50 mg, 0.127 millimole) in a 2: 3 mixture of tetrahydro-furan and ether (25 ml). The reaction mixture was subjected to hydrogenation at 352 kg per cm for 3 hours at 25 °, then filtered through Celite and the solids washed with ether. The aqueous solution is lyophilized to obtain a hygroscopic compound in the form of a yellow powder (30 mg).

EXAMPLE 13.-

6-Ethyl-2-aminomethylpenem-3-carboxylic acid, cis-isomer and isomer, trans.

/ * '' · .-> * s \ / X—

VcK2mi2 I / Ve 2hb2 çfe == · and qsJ- \ o2H X02n a. Cis- and trans-3-ethyl-1- (p-nitrobenzyl-2 '-triphenylphosphora-nylidene-2'-acetate) -2-azetidinone-11 · silver thiolates.

Dilute with methanol (90 ml) a solution of cis- and trans-3-ethyl-l- (p ~ nitrobenzyl-2'-phosphoranylidene-2 acetate) -1! -Acetylthio-2-azetidinones (1.88 g , 3? 0 moles, the solution is cooled to 0 °, then silver nitrate in fine powder (0.51 g, 3.0 millimoles) and potassium carbonate (0.33 g, 2) are successively added thereto. 4 · millimoles) The mixture is stirred vigorously for 15 minutes at 0 °, 3 hours at room temperature and 1 hour at -10 ° C. The precipitated silver mercaptide is collected by filtration and washed with methanol and 1 ether, then dried under vacuum, thus obtaining the desired compound in the form of a greyish solid having a PP of 112-135 ° with decomposition, the IR spectrum of which includes signals for>? c_0 = 1750, 1620 and 1605 cm-1.

b. Ois ~ and trans-3 ~ eth, yI - l- (p-nitrobenzyl-2'-phosphoranylidene-2 * -acetate) -4 ~ azidoacetylthio-2-azetidinones.

A solution of the above crude mercaptide (1.31 g, 2 millimoles) in dichloromethane (15 ml) is cooled to 0 ° and a 2 M solution of azidoacetyl chloride in dichloromethane (1.13 ml, 2.26 millimoles). The mixture is stirred at 0 ° for 1 hour and at room temperature for 5 hours. By filtration on Celite, the insoluble silver salts are separated and washed with dichloromethane.

The mixture of the filtrates is washed with a dilute solution of sodium bicarbonate, then with water, after which they are dried and concentrated. The oily residue is purified by chromatography on a column of silica gel (35 g) which is eluted with ether and ethyl acetate. The appropriate fractions are concentrated to obtain 0.62 mg of a mixture of the cis and trans forms of the acylated compound which is in the form of a semi-solid and whose IR spectrum (CDCl 4) includes signals for >> = 2105, 1760, 1690 and I62I cm c. C- and trans-2-azidomethvl-6-ethvl-penem-3-carboxvTatP! S of p-nitrobenzvle.

A solution of the above crude phosphorane "(0.60 g) in toluene (30 ml) is heated at 105 ° for 1 hour, then cooled and concentrated to obtain an oily residue which is purified by chromatography on a column of silica gel (20 g) which is eluted with "benzene containing increasing proportions of ether. Concentrate the fractions useful to obtain the cis isomer and the trans isomer above. For the cis isomer, the ElffiT spectrum (ppm, GDCl ^) includes the following signals: 8.25 (2H, d, J = 8.8, Ho of p-nitrobenzyl), 7.65 (2H, d, ffia ), 5.93 (1H, d, J - ^, 1, H-5), 5.38 (2H, quadruplet AB, J = 1H-, 0, benzyl), h, 68 (2H, quadruplet AB, J = 15.0, CH2-N3), 3.1 * (1H, m, H-6), 2.0 (2H, m, ÇH2CH3), 1.1 (3H, t, J = 7,: 4- , CH2ÇH3) and for the trans f isomer, the EM spectrum (ppm, CDC13) includes the signals “? following: 8.18 (2H, d, J = 8.8, Ho), 7.59 (2H, d, Bm), 5.52 (1H, d, J = l, il ·, H-5), 5.33 (2Ξ, quadruplet AB, J - 1 ^, 0, benzyl), 4-, 58 (2H, quadruplet. AB, J = 15.0, CH2-H2), 3.7 (1H, dt, J = 1.4, J = 7, H-, H-6), 1.9 (2H, m, oh2oh3), i, i (3H, t, j) 7.4 ·, ch2çh3).

d. Trans-2-aminomethyl-6-ethylpenem-3-carboxylic acid.

A mixture of trans isomers of the above p-nitrobenzyl ester (0.20 g, 0.5 millimole) is reduced at 23 ° for 150 minutes under an initial hydrogen pressure of 2.11 kg per cm. , tetrahydrofuran (6 ml), ether (6 ml), water (12 ml) and 30% palladium on Celite (0.20 g). The catalyst is separated by filtration through Celite and the solids are washed with water. The filtrates are combined and washed with ether and tetrahydrofuran, then 1 Λ ~ Ί Ί A ^ ~ A-UJ Ί! -. * "U -V- ,, -, 4— J" Ί \ ~ A * (12 mg). By chromatography on a column of Sephadex G-10 which is eluted with water, the isomer is obtained pure trans acid (6 mg) in the form of a hygroscopic powder which has an IR spectrum comprising signals for ^ 0 = 0 “- * - 775} l6l5 cm *", a UV spectrum comprising an X at 306 nm (£ = 3 ^ 65) and an RM spectrum (ppm,

ÏH3JX

D ^ O-dimethyl sulfoxide) comprising the following signals S: 5, k0 (1H, d, J = 2.0, H-5), 2.0 (2ÏÏ, m,, 1,1 (3H, t, J = 7λ, gh2çh3).

e. Cis-2-aminomethyl-6-ethylpenem acid ~ 3 ~ carboxylic acid.

By reduction of the cis isomer of the p-nitro-benzyl ester, by operating as for the trans isomer above, the cis isomer of acid (13%) is obtained in the form of a yellowish hygroscopic powder which has an IR spectrum comprising signals for V ç_q = 1775 and I615 cm-1, a UV spectrum comprising a ^ -max at 30 ^ nm y (ε = 3563) and an RM spectrum (ppm, D2 ° “Dim®tkylsulfo3 ^ de) comprising the following signals <5: 5> 75 (1H, d, J = * f, 0, H-5), 2.0 (2H, m, ÇH2CH3), 1.1 (3H , t, J = 7Λ, CH2ÇH3). EXEMPIÆ 14, -

The following compounds can be prepared according to the general procedure of Example 13-co2z

Acylating agent —-— 5_ z

CH3COCl -CH3 -CH3 Na, H

Ac2o -ch3 -ch3 Na, H

ch3co2so2ch3 -CH3 -CH3 Na, H

C2H5C0C1 -CH3 -CH Na, H

0CH2COC1 -CH3 -CH20. Na, K

0OCH2COC1 · -CH3 -CH2O0 Na, H

^ -COCl -CH3 - <] Na, H

Q-C0C1 ’-CH3 _ □ xar H

(CF3C0) 20 -CH3 -CF3 Na C2H502C-C0C1 -CH3 -C02And Na / -r — COCl \ -y

N \ -CH} ^ Na, H

"V 3 V

I i CH3 CH3 ~ CH, X_

1 i -i — CH-COCl  I -I

S ^ N N ^ i N3 (CH2) 2C0C1 -CH3 - (CH2) 2NH2 h

N3 (CH2) 3COC1 "CIi3 'ÎCH2} 3NH2 H

nc (ch2) 2coci -ch3 - (ch2) 3nh2 H

02N (CH2) 3COCl -CH3 - (ch2) 3nhoh Na, I

N3 (CH2) 4C0C1 -ch3 - (ch2) 4nh2 h

N3 (CH2) 20CH2C0C1 "CH3“ CH20ÎCH2) 2NH2 H

N3 (CH2) 2SCH2C0C1 -ch3 -ch2s (ch2) 2nh2 k

AcNH (CH2) 2C02C02Et -CH3 - (CH ^ NHAc Na, i CH3COCl “C2H5 _CH3 Na" 1 C2H5C0C1 “C2H5" C2H5 Na, 1 0CH2COC1 “C2H5“ CH20 Na / 1 0OCH2COC1 ’~ C2H5 -CH2O0,]

Acylating agent Y χ Z

^ -COCl “C2H5 Na, i

N3 (CH2î2COC1 "C2H5 '" ÎCH2) 2NH2 H

N3 (CH2) 3C0C1 ~ C2H5 - (CH2) 3NH2 h

02N (CH2) 3COCl “C2H5“ (CH2) 3NHOH Na, I

N3 (CH2) 4C0C1 "" C2H5 - (CH) 4NH2 H

CH3COCl iso-C3H7 -CH3 Na, J

C2H-COCl iso-C3H? 'C2H5 NS / 1 ^ -COCl iso-C3H7 - <| Na, 1 -r- COC1 x j | iSO-C H] j fl Na '] rjTC0C1 is ° -C3H7 V-dj Na, 1 i2CH2COCl iso-C3H7 -CH20 Na'

h n3ch2coci îso-c3h7 -ch2nh2 H

N3 (CH2) 2C0C1 iso-C3H? - (CH2) 2NH2 h N3 (ch2) 3C ° C1 iso-C3H7 - (CH2) 3NH2 h 02N {CH) 3G ° c1 iso-C3H7 - (CH2) 3NHOH Na, EXEKPLE 15 «-

Acidscis- and trans-6-acetoxymethyl-2-aininomethyl-penem-3-carboxylic.

/ w- \ A0 ° J_1 / ^ ~ CH2NH2 c ° 2H ____ a ·. 3-Acetoxyiaétiijl-I + -trityltiiio-2-azetidinones (cis and trans isomers).

cis and trans isomers of 4-acetoxy-3-a.cétoxyméthyl-2-azétidinone (H ·, 7 g, 25 millimoles) (compound 2b of example 2), in water (200 ml) at a strongly stirred solution of sodium triphenylmethylmercaptide (obtained from 55 »2 g of triphenylmethylme-rcaptan and 9.6 g of sodium hydride in 300 ml of methanol). The mixture is stirred at room temperature for 4 hours, then the solids are filtered off, washed with water and dissolved in dichloromethane. This solution is washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate and water, then dried and concentrated to obtain 85% of a solid which is used as it is for the next experiment.

b. Cis- and trans-3-acetoxym.ethyl-1- (p-nitrobenzyl-2'-hydroxy-2'-acetate) -4-tritylthio-2-azetidinones.

A solution of the above azeti-dinone (8.0 g, 20 millimoles) and p-nitrobenzyl glyoxylate (4-, 54- g "20 millimoles) is refluxed in benzene (100 ml) using a Dean & Stark separator

O

containing 3A molecular sieve. After 24 hours, additional p-nitrobenzyl glyoxylate (4-5.45 g) is added and heating is continued under reflux for 24 hours. The mixture is diluted with ether and washed with 5% aqueous hydrochloric acid, water, 5% aqueous sodium bicarbonate and water. By drying and concentration, a crude mixture of isomers is obtained in the form of an oil with a yield of 100%.

vs. Cis- and trans-3 ~ acetoxymethyl-1-p-nitrobenzyl-2'-ehloro-2 '-acetate) -4 · -'tritylthio-2-azetidinones.

A solution of the azetidinones 2b millimoles) in dried tetrahydrofuran (150 ml) is cooled to -15 ° and thionyl chloride (2.86 g, 2b millimoles) is added dropwise thereto. The mixture is stirred for b $ minutes at -15 °, then the precipitate is filtered off and washed with benzene, then the filtrates are concentrated to obtain a semi-solid (95%).

h · Cis- and trans-3-acetoxymethyl-l- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2'-acetate) -H-tritylthio-2-azetidinones.

The mixture is refluxed for 80 hours, a mixture of the azetidinones obtained in c (12.6 g, 20 millimoles), triphenylphosphine (7 * 8 g, 30 millimoles) and 2,6-lutidine (2.6 ml, 22 millimoles) in tetrahydrofuran (100 ml). The insolubles are separated by filtration and washed with ether. The filtrates are washed> with 2% aqueous hydrochloric acid, 5% aqueous sodium bicarbonate and water, then dried and concentrated. The residue is dissolved in benzene and the solution is filtered slowly over a layer of silica gel (250 g), then the silica is eluted with increasing proportions of ether in benzene. By concentration of the useful fractions, a mixture (65%) of the desired compounds is obtained, the IR spectrum of which comprises signals for V =

OR

17 ^ 0 cm "1, ^ G = P0 = 1620, 1610 cm" 1, O m = 152 5 cm "1, e · Cis- and trans-3 ~ acetoxymethyl-l- (p-nitrobenzyl-2'-tri -phenylphosphoranylidene-2 '-acetate) -2-azetidinone-1f-thio.lates of silver.

The crude azetidinones obtained in d (8.5 g, 10 millimoles) are dissolved in hot methanol (55 ° to 60 °). To this solution, a hot solution (55 "60 °) of

(0.87 g, 11 millimoles) in methanol (80 ml). The mixture is allowed to cool to room temperature in 2 hours and is stirred for 1 hour at O0-. The silver mercaptide is collected by filtration, which is washed with ice-cold methanol, then with ether to obtain 5.7 g (82%) of the desired compound, melting with decomposition and whose IR spectrum

includes signals for "0 = 175-5, 175-0 and 1625 cm" "1.

G “~ U

f. Cis- and trans-3-acetoxymethyl-5 ~ azidoacetylthio-l- (p-nitrobenzyl-2 '-triuhenylphos-phoranylidene-2 1-acetate) -2-azetidinones.

The silver mercaptide obtained in e (1, * + g, 2 millimoles) is reacted in dichloromethane (15 ml) as in Example 13 with azidoacetyl chloride (2.3 millimoles) to obtain 0, 78 g of a yellow powder.

g. Cis and trans isomers of p-nitrobenzyl ester of 6-acetoxymethyl-2-azidomethyl-penem-3-carboxylic acid. t Qn heated at 105 ° for 1 hour, a solution of the above crude phosphorane (0.70 mg) in toluene (35 ml), then cooled and concentrated to obtain an oil which is purified by chromatography on silica gel (25 g) by elution with increasing proportions of ether in benzene. The useful fractions are concentrated to obtain the cis and trans isomers of the desired compound. The cis isomer has an NMR spectrum (ppm, CDCl 4) comprising the following signals <5: 8.5 - 7.5 (5-H, aromatic), 5.67 (1H, d, J = 5, H- 5), 5.31 (2H, quadruplet AB, CH2 bensyle), h, 50 (2H, quadruplet AB, OHJQ, 5-, 33 (2H, d, AcOCH2), 5-, 26 (lïï, dt, H- 6), 2.0 (3H, s, CH3) The trans isomer has an NMR spectrum (ppm, 03301 ^) comprising the following signals S: 8.5 - 7.5 (5-H, aromatic), 5 , 62 (13, d, J = 2, H-5), 5.33 (2H, quadruplet AB, CH2 benzyl), 1. 1./Ί / '- ITT jj- TT ίΝ I. r'rs f ATT J -l - 4- Λ Ή / T TT TVT N on / on d, AcOCH2), 2.0 (3H, s, 0H3).

h. . Trans-6 acid ~ acetoxymethyl-2-aminomethyli) eneiiie-3-carboxylic.

By hydrogenation of the above trans isomer, the procedure is obtained, as in Example 13, the desired compound which has a spectrum. IR including signals for ^ q_q = 177!?, 17 ^ 0, 1616 cm - '*' and a UV spectrum. Including an X at 301! cm (6 = 3192).

i. Cis-6-acetoxymethyl-2-aminomethyl'Denem-3-carboxylic acid.

By hydrogenation of the cis isomer, the procedure is obtained, as in Example 13, the desired compound which is an unstable hygroscopic semi-solid.

EXAMPLE 16, -

The following compounds can be prepared according to the general procedure of Example 15 ·! .

y ÏQ-

C02Z

Acylating agent Y x. _JL

CH3C0C1 -CH2OAc -ch3 h

C2H5C0C1 -CH2OAc "C2H5 H

k-COCl -CH2OAC - <1 H

(JC0C1 -ch2oac

(T “-CH20AC

s'

Acylating agent Y χ 2 N3 (CH2) 2C0C1 -CH2OAc - (CH2) 2NH2 h N3 (Ch2) 3C ° C3. -CH2OAc - (CH2) 3NH2 h n3 (ch2) 4coci -ch2oac - (ch2) 4nh2 h 02N (CH2) 3COCl -CH2OAc - (CH2) 3NHOH h CH3COCl - (CH2) 2OAc -CH3 h

^ -COCl - (CH2) 2OAc - <3 H

N3CH2C0C1 - (CH2) 2OAc -CH2NH2 h N3 (CH2} 2C0C1 - (CH2) 2OAc - (CH2 ') 2WH2 h N3 ^ CH2) 3COC1 - {CH2) 2OAc - (CH2) 3NH2 h CH, I 3

CH-COC1 -CK-OAc -CH0 H

J Δ CH0 i 3 N3 CH2 COC1 -ClI-OAc -CH2NH2 h EXAMPLE 17.- * Sodium salts of cis-ettrans-ô-Çl'-hydroxy-l'-ethyl acids) - 2-methyli) enèiiie-3 ~ carÎ) Oxylics.

OH

(Y = -GH-CHy, X = -CH ^) To a solution of 2-methyl lpenem-3-carbo- xylic acid (100 mg, 0.5½ millimole) in tetrahydrofurarm (8 ml), diisopropylamine (0.08 ml, 0.57 millimole) at 0 ° and n-hutyllithium (0.75 ml, 1.20 millimole) at -78 °. After 2 minutes of stirring at -78 °, freshly distilled acetaldehyde (0.5 ml) is added and stirring is continued for 10 minutes. The reaction is stopped by adding a saturated solution of ammonium chloride (10 ml), then the aqueous phase is washed with ethyl acetate. It is acidified and extracted with ethyl acetate (3 x 20 ml). By concentration of the dried extract in ethyl acetate, an oil is obtained (^ 9 mg). The oil is dissolved in methyl isobutyl ketone and an excess of a solution of sodium methyl hexanoate in methyl isobutyl ketone is added to the solution. By addition of ether, the desired compounds are precipitated in the form of a white amorphous solid (25 "mg) whose spectrum KMÜ (ppm, D ^ O) comprises the following signals δ: 5.6 - 5.83 (1H, m, H ~ 5, cis and trans), 2.27 (3H, s, CH3), 1.22 and 0.09 (3H, 2d, CI ^).

EXAMPLE 18, -

Sodium salt of cis-6- (l'-hydroxy-l'-ethyl) -2-methylpénème-3-carboxylic acid ("D" isomer).

2-methylpenem-3-carboxylic acid (100 mg) is reacted as in Example 17 with acetaldehyde and lithium diisopropylamide. After concentrating the dried extracts in ethyl acetate, 58 mg of a residue are obtained which is extracted with ether, then the ethereal solution is concentrated to obtain an oil (* f8 mg). The oil is converted into the sodium salt by means of sodium methylhexanoate as in Example 17 · This gives 29 mg of a white solid which is identified as. sodium cis-6- (1'-hydroxy-l'-ethyl) -2-methylpenem-3-carboxylate contaminated with a little 5 ”sodium methyl-1,3-thiazole-it-carboxylate. The EMÜT spectrum (ppm, hexadeuterodimethylsulfoxide) includes the following signals 6: 5.5 (PH, d, J = 1, H ~ 5), 2.22 (3H, s, Cïï3), 1.02 (3H, d , J = 5.5, oh3).

EXAMPLE 19.-

Potassium salts of cis- and trans-6- (2 '~ hydroxy-2'-pronyl) -2-ethylpenem-3-‘Carbox3' acids, liques.

(Y = (GH3) 2C-; X = -C2H ^)

OH

By replacing in example 3? 2-methyl-peneme-3-carboxylic acid with an equimolar amount of 2-ethylpenem-3-carhoxylic acid, a mixture of potassium salts is obtained whose BOT spectrum (ppm, hexadeutero-dimethylsulfoxide) includes the signals Next 6: 5? 60 and 5/56 (1H, 2d, J = 4 and J = 2, H-5), 3.92 and 3.60 (1H, 2d, J = 4 and J = 2 H-6), 2.88 and 2.86 (2H, 2q., CB ^ -OH ^), 1.47, 1.4, 1.36 and 1.32 (6H, 4s, Çgg), 1.2 and Ι, Η- (3H , 2t, CÏ ^ ^ CHt), and a spectrum U? including λ at 257 m (£ = 3705) and 302 ma (β = 3815).

EXAMPLE 20.-

Sodium salts of cis- and trans-ô-fl’-hydroxy-l'-ethvl) - 2-methoxymethylpenem-3 “, car'boxylic acids.

To a solution of 2-methoxymethylpenem-3-carboxylic acid (116 mg, 0.55 millimole, see preparation 6) in tetrahydrofuran (10 ml), diisopropylamine (0.08 ml, 0, 57 millimole) at 0 ° and n-butyl-litium (0.75 ml, 1.20 millimole) at ~ 78 °. After 2 minutes of stirring at -780, freshly distilled acetaldehyde (0.5 ml) is added and stirring is continued for 10 minutes. The reaction is stopped using a saturated solution of ammonium chloride (10 ml) - and the aqueous layer is washed with ethyl acetate. The aqueous layer is acidified with 0.1 N hydrochloric acid (18 ml) and then extracted with ethyl acetate (3 x 20 ml). By concentration of the dried extracts in ethyl acetate, an oil is obtained (53. mg) which is converted into a mixture of the sodium salts of the desired compounds by operating as in Example 17 · A powder is thus obtained amorphous hygroscopic (21 mg) whose EM spectrum (ppm, I> 20) includes the following signals $: 5.7 - 5.85 (1H, m, H-5, cis and trans), 3.38 (3H, 2s, 0CH3), 1.22 and 0.92 (3H, 2d, CB ^), and the IR spectrum includes the signals \ Jq_q = 1770 and 1600 cm EMPIE 21.-

Sodium salts of cis- and trans-6-acetyl-2-methyl-penem-3 ~ oarboxylic acids.

0

II

(ï = -C-CH3; X = -Cïï3) To a solution of 2-methylpenem-3-carboxylic acid (100 mg, 0.5 * + millimole) in tetrahydrofuran (10 ml), diisopropylamine (0.08 ml, 0.57 millimole) at 0 ° and n-butyllithium (0.75 ml, 1.20 millimole) at -78 °. After 2 minutes of stirring at -78 °, ethyl acetate (1 'ml) is added and stirring is continued for 10 minutes. The reaction is stopped by adding a saturated solution of ammonium chloride (10 ml), then the aqueous phase is washed with ethyl acetate. The aqueous layer is acidified carefully at 0 ° using 0.1 N hydrochloric acid, and then quickly extracted with ethyl acetate (3 x 20 ml). By concentration of the dried extracts in ethyl acetate, an oil (36 mg) is obtained which is converted into the desired compounds by operating as in Example 17 * The EM spectrum (ppm, D ^ O) includes the following δ signals: 5.90 - 6.10 (1H, 2d, J = H ·, J = 2, H-5), 3.8 (1H, m, H-6 cis and trans), 2.3½ and 2.27 (3H, 2s, CH3), 2.12 and 2.0 QH, 2s, C1).

EZETIPLE 22.-

The following compounds can be prepared according to the general procedure of Examples 3 to ^ and 17 to 21.

ÏQ- * c ° 2z X Y z

OH

-CH- -CH-C-H. -OCH-, K

3 6 4 d

OH

! -CH- -CH-n3u Na

J

0

II

-CH3 -C-0 Na * -CH3 -CH2OH Na

OH

-CH3 -CHCF3 Na

-C2H5 -SCH3 K

OH

-C2H5 ~ C "CH3 Na 0

II

-C2H5 -C-CH3 Na

OH

-C6H5 -CH-CH3 Na

OH

-c6h5 -C (C1I3) 2 K

O

it -C6H5 -C-CH3 Na

X Y Z

ÖOH

-CH-CH3 Na

OH

-ch2och3 -c (ch3) 2 K

OH

-CH2OCH3 -C-0 K

O

11 -CH2OCH3 -C-CH3 Na

O

II

-CH2OCH3 -C-0 Na

OH

i -CH2SCH3 -CHCH3 Na

CH, n OH

3 \ / °> I

-CH2-C ^ J -C- (CH3) r K

EXAMPLE 23 "-

The following compounds are prepared according to the general procedure of Example 3 * Y W- ^ s .îQ “* · co2z

_X Y Z

OH

-H -CHCH3 Na

OH

-H -CH-0 K

X Y Z

OH

“H -CH-CgH40ai3 Na

OH

-H -CH-n-C3H7 Na

OH

l -H -CH-CF3 Na “H -CH2OH Na

O

he h . "C“ CH3 Na

0 II

“H —C-0 Na

-H -SCH-, K

I 3

OH

. . I

- <] -CHCH3 Na

OH

~ <] —CH — 0 K

O

^ 11 "O -C-CH3 Na

OH

-Π -CH-CH3 Na

OH

-CH2O0 -CH-CH3 Na

OH

-CH2O0 -CH-0 K

OH

-CH2O0 -ai (cH3) 2 K

CD.YIL _ i λλ EXAMPLE 2k.-

2- (M · '-phthalimido-1' -but; yl) penem-3-carboxylic acid.

A ^^ v-O · CO H 0 2 (Qr ^ A.

1. 2 To a solution of triethylamine sulfhydrate prepared beforehand by bubbling hydrogen sulfide into a solution of triethylamine (8.8 ml, 63.7 millimoles) [. in methylene chloride (200 ml), a solution of compound 1 (10.65 g, ^ 0.2 millimoles) is added dropwise (see Gabriel Ber. Hl, 2010) in methylene chloride (75 ml) at 0 ° in 30 minutes. The mixture is stirred for 15 minutes at 0 ° and 2 hours at room temperature. The organic solution is diluted with methylene chloride (125 ml) and washed with 1 I hydrochloric acid (2 x 15 ml), water (2 x 15 ml) and brine. dried over magnesium sulfate and the solvent is evaporated to obtain 10.5 g (100%) of compound 2 in the form of a white solid having a PE of 93 - 9½ ° and having a BMN spectrum (CDCl 4) including the following S signals: 7.5 ~ 8 (^ H, m), * +, * + 7 (lh, s large), 3.5 - 3.9 (2H, m), 2.5 - 2, 9 (2H, m), w, h - 1.9 (^ H, m) -

Analysis for C13H13N03S:

Calculated: C, 59.29; H, 4-.97; H, 5.32; S, 12.17%.

Found: C, 58.92; H, 4-, 91; N, 5.4-2; S, 12.31%.

"vs

J — NH

cf NaHC03 ο 3

-NH ° O

4

Stirred at room temperature for 15 minutes in a nitrogen atmosphere, a suspension of compound 2 "(3.0 ^ S, 11.6 millimoles) in a solution of 1 M sodium bicarbonate (11.6 ml). Compound 3 (1.5 S, 11.6 millimoles) is added thereto and the resulting mixture is stirred for 90 minutes at room temperature. The reaction mixture is diluted with water and extracted with methylene chloride. The organic phase is dried and evaporated in vacuo to obtain 3.82 g of the 4-solid compound having a PP of 95 ° 96 ° and having an IR spectrum (CHCl 2) comprising signals at 1775, 1710 cm "' 1 'and an R3W spectrum presenting the following signals 6: 7.8 (4-H, d, J = 2Hz), 7.05 (1H, s broad), - 5.25 (1H, dd, Jcis = 5 Hz , Jtrans = 3 Hz) 3.5 - 3.0 (2H, m), 1.5 - 2.0 (4-H, m).

Analysis for;

Calculated: C, 57.62; H, 4-.85; N, 8.4-3; S, 9.64%.

Found: C, 57.4-3; H, 4-.82; Έ, 8.4-4 ·; S, 9.71%.

j? HO. — V

> -CO CH - (° W

(TV “/ -Λ 0! 5_ \

I

A solution of compound 4 · (3.0 g, 9.0½ millimoles) and p-nitrobenzyl glyoxylate (2.22 g, 9.8 millimoles) in 30 ml of benzene is heated to reflux for 21 hours using a Dean & Stark condenser containing 3 A molecular sieve. By evaporation of the solvent, 5.51 g (100%) of compound 5 are obtained in the form t of an oil having an IR spectrum (pure) comprising signals at 3200 - 3600, 1770, 1710, 1525 cm V and an EMU spectrum (CDCl ^) comprising the following signals 8: 8.21 (2H, d, J = 9 Hz), 7.75 (te, d, J = 2 Hz), 7.52. (2H, d, J = 9 Hz), 5.52 (1H, s broad), 5.32 QH, 2s), b, 55 (1H, s broad), 3, 5 - 3.7 (2H, m), 3Λ5 (1H, dd, Jgem - 15 Hz, Jcig = 5 Hz), 3.02 (1H, dd, Jgem = 15 Hz, Jtrans = 3 Hz), 2, ½ - 2.9 (2H, m), 1, ½ - 2.0 (te, m).

C02CH2- ^ Oy-N02 οθ2 € Κ2 ~ {θ ^ θ2 .. 5 6

Azetidinone glyoxalate 5 (4.9 g, 9.05 millimoles) is reacted with thionyl chloride (15 ml) at 0 ° for 30 minutes and at room temperature for 60 minutes. The excess thionyl chloride is removed by vacuum distillation at the same time as the benzene to obtain compound 6 in the form of a yellow syrup (5.0 g, -100%) having an EM spectrum (CDCl 4) comprising the following signals 6: 8.2 (2H, d, J = 9 Hz), 7.72 OH, wide s), 7.60 (2H, d, J = 9 Hz), 6.1 (1H, wide s ), 5.50 - 5.85 (1H, m), 5.32 (2H, 2s), 3 0 - 4.0 (2H, m), 3.1 - 3.3 (1H, m), 2 , 8 - 305 (1H, m), 2.50 - 2.85 (2H, m), 1.5 - 1.9 OH, m).

! C02CH2 \ Ç / ÎI02 C02CH2-i2 / N02 - 7

A solution of compound 6 (21.6 g, 38.8 millimoles) in tetrahydrofuran (85 ml, distilled on lithium aluminum hydride) is reacted for 18 hours at 40 ° with triphenylphosphine (10, 2 g, 38.8 millimoles) and 2,6-lutidine (5.0 ml, 42.9 millimoles).

The mixture is diluted with a 1: 1 mixture of benzene and ether (30 ml), then washed with water, with 1 H hydrochloric acid, with saturated sodium bicarbonate and with brine and on., dry over, magnesium sulfate. By evaporation of the solvent, a dark brown oil is obtained. The oil is passed over a column of silica salt (700 g) which is eluted with the benzene-ether system to obtain 16.0 g (53%) of compound 7 in the form of a thick oil having a SUN spectrum (CDCl ^) comprising the following signals 8: 8.2 (2H, d, J = 9 Hz), 7.8 (8H, d, J = 2 Hz), 7.52 (16H, s broad), 5.2 (lïï, s large), hJ8 (lïï, 2s), h, 30 - k, $ 2 (lïï, m), 3,5-3,8 (2ÏÏ, m), 2.8 - 3,5 (2ÏÏ , m), 2.1 - 2.9 (Hfl, m), 1.5 - 19 (Η-H, m).

C02CT2 \ P / N02 2 2 '-' 2 1 -

Is heated at reflux for 3 hours, a solution of phosphorane 7 (5.0 S, 6, ½ millimoles) in toluene (35 ml). By evaporation of the solvent, a ^ is obtained. residue passed over a column of silica gel (10g). By elution with benzene, then with ether, 600 mg of ester 8 is obtained in the form of an oil having an IE spectrum (pure) comprising signals at 1790, 1710, 1520 cm -1 and an M spectrum ( CDCl ^) comprising the following Ô signals: 8.22 (2ÏÏ, d, J = 9 Hz), 7.82 (4-H, d, J = 2 Hz), 7.65 (2ÏÏ, d, J = 9 Hz), 5.69 (1H, dd, Jc ± s = h Hz, Jtra2is = a Hz '), 5.35 (2H, 2s), H ·, 12 (1H, dd, Jgem = 16 Hz, Jc ± s = ** Hz) ,. 3.50 (1H, dd, Jgem * 16 Hz, Jtrajas = 2 Hz), 3.1 - 3.8 (2ÏÏ, m), 2.5 - 3.0 (2H, m), 1, ½ - 2.0 (HH, m).

O O

A biphasic mixture formed of ester 8 (196 mg, 0.39 millimole) in ether (2 ml), tetrahydrofuran (½ ml) and sodium bicarbonate (32 mg, 0.39) millimole) in water (2 ml) on hydrogenation on diatomaceous earth palladium on 30% (190 mg) in a Parr apparatus under a hydrogen pressure of 2.8l kg per p cm. ‘After 270 minutes, the mixture is filtered through Celite and washed with water, then with tetrahydrofuran. The filtrate and the washing liquors are mixed, then the organic phase is separated. The aqueous solution is washed with ether, acidified with 1N hydrochloric acid (3 x O, 1 * ml) and extracted (after each addition of acid) with acetate. ethyl (^ 1 2 ml). The organic extracts are washed with brine and dried over magnesium sulfate, then the solvent is removed by evaporation to obtain 67 mg (V7%) of acid 9 in the form of a yellow solid having a IR spectrum (nujol) comprising signals at 1775, 1705, 1690 cm ^ and a BMH spectrum (dimethyl tallow oxide) comprising the following signals 6: 7.92 (te, s), 5.71 (1H, dd, Jc ± s = ^ Hz, Jtrans = 2 Hz), 3.90 (1Ξ, dd, Jgem = 16 Hz, Jcis = h Hz), 3Λ7 (1H, dd,

Jgem = 16 ïïz 'Jtrans = 2 Hz), 3.3 - * f, 3 (3H, m), 2.7 - 3.05 (2H, m), 1.5 - 2.0 (te, m) .

EXAMPLE 25-- 2- (AcetonylmethyloxiTnft>) sodium penem-3-carboxylate.

θ '. 'OCH

'CO ^ Na Γν g ^ SC0CH2-C-CH3 ^ _ ^ SCOCH2-C-CII3 oJ-N ^ OH; '· C02PNB ’C02PN3 1 2

Ketal 1 (2.0 g, ^ -, 5½ millimoles) is reacted at 0 ° with trifluoroacetic acid at 95 $ (20 ml) for 15 minutes. The mixture is diluted with brine and extracted with methylene chloride (4 x 30 ml). The extracts in methylene chloride are washed with water and brine (3 times) then with brine, after which they are dried over magnesium sulfate in order to collect 1 ½½ g (80%) of the required compound having a SIffl spectrum (ppm, CDOl ^) comprising the following signals 6: 8.27 (2H, d, J = 9, aromatic Hm), 8.60 (2H, d, J = 9, Aromatic Ho), 5> 70 ~ 5.25 (m, CHp-PUB, HC-0, 0C1 / HH-, ^ 0 = 0 ^), 75 (1H, si, OH), 3.76 (qAB center ,

ΈΤ ^ OH

CH ^ -CO), 3Λ7 (part of a, dd, cis = 5, H-3), 3.0 ^ (2H, 2dd> Jgem = ^ J3-h trans = 3 'H “3)' 1'3 ° '1'28 (1'675' 2s, CH3), 1.98 (1.33H, s, CH3) and an IR spectrum (CHC13) including signals for Ό 'q = Γ7δθ, 1755 cm ^ N02? 1525 cm-1.

j | ^ n3

S SCOCH - {Î: -CH

^ SCOCH2CCH3 "-p z 3 J = C, -

I CO GNP

C02PNB 2 2

A solution of ketone 2 (1. ^ g, 3.63 millimoles) in methylene chloride (50 ml) is reacted at 0 ° under a nitrogen atmosphere with methoxylamine hydrochloride (33 ^ mg, 1, 1 equivalent).

Then added dropwise to the mixture of triethylamine (367 mg, 0.51 ml, 1 equivalent). The mixture is then stirred at room temperature for 18 hours, then the reaction mixture is diluted with methylene chloride and washed with water and brine (2 times), then brine, after which dried over magnesium sulphate to collect 1.52 g (98%) of the desired compound having an RMH spectrum (ppm, CDCl 4) comprising the following signals S: 8.12 (21%, d, J = 8, aromatic Hm ), 8, h0 (2H, d, J = 8, aromatic Ho), 5.50 - 5.05 (4-H, m, CH2-PEB, H - **, H-0-0), 3, 80 - 3.60 (m, 0CH3, part of H-3 cis, part of OH), 3.55 ~ 2.70 (m, part) of H-3 cis, 3-trans, CH2CO, part of OH ), 1.97, 1.90, 1.88 (3H, 3s, OH ^) and an IE spectrum (CHCl ^) including signals for>) c = 0 = 1770, '1750, 1690 cm "1.

N ~ OCH „I" f- ° cn3 SCOOT2 --ch3 ^ scoch -c-ch - {S0C12 -1 2 3 J OH TT.

(/ —Pyridme ^ —N ^^ Cl

CO PNB co pNB

£ 2 3 1 Â a solution of azetidinone3 (1.52 g, 3.57 millimoles) in tetrahydrofuran (20 ml, distilled on lithium aluminum hydride) at -15 °, pyridine is added dropwise (325 mg, 0.332 ml, h, 10 millimoles,

T TT τΓηΙ arvh 1 λ4 "Λη" vr. J ____ ~ / liDO

0.299 ml, 10 millimoles, 1.15 equivalent) in a nitrogen atmosphere. The mixture is stirred for 15 minutes at -15 ° ·

The solid is filtered off and washed with benzene. The solution is evaporated. The residue is taken up in benzene and clarified with charcoal to collect 1.2 g ($ 76) of the corn. -reference sought with an EM spectrum (ppm, CDCl ^) comprising the following signals S: 8.23 (2H, d, aromatic Hm), 7.80 (2ÏÏ, d, aromatic Ho), 6.12, 6.08 (1H, 2s, HC-Cl), 5.75 - 5.55 (lïï, m, H-if), 5, ^ 0, 5.30 (2H, 2s, Cïï2-PNB), 3.95 - 3 , 80 (3Ξ, 3s, 0GH3), 3.80 - 2.95 (MH, m, 2H-3, 0H2-00), 2.00 -.1.85 (3H, ifs, CH3) and an IR spectrum (CHGl ^) including signals for = 1790, 1765 (shoulder), 1700 cm "1 2," 0 = 1530 cm "*" N — och u-ocu.

It 3 H

SCOCH -OCH. SCOCH -C-CH

✓ * J ——f 2 3

CO_PNB

2 C02PNB 2 3 4 5 To a solution of chloroazetidinone if (1.2 g, 2.70 millimoles), tetrahydrofuran (20 ml, distilled on lithium aluminum hydride), triphenyl phosphine (1 , 06 g, if, 05 millimoles, 1.5 equivalent) and of. 2,6-lutidine (318 mg, 0.3 ^ 6 ml, 2.97 millimoles, 1.1 equivalent). The mixture is stirred for h days at room temperature under a nitrogen atmosphere. It is diluted with ethyl acetate and washed with 2% aqueous hydrochloric acid, water, 2% aqueous sodium bicarbonate, water and brine. The solution is dried over magnesium sulfate and the solvent is evaporated. The corn is purified) which is eluted with ethyl acetate to collect 77 ^ ^ 05%) of the desired compound having an IR spectrum (CHCl ^) comprising signals for "0 q_q = 1755: 1695 cm 163Ο 1610 cm- · 5 *, = 1525 cm "· * ·.

N-> ~ OCH

ü 3, scoch2-c-ch3 r ~ r * \ - Γ00 * 3 I - ♦. I Λ — CH --C-CH.

QJ 3 toluenei ^

Io2PN3 C02PNB

1 6

The phosphorane 5 (700 mg, 1.05 millimole) is heated to reflux in toluene for 270 minutes. By evaporation of the toluene, a residue is obtained which is passed through a column of silica gel (ratio 1:15) which is eluted with h ° / o of ether in benzene. 1 thus 15 mg (62%) of crystalline compound 6 having a P.P.

from 116 - 125 °.

Analysis for C ^ ÏÏ- ^ H ^ OgS:

Calculated: 0.52.17; H, 1 +, 38-, N, $ 10.71.

Found: C, 51.15; H, 1+, 18; R, 10.33%.

This compound has an RfflT spectrum (ppm, CDCl 4) comprising the following signals <5: 7.70 (2Ξ, d, Hm, aromatic), 7.12 (2Ï, d, Ho aromatic), 5.00 (2H, s, CH ^ PÜB), ^ -, 85 (1H, m, H-5), 3.75 - 2.70 (7H, a, C ^ O, CH2, H-6), 1.77, 1, 72, 1.65 (3H, s, CH ^) and an IR spectrum (CHCl ^) comprising signals for Ό ^ = 1787, 17 ^ 2, 1705 cm "" 1, = 1530 cm 1 and a UV spectrum (EtOÏÏ ) including at 318 nm (€ = 8 * + 20) and 262 m (ε = 12.539).

IUgUC

- N — OCH H | ~ S. | ° CH3 C02PNB CQ2Na £ 2

A mixture of ester 6 (1 ^ 1 mg, 0.386 millimole) is stirred in tetrahydrofuran (20 ml), ether (* tO ml) and sodium bicarbonate (32 mg, 0.381 millimole) in l (20 ml) in a Parr hydrogenation machine for 3 hours under pressure

O

2, 6 kg of hydrogen per cm in the presence of 30% palladium on gelite (200 mg) as catalyst. The catalyst is filtered off and washed with ether water.

The resulting aqueous mixture is washed with ether (3 × 60 ml) and lyophilized to obtain 32 mg (30%) of the desired compound having an EMU spectrum (ppm, dimethyl sulfoxide) comprising the following signals: 5i50 (m, H-5), 3.75 (s, OOHj), 0.77 (s, CH ^), an IE spectrum (nuo'ol) including signals for Ό c = 0 = 1770, 1600, 1M- 00 cm-1 and a UV spectrum (ELO) comprising at 300 μm (ε = 2800), and 255 nm (t = 2 ^ 00).

EXAMPLE 26.-

The following 2-penem derivatives can be prepared by acylation of 1- (p-nitrobenzyloxycarbonylmethyltri-phenylphosphoranyl) (argentimercaptidyl) -2-azetidinone using the appropriate acylating agent, followed by cyclization and elimination protective radicals. The general reaction scheme is as follows:

_ ^ Shg _ ^ 1. RCrO-C-O-iBu _ ^ SCOR

| or I

* N \ ^ P (, 3 KC0C1 o N \ ^ P03

CO-PNB

C02PNB 2 g -. \ H ~ / ‘terre" · de-diatoms 1 3 - R palladium at 30% - * · / - ~ f

C02PNB

CO £

for variant 1: BCOgïï + iBuCOGl for variant 2: HCl + PCl ^ · + RCC ^ H

Acylating agent Process Product 0CH2OCONH JCH ^) ^ -CO ^ H 1 2- (H — am.ino'butyl) penem <3-carboxylic acid CII3 0CH2OCONH CH-co2h 2 2- (1-aminoethyl) penem acid (I ) and Ii) 3-carboxylic 0CH2OCONH CH-co ^ H i: Acid 2- (l-aio.inopropyl) penetrates '(3 - and L ·)', - ,. 'J me-3-earPoxylic?> 3 - "æ-CHj - 0CH.OCONH-CH-CO H n. . , n 2 u2a 1 Acid 2- (1-amino-2-metliyl- (D and L) propyl) penem-3 “carboxylic? 0CH2OCONH-CH-CO_H 1 Acid 2- (l-friend nobenzvl) -

Acylating agent Process Product 0CH2OCONH-CH-CO2H ~ 1 Acid 2- (1-amino-2-plienyl- * (P- and L) ethyl) peneme-3-carboxylic CH-OCH-0-NO - p I 2 2 2 0CH2OCONH-CH-CO2H 1 Acid 2- (1-amino-2-hydroxy- (33.-and L) etliyl) penile - 3_carboxylic

CH2CO2CH20-NO2-P

0CH2OCONH-CH-CO2H 1 'Acid 2- (1-amino-2-cartoxy- (P and li) ethyl) penem-3-carboxylic acid CH-CONH- I 2 2 0CH2OCONH-CH-CO2H 1 Acid 2- ( l-amino-2-car'baiaoyl- (JD and-L) ethyl) peneme-3 “Carboxylic * CH-CH-SCH-

| 2 2 J

0CH-OCONH-CH-CO-H 1 Acid 2 “(l-amino-3-metliylthic (j) and L) propyl) p eneme-3-carb oxyli que (CH2) 4NHCO2CH20 —0CH2OC0NH-CH-CO2H 1 Acid 2 - (1,5-diaminopentyl) - (P and -L) p eneme-3-cartoxylic ch3 0CH2'ocONCH2CO2H 1 Acid 2- [methylylidid) metliyl] - p eneme-3-cartoxylic CH ^ 1 Acid 2- [2- methylamino) eth.yl '0CH2OCONCH2CH2CO2H. penem-B- cartoxylic CH3 0CH2OCONCH2CH2CH2CO2H d Acid 2- [3- (metliylamino) - propyl] peûeme-3-ca: rboxylic * ", CH-I 3 0CH2OCONCH2CH2CH2CH2CO'2H 1 Acid 2- [4— (methylamino) tuty: i peneme-3-carboxylic! Ç2h5 i 0CH2OCONCH2CO2H 1 Acid 2 - [(ethylamino) methyl] ·; pénème-3-car'boxyliq.ue <Γ2Η5 0CH2OCONCH2CH2CO2H 1 Acid 2- [2- (ethylamino) etliyl p eneme-3 - c art oxyli que C-H_

J 2. J

0CH2OCONCH2CH-CH-CO2H 1 Acid 2- [3_ (ethylamino) pro-

Acylating agent Process Product C, H- • i2 5 0CH2OCONCH2CH2CH2CH2CO2H 1 Acid 2 - '[4- (ethylamino) l} u tyl] penem-3-carboxylic? i3CH, OCONCH-CO, H 1 Acid 2 - [(phenylaniino) methyl] penem-3-carboxylic? 0CH2OCONCH2CH2CO2H 1 2- [2- (pbenylamino) - etiyl-] p enem-3-carboxylic acid? 0CH2OCONCH2CH2CH2CO2H 1 Acid 2- [3 ~ (pWiylamino) - propyl] penem-3-carboxylic acid? 0CH2OCONCH2CH2CH2CH2CO2H 1 Acid 2- [4- (phenylamino) - butyl] penem-3-carboxylic CH3C0NHCH2C02H 1 Acid 2 - [(acetylamino) methyl] penem-3-carboxylic CH3C0NHCH2CH2C02H 1 .Acid 2- [2] étbyl] pénème ~ 3-carboxylic CH3C0NHCH2CH2CH2C02H 1 Acid 2- [3- (acetylamino) - propyl] pénème-3-carboxyliqu CH3C0NHCH2CH2CH2CH2C02H 1 Acid 2- [1 + - (acetylamino) - butyl] penem-3-carboxylic

CgH3C0NHCH2C02H 1 Acid 2 - [(benzoylamino) - metbyl] penem-3-carboxylic acid

CgH3C0NHCH2CH2C02H 1 2- [2- (benzoylamino) - ethyl] 3-carboxylic acid C6H5C0NHCH2CH2CH2C02H 1 2- [3- (benzoylamino) pr pyl] 3-carboxylic acid

Acylating agent Process Product C6H5C0NHCH2CH2CH2CH2C02H S 1 2 - [^ - Penzoylamino) - 1 Putyl] Penem-3_carPoxylic 0CH2OCONHCH2CONHCH2CO2H 1 Acid 2 - [(glycinamido) methy! p eneme-3-carP oxyli que 0CH2OCONHCH2CONHCH2CH2CO2H 1 Acid 2- [2- (glycinamido) - ethyl] penem-3-carPoxylic 0CH2OCONHCH2CONHCH2CH2CH2CO2H 1 Acid 2- [3 “(glycinamido) - pr opyl] p enyl 3 <0CH2OCONHCH2CONHCH2CH2CH2 “1 Acid 2- [M - (glyc inami do) - CW CO H Put y 1] p eneme -3 -carP oxyli que 2 2 H2NC0NHCH2C02H 1 Acid 2- (ureidomethyl) - pénème-3-carP H2NC0NHCH2CH2CO2H 1 2- (2-ureidoethyl) - 3-carPoxylic acid H2NC0NHCH2CH2CH2C02H 1 2- (3-ureidopropyl) - 3-carPoxylic acid H2NC0NHCH2CH2CH2CH2C02H 1 Acid 2- (4) penem-3-carPoxylic CH, NHCONHCH, C02H 1 Aoide 2 - [(methyloarl> amoyl- ^ ^ amino) methyl] penem-3 ~ carPoxylic CH, NHCONHCH, CH, CO_H 1 Aoide 2- [2 - (»ethylcarl> amoyl JA Â * amino) .ethyl] p eneme ~ 3 -c ar-

Poxylic CH3NHCONHCH2CH2CH2C02H 1 Acid 2- [3- (metPylcarPamoyl amino) propyl] p eneme-3-car-Poxylic

Acylating agent Process Product CH ^ NHCONHCH ^ CH ^ CH ^ CI ^ CC ^ H 1 Acid 2- [^ - (methylcarbamoyl- amino) butyl] penem-3_car-. . boxylic 0NHCONHCH2CO2H ^ 1 Acid 2- [(phenylcarbamoÿl-; amino) methyl] penem-3- 1 carboxylic î 0NHCONHCH2CH2CO2H 1 Acid 2- [2-pb.enylcarbaiiioyl- amino) ethyl] p-eneme-3-carboxylic 0NHCONHCH2CH2CH2CH2CO2 [3- (pbenylcarbamoyl- amino) pr opyl] p eneme-3-carboxylic 0NHCONHCH2CH2CH2CH2CO2H 1 Acid 2- [4-- (phenylcarbamoyl- amino) butyl] peneme-3 ~ carboxylic CH3C0NHC0NHCH2C02H 1 Acid 2 - [(acetylcarb) ] p eneme -3 -carboxylic. CH3CONHCONHCH2CH2C02H 1 Acid 2- [2- (acetylcarba- moylamino) ethyl] p eneme-3 -carboxylic CH3C0NHC0NHCH2CH2CH2C02H 1 Acid 2- [3- (acetylcarba- moylamino) propyl jpenen-3 “carboxyl-CH2CH2C2CH2N2CH2N2CH2N2CH2N2CH2N2CH2CH2N2CH2N2CH2N2CH2N2CH2N2CH2N2CH2N2CH2CH2CH2N2CH2N2CH2CH2CH2N2CH2N2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2N2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2N] - amino) butyl] penem ~ 3-carboxylic 0CONHCONHCH2CO2H 1 Acid 2 - [(benzoylcarba- moylamino) metbyl] penem-3 -carboxylic 1 Acid 2-f2- (benzoylcarba- 0CONHCONHCH_CH_COoH _ - \, -, η -, 2 2 2 mo yl aimo) e tbyl Jp eneme -3 - carboxylic 0CONHCONHCHCH, CHCO, H 1 Aoide 2-D- (b "* ojloaiba- ^ Δ ά * moy lamiuo) pr opy 1] p eneme -3 ~

Acylating agent Process Product 0CONHCONHCH2CH2CH2CH2CO2H 1 Acid 2- [1 + - (benzoylcarbaiiioyl- amino) butyl] peneme-3-carboxylic CH2OCONHCONHCH2CO2H 1 Acid 2 - [(carbomethoxycar-- b amoyl amino) met tiiyl] p enem-3 ”carboxylic CH30C0NHC0NHCH2CH2C02H 1 Acid 2- [2- (carbomethoxy- carbamoylamino) ethyl] penem- 3-carboxylic CH30C0NHC0NHCH2CH2CH2C02H 1 Acid 2- [3 ~ (carbo: methoxy- carbamoylamino) propyljpénème- (CHHC-CHH-CH-CHCH 1 Acid 2- [4- (carbomethoxycarbamoylamino) butyl] p enem-3- carboxylic (CH3) 3Si (CH2) 20C0NHC0NHCH2C02H 1 Acid 2- [X2-trimethylsrlyl-- ethyloxycarbonylcarbamoyl - amino) methyl] p eneme -3 - c arb 0x3 lique (CH3) 3Si (CH2) 2OCONHCONHCH2- 1 Acid 2- [2- (2-trimetbylsilyl- CHnCO_H ethyloxycarbonylcarbamoyl- 4m Cm amino) ethyl] penem-3-carboxylic acid (CH3) 3Si (CH2) 2OCONHCONHCH2- 2-p-CS-trimetliylsilyl-Q ^ G ^ a ^ H éüyloxycarbonylcarbamoyl- amino) propyl] penem-3 “carbox5 lique (CH3) 3Si (CH2) 2OCONHCONHCH2- 1 Acid 2- [4- (2-trimethylsil yl-CH2CH2CH2C02H · ethyloxycarbonylcarbamoyl - amino) butyl] 3-carboxylic penem

Acylation agent Process Product * CH3S2CNHCH2C02H 1 Acid 2- [(methylthiothio- c art) ony 1 amino) methyl] p enem - 3-carboxylic CH3S2CNHCH2CH2C02H 1 Acid 2- [2- (methylthiothio- c art) ony 1 amino) ethyl Jpenem-3 ~ carboxylic CH3S2CNHCH2CH2CH2C02H 1 Acid 2- [3- (methylthiothio- c art) ony 1 amino) propyl Jpenen- 3-carboxylic CH.3S2CNHCH2CH2CH2CH2C0 25H 1 Acid 2- [h- (methylthiothioyl) carbonamino) 3 carboxylic CH3S02NHCH2C02H 1 Acid 2 - [(methanesnlfonylamino) met] lyl] penem “3- carboxylic CH3S02NHCH2CH2C02H 1 Acid-2- {2- (methane tallow onylamino) ethyl th] p eneme" 3 ~ carboxylic CH3S02CH2CH2 Acid 2- [3- (methanesuifonylamino) propyl] penem-3-carboxylic CH3S02NHCH2CH2CH2CH2C02H 1 Acid 2- [h- (methanesulfonyl- amino) hutyl] penem-3 ~ carhoxylic 0SO2NHCH2CO2H 1 Acid 2 - [(benzene) methyl ] penem ~ 3-carboxylic

Acylation Agent Product Process

S

II

H3CNHCNHCH2CH2C02H 1 2- [2- (2-methyltliio-carbamoylamino) ethyl] penem-3-carboxylic acid f H3CNHCNHCH2CH2CH2C02H 1 2- [3- (N-methyltliio-carbamoylamino) propyl] -carboxylic acid

S

II

H3CNHCNHCH2CH2CH2CH2C02H 1 2- [4- (N-methylthiocarba- moylamino) butyl] penem-3-carboxylic

S

0NHCNHCH2CO2H 1 Acid .2 - [(N-plienyltliiocarbamoyl amino) métliyl Jpénème- 3-carboxylic

S

II

0NHCNHCH2CH2CO2H 1 Acid 2- [2- (N-plienyltliio-carbamoylamino) ethyl jpenem “3-carboxylic

S

II

0NHCNHCH2CH2CH2CO2H 1 Acid 2- [3- (N-phenylthio-

carb amoyl amino) propyl] p é-nème-3 - c art »oxyl i que S

w H

0NHCNHCH2CH2CH2CH2CO2H 1 Acid 2- [^ - (Ν-plienylthiocar- b amoyl amino) "butyl] p eneme-3 - •, carboxylic jj1 ^ îj — NHCH2C02H 1 Acid 2 - [(guanylamino) - N metliyl] penem-3-carPoxy - HO 0 lique .N îpNHCH2CH2C02H 1 Acid 2- [2- (guanylamino) - ethyl] penem-3-carboxy-: lique dj ^ J] NHCH2CH2CH2C02H 1 Acid 2- [3- (guanylamino) - propyl] penem-3 ~ carboxy-

HO

lique

Acylating agent Process Product N -— NHC ^ C ^ C ^ C ^ C ^^ H 1 Acid 2 - [^ - (guanylamino) - AJ '““ Putyl] penem-3-carPoxylic HO 0

^ • Ov O

m y 1 Acid 2 - [(acetimidoylamino) -

Jl-N-CH_C02H .metP.yl3penem-3-carPoxylic h3c "-CH2CH2C02H 1 2- [2- (acetimidoylamino) etP.yl] penem-3-carPoxylic" -CH2CH2CH2C02H 1 Acid 2- [3 “(acetimidoylamino) ] penem-3-carPoxylic "-CH2CH2CH2CH2C02H 1 Acid 2- [4 - (acetimidoylamino)

Putyl] p eneme-3-carPoxylic

• 1 Acid 2 - [(formimidoyl) metPyJ

| J_n-CH2C02H penem-3-carPoxylic "-CH2CH2C02H 1 Acid * 2- [2- (formimidoylamino) sthyljpénème-3-carPoxylic" -CH2CH2CH2CO2H 1 Acid 2- [3- (formimidoylamino) propyl] p eneme-3 -c arP oxyl i que M -CH2CH2CH2CH2C02H 1 Acid 2- | J- (f ormimidoylamino)

Putyl] penem-3-carPoxylic 02NCH2C02H 1 Acid 2 - [(Pydroxyamino) - metPyl] p enem-3-carPoxylic 02NCH2CH2C02H 1 'Acid 2- [2- (hydroxyamino) - etPyl] penem-3 ~ carPoxylic C ^ NCH ^^ CH ^^ OC ^ H 1 Acid 2- (Pydroxyamino) -

Putyl] penem-3-carPoxylic

Acylating agent Process Product OCH-I 3 (CH ^) ^ Si (CH2) 2OCON-CH2CO2H * 1 Acid 2 - [(methoxyamino) - methyl] p-3-carboxylic acid * OCH, I 3 (CH ^ Si (CH2 ) 20C0N-CH2CH2C02H * 1 Acid 2- [2- (metlioxyamino).

ethyl] p eneme-3-carboxylic OCH-I 3 (CH ^) ^ Si (CH2) 2 OCONC ^ Q ^ C ^ Ct ^ H * 1 Acid 2- [3- (methoxyamino) pro 'pyl] penem-3- carboxylic ^^ 3 * 1 Acid 2 - [^ - (methoxyamino) - (CH3) 3S1 (CH2) 2 OCONCH2 ¢ ^ 2 ^ 2 ^ 2 ^ 211 butyl] penem-3-carboxylic- NH-. ) 2 ÎCH3'3Sl (CH2) 20 CONCH2CO2H * 2 Acid 2 - [(hydrazino) metiol] - penem-3-carboxylic NH 'I 2 (CH3) .3Si (CH2) 2OCONCH2CH2C02H * 2 Acid 2- [2- (hydrazino ) ethyl] · penem-3-carboxylic m2 (CH3) 3Si (CH2) 2OC0NCH2CH2CH2C02H * 2 Acid 2- [3- (h.ydrazino) propyl penem-3-carboxylic NH2 * 2 Acid 2- [4— (bydrazino) - (CH3) 3Si (CH2) 2 0C0NCH2CH2CH2CH2C02H butyl] penem-3-carboxylic N (CH3) 2 * 2 Acid 2 - [(2,2-dimetliylhydra- (CH3) 3Si (CH2) 2 0C0NCH2C02H zino) methyl] penem -3-car- 1 boxylic N (CH3) 2 S * 2 Acid 2- [2- (2,2-dimethyl- (CH3) 3S1 (ch2) 2 bydrazino) ethyl] p-carboxylic N (CH3) 2 * 2 Acid 2- [3- (2,2-dimetliyl- (CH3) 3Si (CH2) 2 bydrazino) -propyl] penem- 3-carboxylic.

N (CH -) - * 2 Acid 2- [H— (2,2-dimethyl- · -

l 3 Z

(CH3) 3Si (CH2) 2 OCONCH2CH2CH2CH2C02H hydrazino) butyl] p eneme-3- ______ carboxylic * We use the derivative trimétbylsilylétliylé instead of the derivative n — ni troben 5>: V1 é iane 1 'a7.éti dn nnne n ntermediate and we eliminate

Acylating agent Process Product CH3CONHNHCH2CO2H * 2 Acid 2 - [(2-acetylliydrazino) - metliyl] p enem-3-0 ari) oxylic CH2CONHNHCH2 ^ 2 ^ 2 ^ * ^ Acid 2- [2- (2-acetylhydrazinc ethyl) ] p enè me -3 - c art) oxyl i que CH2CONHNHCH2CH2CH2CO2H, * 2 Acid 2- [3- (2-acetylhydrazi- no) propyl] penem-3-carboxyli-: que C ^ CONHNHCï ^ CI ^ Cï ^ CI ^ C ^^ H * 2 Acid 2- [4— (2-acetylhydrazino) butyl] p eneme -3-carboxy-lique (CH3) 2NCH2CO2H 2 Acid 2 - [(dimethylamino) - methyl] penem-3 ~ carboxylic ^ ^ 3 ^ 2 ^^ 2 ^ 2 ^ 211. 2 Acid 2- [2- (dimetbylamino) - ethyl] penem-3 ~ carboxylic ^^ 3 ^ 2NC'H2CH2 <"î12 <" <^ 211 2 Acid 2- [3 “(dimethylamino) - propyl] penem-3 ~ carboxylic ^ CH3 ^ 2NCH2CH2CH2CIi2C02H 2 Acid 2- [H— (dimetliylamino) - but yl] p eneme -3 -carb oxyl i que CH-I 3 CH3CONCH2C02H 1 Acid 2 - [(IT-methylacetamido) - metbyl] penem-3- carboxylic CH3 CH3C0NCH2CH2C02H 1 Acid 2- [2- (N-methylacetamid) etbyl] p-3-carboxylic acid CH ^ CONC ^ C ^ C ^ CC ^ H 1 Acid 2- [3 “(n“ metbylacetamid ) propyl] penem-3-carboxyli- ^ 3 that CH ^ CONC ^ G ^ G ^ G ^ CC ^ H 1 Acid 2- [1f- (IT-mettLylacetamid, o) butyl] p eneme-3-c arb oxy-lique

Acylation agent Process Product

i ^ nA

| 1 N-CH CO H 1 2 “[(phthalimido) methyl] - 3-carboxylic acid IJJ Îî-CH2CH2C02H 1 2- [2- (phthalimido) ethyl] acid - 5 3-carboxylic acid LL 1 Acid . 2- [3- (phthalimido) pro- n / Tf pyl] ~ 3-carboxylic penem

P

Γ N-CH2CH2CH2CH2CO2H 1 Acid 2- [lf “(p] atalimido) 'buyl] penem-3-carboxylic 0CH2OCONHCH2CH2OCH2CO2H 1 Acid 2 - [(2-aminoethoxy) - methyl] penem-3-carboxylic 0CH2OCQNHCH2H22CH2S2 [(2-aminoétbylth.io) - methyl] p eneme -3 - carb o xy1i que <fo2œ20 0CH2OCONHCH2CH2NCH2CO2H 1 Acid 2 - [(2-aminoethylamino) - methyl] peneme-3-carboxylic ch3 0CH2OCONHCH2CH2NCH2CO2H 2 Acid 2- [ (2-aminoétbyl) -N- methyl amino] m thylp enème -3 -carboxylic 0ch2oconh - // V-ch2co2h 1 Acid 2- (p-aminobenzyl) penem-3-carboxylic CH2C02H ^ 0ΟΗ2ΟΟΟΝΗ — y 1 Acid 2- (o-aminobenzyl) penetration- \ - === / me-3 "Carboxylic 00 ^ 000 ^ 111- ^ Λ-οο2Η 1 Acid 2- (p-aminophenyl) penetration-3-carboxylic _ ^ c02h 0CH2OCONH-Y y 1 Acid 2- (m-aminop3ienyl) penetrates / mo- ^ - • nKn-srrrl η πηo

Acylating agent Process Product C ° 2H> - \ 0CH2OCONH — U y 1 Acid 2- (o-aminophenyl) - v \ mJ penem-3-carboxylic 0CH2OCONHCH2 “γ y-C02H 1 Acid 2- [p- (aminoethyl) - phenyl] penem-3-carboxylic

y- ^ C02H

0CH2OCONHCH2-yy 1 2- [m- (aminoethyl) - ^ phenyl] penem-3-carboxylic acid co2h \ 0CH2OCONHCH2 “y / 1 Acid 2- [o- (aminomethyl) - '- phenyl] penem-3-carboxyli - that PXPliPIÆ 27, -

The derivatives of the 2-penem below are reacted in the form of triethylamine salts with (CH 4) 4 II.SO 4 dissolved in methylene chloride at 0 °. By addition of sodium 2-ethylhexanoate in 1-hutanol to the resulting reaction solution, the indicated compounds are precipitated in the form of their disodium salts.

Starting compound Product

r y <cH, j nh, I T

J — J— 0 \ 0 \ C02N (C2H5) 3 C02Na

Exp. A η = 1 A. η = 1

Exp. B n = 2 B. n = 2

Exp. C n - 3 C. n = 3

Exp. D n = 4 D. n = 4 i i 1 28, -

The 2-penem derivatives below can be prepared from the starting compounds indicated by applying the following method.

oiZO- <CH2> n "(CH3,2 -¾ ΪΛ ^ '***" rH3,35

'CO „PNB

co2pnb Δ H2 / P% ^ jX> tca2)> 3) 3 0 'e co2 ° r

Starting compound Product 0 \ 0 CO Q 'C02PNB lü2

Exp. A η = 1 A. η = 1

Exp. B n = 2 B. n = 2

Exp. C n = 3 C. n = 3

Exp. D n4. D. n ° 4 EXAMPLE 29.-

The 2-penem derivatives below can be prepared from the starting compounds indicated by applying the following method.

-, SAg - ^ ^ / SCO (CH-) Cl 1 ’- £ π

C02PNB C02PNB

Δ -r ^ \ Ö ^ -> S _ y_ CO-PNB 0 „xrT>

2 C02PNB

deprotection deprotection * V / f — r / S \ s I V (CH,) C1 Π \ ® / 7 ~ \

i_N> (ch2> „-» Q

, C ° 2 “0 co2®

Starting compound Product -

rrV, cH2, nCx rTV

d— N ^ / 2 n J — N 2 n V ^ / 0 \ Ο Λ Λ

co2pnb C0Q

Exp. A η = 1 A. η = 1

Exp. B n = 2 B. n - 2

Exp. C n = 3 C. n = 3

Exp. D n = 4 D.n = 4 EXAMPLE 30. ~ 0n the following 2-penem derivatives can be prepared from the starting compounds indicated by applying the following process.

O 0 0 0 0

It u \ X It II

_ ^ SC- (cH2) m-c-R TFA ^ _ ^ SC- (CH2) a-C-R

J-N. nrt J-N OH

cq2 z co2z

B

WE

H-NB 11 II

2 y ^ SC- (CH2) m-C-R

Y N \ XH C ° 2z |

NB

li

.SC- (CH „) -C-R

X 2m ·, w „

SOC1 Γ / 1 * $ 2F

- ^ ^ —N \ / Cl T ~ A N

O NX 2 · Δ co2z.

r — r ^ S \ NB

V (CH -) - C-R F ”X-N -> O \ co2z

OH

NOT

I> - <CH2) m-C-R

co2H

m = 0-2 2 = - (CH2) 2Si (CH3) 3 R = H, CH3 b = -0 (CH2) 2Sx (CH3) 3

Starting compound Product

0 I I

O O O OH

^ -SC-lCH.l ^ -C-R -—S „ri>« y.-S- *

1 CO_H

co2pnb 2 ï

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, m = 1 E. R = CH3 / m "1

Exp. F R = CH3 # m »2 F. R - CH3, m = 2.

By replacing, in the above procedure, H ^ OCCHg ^ SiÇCH · ^ with III ^ NOCH ^, the following compounds are obtained. ... _______ NOCH,

C ° 2H

Exp. A m = Û, R = H

Exp. B m = 1, R = H

Exp. C m = 2, R = H

Exp. D m = 0, R = CH ^

Exp. E m = 1, R = CH ^

Exp ... F m = 2, R s CH ^

By replacing in the above procedure the H2N0 (CH2; 2Si (CH3) 3 with (CH ^ SiÇOH ^ OCOÏÏHHEg), the following compounds are obtained.

_nnh CO 2 "

* 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 = CH ^

Exp. F m = 2, R = CH3

By replacing, in the above procedure, the 2NO (C 12, 2 Si (CH 3) 3 with) the following compounds are obtained.

NN (CH,) ^ co2a

Exp. A m - 0 / R = H

Exp. B m = * 1, R = H

Exp .. C m = 2, R = H

Exp. D m = 0 / R = CH ^

Exp. E m = 1, R = CH2

Exp. F m = 2, R = CH ^.

By replacing in the above procedure, the H2E0 (CH2) 2Si (CH3) 3 with (CH ^ SiCCH ^ OCON-HH2) the following compounds are removed.

- ΝΝΗ0

V (CH -) - C-R

J-N ^ / 2 “Y \

C02H

Exp. A m = 9, R = H

\

Exp. B m = 1, R = H

Exp. C m = 2, R = H

Exp. D m = 0, R = CH ^

Exp. E m = 1, R = CH ^

Exp. F m = 2, R = CH3.

EZEMELE 31.- oJZQ / X -? '^> 2' CO H 2 r — r / SA9 I — rsY ^ H2cl C02PNB c ° / nb I II m

Cooled in an ice bath, a solution of compound I (1.1 g, 1.6 millimole) and compound II (0.16 ml, 1.6 millimole) in methylene chloride (30 ml) and there is added, dropwise, a 1 H solution of pyridine in methylene chloride (1.7 ml, 1.7 millimole). The resulting reaction mixture is stirred for 1 hour at room temperature, then filtered through Celite which is washed with methylene chloride. The filtrate and the washing liquors are combined, then washed successively with 1 H * hydrochloric acid (5 ml), water (5 ml), 1 M sodium bicarbonate

(5 ml) and brine, after which they are dried over magnesium sulphate and evaporated under vacuum to obtain in an amount of 900 mg (87%) of compound III in the form of an orange solid. This is used in the next stage without further purification. The IR spectrum (CHCl ^) includes signals at 1755} 1690 cm The RM spectrum (CDCl ^) includes the following signals 6: 8.22 (2H, d, J = 9 Hz), 7.55 (15H, m) , 6.72 (2H, d, J = 9 Hz), 5.7 (1H, m), 5.0 (2H, 2s), 3.55 (2H, 2s), 2.8 (4-H, m).

jnpC ^ “· -> CO PNB 0 '" -O:

ni iv o <J_A

CO.PNB 2

V

Heated for 4 hours at 80 °, a mixture of compound III (1.3 g, 2 millimoles) and compound IV (0.65 ml, 3 millimoles). The reaction mixture is diluted with methylene chloride (10 ml) and washed with water (2x5 ml). The organic layer is dried (MgSO 4) and evaporated under vacuum to obtain 1.4 · g (90%) of compound V in the form of an amorphous solid. This is used in the next step without [further purification. The IR spectrum (OHOl ^) comprises signals at 1755, 1690 cm-1, the RM spectrum (CDCl ^) comprises the following signals 6: 8.25 (2H, d, J = 9 Hz), 7.55 (15H , m), 6.8 (21, d, J. = 9 Hz), 5.7 (1Ξ, m), 5.1 (2H, 2s), 4-, 72. (2ÏÏ, dq, J B 12 Hz, J = 6 Hz), 2.6 (4H, m), 1.4- (6ïï, s), 1.28 (6H, s).

I— ^ ° 2.-y co2pnb

-I CO PNB

2

VI

A solution of compound V (1.6 g, 2.06 millimoles) in toluene (60 ml) is heated at reflux for 5 hours. The filtrate is evaporated in vacuo and chromatographed | the residual oil on a column of silica gel (30 g), i By elution with benzene, then with ether, first remove j! non-polar substances and finally by elution with ethyl acetate, 620 mg (62%) of compound VI are isolated, being in the form of a white solid having a PP of 83-8½0 after crystallization in ether. The IR spectrum (CHGl ^)> —1 includes signals at 1790 and 1710 cm. The NMR spectrum (CDCl ^) includes the following signals <5 8.2 (2ÏÏ, d, J = 9 Hz), 7.6 (2H, d, J = s 9 Hz), 7.5 (2H, s) , 5.65 QH, dd,

Jtrans = ^ ïïz 'Jcis = 2 Hz) »5.22 (2ÏÏ> 2s), k, 75 (2H, dq, J = 12 Hz, J = 6 Hz), 3.85 (1H, dd, Jgem = 15 Hz, Jtrans = ^ Hz), 3.5 (1H, dd, Jgem - 15 Hz, Jcis = 2 Hz), 2.8 - 3.3 (2H, m), 1, ½ (6H, s), 1 , 28 (6H, s).

CO PNB \ 0 R

î 2

VI VII

Sodium bicarbonate (3½ mg, 0, ½ millimole), water (½ ml) and Oelite palladium at 30% (200 mg) are added to a solution of compound VI (200 mg, 0, ½ millimole) in tetrahydrofuran (8 ml) and ether (½ ml), then the hydrogenation is carried out for 2 hours under 2.8 kg per cm ^.

The mixture is filtered and the layers of the filtrate are separated.

After washing the aqueous phase with methylene chloride (2x5 ml), it is cooled in ice and acidified with 1 N hydrochloric acid (1 ml), then it is extracted with chloroform ( 5x5 ml). The organic extracts are dried (MgSO 4) and evaporated under vacuum to obtain 76 mg (52%) of compound VII which is in the form of an oil. The IR spectrum (GÏÏGl ^) includes signals at 1790 and 1710 cm The RMÏÏ spectrum (CDCl ^) includes the following signals: 9.5 (1H, sf), 5.65 (1H, dd, Jtrans = h Hz, J. = 2 Hz), 4-, 72 (2H, dq, 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, s).

EXAMPLE 32.- CO H 2 r-d “3 î. ? +. C1C (CH) P (OC, H) -► i „^ / 3 2 3 2 5 2 · CO PNB .S ^ / (CH2> 3P (OC2H5> 2 ΓΊ» i l 0 / —Βχ ^ ρΦ3 CO PNB 2 2

A 1 M solution of pyridine in methylene chloride (2.2 ml, 2.2 mmoles) is added dropwise to an ice-cooled mixture comprising compound 1 (1.324 · g, 2 millimoles) and compound 2 (0.54 · g, 2.2 millimoles, crude) in methylene chloride (15 ml), The mixture is stirred at room temperature for 1 hour and filtered through Celite. The filtrate is washed successively with 0.5 N hydrochloric acid, water, 0.5 M sodium bicarbonate and brine. The filtrate is dried (MgSO 4) and filtered over Celite mixed with charcoal to obtain after evaporation to dryness 0.9 g of an oil. The oil is chromatographed on silica (10% B ^ O) which is eluted with ethyl acetate to collect 0.5 g (32.8%) of compound 3. The EMU spectrum includes the signals to following: (ppm, CDGl ^), 7.0 - 8.1+ (m, 19 H), 4.8 - 5.8 (3H, m), 4.1 (4H, q), 3.3 - 4.2 (2H, m), 2.7 (2H, m), 1.9 (2H, m), 1.3 (6H, t).

_ (OEt) jXjï, -

COJPNB

3 ojxy ^^^ 2

CC ^ PNB

4

Compound 3 is heated to reflux (0.4 g, 0.52 millimole) in toluene (35 ml) for 4 hours, then the mixture is evaporated to dryness to obtain an oil containing compounds 3 and 4 and tri-phenylphosphite oxide. The oil is chromatographed on silica (10% H2O) which is eluted with ethyl acetate to collect 0.1 g of pure compound 4, then 0.15 g of compounds 3 and 4. The spectrum MNE (ppm, CDOl · ^) includes the following ô signals: 8.3 (2ÏÏ, d), 7, -67 (2B, d), 5.7 (H, q.), 5.33 (2H, d ), 4.2 (4H, q), 3.83 (H, q), 3 Λ (H, q), 2.9 (2H, m), 1.9 (2ÏÏ, m), 1.3 ( 6H, t) and the IR spectrum (pure) includes signals at 1790 cm ^ (ß-lactam) and 17IO cm ^ (ester).

rT ^ V '* Vv / ^ (oEt> 2 - »

C ° 2PNB Γ — 4 / S> sO

ΓΤ XÎ (OEt) 2 1 0 / ”N ^ CO H 2 5

We submit; a mixture of compound h (0 »1 Sj 0.207 millimole), Celite palladium at 30% (0.1 g) and" sodium bicarbonate (17 mg, 0.207 millimole) in tetrahydrofuran (10 ml), ether (5 ml) and water (5 ml) at hydrogenation under an initial pressure of

Q

2.8lkg per cm, for 2 hours. The mixture is filtered through Celite and the layers of the filtrate are separated. The aqueous alkaline layer is washed carefully with ethyl acetate and acidified with 1 M hydrochloric acid. It is extracted with methylene chloride and the extract is dried over magnesium sulfate. The extract is evaporated in methylene chloride to obtain h 9 mg (66.5%) of the compound The IE spectrum comprises signals at 1790 cm - * ^ (ß-lactam) and 1700 cm (-0 -—OH) .

EXAMPLE 33.- r ~ rsy ^ Jms) * C02Na - .Cl

Zi ° +

C02PNB I

CO PNB 7

The mixture is heated at 80 ° for 5 hours, a mixture of compound 1 (1.07 g, 1.66 millimole) and compound 2 (0.42 g, 3 millimoles) in methylene chloride (3 ml). The crude oil is chromatographed on silica (3% H2O) which is eluted with ether, with a mixture of ether and ethyl acetate (1: 1) and with a mixture of acetate ethyl and 5% ethanol to obtain 1.0 g (82%) of compound 3- By standing, this oil crystallizes to give a solid having a P.3 ?. from 138 - 140 ° after recrystallization from ether.The EMET spectrum (CDCl · ^) includes the following signals 6: 8.2 (2Ξ, 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).

9 - o S J? (OMe) _ | o toluene, | f "

i 0> ~ Νχ ^, Φ3 l * N

I CO.PNB

co2pnb 2 2 - i

Compound 3 is heated at reflux for 4 hours (0.5 g, 0.69 millimole) in toluene (30 ml). The mixture is evaporated to dryness and chromatographed on silica (3% EbjO) which is eluted with a 1: 1 mixture of ether and ethyl acetate, then with a mixture of ethyl acetate at 10% ethanol to obtain 0.18 g (58%) of compound 4. The BMtT spectrum (ppm, CDOl ^) comprises the following signals 6: 8.25 (2H, d), 7.6 (2H, d), 5.65 (H, q), 5.3 (2H, d), 3.8 (3H, s), 3.6 (3H, s), 2.7 - 3.6 (2H, m ), 1.5 - 2.5 (W, m).

_ ^ (OMe) 2 I 30% Pd / Celite t (ÿ— N ~ - ^ NaHCO ^ CO PNB 2 4 _ CO ^ a 5

A mixture of compound .b (50 mg, 0.112 millimole), sodium bicarbonate (9.125 mg) and 30% palladium on celite (50 mg) in tetrahydro-furan (5 ml), ether ( 2.5 ml) and water (2.5 ml) at hydrogenation under an initial pressure of 2.8l kg per cm ^, for 2 hours. The mixture is filtered through Celite and the layers are separated. The alkaline aqueous layer is washed carefully with ethyl acetate and lyophilized under high vacuum to obtain 28 mg (75.9%) of compound 5 which is hygroscopic. The IR spectrum (KBr) includes signals at 1770 cm “1 (ß-lactam) and 1610 cm" 1 (-C00 ").

EMCPIE 3 ^ .-

(L'R, 5R, 6R) and (l'S, 5S, 6S) 6 — Ç1 '-hydroxy-l' -éthyl) -2-methylpénème-3 ~ carboxylic (isomer D) (illustration of the process * specially preferred introduction of the substituent in position 6 at mid-synthesis.

OH

C02ïfe, K

A. Preparation of 4H; ritylthio ~ 2-azetidinones intermediates.

1. l-Clrimethylsilyp - ^ - tritylthio-P-azetidinone.

rT · _> ΓΤ '“’ 1 oJ- ^ a ^ "- slWe, 3

A solution of tritylthio-2-azetidinone (3 ^ 5 mg, 1 millimole) of 1,1,1,3,3,3-hexamethyldisilazane (80 mg, 0.5 millimole) and chlorotrimethylsilane is heated at reflux for 18 hours. (55 mg, 0.5 millimole) in dichloromethane (20 ml). By concentration of the reaction mixture, the desired compound is obtained which is practically pure. The EM spectrum (ppm, GDCl ^) includes the following signals: 7.32 (15H, m, aromatics), * +, 22 (1H, dd, H-1 +), 2.67 (1H, dd, J = b, 1, J = 16, H-3), 2.22 (1H, dd, FJ = 2.2, J = 16, H-3), 0.3 (9H, s, CH3).

2. l- (t-Butyldimethylsilyl) -M ~ -tritylthio-2-azetidinone ♦ A. -f.

i (CH3) 3 "

Triethylamine (1.62 ml, 11.6 millimoles) is added dropwise over 5 minutes to a solution cooled to 0 ° and stirred with b-tritylthio-2-azetidinone (3.5 g, 10.1 millimoles) and chloro-t-butyldimethylsilane (1.68 g, 12.7 millimoles) in dimethylformamide (35 ml).

The reaction mixture is stirred at room temperature for 18 hours and diluted with water (250 ml) and ether (”200 mil. The organic nhase is washed with water t (3 x 50 ml ), dried and concentrated to obtain an oil (^ -, 33 g) · By crystallization from pentane, a total of ^, 1 g (89%) of the desired compound is obtained, which is in the form of a white solid with a PP of 113 - 11½0 The BMW spectrum (ppm, ODCl ^) includes the following δ signals: 7Λ5 (w ^ H, m, aromatic), 2 (1Ξ, dd, H-hf), 2.63 (lïï, dd, J = ^ J = 16, H-3), 2.13 (1H, · dd, J = 2, J = 16, ïï-3), 1.0 (9ïï, s, t-Bu ), 0.35 (6H, s, Me). The IE spectrum includes a signal for -O q_q = 1735 cm * "1.

Analysis for C ^ gH ^ FOSSi:

Calculated: C, 73.15; H, 7.24-; F, 3.05; S, 6.97%.

Found: C, 73.27; H, 7.32; F, 2.97; S, 6.9½%.

3. l-Methoxyaethyl ^ -tritylthio-2-azetidinone.

~ T -> rf I Λ— N ,. ev ~~~ N ~ i O O \ H CH2OCH3

A solution of ^ tritylthio-2-azetidinone (1.38 g, ½, 0 millimoles) in tetrahydrofuran (10 ml) is added to a well stirred suspension of sodium hydride (200 mg of commercial product at 50%, ^ 1 millimoles, washed with pentane) in tetrahydrofuran (10 ml) kept at -15 ° - Methanol (12 drops) is added and the mixture is stirred at -15 ° for 15 minutes. Methoxymethyl bromide (0.58 g, 6 millimoles) is added, the new mixture is stirred for 2 hours, then diluted with ether, washed with water and brine, dried and concentrated to obtain an oil (1.72 g). By crystallization from pentane, 1.5 hl g of a white solid are obtained with a m.p. 72-76 °.

TO cner'-h'po "R1W ί'ΠΤΙΓΠ _ ^ ΛηττνητΆηίΙ Ips si tmaiiT Λ ri τι vnrvh" r 7,3 (15 ^, m, aromatic), U-Λ (3H, m, HGH ^ O) and HH ·), 3.22 (3ÏÏ, s, CH3), 2.76 (2ÏÏ, m, H-3).

H ·. l ^ Methosyethoxymethyl) -1 * -tritylthio-2-azetidinone.

εοΦ3 Ä - · jX »

4-tritylthio-2-azetidinone (3 ^ 5 mg, 1 millimole) and methoxyethoxymethyl chloride (187 mg, 1.5 millimole) are added with vigorous stirring to a suspension of tetrabutylammonium bromide (322 mg, 1 millimole) and 85% potassium hydroxide (70 mg, 1.1 millimole) in dichloromethane (10 ml) cooled to 5 ° · The mixture is stirred at room temperature for 2 hours, then the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is concentrated to obtain 15 mg of a viscous oil. By purification by chromatography on a column of silica gel which is eluted with 5% ether in dichloromethane, 206 mg (½%) of the desired compound are obtained, which is in the form of an oil. The spectrum ΒΓ © Γ (ppm, CDGl ^) #: 7.30 (I5S, m, aromatic), * +, 57 (2H, quadruplet AB, 1T ~ CH20),! +, H6 (1H, dd, Hk · ), 3.50 (ifH, s, OGJ ^ CHgO), 3.30 (3H, s, Cïï3), 2.75 (2H, m, H-3) - 5- l- (2 1 -Petrahydropyramyl) - jf-tritylthio-2-azétidinon.e "K '- îÇ 1

N-buty 1 lithium (1.6 M, 1.6 ml, 2.56 millimoles) is added dropwise to a solution of h-trityl-thio-2-azetidinone (863 mg, 2.5 millimoles) in tetra-hydrofuran maintained at -78 °. After 15 minutes of stirring, 2-chlorotetrahydropyran (560 mg, h, 7 millimoles) is added and the reaction mixture is allowed to warm up to room temperature in 90 minutes. The reaction solution is diluted with ethyl acetate, washed with brine, dried and concentrated to give 635 21g of an oil. By chromatography on a column of silica gel which is eluted with a dichloromethane ether mixture, a mixture of the isomers of the desired compound contaminated with a small amount of starting compound is obtained.

The EMM spectrum (ppm, CDCl ^) ^: 7> 28 (15H, m, aromatics), h, h (H, dd, Hh), 2.9 - 2.2 (2H, m, H-3), h, l - 3.2 and 2.2 - 0.7 (tetrahydropyrannyl).

. B. Preparation of 3- (1 '-hydroxy-1' -ethyl) -1-methoxymethyl-h-tritylthio-2-azetidinones.

^ X_YSC ^ 3 a) Isomer (1'S, 3S, hR and l'R, 3R, hS) (C isomer)

A solution of lithium diisopropylamide in tetrahydrofuran (5 ml) at -78 ° is prepared from n-butyllithium (1.6 M, 1.0 ml, 1.6 millimole) and diisopropylamine (Q-, 25 ml, 1.8 h millimole). After 30 minutes, a solution of 1-methosymethyl-h- is added thereto dropwise. tritylthio-2-azetidinone (h9l mg, l, h2 millimole) in tetrahydrofuran (6 ml) and the new solution is stirred for 1 minute. We have it. ernitta to evmtte. acetaldehyde (3.0 ml), then after 20 minutes, water (30 ml).

The mixture is acidified to pH 3 with 2% hydrochloric acid and extracted with ethyl acetate (5 x 20 ml). The organic phases are combined and washed with brine, dried and concentrated to obtain an oil which is crystallized by trituration in ether to obtain 4-4-0 mg (80%) of l isomer C having a PF of 188.5 "- 189 °. The EMN spectrum of (CDCl 4) comprises the following signals 6: 7.3 (15H, aromatic), 4-, 37 (2H, qAB,] J-0H20), 4-, 32 (1H, d, J = 2 , H-4-), 3.17 (3H, s, OCH3), 3.32 - 2.70 (2ÏÏ, m, ïï-3 and ïï-5) and 1.12 ppm (3H, d, J = 7, CBy.

Analysis for C26H27îî03S:

Calculated: C, 72.02; H, 6.28; ÏT, 3.23; S, 7.39%.

Found: C, 71.99; H, 6.02; H, 3.21; S, 7.4-0%.

b) Isomers (l'S, 3S, 4-R and l'R, 3R, 4-S) and (l'R, 3S, 4R and I1 l'S, 3R, 4-S) (C and B isomers).

A solution of lithium diisopropylamide (0.4-82 millimole) at -78 ° in dry ether (3 ml) is prepared from n-butyllithium (0.191 ml of 2.52 M dhme solution in hexane, 0.4-82 millimole) and diisopropylamine (0.067 ml, 0.4-82 millimole). After 20 minutes, a solution of (4-R and 4-S) 1-methoxymethyl-4 ~ tritylthio-2-azetidinone (0.171 g, 0.4-39 millimole) in a mixture of dry ether (1 ml) and dry tetrahydrofuran (1 ml), then the resulting clear solution is stirred for 15 minutes at -78 °. Then a solution of tetrabutylammonium fluoride (0.96 ml of a 0.5 M solution in tetrahydrofuran, 0.4-8 millimole) is added. A precipitate forms while the mixture turns light pink. After 5 minutes at -78 °, the reaction is stopped by adding acce ê “λ1 tt / ^ λ h-ηπ τ“ Τη ΛτΛ Λνι 4 * η4 * · ΐ Ί 1 λ f Γ \ Ο τη 1 πλ · Ϊ 4- · ην »äV /» Year 1 ä4 ~ r \ V> continues stirring for another 15 minutes. Saturated ammonium chloride solution is added and extraction is carried out with ethyl acetate (2 x 25 ml). The organic phases are combined and washed with brine, then dried over anhydrous magnesium sulfate. By evaporation of the solvent under vacuum, an oil (0.228 mg) is obtained which is chromatographed on 10 g of silica gel.

By elution with a mixture (6: 4) of benzene and ethyl acetate, 0.106 g (62%) of starting compound is obtained, in addition to a mixture of the two isomeric alcohols which are separated by layer chromatography · thin (same solvent system). The alcohol with a high Ef (33 mg, 17%) is identical to the C isomer above and has a m.p. of 188.5 - 189 ° after crystallization in the ether-dichloromethane system.

The alcohol having a low Ef (30 mg, 16%) (isomer B) is obtained in the form of an oil which hardly crystallizes in hexane and thus gives a solid having a PP of 94 - 95 ° · The IE spectrum (CH ^ Cl ^) includes signals for \): 3600 cm-1 (OH), 1760 cm ”1. (C = 0), the EM spectrum of XH (CDCl ^) includes the following signals S: 6.9 - 7 »5 (I5S, m, aromatics), 4.2 (2H, center of qAB, J = 11 , 5, ÇH2-0-CH3), 4.28 (1H, d, J = 2, Ό, 4-Ξ), 3.65 (1H, center of wide sextuplet, H-l '), 3.3 ( 1H, dd, J ^, 4 trans = ^ 3 2! = ^ 3 ^ '3.15 (3B ·, s, Q ~ O · ^), 1.55 (1H, s large, OH-1'), 1.05 (3H, d, J = 6.5, H-2 ').

Analysis for ^ 26 ^ 27 ^ 3 ^:

Calculated: C, 72.02; H, 6.28; H, 3.23; S, 7.39%.

Found: C, 71.77; H, 6.36; H, 3.15; S, 7Λ3%.

G. Preparation of trans-3 ~ aoetyl-1-metho: xymethyl H— trit jlthio-2-azetidinone “3. JL l ^ cφ_ ΓΤ - ^ _ ► ° ζ "\

Lithium diisopropylamide is prepared in a nitrogen atmosphere at -78 ° in the usual way from diisopropylamine (0.3½ ml, 2, ½ millimoles) and n-butyllithium (1.1 ml of a solution 2, 2 H in hexane, 2 ½ millimoles) in tetrahydrofuran (3 ml). A solution of l-methoxymethyl - ^ - trityl-thio-2-azetidinone (0.78 g, 2 millimoles) in tetrahydrofuran (3 ml) is added dropwise and after 20 minutes of stirring at -78 °. , ethyl acetate (0.53 g, 6 millimoles) is added in) once and stirring is continued for ½5 minutes at -78 °.

The reaction mixture is diluted with ether and washed with ammonium chloride solution, water and brine, then dried and concentrated to give an oil (0.7 g) . The compound is purified by chromatography on 20 g of silica gel which is eluted with increasing amounts of ether in benzene. The useful fractions are collected to obtain 0.32 g (37%) of the desired compound which is in the form of a colorless oil. The EH spectrum of 1H (CDOl ^) includes the following signals 6,7,7 - 6,8 (15H, aromatic), ^ 85 (1H, d, J = 2, 11-½), ^ 5 (2ÏÏ, s, 3 '9 (1H' d 'J = 2> H ~ 3), 3.22 C3H, s, Cïï3) and 2.0 ppm (3H, s, CH ^). The IR spectrum includes signals for ^ max = 1770, 1710 cm λ.

D. Preparation of trans-3-acetyl-1- (t-butyldimethylsilyl) ^ -tritylthio-2-azetidinone.

bG- -A, / -.

X (CH3) 2 N {CV2

Lithium diisopropylamide is prepared in the usual way from diisopropylamine (0.18 ml, 1.2½ millimole) and n-butyllithium (0.78 ml., Of a 1.6 H solution in hexane, 1.2½ millimole) in tetra-hy & rofuran (8 ml). A solution of 1- (t-butyldimethylsilyl) - ^ tritylthio-2-azetidinone (0 ^ 6 g, 1 millimole) in tetrahydrofuran (8 ml) is added dropwise at -78 °. After 5 minutes of stirring, ethyl acetate (1 ml) is added all at once and the mixture is stirred for | 3 hours at -78 °. The mixture is acidified with 0.5 E cold hydrochloric acid to pH 6, then extracted with ethyl acetate (2 x 20 ml). The mixture of organic phases is dried and concentrated to obtain an oil • (0.5 g) which is crystallized from pentane to obtain a total of 200 mg (h0%) of the compound having a P.P. of 122 - 12½ °.

The IE spectrum includes signals for \) = 1758? 1710 cm \

in SIX

"I

the EM spectrum of H (ODOl ^) includes the following signals <5: 8-7.1 (15H, m, aromatic), ^ 83 (lïï, d, J = 2, 11-½), 3.38 (1H , d, J = 2, H = 3), 1.80 (3H, s, GE ^), 0.92 (9H, s, Bu) and 0.3 ppm (6ü, s, Oïï ^).

E. Preparation of trans-1 “(tHmtyldimethvlsilyl) -3-formyl- * f-tritylthio ~ 2-azetidinone.

_sc <f> 3 ✓ “%! (“) 2 °> ÎCH3} 2

Vbu

A 1.5 M solution of n-butyllithium (1.6 ml, 2, h millimoles) is added dropwise in a nitrogen atmosphere to a solution cooled to -78 ° of diisopropylamine (0.3 * + ml , 2,4- millimoles) in tetrahydrofuran (5 ml). After 30 minutes of stirring, a solution of 1- (t-butyldimethylsilyl) -H-tritylthio-2-azetidinone (1.0 g, 2.18 mmol) in tetrahydrofuran (5) is added dropwise. ml) and the stirring is continued for 30 minutes. y Oh add ethyl formate (0.8 ml, 9.9 mmol) and the cooled solution is stirred for 10 minutes. The reaction mixture is washed successively with cold 1 TJ hydrochloric acid (5 ml), 1 K sodium bicarbonate (6 ml), water (10 ml) and brine. The organic layer is dried over magnesium sulphate and evaporated, then the residue is crystallized from pentane to obtain 810 mg (76%) of the formate in the form of a white solid having a mp of 132-133 ° · The IR spectrum (CHCl ^) includes signals for _e_ = 1760, 1715 cm-1; the spectrum SM of ^ H (CDCl ^) comprises the following signals 6: 9.0 (1H, d, J = 1.25 Hz), 7.30 (15H, m), h, 7 (1H, d, J = 1.5 Hz) and 3? 5 PPm (1H, t, J = 1.5 Hz).

Notes: a) diisopropylamine is distilled over calcium hydride and stored on potassium hydroxide ο lithium aluminum and stored on 3 A molecular sieve; c) ethyl formate is stirred at room temperature with potassium carbonate, then distilled over phosphorus pentoxide; d) excess n-butyllithium is destroyed by means of 1 Ή hydrochloric acid.

P. Preparation of. l- (t-butyldimethylsilyl) -3- (l'-hydroxy-1 '-ethyl) ~ 4 - tritylthio-2-azetidinones (4-isomers).

OH

'r-T *** a) As / -e "* \ #M ^ \ (Me).

(Me) 2

N-Butyllithium (1.6 M, 3.4 ml, 5.4-4 mmol) is added over 5 minutes to a diiso solution. propylamine (0.84-7 ml, 6.23 millimoles) in tetra-k hydrofuran (30 ml) maintained at -78 °. After 30 minutes, a solution of 1- (t-butyldimethylsilyl) -4-tritylthio-2-azetidinone (2.0 g, 4-, 4- millimoles) in tetrahydrofuran (20 ml) is added and after 15 minutes, acetaldehyde (10 ml) is added at once, then after another 15 minutes, 100 ml of water are also added. The mixture is acidified to 5 ~ 6 with dilute hydrochloric acid, then extracted with ethyl acetate (3 x 30 ml). The organic phases are washed with brine, dried and concentrated to obtain an oil which is revealed on thin layer chromatography - consisting of a mixture of the four isomers (isomers A, B, C, D in order of polarity decreasing).

By crystallization of the oily residue in a mixture of ethyl acetate and pentane, the B and O isomers are obtained in the form of a white solid, while the A and D isomers remain in the mother liquors.

Four pure compounds are isolated by preparative chromatography (Waters,!? 00) from the mother liquors and the solid above. The proportions are 17% of isomer A, 32% of isomer B, 39% of isomer C and 12% of isomer D. By replacing in the above reaction the tetrahydrofuran by ether, stopping the reaction after 1 minute at -78 °, isomers A, B and C are obtained in amounts of 12.9%, 30.5%, 38.2% and 18.4%. When the reaction mixture is allowed to warm up to 20 ° in 2 hours, before stopping the reaction, in the case of working in ether, the proportions of the isomers are 13.4%, 24.6%, 44% and 18%. The addition of 1 molar equivalent of anhydrous magnesium bromide to the reaction mixture brings the proportions to 19.2%, 19.7%, 3 °, 1% and 31% · f Isomer A. This isomer presents stereo chemistry in cis in - C ^. It consists of a racemic mixture of the enantiomers (l'S, 3R, 4R) and (l'R, 3S, 4S).

The compounds subsequently derived from compound A are hereinafter called "isomer A". They consist of an enantiomeric mixture and have the same configuration in C- ^, and C ^. The compounds derived from the A isomer by a reaction involving a configuration inversion, are called "D isomer" if the inversion takes place at G ^, and "C isomer" if the inversion takes place at C ^. The compound obtained has a mp of 152 - 153 ° · The RMH spectrum of (CDCl 4) comprises the following signals <5: 8.0 - 6.8 (15H, m, aromatics), 4.30 (1H, d, J = 5.5, H-4), 3.78 (1H, m, H-l '), 3.10 (1H, 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, CH ^).

Analysis for C ^ H ^ HOgSi:

Calculated: C, 71.52 Η, 7Λ0; F, 2.78; S, 6.36%.

Found: C, 71.28; H, 7, hl; N, 2, h8; S, 6.19%.

Isomer B. This isomer has stereochemistry in trans in - C ^. It is a racemic mixture of the enantiomers (l'R, 3S, hR) and (l'S,. Compounds having the same configuration as Cls and are called "isomer B".

This compound has a BP of 158 - 159 °. The IP spectrum (CHCl ^) includes a signal at * 0 = I7h5 cm The BOT spectrum of max (CDCl ^) includes the following signals 6: 7.60 - 7.10 (15H, m, aromatic), h, 02 ( 1H, d, J = 0.8, Hh), 3.32 (1H, dd, J = 3.0, J = 0.8, H-3), 3.55 - 3.15 (1H, m, H-1 '), 0.88 (12H, CH3 and t-Bu), 0.16 (6H, s, OH ^).

Isomer C. This isomer presents the stereochemistry in trans in C ^ - C ^. It consists of a racemic formed by the enantiomers (l> 'S, 3S, hR) and (l'R, 3R, hS). j Compounds having the same configuration in 0 ^, C ^ and C ^ are called "C isomer". The compound has a P.P. from 13h -1360. The RMH spectrum of ^ H (CDCl ^) comprises the following signals 6: 7.60 - 7.10 (15H, - m, aromatics) h, 32 (1H, d, J = 1.8, Hh), 3, 02 (1H, dd, J * "2.7, J = 1.8, H-3). 3.0 - 2.5 (1H, 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, CE ^). The IR spectrum (CHC13) includes a signal at "^ max = 17 ^ 5 cm ^ (C = 0).

Isomer D. This isomer presents the stereochemistry in cis in C ^ 6- C ^. It consists of a racemic formed by the enantiomers (l'R, 3R, * + R) and (l'S, 3S, hS) - Compounds having the same configuration in C ^, and. are called "isomer D". The compound has a P.P. of 171 -I720. The 1H RM spectrum (0D013) includes the following δ signals: 7.80 - 6.90 (15H, m, aromatic), h, 70 (XH, d, J = 4.5, H = 4), 3 02 (1H, dd, J = 4.5, J = 0.5, H-3), 2.39 (1H, dg, J = 0.5, J = 6.5, H-l '), 1, 0 (3H, d, J = 6.5, CH,), 0.97 (9H, s, t-Bu), 0.32 (6H, s, CHj).

Analysis for C ^ QH- ^ liC ^ SSi:

Calculated: C, 71.52; H, 7, ^ - 0; N, 2.78; S, 6.36%.

Found: C, 71.27; H, 7, ^ 3; N, 2.51; S, 6.31%.

OH

Μ-γ ** 3 'bh4- ^ L_p-SC * 3 b) * o ^ -N \ siAB "2 2 2 isomers -trans

A solution of lrans-e- ^ acetyl-l- ^ t-butyldimethylsilyl) -1! · -Tritylthio-2-azetidinone (1.0 g, 2 millimoles) is added dropwise in a nitrogen atmosphere. THF i (30 ml) under 1T2 in a stirred suspension at 0 ° of sodium borohydride (0.38 g, 10 millimoles) in tetrahy-drofuran (120 ml). The ice bath is removed and the mixture is stirred for b hours at room temperature. It is poured into a mixture of ice and cold hydrochloric acid (1 h, pïï 6), then the new mixture is stirred for 15 minutes and an extraction with ether is carried out (in 3 times). The ethereal extracts are combined and dried, then concentrated to obtain an oil (1.0½ g) which crystallizes in pentane to obtain the desired compounds with a yield of 8 * +%, in the form of a 70:30 mixture of the G and B isomers having a PF of 119-121 °.

ο 0Η Αι

ο I - * I

A — N .. —Νν.

V Ai (Cir), ^ \ i (CH)

Vbu3 2 Vb "

Isomer B

• / Ί

Cooled to 0 °, a suspension of cuprous iodide (* +, 78 g, 15 millimoles) in ether (50 ml) and there is added, in a nitrogen atmosphere, a 1.9 M solution of methyl. -lithium (26 ml, 50 millimoles). The brown solution is stirred at 0 ° for 10 minutes, then cooled to -60 ° and there is added dropwise the ll (t-butyldimethylsilyl) -3 ~ formyl-l + -tritylthio-2-azetidinone (2 , ¾ g, 5.0 millimoles) in a mixture of 10 ml of tetrahydrofuran and 40 ml of ether. Agitation is continued for 3 hours. The solution is warmed to -4-0 ° and a 1 M solution of ammonium chloride is carefully added to it. The mixture is filtered over Gelite and the organic phase is washed with a 1 M solution of ammonium chloride (3 × 5 ml), then brine, after which it is dried over sodium sulfate.

By filtration and evaporation, the isomer B alcohol is obtained which is crystallized from hot pentane to obtain 1.6 g (65%) of the compound having a mp 160-116 °.

The IE spectrum (CHCl-,) includes a signal for 0 = 1730 cm ”1. The EM spectrum of 1H (CDCl ^) comprises the following signals 6: 7.32 (15H, m) 4-.05 (1H, s), 3.4 · (1H, d, J = 3 Hz, 3.25 - 3.55 (1H, m), 1.6 (lïï, s), 0.9 (12H, s) and 0.1 ppm (6ïï, s).

Notes: a) tetrahydrofuran and ether are distilled over lithium aluminum hydride.

b) excess methyl lithium destroyed with 1N hydrochloric acid

c) cuprous iodide is purified by continuous extraction using anhydrous tetrahydrofuran in a Soxhlet apparatus for 18 hours, then dried under vacuum for 18 hours in a desiccator on P- on Λ-κ5αφ3 _cnfi-r ^ 3 ä) 0 ^ -% ^ ** tBu ~ ^ tBu

Methyl magnesium iodide (0.1 ml, 0.1 millimole) is added dropwise to a stirred solution cooled to 0 ° of trans-1- (t-butyldimethylsilyl) -3-formyl-V- tritylthio-2-azetidinone (25 mg, 0.05 millimole) in tetrahydrofuran (2 ml). The solution is stirred for 90 minutes at 0 °, then it is poured into a solution of ammonium chloride p and acidified. The whole with a 1 K solution of hydrochloric acid, after which an ether extraction is carried out . By drying and concentrating the organic extracts, an oil is obtained which consists of the starting compound and a small amount of a mixture of the two desired tram isomers in which the B isomer is predominant.

G. Preparation of (1 * S., 38, ½ and the R, 3P ^ S) -l- (t-butyl-dimethylsilyl) -3- (l'-trimethylsilyloxy-1'-ethyl) -h- trityl-thio-2-azetidinone (isomer C).

oh çsi- "s \ ί, A solution of (l'S, 3S, 4R and l'R, 3R, 4-S) -l- (t-butyldimethylsilyl) -3- (l'-hydroxy is stirred at room temperature -l--ethyl) -4 ~ tritylthio-2-azetidinone (15 mg, 0.3 millimole) and azidotrimethylsilane (35 mg, 0.30 millimole) in dry tetrahydrofuran (6 ml) until the compound disappears starting time (15 minutes) By purifying the reaction mixture by chromatography on a column of silica gel eluted with methylene chloride, 128 mg (74%) of the desired compound are obtained, which is in the form of a white solid having a PP of 144 · - 14-6 °. The EMIT spectrum of (ODOl ^) includes the following signals (5: 7,10 - 7? 60 (15H, m, aromatic), 4-, 30 (1H, d , J = 1.5, H-4 ·), 2.25 -2.89 (2H, m, H-3, H-l '), 0.82 - 1.07 (12H, m, t-Bu , ïï-2 '), 0.27 (6H, s, Cïï3), -0.10 (9H, s, -O-SKCH ^. The IR spectrum (CHClO includes a signal for \) = 1736 cm ^ (C = 0).

J IUctX

ïï. Preparation of (L'S., 3R ^ 4-R and l'R, 3S 4-S) -l '~ (t-butyl-dj dimethylsilyl) -3- (l1 -methoscymethoxyether-l 1-ethyl) -4— tritylthio-2-azetidinone (isomer A).

OCH OCHU

PH · X 2 JSCÙ ^ αφ3 I -> J — X / (Me)

J — N-. O \ Si Z

° If (Me) 2 \ t-Bu t-Bu

N-butyllithium (about 12.5 ml of a 1.6 M solution in hexane or 20 millimoles, which is just enough to obtain a persistent pink coloration) is added dropwise to a solution of ( L'S, 3R, 4-S and 1 'R, 3 S, 4-S) -1 - (t-but yldimé thyl silyl) -3- (1' -hydroxy-1'-ethyl) - 4-tritylthio-2 -azetidinone (isomer A), (10.1 g, 20 millimoles) in tetrahydrofuran (100 ml) at -78 °. After 1 4 mi rrnbes fl 1 a cri -ha -hi we r> n ainnbp crrm-h-ha to crnn-h-he. rniPi solution of bromomethoxymethyl ether (2 ml, 2 h millimoles) in tetrahydrofuran (30 ml). The mixture is stirred for 1 hour at -78 ° and for 2 hours at room temperature, then poured into an ammonium chloride solution (200 ml). By extraction with ethyl acetate (3 x 200 ml), washing with brine, drying over sodium sulfate and concentration, the crude desired compound is obtained which is purified by chromatography on silica gel which is eluted with increasing amounts of ether in benzene (10, bg, 95% of the desired compound).

The EM spectrum of (CDCl ^) includes the following signals b: 7.1 - 7.5 (15H, m, aromatics), ^, ^ 7 (1H, d, H-1 · »-), if, 23 ( 2ÏÏ, qAB, J = 7, 0-CÏÏ2-0), 3.1 - 3Λ (2H, m, H-3 and H-l '), 3.23 (3H, s, 0-CH3), 1, 37 (3H, d, J - 6.5, CHj), 0.97 (9H, s, Bu) and 0.25 ppm (6H, 2s, CH ^).

1. Preparation of the (l'S, 3S, hR and 1 Έ, 3ΕihS) -! - (t-butyl-i dimethylsilyl) -3- (1 * -formyloxy-1, -ethyl) -Lf-tritylthio-2- azetidinone (isomer 0).

OH - 9 ° Η0 A 'V "3 _>; n V \

A solution of (1 'S, 3S, hE and 1'E, 3E, hS) -l- (t ~ butyldimethylsilyl) -3- - (1'-hydroxy-l'-ethyl) - is stirred at room temperature h-tritylthio-2-azetidinone (isomer C), (50 mg, 0.1 millimole), p-bromobenzene sulfonyl chloride (100 mg, 0, h millimole) and dimethylamino-pyridine (2 h mg, 0, 2 millimole) in dimethylformamide (3 ml) until the starting compound has disappeared (30 minutes). The reaction mixture is then diluted with water, then

av, * 1 I λ "τ7" 4 "-λ <-" -î 4- A Ί I a4-Vi λ · μ T etrû 1 δο ΰν4 * · τ »ο · ί 4 * o λήοόπί miûC

with brine, they are dried over magnesium sulphate and evaporated. The desired compound is purified by column chromatography. The EMU spectrum of (CDCl ^) includes the following signals: 7580 (1H, s, CÏÏO), 7.20 - 7566 (I5S, m, aromatic), 3 * 90 - h, 36 (1H, m, H- l '), h, 07 (lïï, d, J = 2, Hh), 3.22 (1H, s large, H-3), 1.18 (3ÏÏ, d, J = 6.5, H-21 ), 1.0 (9H, s, t ~ bu), 0.31 (6ïï, s, d-CH ^).

J. Preparation of (l'R) 3S, h ^ letl·lS, 3R, hS) -ll- (t-butyl-dimethylsilyl) -3-CL1-acetoxy-11-ethyl) -h-tritylthio-2- azetidinone (isomer B).

OH OAc * = 2o J — N /; pyridine * J — L χ si- | - \ \

Stirred at room temperature for hO hours, a solution of (E, 3S, hS and 1'S, 3R, hS) -l- (t-hutyldimethylsilyl) -3 ”(1 '-hydroxy-11 -ethyl) - h-tritylthio-2-azetidinone (13.85 g, 27.5 millimoles) in a mixture prepared at 0 ° of pyridine (75 ml) and acetic anhydride (50 ml). The reagents are evaporated, the last traces of which are removed by azeotropic distillation with toluene three times, so as to obtain an almost white solid. The crude derivative is crystallized from a mixture of ether and petroleum ether to obtain 97.5% of the desired pure compound. The EMN spectrum of ^ H (CDCl · ^) includes the following signals S: 7.6h - 7.03 (15E, m, aromatic-), h, 60 (1H, m, J "6, H-l ') , 3.92 (1H, d, J = 2, Hh), 3.55 (1Ξ,. Dd, J * 2, J = 6, H-3), 1.79 (3H, s, CH ^ OO) , 0.98 (3H, d, J = 6, CHJ, 0.88 (9H, s, t-butyl), 0.12 (6H, s, CH ^), the IR spectrum (CHCl · ^) includes signals for 0 = 1775, 17H-0 cnfm (C = 0).

K. Preparation of 1- (t-butyldimethylsilyl) ~ 3 - (-p-nitrobenzyldioxycarbonyl) -! 1-ethyl-H-tritylthio-2-azetidinone (M-isomers).

PH crA OCO PNB

Αν ΑΦ3 Av ^ sc, N

j ^ "Λ-" Νϊ / '2 I N: Bu ^ tBu

Isomer G "n-butyllithium (8.8 ml of a 1.6 M solution in hexane, 1½ millimoles, just enough to achieve a persistent pink coloration) is added dropwise to a solution of isomer C

1- (t-butyldimethylsilyl) -3- (1'-hydroxy-1'-ethyl) -H- jt tritylthio-2-azetidinone (6.55 g, 13 millimoles) in; ‘Tetrahydrofuran (70 ml) maintained at -78 °. After 15 minutes of stirring, a solution of p ~ nitrobenzyl chloroformate (3.2 g, 1H-, 8 millimoles) in tetrahydrofuran (30 ml) is added dropwise. The mixture is stirred for 1 hour at - 78 ° and poured into a solution of ammonium chloride (100 ml). By extraction with ethyl acetate (3 x 100 ml), washing with brine, drying and concentration, 11 g - of a crude product are obtained. The desired pure product is obtained by chromatography on silica gel (220 g) which is eluted with increasing amounts of ether in benzene. 93% of the compound having a m.p. of 118-119 ° is thus obtained (after crystallization from ether). The EM spectrum of (CLCl ^) includes the following signals S: 8.35 “7 (19H, m, aromatic), 5.12. (2H, s, benzyl), ^, 08 (1H, d, J = 1 , 8, HH ·), l ~ 3, 5 (1H, dq, J = 6.5, J = 2, H-l '), 3.10 (1H, dd, J = 2, J = 1, 8, ïï-3), 1,2 (3H, d, J = 6,5, Cïï3), 1,0 (9H, s, Bu) and 0,30 ppm (6Ξ, 2s, CH ^). The IR spectrum (CHCl ^) includes a signal for ^ max = cm-1 (C = 0) *

Analysis for C ^ gH ^ IT ^ O ^ SiS:

Calculated: C, 66.83; H, 6.20; R, ^, 10; S, lf, 69%.

Found: C, 66.90; H, 6.26; R, H ·, 11; S, ^ -, 59%.

Isomer B. The isomer B of l- (t-butyldimethyl-silyl) -3- (1 '-hydroxy-r ^ ethyr) -l · - · tritylthio-2-azetidinone, treated as above, gives l 'pure B-isomer of l- (t-butyldimetliylsilyl) -3- (1' -p-nitrobenzyldioxycarbonyl-l '-ethyl) - ^ tritylthio ^ -azetidinone which is collected in the form of a foamy product (I) »© RM spectrum of (CBCl ^) includes the following signals: 8.32 - 6.90 (19H, m, aromatics), 5.1 (2H, s, benzyl), ^, 65 - 20 \ (1H, m, H-l '), 3.97 (1H, d, J = 1.5, Hl), 3.58 (1H, dd, J = 1.5, J = 5.8, H-3) , 1.1 (3H, d, C10), 0.7 (9H, s, Bu) and 0.2 ppm (6H, s, 0H3). The IR spectrum (film) includes signals for 9 = 1775, 17 ^ 0 cm-1 (C = 0).

Isomer A. The A-isomer of 1- (t-butyldimethyl-silyl-3- (1 '-hydroxy-1' -ethyl) - ^ tritylthio ^ -azetidinone, treated as above, gives the pure isomer l- (t-butyldimethylsilyl-3- (l'-p-nitrobenzyldioxycarbonyl-1'-ethyl) -l · -tritylthio-2-azetidinone which is collected in the form of an oil (95%) * The spectrum RM of (CDC13) includes the following signals b: 8.3 - 6.7 (19H, m, aromatics), M-, 95 (2H, qAB, benzyl), 53 (1H, p, J = 7.5, J = 7.5, H-l '), 31 (1H, d, J = 6, Hl), 3.32 (1Ξ, dd, J = 6, J - 7.5, H-3), IM (3H, d, J = 6.5), 0.95 (9Ξ, s, tBu) and 0.2 ppm (6ïï, 2s, Cïï3).

Isomer B "Similarly, the D isomer of 1- (t-butyl-dimethylsilyl-3" (1-hydroxy-1 '-ethyl) -4 - tritylthio-2-azetidinone, gives the pure D-isomer l- (t-butyldime-thylsilyl) -3- (1 '-p-nitrobenzyldioxycarbonyl-1' -ethyl) -4— tritylthio-2-azetidinone (90%) having a PP of 130 -I320. of (CDCl ^) includes the following signals h: 8.3 - 6.7 (19H, m, aromatics), 5.20 (2H, qAB, benzyl), 4-, 72 (1H, d, J = 5, H-1! ·), 3.50 (1H, dq, J - 6.5, J = 0.5, H-11), 2.85 (1H, 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, C10).

Analysis for O ^ gH ^^^ O ^ S:

Calculated: C, 66.83; H, 6.20; N, 4-, 10; S, h, 70%.

Found: C, 66.56; H, 6.28; ΪΓ, 3.96; S, * +, 89%.

L. Preparation of (S, 3S-ΛΚ and R, 3R-> 4-S) -l- (t-butyl-dimethylsilyl) -3- (l-methane tallow onyloxy-1 * -ethyl) - 4 ~ trityltMo-2-azetidinone (isomer 0).

f OH OMs Χ_γδεΦ3 J — N - * JLi cr \ Si (CH) O V% vSi (CH) w2 - -Va.32

A solution of (l'S, 38,4-11 et l, R, 3H, 4-S) -l- (t-butyldimethylsilyl) -3- (l'-liydroxy “l, ~ ethyl is reacted at 5 ° ) -4 - tritylthio-2-azetidinone (G isomer), (2.0 g, 4 · millimoles) in dichloromethane (80 ml) with methanesulfonyl chloride (0.99 g, 8.6 millimoles) and triethylamine (0.87 g, "8.6 millimoles). After 1 hour of stirring at this temperature in a nitrogen atmosphere, the solution is washed with brine, dried over magnesium sulfate and evaporates to dryness. After crystallization in the ether-petroleum ether system, 1.9 g (81.9%) of the mesylate having a m.p.p. of 120 - 122 ° are obtained. The Mf spectrum of 1II ( CDCl ^) includes the following signals ^: 7.13 - 7.61 (15H, aromatic), 4.50 (lïï, d, J = 2, H-if), 3.62 (1H, dq, J = 6 , 5, 2, Hl '), 2.96 (lïï, dd, J = 2, 2, ïï-3), 2.84 QH, s, tallow methane), 1.22 (3H, d, J = 6.5, ïï-21), 0.99 (9H, s, Si-t-Bu) and 0.30 ppm (6ïï, s, Si- ^ H ^^). The IR spectrum (GHCl ^) includes signals for)) = 1.746 (0 = 0) , 1343 and 1180 cm ^ (SO).

max * · 2 M. Preparation of (1'R, 3S-> 4R and IIS, 3R, 4S) -l- (t-butyldimé-thylsilyl) -3- (1'-methanesulfonyloxy-1'-ethyl) - 4-tritylthio-2-azetidinone (isomer B).

OH IfsO.

Λ-rc * 3 _> -γτ * ”. ° Nxsi ^ 4- f

Stirred for 1 hour at 5 °, a solution of (1'R, 3S, 4r and 1'S, 3R, 3S) -l- (t-butyldimethylsilyl) -3 “(1'-hydroxy-1'-ethyl) - 4-tritylthio-2-azetidinone (isomer B), (5.03 g, 10 millimoles), methane sulfonyl chloride. (2.52 g, 22.0 millimoles) and triethylamine (2.23 g, 22.0 millimoles) in methylene chloride (200 ml). The solution is then washed with brine, dried over magnesium sulfate and evaporated to obtain a residue which is crystallized into a white solid by trituration in ether to obtain 5.40 g (93 %) of the isomer B having a PP of 127 - 131 ° ·

The RM spectrum of (CDCl ^) includes the following signals S: 7.20 - 7.63 (I5H, el, aromatic), 4.51 (III, dq, J = 5.0 - 6.2, H-1 '), 4.10 (lïï, d, J = 2,0, ïï-4), 3,60 (1H, dd, J = 5,0, - 2,0, H-3), 2,03 ( 3H, s, -CE ^), 1.01 (3H, d, J = 6.2, ïï-21), 0.90 (9ÏÏ, s, t ~ Bu), 0.12 (6H, s, - CH ^). The IR spectrum (CIIGl ^) includes a signal for '’aa * - Wom-1 ^ 0).

N. Preparation of (l'S, 3S, 4-R and l'R, 3R, 4-S) ~ 3- (l '-p-bromob enz en suifonyloxy-1' -éthyl) -1- (t-butyl dimethyl silyl) -H ~ tritylthio ~ 2-azetidinone (C isomer).

OH · OS02 <J) Br X- N / J-N y ° ~ 'sA- 0 N ΑΧ v

A solution of (l'S, 3S, 4-R and 1 'R, 3R, 4-S) -l “(t-butyldimethylsilyl) -3- (l--hydroxy-1' -ethyl) is cooled to -78 °. -1 * · - · tritylthio-2-azetidinone (isomer C), (2.5 g, 5 millimoles) in dry tetrahydrofuran (100 ml) and a 2.52 M solution of butyllithium is added thereto. in hexane i (2.38 ml, 6 millimoles). After 3 to 4 minutes, a solution of p-bromobenzenesulfonyl chloride (1.53 g? 6 millimoles) in tetrabydrofuran is added dropwise. The new solution is stirred at -78 ° for 3 hours, then allowed to warm to room temperature. The solvent is then removed by evaporation and the desired product is purified by chromatography on a column of silica gel which is eluted with methylene chloride to obtain 3.36 g (94-.6%) of the compound having a PP of 14 -2 - 1½½0. The RMT spectrum of (ODOl ^) includes the following signals: 7.68 (4-H, s, benzenesulfonyl), 7.28 - 7.60 (15H, m, aromatics), H ·, 59 (1H, d, J = 1.8, HH ·), 3.68 (lïï, dq, J = 6.2, ïï-1 '), 2.99 (1H, dd, J = 1.8, 2.0, H- 3), 1.18 (3H, d, J = 6.2, H-2 '), 1.08 (? H, d, t-Bu), O, 4-0 and 0.38 (6H, 2S , -Cïï ^) - The IR spectrum (CHCl ^) includes —1 a signal for Ό _Q__ = 17 ^ 9 cm (C = 0).

ιΙ19..λ.

0 · Preparation of (Ι'Β, .ΙΒΛΗ and 1 ^, 35, ^) - 3- (1'-methoxymethyl-l '-éthyl) - ** - tritylthio - 2-azétidinone (isomer A).

OCH2OCH3 OCH2 ° CH3 IX ^ SO »3 X- | _ (^ SC $ 3

o ^ -V3rMe2 "*" r-'V

t-bu

Sodium azide (2.7 g, * + 2 millimoles) is added to a solution of the A-isomer of l- (t-butyl-dimethylsilyl) ~ 3 “(1 * -methoxymethyl-1 '- ethyl) -h ~ trityl-thio-2-azetidinone (11 g, 20 millimoles) in a mixture cooled to 0 ° of 116 ml of hexamethylphosphorotriamide and 13 ml of water. The cooling bath is removed and the mixture is stirred for 30 minutes. We then pour it into y. 1300 ml of cold water, then the organic layer is dried.

The desired compound is crystallized from a mixture of ethyl acetate and hexane to obtain 7.2 g (83%) of a white solid having a P.3 ?. of 173 “17½0 · The EM spectrum of 1ïï (GDCl ^) includes the following signals S: 7.10” 7.0 (15H, m, aromatic), 4.85 (2H, qAB, J = 7.1 * , O-OHg-O), 53 (1HV d, J = 5.2, ïï-if), k, k2 (1H, s, M), 15. (1H, m, n-1 '), 3, 5 (1H, m, ïï-3), 3Λ7 (3H, s, 0-0¾), 1.5 (3H, d, J = 6, 0¾). The IE spectrum (KBr) includes signals for ^ max = 3 ^ 00 - 3500 cm-'1 '(ΪΓ-ïï) and 1760 cm ’"' 1 '(G = 0).

P. Preparation of (Ι'δ.λδΛΒ and the R ^ R. ^^^ - Cl'-methoxy-methyloxy-l'-ethyl) - ^ + - tritylthio-2-azetidinone (isomer C).

och2och3 C? CH20CH3 X ^ STr BrCH2OCH3 Nall3 - V * \ \

A 1.6 M solution of n-butyllithium in hexane (13.0 ml) is added dropwise to a persistent pink color to a solution of (L'S, 3S, UR and 1 'R, 3R , ^ S) -l- (t-butyldimethylsilyl) -3- (l -hydroxy-l '-êthyl) -lf-tritylthio-2-azétidinone (5.03 g? 10 millimoles) in tetrahydrofuran (5 ° ml , distilled on lithium aluminum hydride), cooled in a dry ice and acetone bath. A solution of bromomethyl methyl ether (1.19 g, 0.97 ml, 1.19 milli mole) in tetrahydrofuran (20 ml) is added dropwise. We stir the me-. swaddle at -78 ° for 30 minutes and at 0 ° for 3 hours.

It is then poured into an ice-cold solution of ammonium chloride, then an extraction with ether is carried out. The ethereal extracts are combined, washed with water and dried over magnesium sulphate, then concentrated to obtain 5.83 g (100%) of the (l'S, 3S, ^ - R et 1 ' R, 3R, Li-S) -l- (t-buÎyldiméthylsilyl) -3 “(l '-methoxymethyloxy- l .'- ethyl) -i + -tritylthio-2-azetidinone from which the protective radicals are removed as described above after.

1.365 g (21 millimoles) of sodium azide are added to an ice bath cooled solution comprising the above compound (5.83 g, 10 millimoles) in a mixture of 90 ml of hexamethylphosphorotriamide and 10 ml of 'water. The cooling bath is removed and the mixture is stirred at room temperature for 2 hours. It is then poured slowly into 900 ml of ice water and the stirring is continued for 30 minutes. The precipitate is collected by filtration and redissolved in methylene chloride. This solution is washed with water and brine, then dried over magnesium sulfate to obtain 3.0 g (69.3%) of the desired compound having a P.3 ?. 172 - 172.5 ° (after crystallization from a mixture of ethyl acetate-hexane). The IR spectrum (CÏÏCl ^). includes signals for 1? = 3 * + 00 cm ™ · * '(ΙΓ-Η) and lucuX.

I76O cm "* (C = 0) - The spectrum EMfT.de” * Ή (CDCl ^) includes the following signals $: 7.62 - 7.12 (15H, m, aromatic), H-, 63 (2H, center of qAB, J = 6, O-CHg-O), Η-, Η-9 (lïï, s, Ïï-H), H-, MD (1H, d, J = 3, H-1 *), H-, 25 - 3.80 (lïï, m, ïï-1 '), 3.35 - 3.15 and 3.26 (HH, s + m, Cïï3 and Ξ-3) and 1.30 ppm (3H , d, J = 6, CB ^). y Q. Preparation of] a (l'R, 3S, HR et l'S.3R; HS) -3- (l '~ formyloxy- l ^ -éthyp-H — tritylthio -2-azetidinone (isomer B).

OSO φΒΓ OCHO

V '_, -Çp J — N'

V

It is heated to 50 ° during. H-8 hours then at 100 ° for h hours, a solution of (L'S, 3S, HE and E, 3E, HS) -3_ (1 '-p-bromobenzenesulfonyloxy-1' -ethyl) -l- (t -butyldimé-thylsilyl) -H-tritylthio-2-azetidinone (isomer C) in dimethylformamide (3 ml). Dilute with water and extract with 1 ether. The ethereal extracts are washed with brine, dried over MgSO 4 and evaporated. After chromatography on! ! silica gel column (5% acetonitrile in methylene dichloride), the desired compound is obtained in an amount of 2 mg (if, 8%) in the form of white crystals having a PP of 131-132 ° . The 1H EMN spectrum (CDGl ^) i includes the following signals 8: 8.07 (ll, s, CHO), 7.21½ - 7.56 (15s, m, aromatics), 5.23 (1H, dq. , J = 6, if, 7, ^ Ξ-1 '), 38 (1H, dm, J = 2, if, H-if), if, 25 (1H, s, UH),' 3.20 (1H , dd, J - 7, 2, if, H-3), 1, ¾ (3H, d, J = 6, if, H-21). The IR spectrum (CÏÏCI ^) includes signals for 0 = 3 ^ 00 cm “1 (HH), 1765 cm" 1 (C = 0), 1725 cm “1 (C = 0).

read. 9.X

R .. Preparation beyond (1 e ~ k 1 '8,3Ρ · Λ5) -3- (1 I acetoxy-l'-ethyl) -if-tri tylthio-2-azetidinone (isomer B).

i i t OAc OAc J STr X STr

_S NaN3 '"1-S

] i üî * Qj-m f

Dissolve (l'R, 3S, ifR and 1 'S, 3R, ifS) -l “(t-butyldimethylsilyl) -3- (l' -acétoxy-l '-éthyl) -if- (tritylthio-2 -pure azetidinone (5.77 g, 10.57 millimoles) in a mixture of 60 ml of hexamethylphosphorotriamide and 10 ml of water, the solution is cooled to room temperature and nitrogen azide is added. sodium (1.2 g) The mixture is stirred for 5 minutes, observing the progress of the reaction by thin layer chromatography, then it is slowly poured into stirred cold water (800 ml). The crystals are collected for 20 minutes and washed with water, redissolved in dichloromethane, then the solution is washed twice with water, then with brine, after which it is dried over sulphate. magnesium. By evaporation of the solvent, a frothy material is obtained which is crystallized from a mixture of ether and petroleum ether to obtain * +, 90 g (96.5%) of the compound melting at 1¾ - ΐ ¥ · Ϊ́ ·, 50 · The IR spectrum (CH0Clo) includes signals ux for v? = 3395 cm-1. (ΪΓ-Η),

d mayK

1772, 1738 cm "" 'L (C = 0). The RMT spectrum of (ODCl ^) includes the following signals i: 7.9 - 6.8 (15H, m, H, aromatics), 5.12 (ll, center of dq., J = 6.5, 7, 5, H-l '), 33 (1H, d, J = 2.8, H-if), if, 20 (1H, si, HH), 3.17 (1H, ddd, = 7.5, J3_L {. = 2.8, J3-.M = 1, H-3), 2.1 (3H, s, OHjOO), 1.35 (3H, d, J = 6.5, ch3).

S. Preparation of 3 ~ (1'Hydroxy-1'-ethyl) - ^ H; ritylt] lio- 2-az; étidinone (mixture of four isomers).

OH OAc __sSC <j) ^ SC ^ 3 Ac O. ^ SC ^ 3 -f Y3 LDA CH] 2, j -3 CH3CHO »J-J pyridine ^ 1 I? Fi + _j- si-ci DMF-N (Et) 3 * J-

A solution of lithium diisopropylamide (0.7 ^ millimole) · 1 · at -78 ° in dry tetrahydrofuran (5 ml) is prepared with diisopropylamine (0.103 ml, 0.7 * + millimole) and n-butyllithium (0.29 ml of a 2.52 M solution in hexane) · After 30 minutes at -78 °, a solution of the (R and S) -l-trimethylsilyl-if is added dropwise -tritylthio-2-azetidinone (0.292 g, 0.699 millimoles) in dry tetrahydrofuran (2 ml). After 5 minutes, an excess of freshly distilled acetaldehyde (0.2 ml) is added at once. After 20 minutes at -78 °, thin layer chromatography indicates the complete disappearance of the starting compounds and the reaction is stopped by pouring the mixture into a saturated solution of ammonium chloride. By extraction with ethyl acetate (2 x 25 ml), then washing of the mixture of organic phases with ammonium chloride in saturated solution, brine and finally drying over anhydrous magnesium sulfate, an oil is obtained yellow after evaporating the solvent. After passing the oil over 10 g of silica gel (elution with a 6: ½ mixture of benzene and ethyl acetate), 0.215 g (80%) of a mixture of alcohols is obtained. This mixture, which shows the BMN spectrum of ^ H, can not be fractionated either by thin layer chromatography or by liquid chromatography under high pressure.

at. Acetylation.

Acetylation of an aliquot of 0.065 g of the mixture using an excess of acetic anhydride (1.0 ml) and pyridine (1 ½ ml) gives a mixture of the acetates, the liquid chromatography under high pressure indicates the presence of four constituents, namely: a = 3 ^ 6%, b = 17, h%, c = 30.1% and d = 17.9%. Compound a) is identical to isomer B during a direct comparison by k high pressure liquid chromatography.

b. T-butyldimethylsilylated derivatives ♦

0.121 g (0.3½ millimole) of the alcohol mixture is reacted with t-butyldimethylchlorosilane (0.117 g5 0.776 millimole) and triethylamine (0.10 ml, 7.1½ mmol) in dry dimethylformamide (1 ml ) for 36 hours at room temperature. After dilution with ethyl acetate, the solution is washed with a saturated solution of ammonium chloride, then dried over anhydrous magnesium sulfate. By evaporation, 0.716 g of an oil is obtained which appears to contain, on high pressure liquid chromatography, four components, namely a = 3.7%, b = 60.6%, c = 31.1%, at = 4r, 6%. (the identity of each of these constituents is not verified).

Notes.

Butyllithium and lithium hexamethyldisilazane are ineffective.

2

Increasing polarity order.

3 The acetylation of the product from lt ~ butyldimethylsilyl-4 - trityltio-2-azetidinone gives the following reports: "d = 29.5%" c = 24 ·, 1%, b = 33.8%, a = 12.6%.

Ij.

By reaction of a mixture of alcohols derived from (P and S) -1- (t-buty1dimethy1silyl) -4-tritylthio-2-azetidinone, the following proportions are obtained: a = 5.2%, b = 4- 1.3%, c = 4-8%, d = 4-, 6% '; ï. Preparation of q'R, 3S, 4-R and l'S, 3R, 4-SH3- (t · '-benzoxy-l'-ethyl) - 4-tritylthio-2-azetidinone (isomer B). l r

MsO OCOtj) V * · __ V * · o ^ “n \ h ...... o ^ ~ n \ h

Heated at 90 ° for 7 hours and 30 minutes, a solution of (l'S, 3S, 4-R and l'R, 3R, 4-S) -3 "* (l'_niéthane-sulfonyloxy ~ l'-ethyl) -4 — tritylthio-2-azetidinone (isomer C), (35) mg, 2 millimoles) and sodium benzoate (4-32 mg, 3 millimoles) in 10 ml of dimethylformamide containing 10% water. reaction mixture then with water, then it is extracted with ethyl acetate, the organic extracts are washed with brine and dried in magnesium sulphate, then evaporated, purifying the residue by chromatography on a column of silica gel (5% acetonitrile in dichloromethane), 108 mg (23.2%) of the desired compound are obtained, which is in the form of a white solid having a PF of 158 °. The 1H EMET spectrum (CDCl ^) includes the following signals: 7.03 - 8.25 (20H, m, aromatics),. 5.32 (1H, dq, J = 6.1, 9, Hl ' ), h, hO (1H, d, J = 2.5, H-1} ·), h, 30 (1H, s, HH), 3Λ0 (lïï, dd, J = 9, 2.5, H- 3), 1.50 (3Ï, d, J = 6.1, H-2 '). The IE spectrum includes d signals for mri__ = 3 ^ 00 cm ”1 (H-H), 1765 cm" 1 (0 = 0), 1715 cm "1 (C = 0).

II Preparation of 3-Cl1-p-nitrobenzyldioxycarbonyl-11-ethyl) -M-tritylthio-2-a2etidinone (h isomers).

PCO PNB 9C02pnb

Cfj “N'Ns / Me2 CT Ά 'tSu

Isomer C.

a) A solution of the isomer 0 of l- (t-butyldi-methylsilyl) ~ 3 “(1 '-p -ni tr oh enzyl di oxy c arb ony 1) is stirred for 2 days at room temperature. -1 '-ethyl) -V-tritylthio-2-azetidinone (1.3 g) in a mixture of trifluoroacetic acid (5 ml), water (5 ml), dichloromethane (20 ml) and methanol ( 30 ml). The solution is diluted with water and the aqueous phase is extracted with dichloromethane.

The organic phases are combined and washed with sodium bicarbonate and water, then dried and concentrated to obtain an oil. By crystallization from ether, 902 mg of the pure desired compound is obtained having a mp 78 to 80 °. The 1H EMIT spectrum (GDCl ^) includes the following signals (S: 8.25 - 6.75 (19H, m, aromatics), 5.21 (2H, s, benzyl), 5.05 (1H, m, H-l '), k-, 40 (1H, s, HH), 27 (1H, d, J = 2.8, Hk-), 3.37 (1H, dd, J = 5.3, 2, 8, H-3) includes signals for)) = 3390 cm 1 (RH), 1765 and fflcLX.

174-5 (cm * ") (shoulder) (C = 0) and 1525 cm“ 1 (ROg) · b) Sodium azide (1.82 g, 27.9 millimoles) is added to a solution cooled to 0 ° C isomer of l- (t-butyldimethylsilyl) -3- (l'-p-nitro -benzyldioxycarbonyl-1 '-ethyl) -4 - tritylthio-2-azetidinone (9.11 g , 13.3 millimoles) in a mixture of 90 ml of hexa-methylphosphorotriamide and 19 ml of water. The cooling bath is removed and the mixture is stirred for 30 minutes. It is then poured into 1000 ml of water, then an ether extraction (5 1200 ml) is carried out, the ethereal fractions are combined and washed with water (5 x 200 ml) and with brine, then dried over magnesium sulphate As a variant, the desired compound is precipitated by dilution with water, then it is collected by filtration and crystallized from ether, thus obtaining 7.22 gl (89%) of the compound having a PP of 78 - 80 °.

Isomer B. By operating as described above for the isomer C, the B isomer of 3 ~ (1'-p-nitro-benzyldioxycarbonyl-1'-ethyl) -4 - tritylthio-2-azetidinone is prepared. (92%) having a PE of 155.5 - 156 ° after crystallization from ether. The EMR spectrum (CDCl ^) includes the following signals b: 8.25 ~ 6.80 (19H, m, aromatic), 5.20 (2H, s, benzyl), 4-, 95 (1H, m, H- l '), 4-, 35 (1H, d, J = 2.9, H-4-), 4-, 17 (1H, s, RH), 3.20 (1H, dd, J = 10.8 , J = 2.9, H-3) and 1.4-0 ppm (3ÏÏ, d, J = 7.5, CH ^). The IR spectrum (CHOl ^) includes signals for ^ max = 34-80, 3390 cm "1 (RH), 1772, ^. 1750 cm“ 1 (0 * 0) and 1525 cm “1 (ROg). Analysis for 032 ^ 28¾¾ ^:

Calculated i C, 67.59; H, 4-966; R, 4-, 93; S, 5.64%.

Found: C, 67.4-8; H, 4-998; R, ^, 92; S, 5.67%.

Isomer A. By operating as described for isomer C, the isomer A of 3 ~ (11 -p-nitrobenzyl ~ dioxycarbonyl-1 '-ethyl) -4-tritylthio-2-azetidinone having a PB is prepared. from 205 - 206 °. The EMET spectrum of (CDCl ^) includes the following signals i: 8.2 - 6.7 (19H, m, aromatics), 5.22 (2H, qAB, benzyl), 5.57 ~ 4.85 (1H, m, H-l '), 4.65 (lïï, M), 4.50 (1H, d, J = 6.5, H-4), 3.65 (lïï, dd, J = 6.5, 12, JM = 1, H-3) and 1.52 ppm (3H, d,.

J - 7.5).

Isomer D. Using the procedure described for isomer 0, the D isomer of 3- (“p-nitrobenzyldioxycarcaryl-bonyl-1'-ethyl) -4-tritylthio-2-azetidinone is prepared. The EMN spectrum of (CDCl 4) includes the following signals b: 8.15 ~ 6.70 (19H, m, aromatics), 5.23 (2H, qAB, benzyl), 5.20 '(1H, m, Hl '), 4.75 (1H, M) ,. 4.52 (1H, d, J = 5.5, H-4), 3.42 (lïï, J = 5.5, 3, H-3) and 1.5 ppm (3H, d, J = 6 , 5, C ^). (J value for H-3 after exchange with D20).

* V. Preparation of (R, 3S, 4B. And 1'S, 3H, 4S) -3- (l'-methane-tallow onyloxy-1 1 -ethyl) -4-tritylthio-2-azetidinone (isomer B ).

MsO

_, V3 ’\

Stirred for 30 minutes at room temperature, a solution of (1'R, 3S, 4R and 1 rS ', 3R, 4S) -1- (t-butyl-dimethylsilyl) -3- (1'-methanesuifonyloxy-1 '-ethyl) -4-trityl-thio-2-azetidinone (isomer B), (Jf, 95 g, S, 5 millimoles) and sodium azide (1.11 g, 17.0 millimoles) in 50 ml of hexamethylphosphorotriamide containing 10% water. The solution is then diluted with water (250 ml) and extracted with ether. The organic extracts are washed with brine and dried over magnesium sulphate, then evaporated. By crystallization of the residue in a mixture of ether and petroleum ether, 3.33 g (83.8%) of the desired compound is obtained having a PP of 130 ° -131 °. The EM spectrum of (CDCl ^) includes the following b signals. : | 7.20 - 7.62 (15 ^, mj aromatic), 97 (1H, dq, J - 6.4 ·, i '6.1, H-11), 56 (1H, d, J = 2.8 , H-if), if, 22 (1H, m, HH), i 1 3.27 (1H, due, J = 6.1, 2.8, ïï-3), 3.0 (3H, s, -CHj), i 1.63 C3H, d, J = 6, if, H-2 '). the IR spectrum (nujol) includes signals for = 3195 cm 1 (N-H), 1768 cm 1

ïïlclX

(c = o).

W. Preparation of Cl'S, 3S, ifR and R, 3R, ifS) -3- ("methane-tallow onyloxy-1, -ethyl) -1f-tritylthio-2-azetidinone (isomer 0) ,.

OHs OMs Αίγ50 ^ 1 O {CH3J 2 0 Ni. t-bu

Sodium azide (0.65 g, 10 millimoles) is added to a solution of (l'S, 3S, ifR and l'R, 3R, ifS) -l- (t “butyldimethylsilyl) -3“ (l -methane tallow onyloxy-1 '-ethyl) -H- tritylthio-2-azetidinone (isomer 0), (2.85 g, H-, 9 millimoles) in 25 ml of hexamethylphosphorotriamide containing 10% water and stirred mixing at 25 ° for 30 minutes. By diluting the solution with water (250 ml), the reaction product is crystallized. The crude mesy late is redissolved in dichloromethane, the solution is washed with brine and dried over magnesium sulphate, then evaporated. By trituration in ether, 1.8 g of the desired compound is obtained which is presented in white crystals having a P.P. of 155 ~ 160 °. The EM spectrum of ^ H (GDGl ^) includes the following signals i: 7, ½ (15H, m, aromatic), 5.02 (1H, dg, J = 6.9, k, 9, H-l ') , * +, 55 (1H, s, NH), if, 95 (1H, d, J = 3, -H-if), 3.33 (1H, dd, J = * f, 9, 3, H- 3), 1.51 (3H, d, J = 6.9, H-2 '). The LR spectrum includes signals for 9: 3395 cm ^ (H-H), 1768 cm ”'1' (0 = 0).

Analysis for C ^^^ HO ^ S:

Calculated: C, 6M-, 22; H, 5.39; ÎJ, 3.00%.

Found: C, 63.93; H, 5.39; H, 3.2½%.

Σ. Preparation of (1'β, 38ΛΕ and 1 Έ, 3ΕΛ8) -3- (Ί '-p-bromobenzenesulfonyloxy-11 -ethyl) - ^ - tritylthio-2-azetidinone (C isomer).

OSÔ ~ <Î> Br ”’ OS024> Br

Ar_r-SC * 3> Y_ ^ C * 3 - \

If Stirred for 1 hour at room temperature, a solution of (l'S, 3S, ^ R et 1, R, 3E, 1fS) -3 ~ (l '-p-bromoben-zènesulfoxyloxy-1' -éthyl) -l - (t-butyldimethylsilyl) -1i · -tritylthio-2-azetidinone (isomer G) (1, ½ g, 2 millimoles) and sodium benzoate (0.865 g, 6 millimoles) in ^ • 0 ml of hexamethylphosphorotriamide containing 10 % water. The solution is diluted with water (100 ml), then extracted with ether. The ethereal extracts are washed with brine and dried over magnesium sulphate, then evaporated.

The crude crystalline desired compound is triturated in a little ether, then collected by filtration 0.92 g (77%) of the desired compound having a m.p. of 125 - 126 °. The EM spectrum of ^ ÏÏ (CDCl ^) includes the following signals 6: 7.80 (ΜΉ, s, benzenesulfonyl), 7.30 - 7.65 (15H, m, aromatics), 5.13 (1H, dq_, J = 6.5, * +, 0, H-l '), 50 (1H, d, J = 2.9, H-4), (1H, s, HH), 3, ½ (1H, dd, J = h, 0, 2.9, H-3), 1.50 (3H, d, J = 6.5, H-2 '). The IR spectrum. includes signals for 0 = 3 * f00 cm “1 (H-H), 1770 cm“ 1 (C =; 0).

I. Preparation of (1Έ, 35ΛΕ and l'S, 3Ρ · Λ8) -3- (1 '-hydroxy-l ethyl) -VXritylthio-2-azetidinone (isomer B).

OSO ^ Br 9H.

Ai_YSC * 3 Ar_r ^ c "3 J—" L / 'J — ti 0 \ sil, 0 Pt

V

1 ml of water is added dropwise to a hot solution of (Ι'δ ^ δ, ^ Η and 1 'R, 3R,) - 3- (1 1-p-bromo-benzenesulfonyloxy-1' -ethy ^ -l - ^ - butyldimethylsilyl) -1! · -tritylthio-2-azetidinone (isomer C) in hexamethylphosphorotriamide (5 ml). The reaction mixture is kept for 20 hours at 90 °, then diluted with ether and washed four times with brine. The organic solution is dried over magnesium sulfate, evaporated and the desired product hrut is purified by chromatography on a column of silica gel (15% acetonitrile in dichloromethane), 122 mg is obtained (¥ ΐ ·, 5%) of a white solid having a PP of 187 - 189 ° which turns out to be identical to a sample of the desired compound prepared otherwise.

Z. Preparation of 3 “(1 '-hydroxy-l' -ethyp-U-tritylthio- 2-azetidinone.

Χ_γ ° * 3 __ ^

The two isomers, namely (S, 3S, ^ * R and 1'E, 3E, ^ - S) -3- (1 hydroxy-1 '-ethyl) - ^ tritylthio-2, are prepared according to the same procedure. -azetidinone (isomer C) and (E, 3S, 4B and 1 'S, 3R ^ S) -3- (l'-hydroxy-1'-ethyl) ^ -tritylthio-2-azetidinone (isomer B) . For example, stirred for 18 hours at room temperature, a solution of (1'S, 3S ^ R and 1'R, 3R ^ S) -l- (t-butyldimethylsilyl) -3 “· (1'-hydroxy-l '-ethyl) - ^ tritylthio-2-azetidinone (isomer C) (1.0 g, 2 millimoles) and sodium benzoate (0.865 S? 6 millimoles) in ^ 0 ml of dimethylformamide containing 10% water. The reaction mixture is then diluted with water and extracted with ether. The organic extracts are washed with brine, dried over magnesium sulfate and evaporated. By crystallization of the crude desired compound in cold ether, one obtains 0, h7 g (61%) of the compound having a PP of 13½ - 135 ° · The NMR spectrum of (HCl) comprises the following signals: 7 , 12 - 7.56 (15H, m, aromatic), ^ 8 (lïï, s, HH), h, 28 (1H, d, J = 2.8, y H-1 *), 2.9½ (1H , dq, J = 6.5, 6.2, H-1), 3.16 (1H, dd, J = 6.2, 2.8, H-3), 2.18 (1H, s, -OH), 1.30. (3H, d, J = 6.5, ïï-2 '). The IR spectrum includes signals for i? y = 3 ^ 00 cm 1 (H-H), 1760 cm ^ (C = 0). Similarly, the (R., 3S ^ R and S., 3R ^ S) -l- (t-butyldimethylsilyl) -3- (l'-hydroxy-1'-ethyl) - ^ tritylthio-2- azetidinone (isomer B) having a PP of 190 - 192 °. The RMH spectrum of ^ H (CDCl ^) includes the following signals: 7.10 - 7.55 (15H, m, aromatics), ½, ½5 (1H, d, J = 2.5, Η-4), ^ 28 (1H, s, HH), ^ 10 (1H, dq, J = 6Λ, 5.3, H-l '), 3.08 (1H, dd, J = 5.3, 2.5, H- 3), 1.50 (1H, s, -OH), 1.30 (3H, d, J = 6Λ, H-2 '). The IR spectrum includes signals for ___ = 3 ^ 0 cm “1 (H-H), 1760 cm“ 1 (C = Q).

AA. Preparation of (1 'S, 3R ^ R and 1'R, 3S ^ S) ~ 3- (1'-metho: xy- methyl-1, -ethyl) -l- (p-nitrobenzyl-2' '- hydroxy-2 "-acetate) -V · 'tritylthio-2-azetidinone (isomer A).

f och2och3 och2och3 Α_γ3εΦ3 / w «*

> —N J — N OH

"Ni ^ γ · CO PNB 2

It is heated under reflux for 1 hour in a

O

Dean & Stark apparatus containing 3 A molecular sieve, a mixture of the A isomer of 3 ~ (1 '“1-methoxymethyl ethyl) -1 * -' tritylthio-2-azetidinone (7.5 g” 17, 3 millimoles), hydrated p-nitrobenzyl glyoxylate (* +, 7 g, 20.8 millimoles) and toluene (300 ml). The solution is cooled in ice and triethylamine (0.2½ ml, 1.7 millimole) is added dropwise. The mixture is stirred for 1 hour, washed with dilute hydrochloric acid, sodium bicarbonate and brine, then dried and concentrated to obtain 10.5 g (9½%) of the research compound occurring in the form of a frothy mass. The EM spectrum of (CDCl ^) includes the following S signals: 8.2 ^ - 6.8½ (19H, m, aromatic), 5.2½ (2H, s, benzyl), ^ 67 - ^ 83 (3ÏÏ, m , 0-0ÏÏ2 and 11-½), ^ 3½ - ^ 55 (1H, m, H-2 "), ^ 02 (lïï, m, H-l '), 3., 5½ (1H, m, H- 3), 3Λ0 (3H, s, 0-0H3), 1.38 (3H, d, J = 6.5, C ^). The IE spectrum (EBr) includes the signals = 3360 cm 1 (Oïï), 1770 cm-1 (0 = 0 ß-lactam), 1735 cm "1 (0 = 0 ester) and 1605 cm (aromatic).

BB. Preparation of (L'S, 3S> R and 1'R, 3R> S) -3 ~ (1 '-methoxy-methoxy-11-eth; yl) - l ~ (p-nitrobenzyl-2 "-hydroxy-2w -acetate) -Li ~ tritylthio-2-azetidinone (G isomer).

ΩΡΗ nr * w OCH OCH

f 2 3 CHO I 2 —3

X J ** COP »A_A

rf —2-> J ~ T 0H

O * - H Y ..

C02PNB

It is heated under reflux for 2 hours in a

O

Dean & Stark apparatus containing 3 A molecular sieve, a solution of hydrated p ~ nitrobenzyl glyoxylate (1.73 g, 7.11 millimoles) in toluene (90 ml). Is added to the boiling solution of (S, 3S, 4-R and ΙΈ ^ Ε, ^ Ο - ^ - ίΙ1-methoxymethyloxy-1'-ethyl) ~ 1 + -tritylthio-2-azetidinone (3.0 g, 6.93 millimoles) and the mixture is heated to reflux for another 2 hours. The mixture is cooled to room temperature and triethylamine (70 mg, 97 microliters, 0.69 millimole) is added thereto, followed by stirring for 2 hours. The reaction mixture is diluted with ether, washed with 1% aqueous hydrochloric acid, water, 1% aqueous sodium bicarbonate, water and. brine, then dried over magnesium sulfate and · concentrated to obtain ^, 60 g (100%) of the desired compound. The IR spectrum (CHGl ^) includes signals for ^ max = 3530 - 3100 cm "1 (0-H), 1765, 1750 cm" 1 (0 = 0) and 1525 cm "* ^ (H02) · The EMU spectrum de ^ ïï (CDCl ^) includes the following signals: 8,22, 818 (2ÏÏ, 2d, J = 8, Hm, aromatics), 7,67 - 7,0 (17H, m · 'aromatics), 5, 3 (2H, si, 0H2-PRB), 5.30 - .5.02 (m, · Η-2 "), · Λ, 89“>, 52 (m,; 'Hl' and 0-H), >, 63,>, 59> 1H, 2d, J = .2, -H->), ^ 33, - ^ 30 (2H, 2 centers of 2 qÂb, J = 7, J = 7, 0-CHo- 0), k, l - 3.67 (1H, m, H-l '), 3.2 (III, H-3), 3.1, 3.6 QH, 2s, CH3-0) and 1, 15 PP111 (3ÏÏ, d, J = 6,5, CH ^).

CC. Preparation of (ΊιΕ ·, 38ΛΚβ ^, 8.3ΗΛ3) -3- (1, -ηο6Ροχν-1-ethyl) -l- (p-nitrobenzyl-'2n-hydroxy-2tr-acetate) -h-tri tyl th i n- 2-azetidinone »

Ohc PAc I / STr Ff A __ / STr

Π · -2—— ♦ l | OH

/ “» H ΤΕΑ Ο ^ γ · CO PNB 2

Isomer B. A hydrated p-nitrobenzyl glyoxy-late solution (triturated in ether), (1.82 g, 3 mmol) is heated under reflux for 2 hours in a

O

Dean & Stark apparatus containing 3 A molecular sieve

Is added to the solution of (ΙΈ ^ δ, ^ Ε and the S, 3R, hS) -3-i (l'-acetoxy-l'-ethyl) -h-tritylthio-2-azetidinone (10.88 g, 25.2 millimoles) and the mixture is heated for a further 1 hour at reflux. The solution is cooled to room temperature and triethylamine (0.35 ml, 2.5 millimoles) is added thereto. The mixture is then stirred for 2 hours, observing the progress of the reaction by thin layer chromatography. · By evaporation of the solvent, a white frothy substance is obtained quantitatively (100%, mixture of epimers). Alternatively, the solution can be washed with an acid and a base instead of evaporating the solvent. The IR spectrum (CB ^ C ^) includes signals for 1) = 3520 cm ^ (OH), 1775 "17 ^ -5 cm ^ (C = 0). The RUR spectrum of (ODCl ^) includes the following signals <$: 8.2, 8.18 (2H, 2d, J = 8, aromatic Ho), 7.60 · - 6.90 (17H, m, aromatic) , 5î28 ,.

^, 80 (center of m, H-l '), ^, 38 (0.33E, 2d, J = 8.8, CHO), ti-, 22 (0.33ïï, d, J ^ 3 = 2, 5, H-Jf), k, 09 (0.67H, d, = 2.1, ïï-4 ·), 3.66 (0.67H, dd, = 5.8, 3 ^ - 2.1, Μ), 3Λ7 (0.33H, dd, J3-1 = 5.5, ^ 3.4. - 2.5, h-3), 3.33 (0.33H, d, J = 8.8, OH) , 3.23 (0.67H, d, J = 7.5, OH), 1.88, 1.66 (3H, 2s, CH ^ CD), 1.10, 1.06 (3H, 2d, J = 5.8, 6.3, oh3).

DD. Preparation of 3 ~ (1'-p-nitrobenzyldioxycarbonyl-l ethyl) -1 - fp-nitrob enzyl-2> f-hydr oxy-2 n-acét t e) - ^ - trityl-thio-2-azetidinone (k isomers).

OCO.PNB OCO_PNB

_> OJ "13

, -N J-Ns. _0H

(f \ H 0 Y

CO ^ NB

Isomer C. It is heated to reflux for 7 days in a Dean & Stark apparatus containing a molecular sieve.

O

3 A, a mixture of the C-isomer of 3- (l, _p-ui-trobenzyldioxycarbonyl-l'-ethyl) - ^ - tritylthio-2-azétidi-none (1.70 g, 0.3 millimole) , p-nitro-benzylated hydrated glyoxylate (815 mg, 3.6 millimoles) and toluene (50 ml). The cooled solution is washed with dilute hydrochloric acid, sodium bicarbonate and brine, then dried and concentrated to give the desired compound (2.1 g) in the form of a mixture of epimers at the level of the carbon atom 2 ". The compound is purified by chromatography on silica gel. Alternatively, the desired compound can be prepared using a catalytic amount of triethylamine.

Minimole less polar in 2 ". The 1H line (CDC 1 ^) includes the following signals i: 8.25 - 6.80 (23H, m, aromatics), 5.30 and 3.12 (4ïï, 2s, benzyle), * f, 65 (1H ,. d, J - 9, H-2 ”), if, if? d, J - 2.5, H -if), if, 45 - 10 (1H, m, H-11), 3,? 0 (1H, d, J = 9, 2 "-0H), 3.28 (1H, dd, J = 2.5, J = 2.5, H-3) and 1 , 23 ppm (3H, d, J = 6.5, CH ^) · IR spectrum (CHCl ^) includes signals for 9 = 3530 to 3200 cm “1 (0-H), 1765, 1750 cm“ 1.

(C = 0) and 1525 cm ”1 (U02). . . .

Most polar isomer in 2tr. EMET spectrum of ^ (CDCl ^) includes the following signals S: 8.25. ~ 6.85 (23H, m, aromatics), 5.25 and 5.08 (4H, 2s, benzyl), 5.05 (1H, d, J = 7, H-2 "), ^, 35 (1H , d, J = 2.5, H-if), 4.40 - if, 05 (1H, m, Hl) j 3Λ2 (1H, J = 7, 2 "-0H), 3.33 (1H, dd, J = 2.5, 2.5, h-3), 1.23 (3H, d, J = 6.5, CHj). The IR spectrum (CHCl ^) includes signals for 1) max = 3520 to 3200 cm “1 (0-H), 1755 cm” 1 (C = 0) and 1525 cm "1 (NOg). F Isomer B. On heated at reflux for 3 hours in a Dean & Stark apparatus containing a molten sieve-

O

3 A, a mixture of hydrated p-nitrohenzyl glyoxylate (1.74 S, 7.66 millimoles) and (L'R, 3S, ifR and 1 'S, 3R, ifS) -3- (l' - p-nitrobenzyldioxycarbonyl-1 '-ethyl) -4-tritylthio-2-azetidinone (3.63 g, 6.38 millimoles)' in toluene (70 ml). The solution is cooled to room temperature and triethylamine (64.5 mg, 89 microliters, 0.639 millimoles) is added thereto. The mixture is stirred for 1 hour, then diluted with ether and washed with 2% aqueous hydrochloric acid, water, aqueous sodium bicarbonate. 2%, water and brine. It is dried and concentrated to obtain 5.02 g (100%) of the pure target compound. By preparative chromatography on silica gel, the two are separated.

Epimer the least polar in 2 ". The IB spectrum

- * î

(CHCl-j) includes, signals for ύ = 3500 cm (0-ïï), j IHaX

1772, 1750 cm 1 (0 = 0), 1725 cm “1 (ÏÏTOg) · The ÉMÛT spectrum of ^ ïï (CLCl ^) includes the following signals <5: 8.30 - 8.0 and 7? 65 - 6, 80 (23H, m, aromatics), 5.27 and 5.13 (4-ïï, 2s, benzyl), 4-, 71 (1H, m, J = 6.5, 6.5, H-l ') , 4-, 28 (lïï, d, J = 2,2, H-4-), 4-, 23 (1H, d, J = 8,7, H-2n), 3,50 (1H, dd, J = 2.2, 6.5, H-3), 3.28 (iii, d, J = 8.7, 0-H) and 1.18 ppm (3H, d, J = 6.5, CH ^.

Epimer most polar in 2n. The IR spectrum (CHCl ^) includes signals for l) = 3460 cm "1 (0-H), 1722, 1750 cm" 1 (0 = 0) and 1525 cm "1 (ÏÏ02). The BM spectrum of 1ïï (CDOl ^) includes the following signals 6: 8.35 “6.90 (23H, m, aromatics), 5.15 (4-ïï, benzyle), 4-, 72 (lïï, d, J = 7.5, ïï-2 ”0), 4-, 90 - 4-, 50 (lïï, m, J = 6,5, 6,5, H-l '), 4-, 10 (lïï, d, J = 2, ÏÏ-4-), 3.68 (lïï, dd, * - J = 2, 6,5, H-3), 3,28 (lïï, d, J = 6,5, 0 -H) and 1.15 ppm (3H, d, J - 6.5, C13).

Isomer A. The A isomer of 3 “(1 '“ P-nitrobenzyldioxy-carbonyl-1' -ethyl) -4 - tritylth.io-2-azetidinone similarly gives a mixture of the A isomer of 3 “ (1 '“P“ & itrobenzyl-dioxycarbonyl -1'- etïyl) -l- (p-nitrobenzyl-2 ,, - h.ydroxy-2tT-acetate) -4-trityltMo-2-azetidinones epimers. The BM spectrum of 11 (CDCl 4) comprises the following signals: 8.3 - 6.7 (23H, m, aromatics), 5.17 (2H, benzyl), 5.0 (1H, m, H — 1 '), 4-, 9 and 4-, 8 (lïï, 2d, J = 6, H-4-, two epimers), 4-, 32 and 3.96 (1H, 2s, H-2 ", two epimers ), 3.68, (III, dd, J = 6, 6, H-3) and 1.4-7 ppm (3H, 2d, J = 6.5, CH ^ two epimers).

Isomer D. The D isomer of 3 ~ (1'-p-nitrobenzyldioxy-carbonyl-1 '-ethyl) -4 - trityltliio ~ 2-azetidinone gives the same ____ £ -! ---- Λ, ΐί- : „- '-n J« «I _____- J -„ „- u - -------- T _____-> \ 1' -ethyl) -l - (p ~ nitrobenzyl-2u · hydroxy-2 ,, - acetate) -4 - tritylthio- 2-azetidinones epimeres. The EMET spectrum of (CDCl ^) includes the following signals b: 8.30 - 6.60 (23H, m, aromatics), 5.20 (4-Ξ, m, benzyl), 4-, 83 (1H, 2d , J = 5, H = 4), 5.50 - 4-, 30 (2H, m, Hl 'and H-2M), 3.4-8 (1H, m, H-3), 3.15 (1H, m, 0-H), 1.37 and 1.30 ppm (3H, 2d, CHj).

EE. Preparation of (l'S, 3S, 4-R et l - '' R, 3R.4g) -3- (l'-methane-sulfonyloxy-11-ethyl) -1-fp-nitrobenzyl-E "-hydroxy-2w -acetate) - 4-tritylth.io-2-azetidinone (isomer C), (epimers in 2 ").

? Ks jf * SCi, X '-'X · -

C02PNB

Is heated at reflux for 2 hours a solution of hydrated p-nitrobenzyl glyoxylate (9.72 g, f 4-2.6 millimoles) in benzene (350 ml) by separating the water by azeotropy in an apparatus from Dean & Stark. To this solution is added (S, 3S, 4-E and 1 'E, 3R, 4-S) -3 “(1' -methanesulfonyloxy-11-ethyl) -4-tritylthio-2-azetidinone (16, 62 g, 35.2 millimoles) and heating is continued at reflux for 30 minutes. The reaction mixture is then cooled to room temperature and triethylamine (0.5 ml, 3.5 millimoles) is added thereto, then the mixture is stirred for a further 3 hours to complete the reaction. By evaporation of the solvent, a frothy white material is obtained which is used as it is in the following stage. The 1H EMET spectrum (CDCl ^) includes the following b signals: 8.12 (2H, d, J = 9, Hm, aromatic), 7.28 (17Π, part of d, aromatic Ho, trityle), 5 , 28 (2ÏÏ, s, -CEL- PIB), 4-, 88 (0,5ÏÏ, s, Hl "), 4-, 62 (1,5H, m, ïï-2" et H-4), 4 , 00 (2ïï, m, H-1 ", -OH), 3,15 (lïï, m, H-3), 2,73 (3H, s, mesylate) and 1,30 ppm (3H, d, J - = 6 Hz, ïï-2 ') · The IR spectrum includes signals for = max 3520 cm "1 (0-H), 177? Cm" 1 (C = 0) and 1765 cm "1 (0 = 0) .

RR. Preparation of (L'S, 3R, 4R et 111.38145) -3- (1 ^ 11-methoxymethyl -ethyl) -l- (p-nitrobenzyl-2n-chloro-2 "-acetate) -4-tritylthio-, 2 , -azetidinone (isomer A).

och2och3 och2och3 0Χ ^ γ · 0Η ~ '

CO PNB CO PNB

2 2

Pyridine (1.1 ml, 14.2 millimoles) is added to a solution of the A isomer. 3- (1'-methoxymethyl-1 ethyl) -1- (p-nitrobenzyl-2Tt-liydroxy-2n-acetate) -4-trityl-thio-2-azetidinone (7 g, 10.9 millimoles) in tetra - ^ 1 hydrofuran (350 ml) cooled to -15 ° · Immediately after, thionyl chloride (1.0 ml, 14.0 millimoles) is added dropwise and the mixture is stirred at -15 ° for 30 minutes . Separate the precipitate by filtration and wash it with benzene. · Concentrate · the combined filtrates, then dissolve the residue in fresh benzene and add activated carbon to the solution, after which the mixture is filtered and concentrated the filtrate to obtain 6.5 g (90%) of the desired compound which is in the form of an oil. The RMSÜT spectrum of (CDGl ^) includes the following signals 6: 6.65 - 8.35 (19H, m, aromatics), 5.24 (2H, s, benzyl), 3.43 (3H, s, OOH ^ ) and 1.42 ppm (3Ξ, d, J = 6, CH3).

GG ·. Preparation of (L'S ^ SihR and 1 lE, 3R <i + S) -3 ~ Cl ethoxymethyioxy-l1 -ethyl) -l- (p - nitrobenzyl-2lt-chloro-2n-acetate) -1 ^ -tritylthio- 2-azetidinone (isomer C).

och2och3 och2och3] .STr J .STr

_S S ° C12 ^ -S

J- ^ OH V j- ^ Cl

CO PNB CO PNB

2 *

Pyridine (0.696 ml, 8.61 mmol) and thionyl chloride (0.530 ml, 0.61 mmol) are added dropwise to a solution of (L'S, 3S, hR and 1 'E, 3R, ^) - 3 “(1 '-methoxymethyloxy-1' -ethyl) -l- (p-nitrobenzyl-2, r-hydroxy-2 ,, - acetate) -h ~ tritylthio-2-azetidinone (h, 25 g, 6.62 millimoles) in tetrahydrofuran (60 ml, distilled t on lithium aluminum hydride) which is cooled in an ice and methanol bath. We shake it. mixing for 30 minutes at -15 ° · The precipitate is separated by filtration and washed with benzene. The solution is concentrated in benzene and tetrahydrofuran, then the residue is dissolved again in benzene. Activated carbon is added to the resulting solution. The charcoal is separated by filtration on Celite, then the benzene is evaporated to obtain 0.86 g (100%) of the desired compound. The IR spectrum (CHClO includes signals for = 1770 cm ^

2) If, Here JL

(C ^ O) and 1525 cm- "1 (H02). The 1H ROT spectrum (CDCl ^) includes the following signals: 8.15, 8.12 (2ÏÏ, 2d, aromatics), 7.70 - 7 , 00, (17H, m, aromatics) ,, 5.62, 5.02 (1H, 2s, H-2 "), 5.27 (2H, s, CHg-EHB), h, 7 (1H, d , Hh), h, 7 - 3.7 (rn, 0-CH2-0, H-l '), 3.5 - 00 fm u_o 0 T o 0 ηη / or η_πυ "4- i on _ 0.96 ppm (3H, m, CH ^).

HH · Preparation of (R, 3S.> R and 1 'S, 3R, ^) - 3- (1' -acetoxy-l '-' ethyl) -l- (p-nitrobenzyl-2IT-chloro- 2tt ^^ - acetate) -I · l · --tritylthio- 2-azetidinone.

OAc PAc

—► ^ T ~ C

J — N. ~ 0H pyridine J — n Cl

0 νγ 0 Y

CO PNB CO PNB

2 2

Isomer B. By operating at -15 ° (ice and methanol bath) in a nitrogen atmosphere, pyridine (2.19 g, 2.2½ ml, 27.7 millimoles) and thionyl chloride ( 3.3 S, 2.02 ml, 27.7 millimoles) to a solution of (l'R, 3S, hE and l, Sî3R, 1tô) -3- (l, -acétosy-l, -éthyL) -l - (p-nitrobenzyl -2n-; hydroxy-2, '- acetate) -M - tritylthio-2-! azetidinone (10.88 g in distilled tetrahydrofuran

on lithium aluminum hydride). The mixture is stirred for 20 minutes at -15 ° · The resulting salt is separated by filtration and washed with benzene. By evaporation of tetrahydrofuran and benzene from the mixture of phases - liquids, a residue is obtained which is taken up in hot benzene, after which active carbon is added to the solution. The suspension is filtered through Oelite and the solvent is removed from the filtrate to obtain a foamy product. The IR spectrum (CH2C12) includes the signals for Ό = 1780, 17 ^ 0 cm “1 (0 = 0). The RM spectrum of XE

(ODGl ^) includes the following signals S: 8.17, 8.21 (2H, 2d, J = 8, Ho, aromatics), 7.76 - 6.88 (17H, m, aromatics),. 5.31, 5.16, 5.12, 4-, 73 (3H, ks, CH2-PHB, CHCl), 5.12 ->, 55 (1H, m, H-l '), Λ, 35 “ M5 (lïï> Hk ·), 8.80 - 8.½½ Π TT. τη _ H-8 3. 1 .QO (8TT Q f! TT ΠΠ'ΐ IIP. 1.07 OH, J = 6.5, CH3).

II. 3- (1 '- (p-hitrobenzyldioxycarbonyl-l * -ethyl) -l- (p-nitrobenzyl-2, T-chloro-2 "-ac et at e) - ^ - tritylthio-2-azetidinone (mixture of epimers in 2").

ΟΛ-ΝγΟΗ 0 ^ ~ N \ / C1

CO PNB CO PNB

2 2

Isomer C. Pyridine (58 mg, 0.73 millimole) is added dropwise to a solution of C isomer of 3- (l'-p-nitrobenzyldioxycarl> onyl-l, -etliyl) -l - (p-nitrobenzyl-2 "-hydroxy-2" -acetate) -3-tritylthio-2 ~ aze-tidinone (** 70 mg, 0.6 millimole, mixture of epimers in 2 ") in tetrahydrofuran (15 ml ) cooled to -15 ° · Immediately afterwards, thionyl chloride (86.5 mg, 0.73 millimole) is added dropwise and the mixture is stirred at -15 ° for 30 minutes. the precipitate by filtration and washed with benzene, the mixture of filtrates and washing liquor is concentrated, then the residue is dissolved in fresh benzene and the activated carbon is added to the solution, after which the mixture is filtered. and the filtrate is concentrated to obtain 530 mg (100%) of the desired compound in the form of an oil.

The MT spectrum of (CDGl ^) includes the following signals b: 8.7 - 6.8 (23H, m, aromatic), 5.53 (1H, s, HI-2 "), 5.30 and 5.17 (^ H, 2s, benzyl), 52 (1H, d, J = 2, ÏÏ-M-), 20 L 3.70 (1H, m, ïï-1 '), 3.31 (1H, dd, ïï -3), 1.27 and 1.21 ppm (3H, 2d, J = .6.5) · The IR spectrum (CHCl ^) includes the signals for Ό = 1780, 175 ^ cm ^

Isomer B. The B isomer of 3- (l; -p- nitro'ben2yl-l, -ethyl) -l- (p-nitrobenzyl-2 "-chloro-2 ', - acetate) - b-tritylthio is prepared. -2-azetidinones (mixture of epimers in 2n) ($ 100 by operating as described above with respect to the C isomer. The EMU spectrum of _1H (CLCl ^) includes the following signals c $: 8.25 ~ 6 , 90 (23ÏÏ, m, aromatic), 5, if0 ”5,0 (ifH, m, benzyle), 5Λ0“ if, if5 (1H, m, H-l '), if, 82 and k, 57 (1H , 2s, H-2 "), if, 36 and b, 31 (1H, 2d, J = 2.5, H-if), 3.63 (1H, m, J = 2.5, J = 6, 5, H-3), 1.25 and 1.8 ppm (3H, 2d, J = 6.5, CH · ^). The IE spectrum (GHCl ^) includes signals for i) = 1780, 1750 cm ^ (8 = 0) and 1525 cm ^

IÎLcüC

(H02).

Isomer A. The 3 ”isomer (1'-p-nitrobenzyl-dioxycarbonyl-l'-étliyl) -l - (p-nitrobenzyl-2" -cliloro-2 "-acetate) -if-tri tylthio-2 -azetidinones (mixture of 2 "epimers). The EM spectrum of (CDGl ^) includes the following fc ύ signals: 8.30 - 6.80 (23H, m, aromatics), 5, ^ 5 ~ if, 80 ( 1H, m, H-l '), 5.18 and 5.21 (ifH, 2s, benzyl), if, 87 (lïï, 2d, H-if), if, 22 and 3.87 (1H, 2s, H-2 "), if, 05 - 3, bO (1H, m, H-3), 1.57 and 1.50 ppm (3H, 2d, OH ^).

Isomer D. The D isomer of 3 ”(lr” P '“nitrobenzyldio-xycarbonyl-1' -ettiyl) -l - (p-nitrobenzyl-2" -cliloro-2 "-acetate) - • if-tritylth.io -2-azetidinones (mixture of epimers in 2 ").

The 1H EM spectrum (CDCl ^) includes the following S signals 8.30- 6.70 (23H, m, aromatics), 5.32 - 5.1 ° (ifïï, m, benzyl), 5Λ8 and 5.30 (1H, 2s, H-2 "), if, 82 (1H, d, J = 5, H-if), 5.30 - 5.20 (1H, m, Hl), 3.15 (1H, m, H-3), l, ifO and 1.30 ppm (3H, 2d, J = 6.5, OH ^). The spectrum IE (OHOl ^) includes the signals for v> max = 1780, 1750 cm-1 (0-0) and 1525 cm "1 (H02).

NOT A WORD. Preparation of (l'S, 3S, ifR and l'R, 3R.HS) -3- (l'-methanesulfonylo: xy-l'-ethyl) ~ l - ('p - nitrobenzyl-2' '- chlorQ- 2 "-acetate) - ^ - tritylthio-2-azetidinone (isomer 0), (epimeres in 2”).

oms? Ms εοφ 3 v 3 "oP" o "* j -'- y1

COyNB CO ^ NB

Pyridine (3.65 g, b6.2 millimoles) and thionyl chloride (5.5 g, ^ 6.2 millimoles) are added dropwise to a solution cooled to 5 ° of (S ^ SjM -R and R ^ Rji ^ y ^ l'-methanesulfonyloxy-l'-ethyl) -! - ^ - nitrobenzyl-2, T-hydroxy-2 "-acetate) -if-tri tylthio-2-azetidinone (2 ^, 0 g, 35.5 millimoles) in dry tetrahydro-furan (350 ml). After 5 minutes of stirring, 100 ml of ether are added to precipitate the hydrochloride which is separated by filtration. the filtrate is evaporated and the residue is redissolved in "benzene (200 ml), then activated carbon is added to the solution. By evaporation of the solvent from the filtrate, an almost "white" foaming material is obtained which is used as it is in the following stage. The EMH spectrum of CDII (CDCl 4) comprises the following signals: 8.18 (2H, d, J = 9, Hm. aromatic), 7.72 (17H, m, part of d, Ho aromatic, trityl), 5.57 and 5.12 (1H, s, H-2 "), 5.28 (2H, s, -CBÿPHB), 73 (1H, 2d, H-if), 3.21 (1H, 2dq, Ξ-3), 2.78 (3H, 2s, mesylate) and 1.21 ppm (3H, 2d, H-ô ^, H-2 '). The IR spectrum includes a signal for V - 1779 cm ^ (C = 0).

KE. Preparation of (Ι'β, βΕ, ΛΒ and 1Έ, 35, ^ 5) -3- (1 ^ methoxymethoxy-11-ethyl) -l- (p-nitro'benzyl-2t, -triphenyl-phosphoranylidene- ^ rc -acetate ^^ - tritylthio - ^ - azetidinone (isomer A).

OCH2OCH3 och2och3

Xl "

C02PNB C02PNB

The mixture is refluxed for 2 days, a mixture of the 3-isomer A (l ~ methoxyiiethoxy - l'-ethyl) - l- (p-nitro'benzyl-2, f-cliloro-2, r-acetate) -ll — tritylthio-2-azetidinone (6.6 g, 10 millimoles), triphenylphosphine (3.3 g, 12.5 millimoles), 2,6-lutidine (1.3 ml, 11 mil -1 slugs) and dioxane (1 ^ 0 ml). The solution is diluted with ether, then washed with 5% hydrochloric acid, water, a dilute solution of sodium bicarbonate and brine, after which it is dried and concentrated. The residue is purified by chromatography on silica gel which is eluted with 10 $ ether in benzene, and by concentration of the useful fractions, 1.5 g (13.7%) of the desired compound are obtained, obtained under The shape of the foam spectrum IB (KBr) includes signals for 1? = 1750 cm ”1 (C = 0) and 1660 - 1650 cm” 1 (C = C. aromatic).

LL. Preparation of Çl'S, 3S, 4-R and 1 'R, 3R, 4-S) -3-Cl'-methoxy-methyloxy-11 -ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphorany- lidene- 2 "-acetate) -4 - tritylthio-2-azetidinone Cisomer C).

och2och3 och2och3 X STr Ρφ _ STr XL- XL »

C02PNB C02PNB

It is heated to reflux for 4- hours, then stored in a water bath at 100 ° for 16 hours, a solution of (l'S, 3S, 4-S and 1 ^, 3 ^, ^ 3) -3- ( 1 ^^ 6 ^ 0: ^^ 0 ^ 710: ^ 7-1 ^ ethyl) -1- (p-nitrobenzyl-2 "-chloro-2" -acetate) -4 - tritylthio-2-azetidinone (4- , 86 g, 6.62 millimoles), triphenylphosphine (2.60 g, 9.93 millimoles) and 2,6-lutidine (770 ml, 0.837 ml, 7.20 millimoles) in dioxane (100 ml) p - distilled on lithium aluminum hydride. The mixture is diluted with ether, washed with 1% aqueous hydrochloric acid, water, 10% aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate. The solution is concentrated and the residue is passed through a column of 65 g of silica gel (which is eluted with 5 × 10 and 20% ether in benzene) to obtain 2.8 g (4- 8%) of the desired compound. The IR spectrum (CHGlO includes signals for = 1795 cm ^ (C = 0), 1620 and I605 cm "· * · (phosphorane) and 1515 cm” · 1 · (R02).

Μ. (1Ή, 38ΛΒ and the S ^ I ^ S ^ -Cl'-acetoxy-l'-éthyO-l- (p-nitrobenzyl-2tt-triphenylphosphoranylidene-2 '' - acetate) -t * -tritylthio-2-azetidinone Bisomer ).

OAc OAc J .STr Φ, Ρ J .STr

-S _f_ / V

I i Cl 2,6-lutidine I 1, <T ~ ^

CO PNB CO PNB

2 2

2,6-lutidine (2.97 g, 3.23 ml, 27.72 millimoles) and triphenylphosphine (9.91 g, 37.8 millimoles) are added to a solution of (1Έ, 3δ, ^ · Η and l, S, 3R, ^ S) -3 ”" (l, -aoéto-xy-1 '-éthyl) -l- (p-nitrobenzyl-2u ~ chloro-2, T-acetate) - “I + - crude tritylthio-2-azetidinone in dioxane. (100 ml) freshly distilled on lithium aluminum hydride-The mixture is heated at reflux in an oil bath at 130 ° for 18 hours. The solvent is evaporated, then dissolved the residue in methylene chloride. The resulting solution is washed successively with dilute hydrochloric acid, water, dilute aqueous sodium bicarbonate, water and brine. By drying and evaporating the solvent, the desired compound is obtained which is in the form of a solid which is triturated in ether and which is then collected by filtration in an amount of 1 * 1.6 g (65.9%). The spectrum TR ( CH ^ C ^) includes signals for = 1758 cm ^ (0- = 0) and 1620, 16IO cm "" ^ (phosphorane).

ULcQC

[Μ. 3- (1 '-p-Nitrobenzyldioxycarbonyl-l' -ethyl) -l- (p- [nit.robenzyl-2n-triphenylpho sphoranylidene-2tt-acetate) -Ifr- trjtylthio - 2 ~ azetidinone.

oco2pnb oco2pnb

Ar-fsc * 3 _ »V ** 1 J- ^ C1 0J -" - ^ * 3

C02PNB C02PNB

Isomer B. It is heated for 30 hours at reflux in freshly distilled dioxane on lithium aluminum hydride, a mixture of (ΙΈ, βΟ, ^ Ε and 1 'S, 3E, 1i, S) “3- (l1 -p-nitrobenzyldioxycarbonyl -11 -ethyl) -lp-nitrobenzyl- 2, I-chloro-2, '- acetate) - ^ - tritylthioazetidinone (isomer B), (* +, 96 g, 6.22 millimoles, mixture of epimers in 0-2 "), triphenylphosphine (2, * + 7 g, 9, ^ - 2 millimoles) and \ 2,6-lutidine (7 ^ 0 mg, 0.80 ml, 6.91 millimoles). Dilute the solution to ether and ethyl acetate, washed with 5% aqueous hydrochloric acid, water, 10% aqueous sodium bicarbonate, water and brine, then it is dried over magnesium sulfate.

By evaporation of the solvent, a residue is obtained which is passed over a column of silica gel of tenfold weight which is eluted with 10% ether in benzene, then ether and finally l 'ethyl acetate. 3.1 g (4-9%) of the desired compound are obtained, which is in the form of a crystalline solid having a m.p. of 189-190 ° (ether).

The IR spectrum (C1010) includes signals for ^ max = 17 ^ 0 cm ^ (0 = 0), 1620, 1605 cm ^ (phosphorane) and 1 ^ 22 cm ^ (M) 2).

Isomer 0. Prepare as described above at a Ha Ί · -î on-mà-nû * R Ί * -ï ολπιοτιλ C \ r \ q To Q - f Ί · —-n — m 'fnrt'Kûn ιτττΊ - dioxycarbonyl-l'-ethyl) -l- (p-nitrobenzyl-2, T-triphenylphosphoranylidene-2, I-acetate) '- 4-tritylthio-2-azetidinone.

The IR spectrum (CHCl ^) includes signals for \> max = 1750 cm ”1 (C = 0), 1610, 1620 cm 1 (phosphorane) and 1520 cm" "1 (UOg) · The EMET spectrum of ^ ïï ( CDGl ^) includes the following S signals: 8.6 - 6.7 (H, aromatic), 5 ^ 22 and 4.95 (benzyl), 4.70 (ïï-4), 2.6 (H-3) , 1.19 and 1.07 ppm (C10).

Isomer R. A mixture of the isomer D of 3- (l'-p-nitrobenzyldioxycarbonyl-l'-ethyl) -l- (p-nitrobenzyl-2) is heated at moderate reflux for 41 hours in a nitrogen atmosphere. "-chloro-2 ,, - acetate) -4-tritylthio-2-azéti-dinone (4,598 g, 4,45 millimoles, titer of 77% 5 mixture of the epimers in C-2"), of triphenylphosphine (1,425 g, 5.44 millimoles, Aldrich Company) and 2,6-lutidine (0.63 ml, 580 mg, 554 ° millimoles, Anachemia Company) in dioxane (65 ml, distilled on lithium aluminum hydride) observing 1 progress of the reaction by thin layer chromatography with elution using a 3: 1 mixture of benzene and ether. The dark reaction mixture is cooled, diluted with ethyl acetate and washed successively with 0.1 R hydrochloric acid, water, 2% sodium bicarbonate and brine . By drying over sodium sulfate and evaporation of the solvents, 4.18 g of a dark oil are obtained which is purified by chromatography on a column of 88 g of silica (elution with 10 to 25% ether in benzene) to obtain 1.108 g (1.08 millimole, or 24.3%) of the desired compound which is in the form of a yellowish frothy substance. The KW spectrum of 1H (CDCl ^) includes the signal S: 1.08 (d, J = 6 Hz, l'-CH ^). The IR spectrum (pure compound) includes a signal for x = 1745 cm ”1 (C = 0).

00. Preparation of the (S., 3S, 4R and 1 Έ, 3ΒΛδ) - · 3-Γΐ'-metliane- · sulfonyloxy-l1 -ethyl) -lp-nitrol> enzyl-2, t-triphenylpb.o sphora- nylidene-2, t-acetate) -4-tritylthio-2-azetidinone (isomer C).

OMs oms Α_ ^ φ3 X. = c * 3 (/ - “γ ·« ”0 ^ Ηγ? Φ 3

CO PNB C02PNB

Is heated under reflux for 19 hours in a nitrogen atmosphere, a solution of (l'S, 3S, 4R and l'R, 3R, 4S) -3- (l-methane tallow onyloxy-11 -ethyl) -l- ( p-nitrobenzyl-2, r-chloro-2 ,, - acetate) -4-tritylthio-2-azetidinone (24.7 g? 355Î> mülL “moles), d * e triphenylphosphine (11.2 g, 42.7 millimoles) and 2,6-lutidine (4.2 g, 39.1 millimoles) in dry dioxane (350 ml). The solvent is evaporated off and the crude product is redissolved in ethyl acetate, then the solution is washed successively with dilute hydrochloric acid, sodium bicarbonate and brine. The purification is completed by chromatography on an 8.5 x 12 cm column of silica gel. By elution with 1500 ml of dichloromethane at $ 10 ether, then with. 1500 ml of ether, 12.36 g (40%) of the purified phosphorane are obtained.

The EM spectrum of III (ODOl ^) includes the following signals 6: 2.53 and 2.93 ppm (3H, 2s, mesylate). The IR spectrum includes signals for max = 1749 and 1620 cm ^ (0 = 0).

PP. Preparation of (E ^ S ^ R et 1 ^, 3 ^, ^ 8) -3- (1'-hydroxy- 1 l-ét] iyl) -l-Cp-iiitroT3enzyl-2u-trip3ienylpIiospIioranylidene-2tt- Acetate) -1! - (tritylthio-2-azetidinone (isomer B).

OAc OH

A ^ _ / STr X __ ^ STr 1 f. -> Γη 0 ^ -Ν ^ Ρφ3 0 ^ “Ν ^ · ΡΦ3

C02PNB C02PNB

At room temperature, 1% aqueous sodium hydroxide (1 equivalent, 200 mg in 20 ml of water) is added to a solution of (ΙΈ ^ δ, ^ Ε and 1 'S, 3E, 4-8 ) -3- (1 '-acetoxy-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphenylpho sphoranylidene-2 acetate) -V ~ tritylthio-2-azetidinone (4 -, ^ 3 g, 5, 00 millimoles) in methanol (10 ml) and tetrahydrofuran (60 ml).

The progress of the reaction which accelerates upon heating is observed by thin layer chromatography.

The mixture is diluted with ether and ethyl acetate, then washed with hydrochloric acid, water, aqueous sodium bicarbonate, water and brine. By evaporation of the solvent, a residue is obtained which is crystallized from a benzene-ether mixture (3.7 g, 87.7%) and which then has a PP of 169.5 "170.5 ° · The IR spectrum ( CEbjCl ^) includes signals for O = 17 ^ 5 cm (0 = 0) and 1620 cm "'* · (phosphorane).

QQ. Preparation of (1 '8,3Ρ · ΛΡ and R3S, H £) -3- (l'-methoxy-methyl-1'-ethyl) -l- (p-nitrobenzyl-2 "-triphenylphosphoranylidene- 2" - acetate) -2-azetidinone-Li-silver thiolate (isomer A).

och2och3 och2och3

Fr · _- V

/ 3 'C02PNB.

The 3- (l, ~ metho: x ^ ethyl-l, “etliyl) -l- (p-nitrobenzyl-2" -triphenylplio sphoranylidene-2 "-acetate) -3-trityltliio-2-azetidinone (isomer) is prepared. A), as described elsewhere with respect to the C isomer of the p-nitro-benzyldioxycarbonyl derivative. This gives a yield of ^ CP / o.

The IR spectrum (pure compound) includes a signal for O = 17 ^ 5 cm “1 (0 = 0).

RR..Preparation of the S ^ S ^ H and 1 'Κ, 3Κ <Λ5) ~ 2- (1' -methoxy-methyloxy-11 -ethyl1) -1 - (p -ni tr ob enzyl-2 "-triphenylpho spbo rany-lidene-2tt-acetate) -2-azetidinone-L {- silver thiolate (isomer C).

OCHnOCH-3 och2och3. 2 3

AgN03 · A | - ^ 9 0i— \ ^ ρφ3 ^ 0 ^ —Κγ ^ Φ3 CO PNB co2pnb

First, (S, 38.4¾ and E, 3E, i + S) - 3- (l '-metboxymethyloxy-l' -étbyl) -l- (p-nitrobenzyl-2 "-tripbenyl) are dissolved -phosphoranylidene-2 "-acetate) -4 - tritylthio-2-azetidinone (887 mg, 1.0 millimole) in hot methanol (30 ml, * + 0 °), then pyridine (103 mg, 0.105 ml, 1.3 ml 0.15 M silver nitrate (8.7 ml, 1.3 mmol) The mixture is stirred for 1 hour at 23 ° and then cooled in an "ice bath". stirred for 20 minutes, collect the salt by filtration and wash it successively with cold methanol and ether (3 times) to collect an amount of 671 mg (87%) · The IE spectrum (CHOlo) includes signals for i) = 17 ^ 5 ° m (0 = 0),

0 ULclX

1605 cm ^ (phosphorane) and 1520 cm ^ (MOg) SS. Preparation of silver 3- (l'-p-nitrobenzyldioxycarbonyl-l'-ethyl) -l- (p-nitrobenzyl-2 "-triphenylphosphoranylidene-2tt ~ acetate) -2-azetidinone-’t-thiolate.

OCOjPNB OCO PNB

^ '^ YYSA9

CO-PNB CO PNB

2 2 \

Isomer B. We first dissolve (E, 3S, Hîl and S, 3E, HS) -3- (l '-p-nitrobenzylcarbonyldioxy-1' -ethyl) -l- (p-nitrobenzyl-2 '' -triphenylphosphoranylidene-2, '- acetate) -î-i-tri-.tyltbio-2-azetidinone (1.02 g, 1 millimole) in dichlo-romethane (3 ml) and dilute the solution with methanol hot (20 ml, 55 °) · To the hot solution, first add pyridine (0.12 ml, 117 mg, 1, ^ - 8 millimole) and a hot methanolic solution 0.15 H of nitrate d silver (8 ml, 1.2 millimole, 55 °) · The mixture is stirred at room temperature for 15 minutes, then at 0 ° for 2 hours. The rotary evaporator is then concentrated (without bath) to a 10% solution. The mercaptide is collected by filtration and washed twice with cold methanol (-15 °), then three times with ether. 917 mg (100%) of the compound are thus obtained. The IE spectrum (nujol) includes signals for \) = 17 ^ 5 cm 1 (C-0), 1600 cm 1 (phosphorane)

Μα. X

and 1517 cm "1 (N02).

Isomer, C. The G isomer of 3- (l'-p-nitro-benzyldioxycarbonyl-l, -ethyl) -l- (p-nitrobenzyl) -2t, -triphenyl-phosphoranylidene-2,, Tacetate is prepared. ) -2-azetidinone-1 + -thiolate silver as described above with respect to the B isomer. The IR spectrum (nujol) includes signals for Ό max = 17 ^ 5 cm 1 (C = 0) and 1600 cm "1 (phosphorane).

Isomer B. A solution of the isomer D of 3- (l, -p-nitrobenzylcarbonyldioxy-l'-ethyl) -l- (p-nitrohenzyl-2, r-triphenylphosphoranylidene-2, I-acetate) is prepared. l + -tritylthio-2-azetidinone (1 ^ 5 mg, 0.1½ millimole) by dissolving it in dichloromethane (5 ml), then removing the dichloromethane at ^ 5 “60 ° and adding (½ ml) hot methanol . To the above solution is added a} hot solution of silver nitrate in methanol (0.15 Μ, 1.1½ ml, 0.17 millimole, 1.2 equivalent), then pyridine (1½ microliters , 0.17 millimole, 1.2 equivalent). The silver mercaptide immediately begins to precipitate. The mixture is stirred for 2 hours at room temperature and 1 hour at 0 °. The mercaptide is collected by filtration and washed with ice-cold methanol and ether to collect 99 mg (0.11 millimole, 78%) of the desired compound in the form of a brownish solid. The IR spectrum (nujol) includes a signal for = 1750 cm "1 (C = 0).

HicQC

TT. Preparation of (ΙΈ, ^ βΛΒ · and the S ^ R ^ S) ~ 3 ~ (l-hydroxy-l'-ethyl) -l ~ (p-nitrobenz, yl-2, '- triphen: ylphosphoranylidene-2ir-acetate) -2-azetidinon0-If-t3iiolate (isomer B).

OH OH

J .STr 1 .SAg

Agm3 1 J_A Ρφ, CJJ J-N .Ρφ_,

Cr N'V ^ Î '3 5 5 Y3 co2pnb co2pnb A solution (which is obtained by first dissolving the crystals in dicbloromethane) of (L'R, 3S ^ E. And 1' S, 3R ^ S ) -3- (l -h.ydroxy-1 '-ethyl) -l- (p-nitrobenzyl-2 "-t riphenylpho spho ranylidene -2" ~ ac and at e) -H — tr ityl thio -2- az eti -dinone (1 g, 1.19 millimole) in methanol (10 ml), pyridine (12½ microliters, 121.3 mg, 1.53 millimole) is added and at 10 °, a solution is added to 0.15 M> of silver nitrate in methanol (15 ml, 2.25 milli moles' gu until the end of precipitation of silver mercaptyde). The mixture is stirred for 1 hour, then it is concentrated on a rotary evaporator (without bath) to a concentration of approximately 10%. The solvent is separated by filtration. The filter cake is washed once with methanol and three times with ether, then stored. Under high vacuum to obtain 95½ mg (100%) of the salt.

The IR spectrum (nujol) includes signals for = 3500 - 3 ^ 00 cm ”1 (0-ïï), 1752 cm" 1 (C = 0), 1959 cm “l (phosphorane) and 1525 cm” 1 (NO ^ ).

UU. Preparation of (1 Έ., 3Ρ · ΛΡ and 1'S, 3S, ^ - S) - ^ - acetylthio-3 ~ Cl1 -p-nitrobenzyldioxycarbonyl-l 1 -ethyl) -l- (p-nitrobenzyl-2, t- triphenylphosphoranylidene-2n-acetate) -2-azetidinone (Ώ isomer).

OC02PNB 0C02PNB

f SAg I> SAc -f CH ^ COCl-Pyr -Ç

α2α2 O J-H

CO ^ PNB C02PNB

Acetyl chloride (20 micro-. Liters, 0.28 millimole) is added at 0-5 ° to a stirred solution of 3 "(1 '~ P" 2-nitrobenzyl-2M-triphenylphosphoranylidene-2 "-acetate) -2 -azetidinone-V-silver thiolate (P isomer), (85 mg, 0.095 millimole) in dichloromethane (5 ml) containing pyridine (30 microliters, approximately 0.37 millimole, j Company Pisher) and the mixture is stirred mixing for 30 minutes at 0 - 5 ° · Or collect by filtration the precipitate formed which is washed with dichloromethane, the filtrate and the washing liquors are combined and the mixture is washed successively with brine, dilute hydrochloric acid , saturated sodium bicarbonate and finally brine, after which it is dried over sodium sulfate and evaporated to obtain 75 mg (0.091 millimole, crude yield of 95%) of the desired compound in the form of 'a syrup.

The spectrum ΕΙΦΤ of (CDOl ^) comprises a signal 6: 2.33 (s, -SOOOCH ^). The IR spectrum (pure) includes signals —1 —1 for '= 1750 cm (ß-lactam, ester), 1695 cm

ItlcOC

(thioester), 1520 and 1350 cm ^ (-MJg).

W. Preparation of (R, 5R, 6R · and S, 53.6S) -cis _-_ ·, 2-methyl-6- (l> -p-nitrobenzvldioxycarbonylmethyl) -p eneme-V p-nitrobenzyl earboxylate (D isomer).

OCO PNB OC02PNB

T * SAc A

* / 'ΛΝ-f _toluène j I \ .p I nih Ί / ™ 3 0 ^ -Η ^ ΡΦ3 0

T CO GNP

co2pnb 2

Is heated under reflux in a nitrogen atmosphere for 7 hours, a solution of 11acétylthioazétidiaone above (7½ mg, 0.09 millimole) in toluene (30 ml) * After evaporation of the solvent, the residue is purified by liquid chromatography under high pressure on silica (which is eluted with a 3: 1 mixture of benzene and ether) to obtain 2½ mg (0.0½½ millimole, ½9%) of> the penem ester in syrup form. It is possible to crystallize this oil in a tetra-hydrofuran-ether mixture or in a dichloromethane-ether mixture. the EIW spectrum of (CDOl ^) includes the following signals S: 1.40 (3H, d, J = 6.5 Hz, l'-CH ^), 2.38 (3H, s, 2-CH ^) , M7 (1H, dd, 6 = ½ Hz, J6 χ = 9 Hz, 6-H), 5.05 - 5.30 - 5.3½ - 5.59 (2H, type AB, 3-C02ÇH2-Ar) , 5.30 (2H, s, 1'-0C02-0H2-Ar), 5.1 - 5.6 (1H, m, l'-H), 5.68 (1H, d, J5? 6 = 4 Hz, 5-H), 7Λ9 - 7.6½ - 8.18 - 8.33 (^, A2 B2 ', aromatic-Hs), 7.53 - 7.68, 8.18 - 8.33 ( te, A2'B2 ', 3 “Hs aromatic). The IR spectrum (pure compound) includes signals for V = 1780 cm-1 (ß-lactam), iilcLX.

1750 cm- · * "(-0G02 ~), 1710 cm- ^ (ester), 1520 and 1350 cm ~ ^ (-ho2).

WW. Preparation of a'B, 5R, 6R and S, 5S, 6S) -6- (l'-hydroxy-ethyl) -2-metb., Ylpénème-3 ~ caP'boxylate of potassium and sodium (isomer D) " oco2pnb ° h \ H2 / Pd-Celite JL / ^ ΤΗΡ-éthsr-HjO 'UN} ^ a3 0 ^ co2pkb

A solution of the above penem ester (2k mg, 0.0½½ millimole) in tetrahydrofuran (5 ml) is mixed with ether (10 ml), water (5 ml), phosphate buffer (1.00 ml, 0.05 M, pH 7.00, Eisher Company) and 30% palladium on Celite (50 mg, Engelhard Company). The mixture is hydrogenated for 21 hours and 20 minutes at room temperature under a pressure of j 2, * + 6 kg per cm. After having separated the catalyst on

Oelite, the aqueous layer is collected and washed with ether, then lyophilized to obtain 12 mg of the desired mixture of sodium and potassium salts in the form of a white powder. The EM spectrum of H (D ^ O) includes the following signals o: 1.23 (3.H, d, J = 6 Hz, l'-CH3), 2.27 (3H, s, 2-CH3), 3.85 (1H, dd, 6 = k Hz, J6 ± = 9 Hz, 6-H), * t, 3 (1H, m, l'-H) and 5.65 ppm (1H, d, ^ = k Hz, 5 “S). The TR (nujol) spectrum 'includes signals for' O = 1755 Qm ^ (ß-lactam) mcix and 1570 cm ^ (-CO2 ®) · The TJV spectrum (HgO) includes λ at 297 nm (€ 23ΟΟ, calculated in potassium salt) and 258 nm (1900 pounds, calculated in potassium salt). This product is identical to that of a sample of the desired compound obtained by aldolic condensation of acetaldehyde with the dianion of 2-methylpenem-3-carboxylic acid.

X

EXAMPLE 3 5.-

Acid (l'Siffi-.äS and 1 Ή, 5S, 6R) -6- (l-hydroxy-l'-ethyl) -2-methylpenem ~ 3 '~ carLoxyl.ique (C isomer).

OH

ÎQ ~ ”> go2h

Method A

fV ™ 15 OCO PNB

λι ^ ΓΎ ~ Γ ° 0J — hv ^ 3 *

C02PNB CO PNB

2 PC02pnb oh

A-V A

ÎC ^ 3 ^ xChs

CO PNB COJ

^ 2

Process ~ B

OCO PNB OCO PNB OCO PNB

A-ΑΦ3 -A ^ SAg A, ^ SAc A .a AA- * A .— s <H- Nsi ^ - σ \ si ^.

77 ”^ 77“ · __77 “/“ “A o ^ NyOH 0X-k h2

CO PNB CO PNB

Λ 2

Method A

1) (l'S ^ S, ^ et llR, 3R, ^ S) -i + -acétylthio - ^ "(ll-p-iiitro-benzyldioxycarbonyl ~ l, -éthyl) -l- (p-nitrobenzyl-2 ', - triphenyl -phosΌhoranylidene-2>, - acetate) -2 ~ azetidinone (isomer C).

OCOgPNB PCO PNB

✓À ._ / SA3 CHjCOCl ^ - | ^ AC

“Vs5 'co2pnb co2pnb

Pyridine (0.6 ml, 0.7½ millimole) and, dropwise, acetyl chloride (236 mg, 0.213 ml, 3.00 millimole) are added to a cold solution ("ice and methanol) of (L'S, 3S, MH and 1'R, 3R, ^) - 3- (1'-p-nitro-benzyldioxycarbonyl-11 -éthyl) -lp-nitrobenzyl-2M-triphenylphosphoranylidene-2n-acetate) -2 -azetidinone-5 + -, silver thiolate (isomer C), (1.1½ g, 1.30 millimole) in dichloromethane (60 ml) The reaction mixture is stirred for 1 hour at -15 ° · On the precipitate is filtered off and washed with ether. The filtrate is washed with 2% aqueous hydrochloric acid, water, 2% aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate. After evaporation of the solvent, the residue is triturated in ether to obtain 895 mg (83.1 ° / °) of the compound having a PP of 18½ - 185 ° ( The IP spectrum (OHCl ^) includes signals for "Ό = 1755? 1695 cm ^ (C = 0), 1620 and 1605 cm ”" ^ (phosphorane).

Analysis for C ^ H ^ N ^ O ^ SSi:

Calculated: C, 61.38; H, ^ 2; N, 5, H; S, $ 3.90.

Found: C, 61.26; H, ½, ½9; N, ^ 88; S, ^ 26%.

2) (l'S, 5R, 6S et l'R.5S, 6R) -2-methyl-6- (l'-p-nitrobenzyl-dioxycarbonyl-1'-éthvD-pénème - ^ - p-nitro-benzyl carboxylate (isomer C).

OCC> 2PNB oco2pnb CO PNB co2pnb

Is heated at reflux for h hours and 30 minutes, a solution of (l'S, 3S, 4-R and R ^ Rj ^ -h-acetyl-thio-3- (l 1-p-nitrobenzyldioxycarbonyl-1 ' -ethyl) -l- (p-nitrobenzyl-2, t-triphenylphosphoranylidene-2 ,, - acetate) -2-azeti-dinone (isomer C), (855 mg, 1.04 mmol) in toluene (60 ml After concentration of the solution, the residue is passed through a column of 10 g of silica gel (1% ether in benzene) to obtain 3 mg mg (69.6%) of the pure desired compound having a PF from 157 - 158 ° (chloroform-ether). The IP spectrum (CÏÏCl ^) includes signals for Ό = 1785, 174-5, 1710 cm ”1 (0 = 0) and 1525 cm 1 (hO ^) · Le RTffiT spectrum of 11 (ODOl ^) includes the following signals 5: 8.30 - 7.2 (8H, m, aromatic), 5, ^ 6 (1H, d, J = 1.8, H-5), 5 , 4-0 - 5.0 (5H, m, z, 012-PHB) and H-11), 3.95 (1H, dd, J = 1.8, J = 5, h, H-6), 2.35 (3H, s, CH ^) and 1.4-3 ppm (3H, d, J = 5, ^, OH ^).

Analysis for C2lfH21 ^ 010S:

Calculated: C, 53.04 ·; H, 3.89; N, 7.73%

Found: C, 52.76; H, 3.86; N, 7.69%.

3) Acid (L'S., 5Rs6S and L'R, 5S, 6R) -6- (l'-hydroxy-l'-ethyl) - 2-methylpénème-3-carboxylic (G isomer).

oco2pnb 9h • ^ rVcH3 £ Q- «3

C02PNB C02H

We. submits a mixture of (S, 5H, 6S and R, 5S, 6R) - 2-methyl-6- (1 '-p-nitrobenzyldioxycarbonyl-1' -ethyl) -penem- 3-carboxylate of p-nitrobenzyl ( 206 mg, 0.379 millimole), tetrahydrofuran, ether and water (30 ml, ^ 0 ml and 20 ml), d; UIB 0.05 H buffer solution, pïï 7 (7.6½ ml, 0.382 millimole) and Oelite palladium at 30% (500 mg) on hydrogenation under a hydrogen pressure of 2.95 kg ο per cm for 16 hours in a Para apparatus. stirrer. The catalyst is filtered off and washed with water. The aqueous phase is washed with ether (3 times), then it is gradually acidified with 1% aqueous hydrochloric acid to pH 2.5 and extracted with acetate. ethyl (15 x 20 ml) between each addition of hydrochloric acid. The ethyl acetate extracts are combined and washed with brine (3 x 20 ml). By evaporation of the solvent and trituration of the residue in ether, 57 21 g (65.6%) of the desired compound are obtained. The IR spectrum (KBr) includes signals for ^ max = 3580 - 3300 cm ^ (0-H), 1755 and 1660 cm ~ ^ (C = 0). The ITV spectrum (ethanol) includes & 3H nm (ε 6538) and 262 nm (£ 3672).

The EM spectrum of (hexadeuterodimethylsulfoxide) comprises the following signals 6: 5.57 (1H, d, J = 1.7, H-5), **, 02 (1H, Η-l ·), 3.75 (lïï , dd, J = 1.7, J = 3.5, H-6), 2.23 (3H, s, 01i3) and 1.23 ppm (3H, d, CI ^).

Method B

1) (S, 3S, * Æ and 1'R, 3RAS) -l- (t-butyldiiiiOthylsilyl) -3- (1 '-p-nitrobenzyldioxycarbonyl-1' -ethyl) -2-azetidinone-H-thiolate ' silver (G isomer).

OCOjPNB OCO ^ PNB

> - N. _ ^ Me2 * ji - N Jîe-, \ sr 2 2 ^ tBu ^ N: Bu

By stirring in hot methanol (12 ml, * + 0 °), the C isomer of the 1 '- (t-butyldimethylsilyl) -3- (1' -p-nitrobenzyldioxycarbonyl-1 '-ethyl) - * is dissolved. + - 'tritylthio-2-azetidinone (lg, 1, ¾ millimole). A solution of silver nitrate (0.59 g) in methanol (12 ml) is added, followed by pyridine (0.13 ml). The mixture is stirred vigorously for 1 hour at room temperature and for 2 hours at 0 °. The solid silver mercaptide is collected by filtration and washed with ether. The amount obtained is 352 mg (k6%). The IR spectrum includes a signal for O = 1735 cm “1 (0 = 0).

2) (S, 3B, ^ R and 1'R, 3R, ^ S) - ^ - acetylthio-l - (t-butyldimethyl-silyl) -3- (l '-p-nitrobenzyldioxycarbonyl-1' -ethyl) -2-azetidinone (isomer 0).

oco2pnb oco2pnb —j ^ SAg ^ SAc 0 ^ “NNSfMe2 0Χ-Ν ^. ^ Μθ2 tBu ^» tBu

Pyridine (0.57 ml) is added, then, dropwise, acetyl chloride (0. ¾ ml) to a solution of the isomer C of 1- (t-butyldimethylsilyl) -3- (l '-p-nitrobenzyldioxycarbonyl-1' -ethyl) -2-azetidinone-4-silver thiolate (880 mg) in dichloromethane (40 ml) stirred at 0 °. Oir stirred the mixture for 30 minutes at 0 °, then separated the solids by filtration and diluted the ether filtrate, after which it was washed with 2% aqueous hydrochloric acid, water, 2% sodium bicarbonate and brine before drying and concentrating to obtain 610 mg of the desired compound which is oily. The 1H EM spectrum (CDCl ^) includes the following signals: 8.2 and 7.48 (4H, 2d, aromatics), 5, ^ 0 (LH? D, J = 2.2, H-4), 5.2 (2H, s, benzyl), 5.3? 4.9 (1H, m, H-1), 3.42 (1H, dd, J = 2, H-3), 2.32 ( 3H, s, CH3)., 1.40 (3H, d, J = 6.5, C10), 0.95 (9H, s, t-Bu) and 0.2 ppm (6H, O6).

3) C1'S, 3S, 4E and l'K, 3E ^ S) -4-acetylthio-3-a'-p-nitro-benzyldioxycarbonyl-1'-ethyl) -2-azetidinone (isomer 0).

oco2pnb oco2pnb A __ / SAc à ^ sac "^ tBu

The C-isomer of S-acetyl-Itf-t-butyl-methylsilylazetidinone above (1.4 g) is dissolved in a mixture of trifluoroacetic acid (0.5 ml), water (0.5 ml ), methanol (3 ml) and dichloromethane (2 ml) and the solution is stirred for 48 hours at room temperature.

The solution is diluted with water (100 ml) and extracted with dichloromethane (4 x 20 ml). The organic extracts are combined and washed with 2% sodium bicarbonate and brine, then dried and concentrated to obtain the crude desired product which is oily.

The compound is purified by chromatography on silica gel (30 g) which is eluted with 5% ether in benzene.

650 mg of compound are obtained. By crystallization from "benzene, a white solid" is obtained. The EM spectrum of ^ ïï (CDCl ^) includes the following ô signals: 8,15 and 7, H-5 (H-ïï, 2d, aromatics), 6,18 (1H, HH), 5,19 (2H, s, benzyl), 5.05 (2H, m, HH · and H-1 '), 3.35 (1H, dd, J = 2.5, H-, 5, H-3), 2.3Π · (3H, s, CH3) and 1 ½ ppm (3H, d, J = 6.5, CH ^). The IE spectrum includes the signals for

Vmax = 1780 ’17? °’ l69? om_1 (0 = 0) H-) (l'S, 3S, HR and 1'R, 3R, HS) -H-acetylthio-3 - (l'-p-nitro- benzyldioxycarbonyl-1 '-ethyl) -l - (p-nitrobenzyl-2tt-hydroxy-2tt-acetate) -2-azetidinones (C-2 ”epimers) (isomer 0).

oco2pnb oco2pnb

Xl ^ SÀc _ "τ ~ <5Αα C02PKB '

It is heated under reflux for 3 days in a

O

i Lean & Stark apparatus containing 3 A molecular sieve, a mixture of 0 isomer of H - acetylthio-3 ~ (l'-p-nitro-benzyldioxycarbonyl-1'-ethyl) -2-azetidinone (750 mg ), hydrated p-nitrobenzyl glyoxylate (525 mg) and benzene (50 ml). An additional 52 mg of glyoxylate is added and heating under reflux is continued for 2 days. The mixture is diluted with ether and washed with 2% hydrochloric acid, water, 2% sodium bicarbonate and water, after which it is dried and concentrated to obtain 975 mg of an oily residue. By chromatography on silica gel and elution with a mixture (85:15) of benzene and ether, the compounds obtained are obtained. The EM spectrum of ^ H (CDCl ^) comprises the following signals 6: 8.25 - 6.75 (8Ξ, m, aromatics), 5.30 and 5.12 (HH, 2S, benzyl), 5.05 - H-, 70 (1H, H-2 "), Η-, Π-5 - H ·, 35 (1H, 2d, HH ·), H-, 50 - H-, ÎO (1H, m, H-l '), 3.30 (1H, m, III-2) and 1.25 ppm (3H, 2d, CH ^).

5) (l'S, 3S., MR et 1 lR, 3R, Ît-S) -If-acetyltIiio-3-Cl'-p-nitro-benzr / ldioxycarbonrfl-11-ethyl) -l- (p-nitrobenzyl-2tT -tri-phenylphosphoranylidene-2n-acetate) -2-azetidinone (isomer 0).

oco2pnb oco2pnb Çco2pnb

Ar> ÂC ΛΙγ'-ο j-ίγ * Λγ> / -N ^ 3 co2pnb co2pnb co2pne

The G-isomer of ^ -acetylthio-S ^ l '-p-nitrobenzyldioxycarbonyl-l'-ethyl) -l- (p-nitrobenzyl-2, r-hydroxy-2 "-acetate) -2-azetidinone is dissolved. 577 mg, 1 millimole) in anhydrous tetrahydrofuran (10 ml) and pyridine (95 mg, 1.2 millimole) is added to the solution. The solution is cooled to 0 ° and slowly added * thionyl chloride (1¾ mg, 1.2 millimole) The mixture is stirred for 30 minutes at 0 ° and diluted with a little ether, then the insoluble salts are filtered off and washed with ether. the filtrates and they are concentrated to obtain the crude mixture of the epimers of the chlorinated compound at C-2 ". Dissolve the mixture in tetrahydrofuran (20 ml) and add triphenylphosphine (31½ mg, 1.2 millimole) and 2,6-lutidine (129 mg, 1.2 millimole), then stir the solution for ^ days at h5 ° · The solids are separated by filtration and washed with benzene, then the filtrates are combined and concentrated to obtain an oil whose spectroscopic and chromatographic properties in a thin layer are identical to those of a sample of the desired compound obtained by acylation of the silver thiolate correspondingly.

Can the desired penem derivative be prepared by reaction of the title compound by operating as in stages 2 and 3 of Example 3? (Method A). EXAMPLE 36.-

Acid (ΙΈ, ^ Β, βΒ and l'S, 5B, 6R) -6- (l--liydroxy-l, -éthyl) -2-methylpénème-l-carboxyligue (isomer B).

______QH

\ ° 2H

Method A

oco2pnb çco2pnb "Çç--

CO PNB CO PNB

2 Δ

OH

OCO PNB .1 T »PNB 2

Method B

OH OH

Λ- / SAg DTMS / TEA - ^ SAC

i-Υ3 2pyridine ’C02PNB 3) H30 + co2pnb OH f" jiQ ^ ch 3 - ^ XT> ch3

^ bozPNB c02H

Method A

1) (R ^ SM and 1'S, 3R ^ S) - ^ acetylthio-3 ~ (l'-P-nitro-benzyldioxycarbonyl-l1 -éthyl) -l-fp-nitrobenzyl-2 ”-triphenyl ~ phosphoranylid.ene -2n-acetate) -2-azetidinone (isomer B).

OCO PNB OCO-PNB

J ^ SAg I SAc

AcCl_ 0 ^ -Ν-γΡΦ3 C5H5H '0 ^ γ.ϊφ3

C02PNB COjPNB

Operating at -15 ° C. (ice and methanol bath), pyridine (2½ microliters, 237 mg, 3? 13 milli-! Moles) and, drop by drop, acetyl chloride (1½ microliters) are added. , 157 mg, 2.0 millimoles) to a solution of (1 ^, 30, ½ and l, S, 3R, ^ S) -3 ~ (“P_nitro'benzyldioxycarbonyl-1 '-ethyl) -1 (- p-nitrobenzyl-2 "-triphenylphosphoranylidene- 2 ,, - acetate) -2 ~ silver azetidinone-lt-thiolate (isomer B), (917 mg, 1.03 millimole) in dichloromethane (20 ml).

The mixture is stirred for 15 minutes at -15 ° and the solid is filtered off, then washed with ether. The organic solution is washed with 2% aqueous hydrochloric acid, water, 2% aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate. After evaporation of the solvent,. the residue is crystallized from ether. We obtain 710 mg (80 $) - of the compound having a PE of 183 - 18 5 ° -'I · ® IR spectrum (GHOl-j) includes signals for Ό = 1755¾ 1695 cm ^ (C = 0), 1620. 1605 cm- "1 (phosohorane) and 1625 cm ^ (RO-).

2) (R, 5R, 6S and S, 5R, 6R) -2-methyl-6- (l> -p-nitrobenzyl-dioixycarbonyl-l'-ethyl) -péuème-3-carboxylate de p-nitro- benzyl (isomer B).

0C0 PNB OC02PNB

A.r_ ^ SKc A-.T — r '\ ΓΊ _-, - f ΓΊ> -σ · 3 oj_N ρφ3 a J - * - /

T ’ΤΟ GNP

CO GNP 2 2

A solution of (L'R, 3S, 4-R and 1 'S, 3E, 1 + S) -1 + -acetylthio-3- (l'-p-nitro-b enzyldioxy) is heated at reflux for 7 hours. c arh ony 1-1'-ethyl) -1- (p-nitrobenzyl-2 "-triphé-nylphosphoranylidene-2, f-acetate) -2-azeti (iinone (650 mg, O, 791 millimole) in toluene. The solution is concentrated by evaporation of the solvent, then it is passed through a column of silica gel (10 times its weight) and by elution with 0.5% to 2% ether in benzene, \ we obtain 329 mg (77%) of the desired white compound having a PR of 13½ - 135 ° (dichloromethane-ether). The IR spectrum (CHCl-j) includes signals for 'O = 1785, 17 ^ 5, 1705 cm "1 ( 0 = 0) and 1525 cm "1 (NQ2). The ROT spectrum of λΕ (CDCl ^) includes the following signals δ: 8.20 (2ÏÏ, d,

Ho ^ aromatic), 7.60 (2ÏÏ, d, Hm aromatic), 5.55 (1H, d, J = 1.5, Hs), 5.5 - 75, (5H, m, 2CH2-PRB, Hl '), 3.86 (lïï, dd, J = 7.8, J = 1.5, H-6), 2.38 (3H, s, CH ^) and 1.50 ppm (3H, d, J = 6.3, OH ^).

Analysis for 02 ^ 21¾0 ^^:

Calculated: C, 53.0 ^; H, 3.89; N, 7.73; S, 5.90%.

Found: C, 53.05; H, 3.98; R, 7.63; s, 6.02%.

3) Acid (L'B, 5R, 6S and 1 'S,? S, 6B) -6- (1' -hydroxy-l'-ethyl) - 2-methylpénème ~ 3 ~ carboxyIique (isomer B) "- oco2 ? nb oh '———> ri y ~ cH3

C02PNB 'c ° 2H

A mixture of (R, 5R, 6S and S, 5S, 6R) - 2-methyl-6- (l '-p-nitrobenzyldioxycart) ony 1 -1' -ethyl) -penem-3-carboxylate is stirred p-nitrobenzyl (isomer B), (65 mg, 0.12 millimole), 0.05 M buffer solution of pïï 7 (1.06 equivalent), water, tetrahydrofuran and ether (10 ml, 10 ml and 25 ml) in a Parr hydrogenation apparatus in the presence of 200 mg of 30% palladium on Celite for 16 hours under a hydrogen pressure of f- 3.52 kg per cm. The catalyst is filtered off and washed with a little water * The aqueous layer is washed with ether (3 times), then it is gradually acidified with 1% aqueous hydrochloric acid in extracting it with ethyl acetate between each addition of hydrochloric acid, then saturating it with salt and extracting it completely with ethyl acetate. The ethyl acetate extracts are combined and washed with brine (5 times), then dried over magnesium sulfate. By evaporation of the solvent, a residue is obtained which is triturated in methylene chloride. 19.1 mg (71%) of the compound are obtained. The IR spectrum (nujol) includes signals for “0„ = 3500 cm “1 (0-H), 1785, 1672 cm“ 1 (0 == 0). The UY spectrum (ethanol) includes „at 260 nm (ε 3 * + 5Ό) and 309 nm TROSS.

(£ 6H-00). The 1H RM spectrum (hexadeuterodimethylsulfoxide) r * .nnrnT> P * nrl Iôo ci ο * μϊπιυ Λ envi ττα-ηΊ- a · £ CÏÎ4. flTT rî .T - 1 £ TT— cf ^ 3.88 (1Ξ, m, H-11), 1 +, 2 - 3.5 (2H, si, 0-H), 3.65 (lïï, dd, J = 6.5, J = 1.5, H-6), 2.28 (3H, s, CH3) and 1.15 ppm (3H, d, J = 6, 0H3).

Method B

1) (l'S, 3S, l + R and 1 'S, 3R ^ S) -i + -acétylthio-3- (l' -trimethyl-silyloxy-l l-ethyl) -l- (p ~ nitro'ben2yl-2t , -triphenylp] iosphorany-lidene-2ll-acetate) -2-azetidinone (isomer B).

;> H otms N r ^ Ag · TMSCl AcCl J "‘ ,, - ^ SAc TEA * C5H5N qJ—

CO „PNB CO PNB

2 2

A suspension of (l'R, 3S, l + R and 1'S, 3R, * + S) -3- (l '-hydroxy-1' - is cooled to -15 ° (with ice and metha-nol). ethyl) -1- (p-nitrobenzyl-2 "-triphenylphosphorany-f liene-2, r-acetate) -2-azetidinone-I + -thiolate silver (505 mg, 0.715 millimole), in tetrahydrofuran (25 ml) , then there is added, drop by drop, triethylamine (289 mg, 398 microliters, 2.86 millimoles), trimethyl-chlorosilane (310 mg, 362 microliters, 2.85 millimoles) and finally imidazole (50 mg, 0.73 * +. millimole), then the whole is stirred for 3 hours at -15 ° and 16 hours at room temperature. The IR spectrum of an aliquot reveals the absence of hydroxyl radicals. The mixture is cooled at -15 ° and diluted with dichloromethane (20 ml), then added pyridine (226 mg, 231 microliters, 2.86 millimoles) and acetyl chloride (168 mg, 152 microliters, 2.15 millimoles), after which the mixture is stirred for 30 minutes, diluted with ether, washed with aqueous hydrochloric acid d diluted, water, 5% aqueous sodium bicarbonate, water and brine, before drying. The solvent is removed on a rotary evaporator and the residue is purified on a gel column. silica (1:10 ratio, 3 to 10% ether in benzene) to obtain the desired compound (360 mg, 8 h, 2%) mixed with a little of the desilylated derivative (30 mg, 7.8% ). The IR spectrum (liquid layer) includes signals for \ 7 = “max 1750, 1790 cm (G = 0), 1620 cm ^ (phosphorane) and 1518 cm- · 1 · (ho2).

2) (l'fi ^ SsM-R et l'S3R ^ 8) -h-acetylthio ^ - (l'-hydroxy-l * -hydroxy-1 '-éthyl) -l- (p-nitrobenz: / l- 2n-triOhenvlpho sphorany-lidene-2n-acetate) -2-azetidinone (isomer B).

otms 9H

Λ / SAC h # X-fSAc 0ί-θΦ3 ^ θ ~ θΦ3 CO PNB co2pnb *

3 drops of trifluoroacetic acid are added to a solution of (1'R, 3S, hR and 1'S, 3R, hS) -h-acetylthio-3-ÇL '-trimethylsilyloxy-1' -ethyl) -l- (p- nitrobenzyl-2M-triphenyl-phosphoranylidene-2 "-acetate) -2-azetidinone (360 mg, 0.50 h mmol) and the mixture is stirred for 18 hours at room temperature. The mixture is diluted with acetate ethyl, then washed with water, dilute aqueous sodium bicarbonate, water and brine, after which it is dried over magnesium sulfate.

By evaporation of the solvent, 33 h mg (100%) of the desired compound are obtained. The IR spectrum (CHCl ^) includes signals for • Omax = 1755î 1090 cm-1 (0 = 0), 1620, 1605 cm ”1 (phosphorane) and 1520 cm ^ (HO ^).

3) (1Ή, 5Ε, 6Β and 1 'S, 5S, 6R) -2-methyl-6- (11-hydroxy-1 * -ethyl) penem-3-p-nitrobenzyl carboxylate (isomer B).

OH ° H

ArfSÂC '......... * - »Arrw3

T NCO GNP

CO GNP 2 2

Is heated to reflux for 7 hours, a solu ~ tion of 4l0 mg (0.638 millimole) of (l'R, 3S, 4R and l'S, 3R, 4S) - 4-acetylthio-3_ (l'-hydroxy-1'- ethyl) -l- (p-nitrobenzyl ~ 2n-triphenylphosphoranylidene - 2, <- acetate) -2-azetidinone in toluene (40 ml). The toluene is partially evaporated. The residue is passed through a column of silica gel (ratio of 1:12) which is eluted with 3%, 4% and 5% ether in benzene in order to obtain 1 ^ 1 mg (65%) of the desired compound> in the form of a white solid having a P. from l6l - l6l, 5 ° · The IR spectrum (GDC1-.) includes signals for \> = 3600, 3500 - 3400 cm (OH), 1780, 1608 cm "1 (C = 0) and 1525 cm" 1 ( HOg). The 1H RM spectrum (CDCl ^) includes the following δ signals: 8.20 (2ÏÏ, d, J = 7, Ho aromatic), 7.60 (2H, d, aromatic), 5.57 (1H, d, J = 2, H-5), 5.29 (center of qAB, J = 15, Cïïg-PÎFB), 4.2 (1H, dq., J = 7, J = 6, Hl '), 3.67 (1H, dd, J = 7, J = 2, H-6), 2.33 (3H, s, 0H3) and 1.33 ppm (3H, d, J = 6, 0H3).

Analysis for ^ pôH ^^ IÎigOgS:

Calculated: C, 52.74; H, 4.43; H, 7.69; S, 8.80%.

Found: C, 52.67; H, 4.41; N, 7.71; S, 8.96%.

* 0 Acid Cl'B, ^ R, 6S and 1'S, 5S, 6R) -6- (l'-hydro: xy-l'-ethyl) - 2-methylpénème-3 ~ “qarboxylic (isomer B).

OH OH

xco2pnb Χο ° 2η

The mixture is stirred for 210 minutes in an apparatus. hydrogenation of Parr under a hydrogen pressure of 3.16 kg per cm ^, a mixture of (E., ^ R, 6S and 1 # S, 5S, 6R) - 6- (l'-hydroxy -l'-ethyl) -2-methylpenem-3-carboxylate p-nitrobenzyl (89 mg, 0.2 ¥ + millimole), tetrahydrofuran (15 ml), water (10 ml), ether (30 ml) and a 0.05 M buffer solution of pïï 7 (5> 06 ml, 0.253 millimole) containing 250 mg of pallitized Celite at 30%. By - * continuing operations as indicated above, 32 mg (57%) of the desired compound are obtained.

EXAMPLE 37.-

Acid (l'S, 5R ^ 6R and l'R, 5S, 6S) -6- (l'-hydroxy-11-Pithyl) -2-methylpenem-3-carboxylic (isomer A).

c ° 2h 1) (Ι'δ ^ ΒΛΒ and E, 3S, IfS) -H-acetylt] iio-3-a, -methoxy-meth.oxy-11 ~ ethyl) ~ l- (p-nitrobenzyl- 2 '' - trip: iiénylp: iiospiiorany ·· * lidene-2'r - acetate) -2-azetidinone (isomer A).

och-, och3 och2och3 -¾. - V; -,

T CO.PNB

CO-PNB 2 2

With a yield of 85%, the A-isomer of H-acetyltliio-3- (l, -métlioxymét] aoxy-l'-étliyl) -l- (p-nitroï> enzyl-2 "-trip] jénylph is prepared .osp] ioranylidene-2 ,, - acetate) - ~ 2-azetidinone as described in connection with the isomer 0 of the dioxycarbonyl derivative p-nitrohenzyl. The IR spectrum (pure compound) includes signals for V = 1750 and 1690 cm " ^ (0 = 0).

) 2) (l'S ^ Ri ^ S et l'R, 3S ^ I + 5) ~ lt, ~ 'acetylthio-3 ~ (ll ~ b.ydroxy-l'-ét] iyl) - l - (p ~ nitro'benzyl-2 ,, - tripl·lénylpllosphoranylidène-2n-acetate) ^ ~ 2-azetidinone (isomer A).

och2och3 oh / <___ z / SAC> SAc Ο * —Κγ? Φ3 Ο ^^ Ύ2 ^

CO PNB CO-PNB

2

Adding the A-isomer of V-acetylthio-3 "* (11-metiioxymethoxy-" eth.yl) -l- (p-nitro'benzyl-2 "-tri-phenylpliosp] aoranylidene-2" -acetate ) -2 ~ azetidinone (500 mg, 0.68 millimole) to a 0 ° solution of 5 ° ml of trifluoroacetic acid and 10 ml of water and the mixture is stirred for 15 minutes in ice and for 3 hours at room temperature The reaction mixture is concentrated, dichloromethane is added thereto and the solution is washed with sodium bicarbonate, water and brine, then dried and concentrated to obtain 4-50 mg (96%) of the desired compound The IR spectrum (pure compound) includes signals for ^ max = 34-00 cm “1 (OH), 174-5 and 1690 cm“ 1 (C = 0).

3) (L'S, ^ R, 6R and llR-, 5S-, 6S) -6-ni-hydroxy- "ll-ethyl) -2-methylpenem-3-carboxylate u-nitrobenzyl (isomer A).

oh oh V “_- ΐτν,

CO ^ NB CO ^ PNB

Isomer A ii is prepared, with a yield of 4-5%, as described with respect to the C isomer of the p-nitrobenzyl dioxycarbonyl derivative. The 1H RMH spectrum (CDCl 4) comprises the following signals 8: 7.93 (4-III, qAB, aromatic), 5.68 (1H, d, J = 4-, 0, H-5), 5, 33 (2H, qAB, benzyl), 4-, 3 (1H, m, Ξ-1 '), 3.8 (1H, dd, J = 4-, 0, ïï-6), 2.4-1 ( 3H, s, CH ^), 2.31 (1H, s, OH) and 1.4-2 ppm (3H, d, J = 6, CH ^). The IR spectrum (CHCl ^) includes signals for. 'Ό = 3100 - 3600 cm “1 (OH), 1780 and 1710 cm“ 1 (C = Û).

10. cQC

4 ·) Acid Çl'S.5R, 6R and l'R, 5S, 6S) -6- (l .'- hydroxy-l '-éthyl) - 2-méthyjpénème-3-carboxylic (isomer A).

oh oh inô- “· - ·

CO PNB "COoH

2 z

A mixture of p-nitro-bensyl 6- (l'-hydroxy-1'-ethyl) -2-methylpenem-3-carboxylate (82 mg, 0.2 millimole), palladium celite 30% (4-00 mg), tetrahydrofuran (10 ml), ether (25 ml), water (10 ml) and buffer (0.05 M buffer, pI 75 Fisher Company No. S0- B-108) (½ ml) on hydrogenation in a Parr apparatus with agitator for * + hours under an initial near hydrogen of 3.16 kg per cm. The catalyst is filtered off on Celite and washed with water. The mixture of filtrates is washed with ether, then the aqueous layer is acidified with cold hydrochloric acid (0.25 M) and extract with ethyl acetate (5 x 10 ml). The organic extracts are combined and washed with brine, dried and concentrated. The frothy solid is triturated in ether to obtain 20 mg (hh ° / o) of a white solid. The spectrum IE (nug'ol)> includes signals for Ό = 3500 cm-’1 (OH), 1765 and 166 cm-'1 '(0 = 0). The UV spectrum (ethanol) includes λ ™ = 301 nm (ε 5922) and 260 nm (f M-280).

BXETÎPhE 38.-

Acid (E, 5Ri6S and S, 5S, 6R) -2-aminomethyl-6- (l'-hvdroxy-1 '-ethyl) penem-3- ~ oarboxylic (isomer B).

? H3

co2H

(l'R, 3S., MR et l'S, 3R, ^ S) - ^ - azeidoacetylthio-3 ~ (l '- hydro: xy- · -!' - ethyl) ~ l- (p-nitrobenzyl-2t , -triphenylphosphoranylidene-2n- acetate) -2-azetidinone (isomer B).

OH OH

^ SAg TMSCl C1C0CH2N3 dd ±) Λ -'.- | ^ SCOCH2N3 O ^ -1νΡφ3 ~ ^ ^ '* .Λ * ν ^ 3

C02PNB C02PNB

Trimethylchlorosilane (0.695 ml, 595 mg, 58 millimoles), triethylamine (0.765 ml, 555 mg, 5 ^ 9 millimoles) and imidazole (50 mg, 0, 73 ^ millimole) to a cold suspension (ice and methanol bath) of (ΙΈ, βδ, ^ Ε and 1 ^, 3 ^, ^ 8) -3- (11-hydroxy-l--éthyl) -1- (p-nitrobenzyl-2n-triphenylphosphora-nylidene-2 "-acetate) -2-azetidinone-l + -thiolate silver \ (970 mg, 1.37 millimole, obtained from 1 g of the corresponding tritylated compound) in tetrabydrofuran (! +0 ml). The mixture is stirred for 17 hours in a nitrogen atmosphere, then cooled to -15 ° (ice and methanol bath) and azidoacetyl chloride is added (^ 06 mg, 35 * + 0 millimoles) The mixture is stirred for 30 minutes while observing the progress of the reaction by thin layer chromatography. The solid is filtered off and washed with ether. The filtrate is diluted with additional ether, then washed with 1% aqueous hydrochloric acid, water, 1% aqueous sodium bicarbonate, water and brine, before drying over magnesium sulfate. After evaporation of the solvent, the residue is taken up in wet methylene chloride (50 ml) and added to the solution of trifluoroacetic acid (3 drops), observing the decomposition of the trimethylsilyl ether by thin layer chromatography. The methylene chloride solution is washed with 1% aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate. The residue is passed through a column of silica gel (8 times its weight) which is eluted with a 1: 1 mixture of benzene and ether, then ether and a 1: 1 mixture of acetate d ethyl and ether to obtain 56 5 mg (69.8%) of the desired compound. The IR spectrum includes signals for V = 3500 - 3200 cm- ^ (OH), 2100 cm ~ ^ () 1- ^), 1755, 1609 cm ^ (C = 0), 1620 - 1605 cm "*" 1 ' (phospho-rane) and 1518 cm * "'1' (R02) · (l'R, 5R, 6S and 1 'S, 5S, 6R) -2-azidomethyl-6- (l-1-hydroxy-ethyl) penemates ~ p-nitrobenzyl 3-carboxylate (isomer B).

OH

0H I

I SCQCHN x Λ .. ^ -S,

0 0 xCO GNP

co2pnb 2

Is heated under reflux for 30 minutes in a nitrogen atmosphere, a solution of (1 ^, 33, ½ and the S, 311, ^ 0) -4-azidoacetylthio-3- (l '-hydroxy-1' -ethyl) - l- (p - nitrobenzyl-2'r-triphenylphosphoranylidene-2u-acetate) - 2-azetidinone (500 mg, 0.731 millimole) in 100 ml of toluene. The solution is concentrated in vacuo and the residue is passed through a 5 S column of silica gel (which is eluted with 375 to b% ether in benzene) to obtain 193 mg, (65.1 %) of the desired compound which is a yellowish solid. The EMN spectrum of (CDCl 4) comprises the following signals 6: 8.13 (2H, aromatic Ho.), 7.52 (2H, d, Hm, aromatic), 5.59 (1H, d, J = 1, .8, H-5), 5.27 (2H, center of qAB, J = 13.5, CHn-PHB), 4-, 50 (2H, center of qAB, J = 16, CH ^ ÏT ^), ^ 15 (1H, m, H-11), 3.73 (1H, dd, J = 6.3, J = 1.8, H-6), 1.92 (lïï, d, J = h, 0 -H) and 1.33 ppm (3H, d, J = 6.3, OH ^). The IR spectrum (CHCl ^) includes signals for ^ = 2110 cm 1 (X,), 1875 "1705 cm" 1 (0 = 0) and 1250 cm "1 (H02).

Acid (R, 5R, 6S and S, 5S, 6R) -2-aminomethyl-6 - ('l 1-hydroxy-1, -étIiyl) penem-3-carboxylic (B isomer).

oh J

”'' ^ 0 ^ PNB C02H

2 44

A solution of (R, 5R, 6S and S, 5S, 6R) of azidomethyl-6- (1'-hydroxy-11-ethyl) p-nitrobenzylpenem-3-carboxylate (25 mg, 0.062) millimole) in tetra-> hydrofuran (6 ml), ether (6 ml) and water (15 ml) in a Parr hydrogenation device (150 minutes) p under hydrogen pressure of 2.81 kg per cm in the presence of 100 mg of 10% palladium on carbon. The catalyst is filtered off and washed with small volumes of water. The aqueous layer is washed with ether (3 times) and lyophilized to obtain 11 mg (73%) of the desired compound. The 1H EMU spectrum (D20) includes the following S signals: 5.75 (1H, d, J = 2, H-5), * +, 30 (1H, center of m, J = 6.5, H- l '), h, 02 (1H, dd, J = 6.5, J = 2, H-6) and 1.37 PPm (3H, d, J = 6.5, CH ^). The IR spectrum (nujol) includes signals for »max = 3,550 - 2h50 cm" 1 (0-H, NH), 1765 cm "1 (0 = 0) and 1600 cm“ 1 (C02 ©>. The U spectrum ? (H2O) includes Xmax at 309nm (ε 3,650), 255nm (£ 2,815).

EXAMPLE 39.-

Acid (R, 5R, 6S and S, 5S, 6B) -2- (M - aminobutyl) -6-1 (1 '-hydro: xyétIiyl) penem-3-carboxylic (B isomer).

COOH

(the R ,, 3S, 5B. and the S ^ R ^ HS ^^ - ^ - azidobutanoylthio) ^^! '-] iydroxyethyl) -l- (p-nitrobenzyl ~ 2n “triphenylphosphoranylidene-2tt-acetate) -2- azetidinone.

OH

/ '··· —rSAg THSC1 n3 (ch2) 4coci

J_JL TEA, Im. * C_H_N

θ '^ C = PPh3

COOPNB

H +

COOPNB

Cooled to -25 ° under a nitrogen atmosphere, a solution of (1'R, 3S, 4-R et 1 ^, 32 -, ^) - 3- (1 '-hydroxy-ethyl) -1- (p -nitrobenzyl-2 "-triphenylphophoranylidene-2n-acetate) -2-azetidinone-1h-silver tliiolate (3.03 g, H ·, 28 millimoles) in dry tetrahydrofuran (55 ml) and successively added triethylamine (2.39 ml, 17.12 mmol), trimethylchlorosilane (2.18 ml, 17.12 mmol) and imidazole (0.1 g, 1, ^ - 7 mmol). The reaction mixture is stirred at -25 ° for 15 minutes, then the cooling bath is removed and the reaction is carried out at 0 ° and diluted with methylene chloride (55 ml), then py-ridine (0.73 ml, 9.0 millimoles) and a solution of h-aminobutanoyl chloride (1.36 g, 8.56 millimoles) in methylene chloride (10 ml) The reaction mixture is stirred at 0 ° for 1 hour, then the filter on Celite. The Gelite is washed with methylene chloride (25 ml), then the filtrates and washing liquors are combined diluted with 300 ml of ethyl acetate. The organic solution is washed with 1% hydrochloric acid solution, water, saturated sodium bicarbonate solution and water, after which it is dried over · anhydrous magnesium sulfate and concentrated on a rotary evaporator to obtain 3.83 g of an orange syrup. The syrup is dissolved in methylene chloride (75 ml) and water (k ml) and trifluoroacetic acid (0.2 ml) are added to the solution, then the reaction mixture is stirred at 23 ° for 90 minutes, it is washed with sodium bicarbonate and water, dried over anhydrous sodium sulphate and concentrated to obtain 3.5 g of an orange syrup.

The syrup is purified by chromatography on a column of silica gel G 60 (80 g) which is eluted with 10% to 75% of ethyl acetate in methylene chloride. By evaporation of the appropriate fractions, 2.1½ g (67%) of an oil are obtained.

Analysis for:

Calculated: C, 61.23; H, 5.00; N, 9.65; S, h, h2%.

Proven: G, 61, 17; H, 5.10; N, 10.02; S, 3.71%.

fl'R, 5R.6S and S, 5S, 6R) -2- (<5 -azidobutyl) -6- (1'-hydroxyethyl) p-nitrobenzyl 3-carboxylate.

° H O 9H

Ar - / “1“! ’* Δ ^ '- r — rs \ JJ Toluène’ * Ç = PPh3 COOPN3

COOPNB

Is heated under reflux for 9 hours in a nitrogen atmosphere, a solution of (E, 3S, te etl'S ^ H ^ S ^ V- ^ tS-azido-butanoylthio) -3- (1 '-hydroxy-1' -ethyl) - l- (p-nitrobenzyl-2, t-triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (2.0½ g, 2.81 millimoles) in a 30: 1 mixture of toluene and methylene chloride (310 ml), after removing the methylene chloride at the start of the reflux heating, the reaction mixture is cooled to 23 ° and the toluene i is removed in vacuo to give an orange residue which is purified by chromatography on a silica gel column G 60 (b-5 g which is eluted with ether in petroleum ether in a ratio of 1: 1 to 9: 1) · Combine the appropriate fractions and concentrates them to obtain a syrup which is crystallized from a mixture of ether and petroleum ether to obtain 0 ¥ t3 g (35.2%) of the compound melting at 85 °.

Analysis for C19Ï21% 06S:

Calculated: C, 51.00; H, b, 7 ^; H, 15.65; S, 7.17%.

Found: C, £ L, 05; H, 86; H, 15.86; S, 8.19%.

Cyclization is carried out on the fractions corresponding to the unchanged starting compound, operating as described above so as to obtain a supplement (0.276 .g, 21.9%) of the desired compound. The Iß spectrum includes signals for Ό = 2100 cm-1 (ÏL), 1770 cm-1 (C = 0, ß-lactam) and 170 ^ cm ^ (0 = 0, PNB ester). The ÜV spectrum (H ^ O, 23 °) includes, at 268 nm (£ 13757) and 316 nm (£ 9826). The EM spectrum of 1ïï (CDCl ^) includes the following signals: 1.36 (d,% _2 "-Η-1" = 6.3 Hz, 3H, methyl), 1.52 - 1.77 (m, hH, H-2 ·, H-3 '), 2.57 - 3.00 (m, 2H, H-h'), 3.00 - 3, h2 (m, 2H, H-l '), 3 , 72 (dd, = 6 Hz, Jg_5_g_pn = 6, h Hz, H-6), h, 02 - h, h2 (m, 1H, H-1, T), 5.32 (qAB, Ja_b = 13, 16 Hz, 2H, 0¾ PNB ester)., 5.60 (d,.% _ £ _Η_6 = 1.6 Hz, 1H, H-5), 7.61 (d, = 8.8 Hz, 2H, Hm ester PÏÏB) and 8.21 ppm (d, JH 2 ^ = 8.8 Hz, 2H, Ho ester PIB).

Acid (1 Έ, 5R, 6S. And l'S, 5S, 6R) -2- (h-aminobutyl) -6- (l'-hydroxyethyl) penem-3-carbo: xylic. .

OH

OH s Λρ-ν - »Τχν ^ Λ J — N2 4 3 D®- And O, H O 0 ^ ~

0 z z> COOH

1 COOPNB

Ether (50 ml), water (50 ml) and 10% palladium on carbon (0.5 h g) are added to a solution of (E, 5E, 6S and 1'S, 5S, 65 ) -2- (δ -azidohutyl) -6- (1'-hydro-xyethyl) p-nitrohenzyl penem-3-carboxylate (0.5 h g, 1.21 mmol) in 50 ml of dimethoxyethane. The reaction mixture is hydrogenated under a hydrogen pressure of 3.16 kg per cm at 23 ° for 3 hours. The reaction mixture is filtered through Celite and the filtrate is diluted with ether. The aqueous phase is evaporated, washed with ether and lyophilized. The crude sought compound is purified by high pressure liquid chromatography. The IR spectrum (KBr) includes signals for Ό = 1760 cm ^ (C = 0, ß-lactam) and 1565 cm ^ (C = 0, carboxylate). The RM spectrum of ^ H (H ,, 0) comprises the following signals ô: 1.32 (d, JCÏÏ -Hl "= 6'h Hz '3H' CH3 ^» ^ H-11, H-3 '), 2.50 - 3.20 (m, 4-H, Hl, H-4 · '), 3.8 ** (dd, = 6'1 ïïz' JH-6-H-5 = 1 ”1 * · Ïïz> J “ïï 'H“ 6)' ^ 00 "W '(m, 1H, Hl”). and 5.62 ppm (d, JH _ ^ _ H_6 = 1.4- Hz, 1H, H ~ 5).

The UV spectrum (H2O) includes λ at 260 nm (6 4-24-0), 302 nm (& 54-80).

EXAMPLE 4-0.-

Acid (1îtR, 5R, 6S and l'S, 5S, 6R) -2 -. (Trans-3 '-amino-l' -cyclohutyl) - 6- (l, LIiydroxy-l ,, - ethyl) penem-3-car 'boxylic (isomer B).

__at---. oh oi-N / - \ / * \: ooh (ltiR, 3S <4-R and l ”S, 3R ^ 4-S) -4" - (trans-3 '-azidocyclohutaiioylthio) -3-Cl, I- liydroxy-llt-et] iyl) -1-Cp-nitro'benzyl-21 * 1 -triphenylpho sphora-nylidene-2t11-acetate) -2-azetidinone.

A ._ / SAg Cl ^ - <^> "" N + ^ '1-f TMSCl ^ 3 __H_ f N / 3 1 A TEA, Im C H- * 2 °> “N \ cr ^ C-PPh 55 - ^ Ç = PPh_ _ 1 3 1 3

COOPNB COOPNB

Cooled to -4-0 ° -a solution of (l'R, 3S, 4-R and 1 'S, 3R, 4-S) -3- (l' -hydro: xyethyl) -l- (p- nitrobenzyl-2 ,, - triphenyl-phosphoranylidene-2 "-acetate) -2-azetidinone-4-silver thiolate (1.01 g, 1, ¾ millimole) in dry tetrahydrofuran (25 ml), operating in an atmosphere of nitrogen and successively adding triethylamine (0.80 ml, 5.74 mmol), trimethylchlorosilane (0.726 ml, 5.72 mmol) and imidazole (0.10 g, 1 , 4-7 millimole) The reaction mixture is warmed to -15 ° and stirred for 3 hours, then the "cooling bath is removed and stirring is continued for 18 hours. The reaction mixture is cooled to -15 ° and diluted with methylene chloride (25 ml), followed by addition of pyridine (0.15 ml, 1.85 mmol) and trans-3 chloride -azido-cyclohutanoyl (0.27 ^ g, 1.72 millimole). The cooling bath is removed and the solution is stirred for 1 hour, then pyridine (0.15 ml, 1.85 millimole) and trans-3-azidocyclobutanoyl chloride (0.27 * + g, are added thereto. 1.72 mmol) The reaction mixture is stirred at 23 ° for 1 hour, then filtered through Celite, the filtrate is diluted with ethyl acetate (100 ml) and washed with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and water, after which it is dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator to obtain 1. ^ 7 g of an orange syrup 1. Water (2 ml) and trifluoroacetic acid (0.2 ml) are added to a solution of the syrup in methylene chloride (50 ml). the reaction mixture is stirred at 23 ° for 2 hours, washed with saturated sodium bicarbonate solution, then with water, then dried over anhydrous sodium sulfate and concentrated to obtain an orange syrup (1.1 g).

The syrup is purified by chromatography on a column of silica gel 60 (20 g, which is eluted with a mixture of ethyl acetate and ether in a proportion of 35% up to 70%). By evaporation of the appropriate fractions, 0.77 g (75-, ½%) of the desired compound is obtained, which is an oil. The IR spectrum (pure compound) includes signals for \) = 3 ¥ * 0 cnT1 (OH), 2100 cm “1 (H3), 1755 cm-1 (C = 0, ß-lactam), 1735 cm“ 1 (0 = 0), 1680 cm “1 (0 = 0) and 1625 cm“ 1 (aromatic).

(l, rR,, 6S and lnS., 5S, 6R) -2 ~ ('trans-3 l- ~ azidocyclol ^ utyl) - 6- (lτt-] lytiroxy-I ,, - ethyl) peIleme ~ 3wcarl30xylate p -nitrobenzyl.

COOPN ^ COOPNB

Dilute with 300 ml of toluene a solution of (1 "R, 3S, ½ and l ,, 3.3R, 1 + S) -Li— (trans-3'-a2; idocyclo'buta-noylthio) -3- (l "“ hydroxy-ln-ethyl) -1- (p-nitrobenzyl-21 'triphenylphosphoranylidene-2' '' -acetate) -2-azetidinone (2.27 g, 3.1½ millimoles) in chloroform (4- 0 ml) and the mixture is heated at reflux for 6 hours in a nitrogen atmosphere. The first 60 ml of distillate (chloroform f and toluene) are separated using a Dean & 'Stark trap. The reaction mixture is cooled to 23 ° and the solvent is evaporated off under reduced pressure to obtain an orange syrup which is purified by chromatography on a column of silica gel 60 (35 g) which is eluted with a mixture of ether and benzene in proportion from 0 up to 6%.

By evaporation of the suitable fractions, 0.39 g (27.3%) of the desired compound is obtained having a P.P. of 13½ - 135 °.

Analysis for ° 19W6S:

Calculated: C, £ L, 2b; H, ^, 30; H, 15.73; S, 7.20%.

Found: C, 50.98; H, 20; h, 15.83; S, 7.10%.

IR spectrum (KBr) includes signals for = 2110 cm “1 (H ^), 1765 cm“ 1 (0 = 0, ß-lactam), 1690 cm “1 (C = 0, PKB ester), 1510 cm” 1 (M> 2) and 1355 cm 1 (ÎJ02).

The RM spectrum of% (CDCl ^) includes the following S signals: 1.36 fd. ...... = 6.3 Hz, 3H, CH.), 2.0 - 2.75 (m, 4-H, H-2 ', H-4'), 3.67 (dd,% _6_Η_5 = 1.5 Hz,

Jh_6-H-1 "= 6> 5 Hz, 1H, H-6), 3.8 - 4.55 (m, 3H, H-l ', H-3' and Hl"), 5.30 (qAB , = 13.6 Hz, 2H, CH2-Ph-N02), 5.60 (d, Jïï_5_ïï_6 = 1.5 Hz, 1H, ïï-5), 7.59 (d, = 8.8 Hz, 2Ξ, Hm of PNB) and 8.20 (d, = 8.8 Hz, 2H, Ho of PNB). The UV spectrum (CHCl ^, 23 °) includes Xmay = 266 nm (ε 13050) and 322 nm (ε 10008 The unchanged phosphorane is collected as a mixture with triphenylphosphine oxide and cyclized as described above to obtain an additional 0.14-5 g (10.4%) of the desired compound, the total yield being 37.1 ° / ° ·

Acid (1 "B, 5H, 6S and 1" S, 5S, 6R) -2- (trans-3'-amino-l'-cyclohutyl) -6- (1>, - hydroxyethyl) penem-3-car ' boxylic.

10% .Pâ / c_► ^ v / y, .K2 J_3 DME, ether, HgO \ /

f '^' COOPNB C00H

4-0 ml of ether and 0.33 g of 10% palladium on carbon are added to a solution of (1 "R, 5P, 6S and 1" S, 5S, 6R) - 2- (trans-3'- azidocyclobutyl) -6- (1 "-hydroxyethyl) peneme-3 ~ p-nitrobenzyl carboxylate (0.33 g, 0.74 millimole) in 40 ml of dimethoxyethane. The reaction mixture is hydrogenated under hydrogen pressure of 3.16 kg per cm for 3 hours, then it is filtered through Oelite, the Celite is washed with water, the filtrate and the washing water are mixed and the mixture is diluted to 1 ether The aqueous phase is separated and washed with ether and lyophilized

to obtain 0.20 g (95%) of the compound whose UV spectrum

(H „0, 23 °) comprises X at- 258 nm (€. 2725) and 306 nm (ε 3613) · The crude product is triturated in water, then the white solid is collected by filtration and dry in the presence of phosphorus pentoxide under high vacuum for 5 hours to isolate 8h mg (b0%) of the desired compound. The EMU spectrum of (D ^ O) includes the following S signals: 1.3½ (d, ^ H_2n-H-ln == Hz, 3H, ïï-2 "), 2.3 - 2.7 O, hH, H-2 ', H-h'), 3.90 (dd, Jïï_6_ïï ^ = 1.5 Hz, ^ H — 6 — H — 11 '- 6.1 Hz, 1H, H — 6) and 5.68 (d, Jg_ = 1.5 Hz, 1H, H-5) · The UV spectrum (Η "0.23 °) includes λ at 258 nm (E H-738) and 306 nm (£ 6318). the filtrate by high pressure liquid chromatography, 58 mg of the compound are obtained, the TJV spectrum (B ^ O, 23 °) of which includes at 257 nm (£ 3580) and 306 nm (£ 5033) · EXAMPLE hl.-

By applying the general procedure of Example 3h, the 2,6-disubstituted penemes below can be prepared using the electrophilic reagents indicated.

i Electrophilic reagent Product tC / · “3 co ^.

R = CH3I .CH3 “CH3CH20SO2 - ^^^ - CH3 CH3CH2 ~ CH3CH2CH20S02- ^ ~~ ^ -CH3 CH3CH2CH2- CH2 = CH-CH2-Br CH ^ CHCH, - HC = C-CH2Br HC-CCH2 O— \> - \

Br Electrophilic reagent R = rp-O- O- 0CH2Br 0CH2-

JL - Br J \ ^ pJ

N / V CH3 / Γλ / v.

0ch2ch2ch2oso2 - ^ / \ Vch3 0 ^^^ \ 0CH = CHCH2Br 0C = CCH2Br 0C = CCH2- X / "" 31

Br CH3CH-CH3> v

If CH3QCH2C1 CH3OCH2- (a) CH3SCH2C1 CH3SCH2- ^ α. o - CH30CH2CH2C1 CH3OCH2CH2- CH3SCH2CH2C1 CK3SCH2CH2- ^ HCHO HOCH2 ~ w 0 0 _ tt (a) can be oxidized to CH ^ SCH2- and CH ^ SGH ^ - 0 0 t (b) can be oxidized to GÏÏ ^ SGH ^ GH ^ - and CH ^ SC ^ CH ^ CH ^ - 0 ^, Il

{cj hydroxide radical protected in form -C-OPRB

Electrophilic reagent R =

0H

ch3ch2cho ch3ch2ch- ® / \ HOCH2CH2- ®

OH

/ \ / ° CH3CH-CH2- ® / \ hsch2ch2- ® ®

5 SH

Λ / CH3CH-CH2 ~ ® ©

Cr CT

0OCH2C1 0OCH - 0CH2OCH2C1 0CH2OCH2- 0OCH2CH2C1 0OCH CH2- 0CH2OCH2CH2C1 0CH2OCH2CH2- 0SCH2C1 0SCH2 "g 0CH2SCH2C1 0CH2SCH2- 0SCH2CH2C1 0SCH2CH2- ® ® ® 0CH2SCH2CH2C1 0CH2SCH2CH2-

O OH

0 ^ Cl 0—1 ©, ® 0 ®ll

SH radical protected in -C-O-PHB form

© can be oxidized to HO ^ SCH ^ CH ^ - © can be oxidized to GE ^ OH-GHg- 0 so3h: © can be oxidized to 0SCH2 and 0SO2CÏÏ2- 0 (h ^ can be oxidized to 0CH2SCH2 “and 0CH2SO2CH2 ~ 0 ( T) can be oxidized to 0SCH2CH- and 0SO2CH2CH2- Electrophilic reagent R _

.S

‘I © ©

SH

„OH _ 0CH2CHO 0 \ ©

OH

0CH = CH-CHO 0 © CH3CH2C ° 2CH3 CH3CH2C- 0 ^ X ^ ci

O

s s 11 11 CH3C-SC2H5

O

0CO2CH3 0 © can be oxidized to S03h Electrophilic reagent r = o

HE

m nt fi- * î o ^ s'VXSsvx ^ Ns LJ 0 o 0CH = CHCO2CH3 0 ^^^^

OH

I <c) 0C = C-CHO 0C = C-CH- ^ 0

II

0CHC-CO2CH3 0C = C-C-

SH

f 0CHS 0 V '' ^ N'S '©

OH

’© 0 0 0. 0 Λ- “0

One - US

Of '· 1 [jU

Electrophilic reagent R = UC 'ÛT'

Uw lT- ûc ôf- ûr

Oo ^ ”Cc> ^ r fY'- en ^ 00 ^" K oc? ^ O o

H H

C2H50C-C1 C2H5OC- o o

11 II

C2H5OCCH2Br C2H5 ° C

n = c-ch2ci Electrophilic reagent _ £ - 0 fch2ch2co2ch3 f 02N-CH2C1 honh s- \ y- OCH2Cl -

O

. ί * Η, Ο, Ρ ^^ (PNB-0) 2P 2 3 NH2 CH3CHO Φ ® © OH ° f Γ * ^ Χ_ ^ 3ΤΓ / tr ^ S— (φ by la ->.; -> <^ / A 1 g \ 0 If ^ / 0 'yt

NHCO-PNB

\ ___ ch as in the example- <J_N3 ^ pie 58 g- \ \ o2h CH, 1 ^

mw N-CO-PNB

NH2 NHCH3 J 2 @ similarly, C / >>, - Λ ~ "f g l 0 ^ 0.

l · 1 / NHCH3 tQ- “· OR j 0 \; co2h NH_ .X ”(CS,), (- ^ —i - ^ ^ A - ^ \ é ~ 'i_ | J ^ Lr“ “3 Ο K Ο Λ.

co2h or * ®2 nhcoch3 nhcoch3 or 'ΝΗ2 NHCONHR î®0 ™ "l (- ^"] {\ ~ Χ * Υ-α3 14 <Μ

ο ο XC02H

R = Η, CH3, ch3co-

OR

ΝΗ2 nhco2c2h5 nhco2c2h5 X? t <? <° \ o2h © De mene,

OCOCH OCOCH

° H I J 3 / k —ΑΤΓ —r A — r ^ \ I - ^ 1 / ~ ch3

i -% / J — i o ^ -NA

° fXY C02H

OR

ΠΜ OCONHCH OCONHCH,

A-r "Λ-4 A_A

a, - q "" ji} · "'O if O K ° \ / y co2h or

N-N

N he

OH 0MS CH ASH

A_ATr 1 s- <CH- x —s _ ^ j if 3 J- / S / Ά ^ ϊ

Ο ς T 'P? I

/ Sly 0ζ ^ O ’l · .XJ"

Va ψ * Electrophilic reagent ÇRR 'R RI - UC „0CH, CHO' '3 <D ® ® IR, R *» H, CH, RR'N G% CH30C1 CH3 ° - EMPIE k2. ~ (Ι'Β, & , βΒ and ΙΈ, 5S, 6R) -6- (1 '-acetoxy-l' -ét3iyl) -2-methylpénème ~ 3 - gT-trimethylsilylethyl carT30xylate (C isomer).

OAc

I H H

'"tTV * co2 / ^ = i- 3" (1'-Hydroxy-l l-éth.yi) -l- (g-trimethylsilylétIiyl-2 ”-tri ~ phenylpho sphoranyli dene-211 -ac ty) -H — tri tyl thi o-2 ~ azetidinone “_ ^ STr STr I 1 1) LPA? Me - [. 21 CH3CH0 ”T ~> SiMe ° ^ .SiMe_ 3 io 3 2 2

With stirring, n-tutyllitliium (1.3 ml, 2.0 millimoles) is added to a solution of diisopropylamine mtr. 1 .Rl + m-î 1 Ήτηηΐ a ") rinris fin tét'ra'h Vfirnfn / PAnn a (5 ml) at -78 °. After 5 minutes, a solution is added dropwise with stirring over 20 minutes. l- (p-trimethylsilylethyl) -2 '-triphenylphosphoranylidene-' 2'-acetate) -lf-tritylt] aio-2-azetidinone (1.27 g, 1.67 millimole) in tetrahydrofuran (15 ml). minutes, 1 ml of freshly distilled acetaldehyde is added and the solution is stirred for 5 minutes, hydrochloric acid (12.6 ml, 0.3 M) is added and the mixture is allowed to warm to 23 °. add water (20 ml) and ethyl acetate (20 ml), then stir the mixture and separate the phases The organic phase is washed with water (20 ml) and chloride of saturated sodium (20 ml), then it is dried and the solvent is evaporated under vacuum to obtain 1.37 g of the crude product, which is absorbed from a solution in methylene chloride over 7 g of silica gel which is deposited dry on a column of 28 g of silica gel. lonne with ether (100 ml), then a 1: 1 mixture of ether and ethyl acetate (50 ml).

The first 20 ml eluted are discarded. The following fractions are recombined and the solvent is evaporated under vacuum to obtain 1.03 g of a product which is absorbed from a solution in ether on a column of 50 g of silica gel (wet ). The column is eluted with ether (680 ml), then with ethyl acetate (200 ml). The subsequent fractions are recombined (strong spot of weak Rf on thin layer chromatography) and the solvent is evaporated under vacuum to obtain Hh-0 mg (33%) of the sought compound, partially purified. The IR spectrum includes signals for = 3 ^ 00 cm ^ (OH) and 1750 cm ^ (ß-lactam and ester). The RM spectrum of (CHCl ^) is insufficiently resolved to identify other peaks than those due to the aromatic radicals and to the trimethylsilyl radical.

3- (11-Hydroxy-1 l-ethyl) -l- (P ~ -trimét] gylsilyléthyl-2tt-triphé-nylpb.osphoraiiylidène-2tI-acetate) -2-azétidinone-1 + -thi olate d1 argent.

OH OH

Me ^ δΤΓ AgNO / pyridine ^ Me ^ - ^ Ag J — N JPPh J — N PPt, 0 T A ^ 1Me3 0 Ύ io2 co2

A solution of silver nitrate (b2 $ mg, 2.5 millimoles) and pyridine (79 mg, 1.0 millimoles) in water (10 ml) is added to a solution of the above compound (* f03 mg, 0.50 millimole) in ether (10 ml). The mixture is stirred vigorously for 1 hour. The precipitate is separated by filtration and washed with water and ether to obtain 267 mg (80%) of the desired mercaptide. The IR spectrum includes signals for = 3 * + 00 cm 1 (OH) and 1750 cm (ß-lactam and ester).

* en-Acetylthio-3 ~ (11-acetoxy-1'-ethyl) -l- (p-trimethylsilylethyl-2n-triphenylphosphoranylidene-2 ”-acetate) -2-azetidinone.

oh? Ac SÂc

-✓SAS AcCX / pyridine -S

2 2

A solution of acetyl chloride (70 mg, 0.88 millimole) in methylene chloride (1 ml) is added dropwise to a solution of the above silver mercaptide (267 mg, 0, ^ 0 millimole) and pyri-dine (70 mg, 0.88 millimole) in methylene chloride (£ ml ^ to Π0. End nui-hp 1 P τηρίηησα at 0 ° npnrinrrh QO τηιτιιτΗρρ.

then at 23 ° for 15 minutes. The precipitate is separated by filtration and the solution is washed with 0.1 M hydrochloric acid (10 ml) and 0.1 H sodium bicarbonate (10 ml). The solvent is evaporated in vacuo to obtain 153 mg (59%) of the desired compound. The IR spectrum includes signals for ^ Tnax = 3 ^ 5 ° cm 1 (OH), 1750 cm ™ 1 (ß-lactam and ester) and 1690 cm (thioester). The H NMR spectrum (GDCl ^) includes the following signals δ: 7.5 “8.2 (m, 15H, Pii), 5.85 (si, 1H, H - **), 3.0 - 5, 0 (unresolved, ΛΗ, OCÏÏ, 0CH2, H-3), 2.0 - 2.6 (3 singlets, 6H, OAc, SAc), 0.9 - 1.7 (m, 5H, CH ^, Cïï2Si ) and 0.20 ppm (s, 9H, SiMe ^. (l'S, 5R-.6S et l'R, 58 ^ 6iR) ^ 6- (ll-acetoxy-ll-ethyl) “2-methyl-penene-3 β-trimethylsilylethylcarboxylate (0 isomer).

_ OAc h ts "'" rT —i— »~ rw. J- · K * ™ 1 * / -N-f ^ .SiMe3 X2 ^ "" * 3

A solution of the above phosphorane (150 mg, 0.23 millimole) in toluene (15 ml) is heated at reflux for 2 hours. The solution is mixed with 1 g of silica gel and the solvent is evaporated under vacuum. This silica is deposited on a column of H · g of silica gel (dry) which is eluted with ether. The first fraction of 5 ml (single spot of Rf high on thin layer chromatography) gives by evaporation of the solvent 65 mg (76%) of the desired compound which is a waxy solid. The IR spectrum includes signals for "0 = 1790 cm 1 (ß-lactam), 17 * + 0 cm ™ 1 (ester) and 1700 cm 1 (OAc). The 1 H NMR spectrum (CDCl ^) includes signals < 5 following: 5.6 (d, J = 2 Hz, 1H, H-5), <k 1 TT TT — .1 “h. T (m on ηηττ T ί on (n .T - O TT * 7: ^ Hz, 1H, H-7), 2.37 (S, 3H, 2-CH3), 2.11. (S, 3H, OAc), 1H-2 (d, J = 6.5 Hz, 3H, 2'-CH3), 1.1 (m, 2H, CHgSi) and 0.05 ppm (s, 9H, SiMe3) This compound appears to be a single isomer.

EXAMPLE * 4-3.-

Acid (L'P, 5R? 6S and 13S, 53,6R) -6- (l'-amino-l'-ethyl) - ^ - methylpénème-3-carboxylic.

\ X-Î ^ ”ch 3

b02H

Method A

(1Ή, 35ΛΗ and 1 ^, 3 ^, ^) - 3- (1 '-azido-l'-ethyl) -1-Çp-nitro- * henzyl-2n-triphenylpho sphoranylidene-2ff-acetate) -M — tri -tylthio-2-azetidinQne (isomer B).

! ^ JL · * 0 *, <τ “Η · γ> · ρφ3 <x ~ ύ * 3

C02PNB CO ^ NB

The mixture is heated at 85 ° for 7 hours in the presence of sodium azide (1.75 S? 27.0 millimoles), a solution of (1 'S ^ Sj ^ R and the R ^^ H ^^ - ^ - n ^ thanesulfonyloxy-l'-ethyl) -l- (p-nitrohenzyl-2n-triphenylphosphoranylidene-2, lr-acetate) -1fH; ritylthio-2-azetidinone (isomer C) (12.36 g, 13, ½ millimoles) in hexamethylphosphorotriamide containing 10% water (135 ml). The solution is poured into cold water (1000 ml) and the reaction product which crystallizes is collected by filtration. By redissolving in methylene chloride, then washing with brine and drying over magnesium sulfate, 11.5 g (98.9%) of the azidophosphorane which is a yellow frothy material are obtained, after evaporation of the solvent. . We use it as: guel in the next stage. The IR spectrum (CÏCl1) comprises signals; for max = 2100 cm 1 (ΐΓ ^), 175-0 and 1610 cm "1 (0 = 0).

(l'R, 38,5-R and l'S, 3R, 5-S) -5-acetylthio-3- (l'-azido-l, -éthyl) - 1- (p-nitrobenzyl-2 "-triphenylphosphoranylidene- 2 "-acetate) - 2- azetidinone (isomer B).

j. ] Αγ *** 3 / -γ3 “" ο1- ”ΎΡΦ3

CO ^ PNB C02PNB C02PNB

[! A solution of mercuric acetate (2.12 g, 6.66 millimoles) in methanol (30 ml) is added to 1 d, solution cooled to 5 ° from (R, 38.5¾ and 1 'S, 3R , 5-S) -3 ~ (1 '-azido-l' -éthyl) -l- (p-nitrobenzyl-2 "-triphenylphospho-ranylidene-2" -acetate) -5-tritylthio-2-azetidinone (8, 9 g,.

10.25 millimoles) in dichloromethane (30 ml). After stirring at 5 ° for 30 minutes and at room temperature for 90 minutes, the product is evaporated. solvent and the crude mercury salt is redissolved in dichloromethane, then the solution is washed with dilute sodium bicarbonate and brine. After drying over magnesium sulfate, the solution is cooled to 5 ° and pyridine (1.66 g, 21 millimoles) is added directly thereto and, dropwise, acetyl chloride (1.65 g, 21 millimoles). The reaction mixture is stirred at 5 ° for 1 hour. The precipitated mercuric chloride is filtered off and the filtrate is washed successively with acid. V "" l / -x-rVU-tr / ^ -r * -î nn a rin 1 nû rhi bi no -ρΉηη a -ho Hû ολΗπ π τη o * h Hô 1 Λ brine The organic solution is then saturated with (5) hydrogen sulphide to precipitate the resulting mercuric impurities in the form of sea-curic sulphide. After evaporation of the solvent, the thioester hrut is purified on a column of silica gel (8.5 cm × 9 cm) than eluted with dichloromethane (500 ml) and 15% acetonitrile in dichloromethane to collect 5.1 g (7 ^, 6%) of the desired compound. The spectrum ΕΜΓ of (CDCl 4) comprises the following signals S: 3.70 (III, m, H-1), 2.98 (1H, m, H-3), 2.33 and 2.20 .QH, 2s, acetyl), 1.28 (3H, d, J = 6 , 2 Hz-, H-2 '). The spectrum IE (CHCl ^) includes signals for = 2115 cm 1 (M ^), 1758, 1693 cm "1 and 1620 cm" 1 (C = 0).

(E, 5H, 6S and S, 5S, 6E) -6- (1-azido-l'-ethylj ^ -methyl-penème ^ -carboxylate p-nitrobenzyl (isomer B).

y "'' N, .........- - - -..

N | 3

Jr jscoch —s, 'jo ΡΦ3 - JI / “3

0 ^ 'Ύ' 3 0 1302PNB

C02PNB

Is heated under reflux for 2 hours, in a nitrogen atmosphere, a solution of (E, 5E, 6S and S, 5S, 6E) -I + -acetylthio-2- (l '-azido-1' -ethyl) -1- (p-nitrohenzyl-2M-tri-phenylphosphoranylidene-2ft-acetate) -2-azetidinone (5.1 g, 13.1 millimoles) in toluene (100 ml). The solvent is evaporated off and the reaction mixture is purified by chromatography on a column of silica gel (7 cm × 5 cm).

The azidopenem is eluted with dichloromethane (continuing the elution with 10% ether in dichloromethane, 1.82 g of unreacted phosphorane is collected), rinmi nTrhorri T> 1 Q ~ \ 0 * onirmnoa -PfN-nrlο "+ - to - 1 ^ Ll-0.

η

The EM spectrum of H (CDCl 4) comprises the following signals S: 8.21 (2H, d, aromatic Hm), 7.60 (2H, d, aromatic Ho), 5.51 (LH, d, J = 1 , 6 Hz, H-5), 5.33 (2H, qAb, H-benzyl), 3.92 (1H, dq, J = 8, 6.4- Hz, H-1), 3.67 ( 1H, dd, J = 1.6, 8 Hz, H-6), 2.37 (3H, s, 0 ^), l, 4-6 (3H, d, J = 6.4- Hz, H- 2 ') · The IR spectrum (CDCl ^) includes signals for = 2123 cm 1 (N ^), 1788 and 1712 cm "1 (0 = 0).

Acid (l'R, 5R, 6S and l'S, 5S, 6R) -6- (l'-amino-11-ethyl) -2-methylpenem-1-carboxylic (B isomer).

N3 T2 '

NCO PNB CO H

Z 0

Hydrogenation is carried out for 1 hour at a pressure of f 2 ^ 3.52 kg per cm in the presence of palladium on carbon at 10! $ (4-4-0 mg) ', a solution of (l'R, 5R, 6S and l'S , 5S, 6R) -6- (1'-azido-l'-ethyl) -2-methylpenem-3-p-ni-trobenzylcarboxylate (4r4-0 mg, 1.13 millimole) in a 1: 1 mixture : 1 of tetrahydrofuran, ether and water (120 ml). The catalyst is filtered off, the filtrate is extracted with ether and the aqueous phase is lyophilized. The crude amino acid (100 mg) is purified by high pressure liquid chromatography to obtain 19.5 mg of the desired compound. The RMH spectrum of ^ H (D ^ O) includes the following signals: 5.69 (1H, d, J = 0.9 Hz, H-5), 3.94 · (2H, m, H-6, H-1 '), 2.28 (3H, s, CH ^), 1.50 (3H, d, J = 6.4- Hz, H-2'). The IR spectrum (nu {pretty) includes signals for "0 = 1767, 1576 cm" 1 (0 = 0). The UV spectrum (H2O) includes an X at 300 ™ f t 1326 ^.

Method B

(1'R, 3S, H-S et l'S, 3ΗΛβ) -3- (11 -azido-1'-ethyl) -H-trityl-thio-2-azetidinone (B isomer).

- · ^ c ·

If CCH) H

\ * t-Bu

Heated at 75 ~ 80 ° for 3 hours, in a nitrogen atmosphere, a solution of (l'S, 3S, HR and l'R, 3R, H * S) - l- (t-butyldimethylsilyl) -3 ”(l '-methane tallow onyloxy-1' -ethyl) -H- tritylthio-2-azetidinone (isomer C) (1.75 g, 3 millimoles) and sodium azide (0.39 g, 6 millimoles) in l 'hexa-methylpho sphorotriami.de containing 10% water (15 ml). The reaction mixture is then diluted with ethyl acetate k and washed several times with brine. The organic phase is dried over magnesium sulfate and evaporated to obtain an oil which spontaneously crystallizes.

By trituration in ether and filtration, 951 mg (76.5%) of the azide compound are collected, which is a white solid having a m.p. of 185-190 ° with decomposition. The RMH spectrum of ^ ïï (CDCl ^) includes the following signals 6: 7.23 - 7.78 (15H, m, aromatic), Η-, Η-3 (1H, d, J = 3, HH ·), H-, 37 (1H, s, HH), 3.89 (1H, dq, J = 7, 6.5, H-l '), 3.16 (1H, dd, J = 7, 3, H- 3), 1.50 (3H, d, J = 6.5, H-2 '). The IR spectrum (CHC1-,) includes signals for a) = 3H-10 cm "1 (H-H), 2123 cm" 1 (^) and 1765 cm "1 (0 = 0).

1 's, 3R Λβ) -3 - ί 11 -amino -1' -ethyl) - ^ - trityl- ^ Î? ~ ^^ aZ4ticLinoD.e (isomer B).

N ΨΗ2 SCcJ) 'V “* 1 - ^

cA- ^ h. 0 VtI

Hydrogenation is carried out for 1 hour under a pressure of 3 5 ^ 2 kg per em ^, a suspension of (ΙΈ ^ β, ^ Ε and the S ^ Bj ^ S) - 3- (l'-azido-1, -éth.yl ) -M — tritylth.io-2-azetidinone (isomer B), (1, ° g, 2, hi millimoles) and platinum oxide (100 mg) in ethyl acetate (100 ml). Since the reaction is incomplete, an additional 200 mg of platinum oxide is added and the hydrogenation is continued for 1 hour, finally, another 200 mg of platinum oxide is added and the reaction is continued for a further 150 minutes. The total quantity of catalyst is 500 mg and the total duration Γ! reaction time is h hours and 30 minutes. The catalyst is then separated by filtration and the solvent is evaporated. By crystallization of the raw amine from ether, 700 mg (80%) of the compound, melting at 128-130 °, are obtained. The BM spectrum of (CDCl ^) includes the following signals 6: 7.13 -j 7.63 (l '> 5ïï, m, aromatic), h, hO (1H, d, J = 2,?, H-Λ ), j · 1 +, 30 (1H, wide, Hl), 3.30 (1H, dq, J '= 5.1, 6.3, H-l'),] 3.03 (1H, dd, J = 5.1 "2.5, ïï-3), 1.20 (3H, d, J = 6.3, H-2 ') and 1.0 - 1.80 ppm (2H, large, KH ^ ) ·. (L'R ^ S ^ R et l'S, 3R, ^ S) -3 - (ll ~ P'-nitrobenzyloxycarbonyl-amino-I »-éthyl) - ^ - tritylthio-2-azétidinone (isomer B) .

NH hnco2pnb AL_ ^ SC * 3 Αγ — j ^ C <|, 3 J— N> J-N ^ 0 Nî 0

A solution of (1'R, 3S, hR and 1, S, 3R, ii-S) “3 - '(l f-amino-l'-ethyl) - ^ - tritylthio-2-azéti & inone is cooled to 5 °. (isomer B) (1.00 g, 2.57 millimoles) in dichloromethane (100 ml) and p-nitrobenzyl chloroformate (0.61 g, 2.83 millimoles) and pyridine ( 0.22 g, 2.83 millimoles). After stirring for minutes at 5 ° and 135 minutes at room temperature, the reaction mixture is washed with dilute hydrochloric acid, and brine, then dried over magnesium sulfate and evaporated finally dry. The crude carbamate is crystallized from ether to collect 1.03 g (7055%) of the compound melting at 1b7 - 150 °. The RMI spectrum of (CBCl ^) includes the following signals: 7.10 - 8.33 (19H, m, aromatics), 5.23 (2H, s, benzyl), 5.08 (1H, ΪΓ-Η) , h, bO (1H, s, RH), 29 (1H, d, J = 2.2, Eh),

4.10 (1H, dq, J = 8, 6, ïï-1 '), 3.18 (lïï, dd, J = 2.2, 8, H-3) and 1.23 PPm (3S, d, J = 6, H ~ 2 '). The IR spectrum

(CHClo) includes signals for S) = 3395 cm "* ^ (R-H), msLx 1765 and 172½ cm ^ (C = 0).

(R, 55.6s and S, 58.6R) -2-methyl-6- (l1 -p-nitrobenzyl- · oxycarbonylamino-l'-ethyl ^ eneme - ^ - p-nitro-benzyl carboxylate (isomer B ).

NHCO-PNB NHCO PNB

îC - ^

NCO GNP

It is prepared in the conventional manner from (R, 5R, 6S and S, 5S, 6R) -3- (l'-P “nitrobenzyloxycarbonyl-amino-1'-ethyl) -4 - tritylth.io- 2-azetidinone (isomer B) the reclierclié compound having a PR of 108 - 110 °. The RKN spectrum of (CDOl ^) includes the following signals: 7? 50 “8.4-0 (8H, m, aromatic), 5558 (1H, d, J = 1.20, H-5), 5, 35 (2H, qAB, benzyl ester), 5> 20 (2H, s, benzyl carbamate), 4-, 90 (lïï, large NH), 4-, 20 (1H, dq, J = 6, j 7, Hl '), 3.80 (1H, dd, IJ = 1.2, 8.0, H-6), 2.4-0 (3H, s, Cï ^.), .1.4-0 (3H, d, J = 6, CH ^). The IR spectrum includes signals for -O = 3 ^ 35 cm ^ (N-H), 1777 and 1717 cm- "· * · max (o = o).

The p-nitrobenzyl ester can be subjected to catalytic hydrogenation as in Example 4-3 (Method A) to obtain the corresponding carboxylic acid.

EXAMPLE 4-4 -.-

6-dimethylaminomethyl ~ 2-methylpenem-3-carboxylic acid.

CH_ _ \ o2h l-Çt-Butyldimethylsily ^^ - dimethylaminomethyl - ^ - tritylthio ^ - azetidinone (cis and trans).

Θ 1? ï 3C (J> CH3 \ / νΛ

Me NH N ^ T-f 3

H T 2 y / I

I Me_ NaBH CN CH J-N Me d * - * ^, * '2 3 2 N: -Bu \: ~ Bù

Add a solution of hydrochloric acid in methanol (2.5 ml of a 5 ^ 0 solution, then trans- l- (t-hutyldim.ethylsilyl) -3 ~ forniyl -! + - tritylthio-2- azetidi-none (3.0 g, 6.16 millimoles) and sodium cyanohorohydride (0.27 g, 31 millimoles) to a solution of dimethylamine (18.5 ml of a methanolic solution 2 îT, 36, 9 millimoles) in methanol (80 ml) The mixture is stirred at room temperature for 210 minutes, poured into a mixture of ice and hydrochloric acid (pH = 2) and made alkaline with sodium hydroxide 1 ÎT to pH 9. The mixture is extracted with ether and the ethereal phase is washed with brine, then dried and evaporated to obtain 3.0 g of the desired compound which is crude oil.

3-Dimethylaininomethylr ^ —tritylthio-2-azetidinone (cis and trans).

M ^ / Nj__j ^ sc <1,3 NaM3 - | ysc <î, 3

Me J — m HMPT Me J — N.

0 2 \: - Bu

Cooled to 5 °, a solution of the above crude compound (3.0 g, 6 millimoles) in hexamethylphospho-rotriamide (16 ml) containing 10% water, then added azide. sodium (0.78 s. 12 millimoles) The mixture is stirred for 90 minutes at room temperature and poured into a mixture of water and ice, then the aqueous phase is extracted with ether (5 x 30 ml The organic phases are extracted with 1 If hydrochloric acid, then the acid extracts are washed carefully with ether to collect the hexamethylphosphorotriamide. The acid phase is alkali-nized using 1 N sodium hydroxide and the dichloromethane extract. The organic phase is washed with brine, dried and concentrated to give 1.5 g (62.5% overall) of the desired compounds in the form of a white amorphous solid. The mixture of isomers is separated using a Waters Prep 500 apparatus, eluting with methanol (5%), such as ammonia (0.2%) and ethyl acetate. e (95%).

1.0 g of the trans isomer, melting at 129-131 ° (pentane), is thus obtained. The EMf spectrum of ^ ïï (ppm, CDOl ^) includes the following signals 6: 6.8-7.8 (15H, m, aromatic), 4-, 5 (1H, îf-ïï), 4-, 28 ( 1H, d, J = 2.5, H-4)), 3.35 (1H, m, H-3), 2.75 - 2.1 (2ÏÏ, m, H-l '), 2.3 (6H, s, GÏ ^).

0.5 g of the cis isomer, melting at 132-133 ° (ether-pentane), is also obtained. The BMN spectrum of (CDOl ^) includes the following $ signals 7.7 - 6.7 (15H, m, aromatics), 4-, 72 (lïï, NH), 4-, 5 (lïï, d, J) 5 , 3 (H-4 ·), 3.5 (1H, m, H-3), 2.85 - 2.35 (2H, m, H-l '), 2.31 (6H, s, CK3) .

The cis: trans ratio can be modified by acting on the operating conditions.

6-Dimethylaminomethyl-2-methylpenem-4 “Carboxylic acid (cis and trans).

r \ __ f ____- i __ / __ί _ 'i. -, T

3-dimethylaminomethyl-if-tritylthio-2-azetidinone (cis and trans) by operating as in Example 3½. The PME spectrum (CDCl ^) includes the following signals S: 5.5 (LÏÏ, d, J = 1,3), 3,7 (1H, dt, J = 1,3, J = 8), 2,8 (2H, d, J = 8), 2.35 (6H, s), 2.3 (3H, s).

EXAMPLE

2-aminoaceto acid: xymethylpenem ~ 3 ~ carboxylic (by the intermediate mercaptide).

—R ^ £ \ î oJ_ i ^> ^ H20CCH 2NH2

'CO H

h-Azidoaceto: xyaoetylthio-l- (p-nitrobenzyl-21 -triphenyl-phosphoranylidene-2 '-acetate) -2-azetidinone.

o 1— r / SNY ^ v'oH c1coch2m3, π / εγ ^ ° / Λ ^ Ν3] _J. J? C_H N J_N P <b J— Ν> γ · ΡΦ3 6 5

CO „PNB CO PNB

2 2

Azido-acetyl chloride (2h0 mg, 2.01 millimoles) is added successively and, dropwise, pyridine (226 mg, 231 microliters, 3.0 millimoles) in methylene chloride (10. ml ) to a cooled solution (ice and methanol bath) of ^ -hydroxyacetylthio-l- (p-nitrobenzyl-21-triphenylphosphoranylidene-2'-acetate) - 2-azetidinone (586 mg, 0.95½ millimole) in chloride methylene (15 ml). At the end of the addition, thin layer chromatography reveals the disappearance of the starting compound. The mixture is diluted with ether, washed successively with dilute hydrochloric acid, water, dilute aqueous sodium bicarbonate, water and brine. The organic phase is dried over sodium sulfate. The residue is purified on a column of 10 g of silica gel which is eluted with 20% ether in benzene, then ether and finally 30% ethyl acetate in ether. By concentration of the appropriate fractions, 533 mg (80.1%) of the desired compound, which is a frothy substance, is obtained. The IB spectrum. (GïïCl ^) includes signals for ° max = 1763 ’· 1702 om-1 (0 = 0)> 1625 1? 22 0“ _1 (JÎ02) and 2110 cm-1 (H,).

P-nitrobenzyl 2-Azidoacetoxymethylpenem-3-carboxylate.

T CO-PNB

CO PNB - 2-- \

The mixture is heated at reflux for 30 minutes, in the presence of a catalytic amount of hydroquinone, a solution of phosphorane (533 mg, 0.76 * f millimole) in toluene (90 ml). The solution is concentrated in a rotary evaporator, then it is passed through a column of 10 g of silica gel (elution with a benzene mixture: U-8: 2 ether). 236 mg (73.7%) of the desired compound, which is an oil, are thus obtained. It turns out to be unstable at room temperature. We keep it at -780 until the required time. The EM spectrum of H (CDCl ^) comprises the following signals δ: 8.21 (2H, d, aromatic Hm), 7.57 (2H, d,

Aromatic Ho), 5.68 (1H, dd, J ^ _6 cig = b, J ^ _6 trans = 2., H-5), 5Λ3 (2ÏÏ, qAb center, J = 16, CH2-PHB), 5 , 39 (2ÏÏ, CH20), 3.93 (2H, s, CH ^), 3.72 (part of dd, J, *. = B, H-6) and 3.50 ppm (1H, dd, J = 17, il; J6-5 trans = spectrum IE (CÏÏOl ^) includes, signals for Ό fflax = 1795, 1755, 1710 cm 1 (C = 0), 1525 cm "1 (E02), 2110 cm" 1 ( 3 ^).

E-aminoacetoxymethylpenem acid - ^ - carboxyliaue.

jry ^^ · η, CO ^ PNB 'c ° 2h

A mixture of the above ester (219 mg, 0.522 millimole) is stirred in a mixture of tetrahydro-furan (16 ml), ether (30 ml) and water (16 ml), in an apparatus for hydrogenation of Parr, for 135 minutes ο under a hydrogen pressure of 3.52 kg per cm in the presence of 10% palladium on carbon (24-0 mg) as catalyst.

The catalyst is filtered off and washed with water and ether. The aqueous phase is washed with r ether (3 x 30 ml) and lyophilized. The resulting crude powder is purified by liquid chromatography under high pressure with phase inversion to obtain 8 mg (6.7%) of the desired compound which is a white powder. The EM spectrum of 1 H (DgO) comprises the following signals S : 5.72 (1H, da, J5_6 cis - 3.5, J? _6 trms - 2, HJ), 5.37 (2H, center of qAB, J = 13.5, CH ^ -O), 3, 96 (2H, s, C ^ -EH ^), 3.87 (1H, dd, Jgem = 16.5, J6_5 cis = 3.5, Ξ-6) and 3, ^ 9 (1H, dd, Jgem = 16.5, J6_5 trans = 2, H-6). The IE spectrum (nujol) includes signals for "Jmax = 1775, 1755 and 1600 um" 1 (0 = 0). The UV spectrum (HgO) includes Xmax at 306 nm (£ 4-900), 256 nm (8 3000).

EXAMPLE * 4-6.- 1- (β-Trimethylsilyl ethyl-21 -triphenylphosphoranylidene-21 -acetate) -2-azetidinone - ^ - thiolate A * silver _ / SAg J — Ν, ^ - Ρφ OT / CH3 CO_CH_CH Si— CH3 2 2 2 \ J nch3

Di-p-trimethylsilylethyl pumarate

q pyridine 33 O

Operating in a nitrogen atmosphere, fumaryl chloride (3.78 ml, 35 millimoles) dissolved in ether (10 ml) is added dropwise over 15 minutes to a solution at -10 ° formed by 2-trimethylsilylethanol 0 +, 73 g, ^ + 0 millimoles) [H. Gerlach Helv. Chim. Acta 60, 3039 (1977) 1 and pyridine (5.66 ml, 70 millimoles) in ether (20 ml). The black mixture is stirred for 5 minutes at -10 ° and 10 minutes at room temperature. Charcoal is added to the mixture which is then filtered through Celite. The filtrate is washed with a 1: 1 mixture of 1% sodium bicarbonate and brine (150 ml). The aqueous phase is extracted back with ether (30 ml). The ethereal solutions are combined, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain a brown solid. This compound is purified on a column of 30 g of silica gel 0+ cm x 5 cm) which is eluted with benzene (300 ml) to obtain * +, 855 S (77%) of an oil giving a rest solid with 33 ”PP 3 * + ° ·

Analysis for G2LfH280ifSi2:

Calculated: C, 53.12, H, 8.91%.

Found: C, 53.35, H, 8.91%.

The RM spectrum of (CDCl ^) includes the following signals S: 6.78 (2H, s, C = CH), * f, 26 O + H, m, CH ^ -O), 1.03 0 + H, m, CH ^ -Si) and 0.06 ppm (18H, s, (CH ^) ^ Si). The IR spectrum (GEClO includes signals for = 1710 (C = 0 ester), 16H-3 (C = C), 1267, 1258, 862 and 840 cm “1 (Si-C).

Trimethylsilyl ethyl hydroxylate hydrate 'ο A _ ^ Si (CH_) _ (CH3) 3Si' / ^ s / ^ sJ 2) (CH3) 2S C02

A solution of di-p-trimethylsilylethyl fumarate (37 g, 117 millimoles) in methylene chloride (1100 ml) is reacted with -780 with ozone until the color "blue" persists. of nitrogen, the excess ozone is removed, then aimethyl sulfide (25.7 ml 335 mmol) is added. The solution is gradually warmed to 23 °. The reaction mixture is brought to 2000 ml using carbon tetrachloride and then washed with 1% aqueous sodium carbonate (500 ml). The organic phase is dried over sodium sulfate, filtered through Celite and evaporated at about 21 ° to dryness to obtain ^ 3.9 g (97%) of the desired compound. The IR spectrum (pure compound) includes signals for ° max = 3 ^ ° 17k0 (ester), 1255, 860 and 8 ^ -0 cm “1 (Si-C) l- (0-3? Riméthylsilyléthyl-21 -hydroxy -21 -acetate) -1! —Trityl- thio-2-azetidinone r- / Ir __> rf "Ir

Γ_i c02 Δ J— N JOE

cr ° Y if {ch J

C02 / ^ 3-3

The mixture is heated to reflux in a nitrogen atmosphere for 2 hrs of hydrated trimethylsilylethyl glyoxylate C + jOOO g, 11.6 millimoles) and * f-1 ritylthio-2-azetidi-none (^, 8 g, 2 ^, 96 millimoles) in 25 ml of benzene using a Dean and Stark condenser. The solvent is evaporated in vacuo. The product is chromatographed on a column of silica gel (5 ° g * 8.5 cm x 1.5 cm) which is eluted with a 1:19 mixture of ethyl acetate and methylene chloride. until the desired compound appears in the fractions (approximately 1500 ml), then with a 1: 9 mixture of ethyl acetate and methylene chloride (2000 ml).

The fractions containing the desired compound are combined and evaporated to dryness to obtain 5 * 15 g (89%) of the desired compound, the EM spectrum of (CDGl ^) comprises the following signals 7: 7 * 80 to 6, 70 (15H, m, trityle), 5 * 23 and * +, 90 (1H, 2s, HGO), ^, 50to ^, 10 (3ÏÏ, m, H-3 and 0-¾), 2.60 (2ÏÏ , m, H-2), 0.95 (2ÏÏ, m, GEL ^ -Si) and 0.1 ppm (9H, s, Si-CH ^). the spectrum IE (CHCl ^) includes signals for Λ? = 3520 (-OH), 1765 (C = 0 ß-lactam), 17 ^ 0 (C = 0 ester), 1595 (C-H, aromatic), 1257, 860 and 8Vo cm ^ (O-Si).

1- (B-Trimethylsilylethyl-21-chloro-2 * -ac state e) - ^ - trityl- thio-2-azetidinone I- <STr SOC12 | —fSTr J_I oh PpHdSi], j Cl Y Λ / ϋα,). 0 V / v / sl (aV3 “2 co2

A solution of thionyl chloride (0.7½ ml, 10.37 millimoles) in dry tetrahydrofuran (9 ml) is added dropwise with stirring to a solution of 1- (β-trimethylsilylethyl-21-hydroxy-2 '). -ac et at e) -H — t ritylthio-2-azetidinone C ^, 9 g, 9.37 millimoles) and pyridine (0.8½ ml, 10.38 millimoles) in dry tetrahydrofuran CfO ml) at -15 °, operating in a nitrogen atmosphere. The mixture is stirred at -15 ° for 2 hours. The precipitate is separated by filtration on Celite and the solids are washed with benzene (50 ml). The filtrate is evaporated in vacuo at 30 ° · 1 the residue is dissolved in benzene (100 ml), activated carbon is added to the solution and the whole is filtered through Celite.

By evaporation of the solvent, a residue is obtained which is purified on a column of silica gel (100 g, ^ 4-, 7 cm x 11 cm) which is eluted with a 1: 1 mixture of hexane and benzene 0 + OO ml) and a 1:19 mixture of ether and benzene (1000 ml). By evaporation of the appropriate fractions, ^ 6½ g (92%) of the desired compound are obtained. The EM spectrum of% (CDCl ^) includes the following signals 6: 7.30 (15H, m, aromatic), 5.77 and 5, ^ 3 (1H, 2s, CH-C1), k, 7 to * f , 2 (3H, m, Eh and CH2-0), 2.85 to 2.50 (2ÏÏ, m, H-3), l, 15 (2H, m, Cï ^ -Si) and 0,06 ppm ( 9H, s, Si-CÏ ^). The IR spectrum (pure compound) includes signals for ~ ^ max = 17 ^ 0 (C = 0), 860 and 8 ^ 0 cnT "*" (C-Si).

1 ~ (ß-Trimét hyl silyl ethyl-21 -triph.ényIph.osph.oranylidène-2.

ac and at e) - ^ - tritylthio-2-az étidinone, rT —X, —v rf 1 N Cl 2,6-lutidme J_N Ρφ "Si (CH,), °‘ 31! 3 3 Î02

Triphenylphosphine (2.209 g, 8, ^ + 2½ millimoles) and 2,6-lutidine (0.98 ml, 8, ^ 2 ^ millimoles) are added to a solution of the above chloroazetidinone 0 +, 12 g, 7.568 millimoles) in dioxane (20 ml). The mixture is heated at reflux for 210 minutes. The cooled solution is filtered and the white solid is washed with tetrahydrofuran. The filtrate is evaporated to dryness. The residue is purified on a column of silica gel (200 g, cm x 31 cm) which is eluted with mixtures. ethyl acetate * and hexane (3: 7 3 1000 ml and 7-3 9 1000 ml) to obtain * +, 836 S (83%) of the phosphorane sought. The spectrum IB (layer) presents signals for "0 = 1755 (C = 0), 16l5 (phosphorane) ·, - 850 and 830 cm 1 (Si-C).

Analysis for O ^ H ^^ ITO ^ PSSi:

Calculated: C, 73.89, H, 6.07, H, 1.81%. Found: C, '72, 18, H, 6.08, E, 1.83%.

1- (ß-Irimethylsilylethyl-21 -triphenylphosphoranylidene-21 - • acetate) -2-azetidinone-i + -thiolate silver _> -STr

i 1 + ÄgNO + (nBu) N + CF CO H

3 3 3 2 lo 2 r-Y "“ 9 ether / HgO JTI Ρφ3 X <CH3) 3 2

1- (ß-trimethylsilylethyl-2'-tri-phenylphosphoranylidene-21-acetate-2-azetidinone (7.6 * 4- g, 10 millimoles) is dissolved in ether (60 ml). aqueous silver nitrate solution (0.5 M, 80 ml, * 4-0 millimoles), then quickly (1 minute) a solution of tributylamine (3 ml, 12.58 millimoles), and, trifluoroacetic acid ( 0.15 * 4-ml, 0.9 millimole) in 20 ml of ether, stir for 19 minutes, filter the precipitate, rinse with ether (200 ml), and triturate in 1 ' water (70 ml), it is collected again by filtration and rinsed with ether (100 ml). The light brown solid is dried there for 10 minutes under the vacuum of the water pump and 65 minutes under vacuum of the pump, to obtain 6 * 4-2 g of the desired compound. The IR spectrum (CSCl-j) includes signals for A3 = 1862 (C = 0), 1630 (phosphorane), 860 and 8 * 4-0 cm ^ (Si-C).

EXAMPLE V7.-

Sodium salt and potassium salt of 6-formamido-methyl-2-methylpenem-3-oaJ? Boxylic acid.

HH

»XX / cfi3

0 iP

(Drans-1- (t-butyldimethylsilyl) -3-methanesulfonyloxymeth.yl-1f-tritylthio-2-azetidinone.

OH

I H H HH

(f -] \ cT ~ \ SNi (CH3> 2 S {(CH3> 2 t-Bu t-Bu

A solution of trans-1- (t-butyl-dimethylsilyl ^ -hydroxymethyl - ^ - tritylthio ^ -azetidinone (8.0 g, 16.36 millimoles) in diehloromethane (50 ml) is reacted with chloride tallow onyl methane (1.5 ml, 18 millimoles) in dichloromethane (10 ml) and triethylamine (2.5 ml, 18 millimoles) The stirring is continued for 1 hour in a nitrogen atmosphere. The solution is then washed ► successively with cold 1 N hydrochloric acid, 1 M sodium bicarbonate and brine, then dried over magnesium sulphate and evaporated in vacuo. as above, the residue, which is a mixture of the hydroxylated compound and methanesulfonate, so as to obtain 9.0 g (97%) of methanesulfonate which is an amorphous solid. It is used as it is in the following stage without further purification. An analytical sample recrystallized from methylene chloride has a Ρ.Γ. of 167 - 168 °. The IR spectrum (pure compound) includes a signal for Ό = 1755 cm Le spectrum EMU of (JDCl ^) includes the following signals ô: 7.3 (l5H, -m), h, h (lïï, d, J = 2 Hz), 3.9 (lïï, dd, J = 8 Hz, k Hz) 3.2 (2H, si), 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.

HH HH X HH

sa ", SC <|, 3 /% L_pSC (*

MsCf ^ '' J 3 _ „Ms0] Π -► N3 l

/ -N \ 0 ^ ΝΗ H

^ if (CH,) 0 3 2 t-Bu

A solution of trans-1- (t-butyldimetliylsilyl) -3-methane tallow onylmethyl-4-tritylthio-2-azetidinone (21.0 g, 37.0 millimoles) in hexamethylphosphorotriamide (90) is cooled in an ice bath. ml) and sodium azide (2.7 g, 4-1.2 millimoles) in water (10 ml) is added thereto. The reaction mixture is stirred at room temperature for 1 hour, diluted with ethyl acetate, washed with water (5 x 100 ml), dried over magnesium sul-fate and it is evaporated under vacuum. The tallow trans-3-methane onyloxymethyl-4-tritylthio-2-azetidi-none is diluted with hexamethylphosphorotriamide (90 ml), then the azide is added thereto at room temperature. sodium (2.7 g, 4-1.2 millimoles) in water (10 ml), after which the mixture is heated for 2 hours at 60 ° and triturated in cold water. The crude azide is diluted with a 5: 1 mixture of benzene and ether and the organic phase is washed with water (5 × 20 ml). By evaporation of the solvent, then crystallization from ether, 1.8.0 g (77%) of the azide is obtained, which is a white solid.

An analytical sample recrystallized from a methylene chloride-ether mixture has a P.P. of 174 · “175 ° ·

Analysis for C23H20 \ 0S:

Calculated: C, 68.97; H, 5.03; ÎT, 13.99%.

The IR spectrum (nujol) includes signals for Ό = max 2100, 1765 cm ^. The RMH spectrum of ^ ïï (CDCl ^) includes the following signals 7: 7.35 (152, m), * +, 75 (12, si), 4, ½ (lïï, d, J = 2 Hz) and 3.1 - 3.7 ppm (3H, m). Irans-3-aminomethyl - 4-tritylthio - 2 - azetidinone.

H h ----- h h N3X'1-f 3 __ àjrfJ '***

19.0 g of ammonium chloride and 1.0 g of zinc powder are added to a solution of trans-3-azido-methyl-4 ~ tritylthio-2-azetidinone (10.0 g, 47.5 millimoles) in dry methanol (500 ml) and the suspension is stirred for 5 hours at room temperature. The reaction mixture is filtered and the filtrate is evaporated. We submit f. the residue is partitioned between hydrochloric acid L N and benzene. The aqueous layer is made alkaline with 1 M sodium bicarbonate and extracted with methylene chloride. The extracts are washed with brine, dried over magnesium sulfate and evaporated in vacuo. After crystallization from ether, 14.05 g (79%) of the crude amine are obtained, having a m.p. of 138-139 °.

Analysis for Cg ^ Hg ^ NgOCl.lA C ^ Clg:

Calculated: C, 70.56; H, 5.73; N, 7.08%.

Found: C, 70.68; H, 5.94; H, 7.27%

The IR spectrum (GHCl ^) includes signals for "° mgu_ = 3400 and 1760 cm" "1. The EM spectrum of 1H (CDCl ^) includes the following signals 8: 7.35 (152, m), 5.15 (12, m), 4.3 (1H, if), 2.7 - 3.5 (3H, m) and 1.3 ppm (2H, m).

5-10-Ohtalimidomethyl - ^ - tritylthio-2-azetidinone.

ο rtP - · <§ΦΐΓ

<f (f H

A solution of trans-3-aminomethyl-lf-tritylthio-2-azetidinone (13.9 g, 37.2 millimoles) and N-carbethoxyphthalimide (8.3 g, 37.9 millimoles) is heated at reflux for 15 hours. ) in benzene (200 ml). The solvent is evaporated under vacuum and the residue is crystallized from ether to obtain 17.1 g (93%) of the desired compound having a P.P. of 172 -173 ° *

Analysis for C31H2hF2 ° 3S:

Calculated: C, 73.78; H, 4.79; H, 5.55%

Found: C, 73.92; H, M-, 87; H, 5, ^ 9%.

I The IR spectrum (OHCl ^) includes signals for ^ max = 1770 and 1715 cm The EMN spectrum of 1H (CDCl ^) includes the following signals <5: 7.8 (* fH, m), 7.3 (15H , ni), (1H, d, J = 2 Hz), 3.3 - b, l (3H, m) and 3.3 - ^, 6 ppm (1H, m).

Trans-3-nthalimidomethyl-1- (p-nitrobenzyl-21-hydroxy-2l-ac etate) - ^ - tritylthio-2-az etidinone.

(grW4 ^ »_— (§iWysc'3 o O γ '

C02PNB

Stirred for 20 hours at room temperature, a mixture of trans-B-phthalimidomethyl - ^ - tritrvd thi o-2-azetidinone (17 .h er. 3 ^ -. ^ 2 millimoles'), p-nitrobenzyl glyoxylate hydrated (9½ g, ^ 1, ½ millimoles) and triethylamine (* +, 8 ml, 3 ^, 5 millimoles) in tetrahydrofuran (250 ml). The reaction mixture is evaporated in vacuo and carbon and benzene are added to the residue. The mixture is filtered and by evaporation of the solvent from the filtrate, 25 g (100%) of the crude hydroxy-glyoxylate which is an amorphous solid are obtained. It is used as it is in the next stage without purification. The spectrum IE (CÏÏCl ^) includes signals for λ) x = 1770 and 1715 cm "" 1.

The RMtT spectrum of (CDCl ^) includes the following S signals: 8.1 (2H, d, J = 9 Hz), 7.55 (3H, d, J = 9 Hz), 7.3 (19H, m) , 5.0 - 5Λ (2H, si), »f, 3 -. 5.0 (2ïï, m) and 2,8 - 3,8 ppm (è-ïï, m).

ü} rans-3-phthalimidomethyl-1- (p-nitrobenzyl-21-chloro-21-acetate) -è-tritylthio-2-azetidinone.

(sxUt ". -.

O 0J— ". ° H S

C02PNB co2pnb. . "

A 1 M solution is added dropwise

of thionyl chloride in tetrahydrofuran ('hô ml, * + 6 millimoles), then a 1 H solution of pyridine in · * tetrahydrofuran (M3 ml, 4-6 millimoles) to a cooled solution (ice bath, 0 ° ) of trans-3-phthalimidomethyl- l- (p ~ nitrobenzyl-2'-hydroxy-2'-acetate) -4 ~ tritylthio ~ 2-azetidinone (25 g, 35 millimoles) in tetrahydrofuran (150 ml). The reaction mixture is stirred for 20 minutes at room temperature, diluted with 50 ml of petroleum ether and filtered through a layer of Celite and

r> Vi a -nh nn. On cam-nm-H esn "l Trant rin fi Ί +: τ · η +: snns nmiP

obtain 2ό g (100%) of chloroazetidinone which is an amorphous solid. This is used in the next stage without further purification. The IR spectrum (CHCl ^) includes signals for -O = 177? and 1720 cm The EMU msix spectrum, of n (CDCl ^) includes the following signals S: 8.12 (2H, d, J = 9 Hz), 7.60 (2H, at, J = 9 Hz), 7 , 3 (19H, m),?, 2? (2Ξ, m), H ·, 7 -? Λ (1H, m), h, 55 (1H, si) and 3.3 - k, 0 ppm (3H, m).

Irans-3-Phthalimidomethyl - 1- (p-nitrobenzyl-21-triphenyl-phosdhoranylidene-2 1 -acetate) -1 ·! —Tritylthio-2-azetidinone.

^ i h h.

igrVs-pi _ „

C02PNB C02PNB

f A mixture of trans-3-phthalimidomethyl-1 ~ (p-nitrobenzyl-2'-chloro-2'-acetate) -H · -'tritylthio-2-azetidinone (26 g, is heated at 100 ° for 20 hours. 3?,? Millimoles), triphenylphosphine (10.2 ?, g, 39.1 millimoles) and 2,6-lutidine (^, 6 ml, 39.1 millimoles) in dioxane (200 ml). The reaction mixture is filtered through Celite and the filtrate is evaporated. The residue is chromatographed on a column of silica gel (3.00 g) eluted with benzene containing increasing amounts of ether up to a ratio of 1: 1 in order to obtain the phosphorane (21 g, 62 %) which is a white solid. The IR spectrum (GHClO includes signals for V. = 17? 0 and 1710 cm The EMH spectrum of ^ H (CDOl ^) includes the following signals S: 7, ^ (38H, m), H ·, 8 - 5, * + (3H, m), H. ·, 6 (2H, m) and 3.7 ppm (1H, if).

Trans-3-Phthalamidomethyl-1 (p-nltrobenzvl-2’-tri ^ envlOhOSi) hQranylidene-2’-acetate Vt-tritvlthio-2-azetidinone.

^ j? h h A ’m 11 h, at <^ - Νν ^ Ρφ3 ^ Ϊ02Η ^ γΡφ3

CO ^ NB CO ^ PNB

Sodium sulfide 0f, 97 g, 20.7 millimoles) is added dropwise in a 1: 1 mixture of acetone and water (30 ml) to a cooled suspension (ice bath) of 3-phthalamidomethyl-1- (p-nitrobenzyl-2'-triphenyl-phosphoranylidene-2'-acetate) -k-tritylthio-2-azetidinone (18.02 g, 18.83 millimoles) in tetrahydrofuran (30 ml), then the mixture is heated at reflux for 8 hours. The reaction mixture is diluted with water, acidified ► with 1N hydrochloric acid and extracted with dichloromethane.

The organic extracts are washed with brine and evaporated under vacuum to obtain 17.1 g ($ 88) of the desired compound which is a light yellow amorphous solid. This is used without further purification in the next stage. The IR spectrum (pure compound) includes signals for ^ max = 3150 -3600, 1750 and 1700 cm-1. The NMR spectrum of% (CDCl ^) includes the following signals <5: 7, ½ (3ÖH, m) and 3.3 - 5.5 ppm (8H, m).

Trans-VOhtalisoimüométhvl-l- (p-nitrobenzyl-2 ’-triOhenyl-phos-phoranylidene-2? -Acetate) - ^ - tritylthio ^ -azetidinone.

î? ? jscé yÿ H? , (Sr- ^ Hr _> K 3 ^ C02H O · 1 - »^ * 3

CO PNB CO PNB

^ 2

N, N * -dicyclohexylcarbodiimide (3.62 g, 17.5½ millimoles) in dichloromethane (30 ml) is added dropwise at room temperature to a solution of trans-3-phthalimidomethyl-1- (p -nitrobenzyl-2, -triphenylphosphoranylidene-2 '-acetate) -H-tritylthio ^ -azetidinone (17.1 g, 17.5 ^ millimoles) in dichloromethane (125 ml). The solution is filtered through Celite 1 and the filtrate is evaporated to obtain 18.23 g ($ 100) of the desired compound which is an oil. This is used in the next stage without further purification. The IR spectrum (pure compound) includes signals for V = 2110, 1755 and I7IO cm “· *“. The RM spectrum of (CDCl ^) includes the following signals 6: 7.5 (3ÖH, m), * +, 6 - 5? 3 (^ H, m) and 3.9 ppm (2H, si),

Trans-3-aminomethyl-1- (p-nitrobenzyl-27-triphenylphosphoronylidene-2 7 -acetate) - * f-tr itylthio-2-azé t idinone.

\ 2 / HH, H H n.i 0 ^ h / U-> cl _f / - »γρφ3 εΛ-ΗγΐΦ3

CO PNB CO PNB

2 2

Hydrazine (0.2 ml, 6.16 millimoles) is added dropwise in a nitrogen atmosphere to a stirred solution of trans-3-phtalisoimidométhÿl-l- (p-nitrûbenzyl-27-triphenylphosphoranylidene-27 - acetate ) -è-tritylthio-2-azetidinone (5.9 g, 6.16 millimoles) in tetrahydro-furan (^ fO ml) which has been cooled to -20 ° and stirring is continued for 3 ° minutes. The reaction mixture is acidified with 1 H hydrochloric acid and washed with ether, then the aqueous phase is made alkaline with 1% sodium bicarbonate and extracted with methylene chloride. The organic extracts are washed with brine, dried over magnesium sulfate and evaporated. The residue is purified on a column of silica gel (60 g) which is eluted with ether to ethyl acetate to obtain 3538 g ($ 66) of aminophosphorane which is an amorphous solid. The IR spectrum (CHCl 4) includes signals for V = 173, 1710 cm "1. The 1 H NMR spectrum (CDdL ·) includes the following signals 6: 6.5 - 8.1 (3 ^ H, m), 3.8 - 5.3 (6H, m) and 0.9 - 1.9 ppm (2E, m).

Trans-8-f ormamidomethyl-l- (p-nitrobenzyl-2 ’-triphenyl- phos-phoranylidene-2’ -acetate) -Λ - tritylthio-2-azetidinone.

^ h ^ - .. 0 ^ SC * 3 J ~ R γ ^ 3 J ~ '“· γ? Φ3

CO PNB CO PNB

6 "

A solution of formic-acetic anhydride (600 mg, 6.8 millimoles) in dichloromethane (5 ml) is added dropwise in a nitrogen atmosphere, followed by a solution of triethylamine (1 ml, 7 millimoles) in dichloromethane (2 ml) to a stirred and cooled solution (ice bath) of trans-3 - aminomethyl-l- (p-nitrobenzyl-2'-triphenylphosphoranylidene-2 '-acetate) -lf-tritylthio-2-azetidinone (5.0 g, 6.0 * + millimoles) in dichloromethane (50 ml). The agitation is continued for 30 minutes. The solution is washed successively with 1 N hydrochloric acid, water, 1 M sodium bicarbonate and brine. The organic layer is dried over magnesium sulfate, evaporated and the residue is chromatographed on a column of silica gel (50 g). By eluting with ether to ethyl acetate, 2.0 g ($ 39) of formamide, an amorphous solid, is obtained. The IR spectrum (CHOlO includes signals for "O _____ = 17 ^ -0, 1685 and 3 IucLa.

-1 1 1620 cm. The H NMR spectrum (CDCl ^) includes the following S signals: 6.6 - 8.2 (35 ^, m) and 2.5 - 5) 3 ppm (7H, m).

Trans-Vf ormamidomethyl-1- (p-nitrobenzyl-2 '-triphenylphos- • phoranylidene-2'-acetate) -2-azetidinone-V-silver thiolate ♦ J- * γ®Φ3 / - "γ" 3 CX ^ GNP co2pnb

A solution of trans-3- is evaporated to dryness. formamidomethyl-1- (p-nitrobenzyl-2 '-triphenylphosphorany-lidene-2'-acetate) -V-tritylthio-2-azetidinone (550 mg, 0.6V millimole) in dichloromethane (10 ml) and the residue is taken up in hot methanol (20 ml). The solution is stirred at 60 ° and a 0.15 M preheated (60 °) solution of silver nitrate in methanol (5.7 ml, 0.86 millimole) is added thereto, followed by a 1.5 M solution of pyridine in V methanol (0.57 ml, 0.86 millimole). The cream solution is stirred at room temperature for 30 minutes, then in an ice bath for 2 hours. The solid is separated by filtration, washed with cold methanol and ether, then dried to collect 300 mg (65%) of the sodium salt which is a beige solid. This is used in the next stage without further purification.

Trans-V-aoetylthio-3-formamidomethyl-1- (p-nitrobenzyl-2’-trinhenylphosphoranylidene-2’-acetate) -2-azetidinone.

_> h ^ 'H ^ ac ν ^ Φ3

C02PNB C02PNB

A 1 M solution of acetyl chloride in diehloromethane (1.33 ml, 1.33 millimole) is added dropwise, under a nitrogen atmosphere, then a 1 M solution of pyridine in dichloromethane ( 1.33 ml, 1933 millimole) to a cooled solution (ice bath) of trans-3-formamidomethyl-l- (p-nitrobenzyl-2'-triphenylphosphorany-lidene-2 '-acetate) -2-azetidinone - ^ - silver th.iolate (800 mg, 1.11 millimole) in dichloromethane (10 ml), s The solution is stirred in a cooling bath for 1 hour, then filtered through Celite. The filtrate is washed successively with 1 N hydrochloric acid, water, 1 M sodium bicarbonate and brine, then the organic layer is dried over magnesium sulfate and evaporated. The residue is purified on a silica gel column (5.0 g) which is eluted with ethyl acetate up to 10 $ of methanol in ethyl acetate in order to obtain k ^ O mg ($ 62) of the desired compound. The IR spectrum (CHC1-.) Includes signals for Ό = 1755, 1685

„3 ŒLclX

and 1620 cm * ”1. The NMR spectrum of (CDCl 4) comprises the following signals 6: 8.18 (2H, d, J = 9 Hz), 7.0 - 8.0 (20H, m), 6.75 (2H, d , J = 9 Hz), 6.3 (1H, m), 5 ,? (1H, m), 5.2 (2H, si), if, 9 (1H, si), 3.6 (1H, m), 3.0 (1H, m) and 2.2 ppm (3H, two s).

e-Formafflidomethyl ^ -methyl-penem-1-carboxylate -p-nitrobenzyl. H 0λ- * γ * 3 ^ C02PNB 2

A solution of trans - ^ “acetylthio-3-formamidomethyl-l- (p-nitrobenzyl-2 '-triphenylphosphoranylidene-2' -acetate) - 2-azetidinone (* + 50 mg, 0.686) is removed at reflux for 12 hours. millimole) in toluene (10 ml). By concentration, then purification on a column of silica gel which is eluted with ether up to $ 10 of methanol in ether, we obtain 100 mg ($ 39) of the penem which is an amorphous solid. The IR spectrum (CHCl ^)

T

includes signals for Ό max = 1780 and 1690 cm “.

> The NMR spectrum of (CDCl ^) includes the following signals: 8.2 (2H, d, J = 9 Hz), 8.2 (1H, s), 7.6 (2H, d, J = 9 Hz), 6.9 dH, m), 5.55 (1H, s), 5.35 (2H, 2s), 3.3 - * f, l (3H, m) and 2.33 ppm (3H, s).

Sodium salt and potassium salt of 6-formamido-me thvl-2 -methylpenem -3 - carboxylic acid.

O 3 H h '' f * ® HCN -Y * S \

V \ ofkß and P

We submit a mixture of p-nitrobenzyl 6-formamidomethyl-2 ~ methylpenem-3-carboxylate (80 mg, 0.21 millimole), palladium celite at $ 30 (100 mg), tetrahydrofuran (10 ml), ether (25 ml) and solution j_______ _ r \ / * \ r- * 1 τι · n I. / η λ λλλ - \ v drogenation in a Parr agitator under an initial pressure of hydrogen from 3.16 kg per cm for 3 hours. The catalyst is filtered off on Celite and washed with water. The filtrate and the washing waters are mixed, then the phases are separated. The aqueous phase is washed with ether (3 x 15 ml) and lyophilized. The crude solid is purified by liquid chromatography under high pressure to obtain 18 mg of a mixture of the potassium salt and the sodium salt. The UV spectrum (ïï20) includes λ at 299 nm (S ^ -933), 259 nm (£ ^ 09 ^). The IR spectrum (nujol) includes signals for -J ^ = 3100 -3650 and 1755 cm "· * ·. The NMR spectrum of (D20) includes the following signals <5: 8.15 (1H, s), 5, 53 (1H, d, J = 1, V Hz), H-, 0 (1H, m), 3.7 ^ (2H, d, J = 5Hz), 3.25 - ^, 25 (1H, m) and 2.27 ppm (3H, s).

EXAMPLE kQ.-! Acid sodium salt (S, 5R.6S and R.5S.6R) -6- (1'-hvdroxy-1’-nronyl) "2-methvlOénème-3-carboxylic (G isomer).

h ^) <VCH3 \ x> Na

Trans-1-t-butyldimethylsilyl - ^ - uropionyl-V-tritylthlo ^ - azetidinones.

_1 ^ Tr 0 _p> sTr I + LDA + CH CH C-OCH --V |

J N J 2 3 J — N

0 ^ SiMe C XS: Me + 2 + 2

N-butyllithium (37.5 ml, 1.6 M in hexane, 60 millimoles) is added dropwise in a nitrogen atmosphere to a stirred and cooled solution (carbon dioxide and acetone bath) diisopropylamine (8.50 ml, 60 millimoles) in dry tetrahydrofuran (200 ml). The mixture is stirred cold and 1-t-butyldimethyl-Silyl-1 * -1 ritylthio-2-azetidinone (22.9 g, 50 millimoles) is added to it in dry tetrahydrofuran (100 ml). After 15 minutes, an excess of methyl propionate (^ K) ml) is added and the reaction mixture is kept for hours at -78 °. The cooling bath is then removed and the internal temperature is allowed to rise to 0 ° (approximately * f0 minutes). The reaction mixture is poured onto a mixture of hydrochloric acid and ice (pH about 6) and the whole is extracted with ether. The layers are separated and the aqueous layer is extracted with ether. The ethereal solutions are combined, washed with water and brine, then dried over magnesium sulfate. The ethereal phase is evaporated to obtain an oil with a quantitative yield. This is formed from a mixture of the starting compound and the desired compound.

The mixture is used as it is in the next stage. The IR spectrum (pure compound) includes signals for \> =

fflcUC

1710 cm-1 (^ C = 0) and 1750 cm "1 (ß-lactam).

1- t-Butyldimethylsilyl - ^ - d ’-hydroxy-1 ′ -oro-pyl) d-tritylthio- 2-azetidinones.

OH

"" S j * f, aBH4 jif J 1 —N ^ Qy. O ^ SiMe2 SlMe2

A solution of lt-butyldimethylsilyl-3-propio.nyl - * + - tritylthio-2-azetidinone (26 g, 50 millimoles) and sodium borohydride (7.6 g, are stirred for 18 hours at room temperature. 200 millimoles) in tetrahydrofuran (* + 00 ml). The solution is poured onto a mixture of ice and 1 N hydrochloric acid with a pH of 6, then an extraction with ether is carried out. The acid phase is extracted several times with ether, the ethereal extracts are combined and washed with brine, then dried over sodium sulfate and evaporated to obtain 25.0 g of an amorphous solid . This crude product is chromatographed on * + 00 g of silica of activity 1, which is first eluted with methylene chloride to collect 10.8 g of l-t-butyldimethylsilyl - * + - tritylthio-2-azetidinone. By elution with 20% ether in methylene chloride, 10.3 g of the desired compound is obtained in the form of a me ~! mixture of the two isomers in trans. The alcohols are separated by high pressure liquid chromatography (500 Water Associates system), using 10% ethyl acetate in methylene chloride as eluent.

3.8 g of the isomer C are thus obtained, which is a white solid having a m.p. of 13 ° + - 136 ° (petroleum ether).

The NMR spectrum of ^ H- (CDCl ^) includes the following signals 6: 7.1 - 7.8 (15H, m, STr), * +, 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).

Analysis for C ^ M ^ SSi:

Calculated: C, 71.91; H, 7.59; N, 2.71%.

Found: C, 71.51; H, 7.60; N, 2.96%.

We obtain 5, * + g of the isomer B which is a white solid having a m.p. of 90 - 99 ° (pentane-petroleum ether). The RM spectrum of (CDCl ^) includes the following S signals: (H, m), 0.7 - 1.7 (5H, m), 0.85 (9H, s) and 0.1 ppm (6ïï, s ).

The total yield of the two alcohols, taking into account the starting compound recovered, is 67%.

(S.lSAR and R, 3RAS) - l-t-Butyldimethylsilyl-3- (1'-p-ni trobenzyldioxycar bonyl-1’-prouyl) A-tritylthio-2-azetidinone (C isomer).

oh oco2pnb -f‘STr + C1COPHB ”-BlÆ1 ^^ SiMe2

A 1.6 M solution of n-butyllithium in hexane A, 88 ml, 7.8 millimoles) is added dropwise in a nitrogen atmosphere to a cooled solution (hate of dry ice and acetone) of (S, 3SAR and R, 3RAS) -l- t-butyldimethylsilyl-1-hydroxy-propyl) A-tritylthio-2-azetidinone (C isomer), (3.1 g, 6 millimoles ) in 1 dry tetrahydrofuran (20 ml) and the mixture is stirred at -78 ° for 25 minutes. P-nitrobenzyl chloroformate (1.56 g, 7.2 millimoles) is then added dropwise to dry tetrahydrofuran (10 ml), then the resulting mixture is stirred at -78 ° for b hours. The mixture is diluted with ether and washed with a solution of ammonium chloride and 1a. brine. We dry 1a. organic phase on sodium sulfate and evaporated to dryness to obtain ifj2 g ($ 100) of the desired compound. The NMR spectrum of (CDCl 4) includes the following signals 6: 8.2 (2H, d), 7.0 -7.7 (17H, m), 5.13 (2H, s), * f, 05 ( H, d), 3.75 (H, dt), 3.25 (dd), 0.55 - 1.8 (5H, m), 0.9 (9H, s) and 0.25 ppra (5H, d).

t (S, 3SAR and R, IRASl-Vd'-p-Nitrobenzyldioxycarbonyl-l'-proPYlV ^ - tritvlthio-2-azetidinone (C isomer).

oco2pnb oco2pnb v X. »sTr '<y <.. / STr J_ | + HMPT + San - * · Fj · Νλ, 2 î10% H2 °>

Sodium azide (0.78 g, 12 millimoles) is added to a cooled solution (ice bath) of (1'S, 30, ^ ¾ and l'R, 3R, è-S) -lt ~ butyldimethylsilyl- 3- (1 * -p-nitrobenzyl-dioxycarbonyl-1'-propyl) - ^ - tritylthio-R-azetidinone (isomer C), (^, 2 g, 6 millimoles) in hexamethyl phosphorotriamide (^ 0 ml) containing $ 10 of water. The mixture is stirred for 1 hour at room temperature. It is diluted with water (100 ml) and extracted with a mixture (1: 1) i. benzene and petroleum ether (è- x 15 ml). Wash 1a.

organic phase several times with water (6 x 30 ml) and brine. We 1a. dry over sodium sulfate and evaporate to dryness to obtain 3.5 g ($ 100) of a solid. This is treated with pentane and the whole is filtered to obtain 3} * +. g of a pale yellow solid with a m.p. of 8½ - 86 °. The NMR spectrum of% (CDCl ^) includes the following signals 8: 8.2 (2H, d), 7 - 7.7 (17H, n), 5.2 (2H, s), 11 ·, 95 (H , dt), (NH), ^, 25 (H, d), 3Λ. (H, dd), 1.7 (2H, m) and 0.95 ppm (3H, t).

(the S. ^ SAR and the R.3RASA3- (l'-p-Nitrobenzyldioxyca.rbonvl- l'-propvl ') - l- (p-nitrobenzyl-21, -hydroxy-2tl acetate) A-tritvlthio-2- a.zetidinone (isomer O.

0CO2PNB PV ™

^ • r-rSTr «P

Avh + SSSÄi. ......... "....... ~ o> -va co2pnb

Add a catalytic amount A drops) of triethylamine and sodium sulfate (to absorb the water which is released) to a solution of (l'S, 3S, ifR l'R ^ RAS) - 3- (l, -p- nitrobenzyldioxyca.rbonyl-l'-propyl) A-tritylthio-2-azetidinone (isomer C), (3.2 g, 5.5 millimoles) and p-nitrobenzyl glyoxylate hydrate (1.362 g, 6 millimoles) in tetrahydrofuran dry (50 ml). The resulting mixture is stirred for 6 hours at room temperature. It is filtered and evaporated to dryness to collect * t, 35 g ($ 100) of an amorphous solid. The 1 H NMR spectrum (CDCl 4) comprises the following signals: 8.25 AH, dd), 7 - 7.9 U9H, m), 5.28 (2H, s), 5.1 (2H, s) , if, 8 (H, d), if, if (H, dd), if, 1 (H, dt), 3Λ (H, m), 1.1 - 1.8 (2H, m) and 0, 8 ppm (3H, t).

(l'S, AH et l'R, 3R.ifS) -V (l'-p-Nitrobenz: yldioxycarbonyl-1 '-propyl) -1- (p-nitrobenzyl-2 "-chloro-2tt-acetate ·) -if -tritvl-thio-2-azetidinone (isomer O.

OCO PNB OC02PNB

sA, _sSTr vA, _> sTr

Py / THF I T

cr ΝγΰΗ soci2 / thf CO PNB *

2 C02PNB

A 1 M solution of pyridine in tetrahydrofuran (7 ml, 7 mmol) is added, then, dropwise, a 1 M solution of thionyl chloride in tetrahydrofuran (7 ml, 7 mmol) to a cooled solution (bath salt and ice) of the above glyoxylate (if, 35 g, 5.5 millimoles) in dry tetrahydrofuran (30 ml). The resulting mixture is stirred at the indicated temperature for 1 hour. Dilute it with benzene (30 ml), then stir it cold (ice water bath) for 30 minutes before filtering it through 1a. Celite and coal.

The filtrate is evaporated to dryness to obtain 3.8 g ($ 85.3) of an amorphous solid. The NMR spectrum of (CDCl ^) includes the following δ signals: 8.15 (HH, d), 6.75 - 7.7 (19H, m), 5.65 (H, s), 5.2 (2H , s), 5.1 (2H, s), if, 5 (H, m), 3.85 (H, m), 3, ^ (H, m), 1.25 - 2.0 (2H, m) and 0.9 ppm (3H, t).

(the S. 3S.è-R and the R. 'lRAS ^ VCl'-p-Litrobenzvldioxvcarbonyl-l'-proOvl> -l- (p-nitrobenzyl-2l, -triphenylphosphora, nylidene-2 "-acéta.te) -è ~ tritylthio-2-azetidinone (isomer C).

OCO PNB 0C02PNB

OL _L ^ STr Φ P STr rf —-2—> Γί ρΦ o <Jj — N ^^ Cl lutidine V3

CO PNB CO PNB

2 *

Triphenylphosphine (1.197 g, • 5 millimoles) and lutidine (0.5 * + g, 5 millimoles) are added to a solution of the above chlorine compound (3.7 g, è-, 568 millimoles) in dioxane (37 ml). The mixture is heated in an oil bath at 100 ° for 3 days. The mixture is cooled, diluted with ether and washed successively with 1 N hydrochloric acid, 1 M sodium bicarbonate and brine. The organic phase is dried over sodium sulfate and filtered over Celite and charcoal. The filtrate is evaporated to dryness to obtain 3) 6 g of an oil. This is chromatographed on 120 g of silica which is eluted with benzene and a mixture of benzene and ether to obtain 1.5 h g ($ 31) of the desired compound which is an amorphous solid. The IR spectrum (pure compound) includes a signal for * \> max = 1750 cm-1 (wide).

(l'S, 3S, è-R et l'R, 3R, IfS,) - i4 - AcétYlthio-V (l '- D-nitrobenzyl- dioxvcarbonvl-1'-prouvl) -1- (c-nitrobenzvl-2 triohenvluho suhor anylidene-2ll-a.cetate) -2-azetidinone (C isomer).

oco GNP? co2pnb. 1> -STr x ^ A, _> SAg AA Ί 1 AgN03 --Γ

Py / MeOH 0 ^ Ν \ ^ ΡΦ3

CO PNB CO PNB

2 2 I

OCO-PNB

Ç J 2 .BAG

CH3CC1 ΆΑ "χ, —p

Py / MeOH * 0ί1_ΝΝΡφ3 CO PNB 2

A hot solution of r is added with stirring.

silver nitrate (0.3 gj 1.76 millimole) in methanol (10 ml), then 1a. pyridine (0.107 g, 0.11 ml, 1.76 mmol) to a 60 ° solution of the above phosphorane (1.1 g, 1.35 mmol) in methanol (U-0 ml). The silver mercaptide immediately begins to precipitate.

The mixture is stirred at room temperature for 15 minutes and at 0 ° for 2 hours. It is filtered and the solids are washed thoroughly with cold methanol and ether. 1.2 g (100 $) of the solid are thus obtained having a m.p. of 113 -115 ° (decomposition). The IR spectrum (nujol) includes signals for V = 17 ^ 0 - 1760 cm - ** "(wide). The compound is used as it is. Acetyl chloride (0.118 g, 0.107 ml, 1.5 is added) millimole) in methylene chloride (2 ml), then pyridine (0.119 g, 0.122 ml, 1.5 millimole) in methylene chloride (2 ml) to a cooled solution in methylene chloride (15 ml) The mixture is stirred at 0 ° for 30 minutes, filtered through Celite to separate the silver salt and the filtrate is washed successively with 0.5 N hydrochloric acid, water, bicarbonate of 0.5 M sodium and brine The organic solution is dried over magnesium sulfate and evaporated to dryness to give 0.9 g (83, b%) of the desired compound which is an amorphous solid. The IR spectrum (pure compound) includes a signal for Ό m = 1750 cm-1 (wide). (L'S, 5R.6S and l'R, 5S.6R) -6- (l'-p-HLtrobenzvldioxvcarbonvl-l ' -propvl ~) -2-methvlpénème-3-carboxvlate of n-nitrobenzyle (isomer C).

oco2pnb oco2pnb XÇ, -

^ C02PNB CO PNB

2

A solution of the above phosphorane (0.1 g, 1.077 mmol) in toluene (35 ml) is heated to reflux and 5 ml of toluene is distilled off. The yellow solution is heated at reflux for 7 hours and 30 minutes. It is then evaporated to dryness to obtain 0.76 g of a thick oil. This is chromatographed on 1.30 g of silica (activity 1) which is eluted with benzene and a mixture of benzene and ether to obtain 0.32 g (53 of the desired compound which is a solid having a PF ( pentane) of 160 -162 °. The RMÎT spectrum of (CDCl ^) includes the following signals <5: 7.3 - 8, * + (8H, m, aromatic), 5Λ (H, d), 5.3 ( è-H, benzyl, m), 5.0 (H, dt), k, 0 (H, dd), 2.35 (6H, s), 0.8 (2H, dq) and 1.0 ppm ( 3H, t).

Acid sodium salt (S. 5R.6S and R. 5S. 6R) -6- (1'-hvdroxy-l'-propyl) -2-methylpénème-3-carboxvlique (isomer C).

oco2pnb S

EL / Celite pa.1- hd ^ '' 'i-r ^ s \ I /) - ch3 _; said., .__ ", | ch3 ^ —Nv / buffer a.u nhos- '

Vh3 Phat® \ o., - Na +

Hydrogenation is carried out for 23 hours, at an initial pressure p of 3.52 kg per cm, a mixture of 1; ester above (t-8 mg, 0.086 millimole) and Celite palladium at $ 30 (100 mg) in tetrahydrofuran (10 ml), 1 * ether (20 ml), water (10 ml) and phosphate buffer (pH 7, 2 ml). The mixture is filtered through Celite and the layers of the filtrate are separated.

The organic layer is washed with water (2x5 ml), then the mixture of aqueous layers is washed with ethyl acetate f (2 x 10 ml). The aqueous layer is then lyophilized to obtain 30 mg of the desired compound which is a white salt. The IR spectrum (KBr) includes signals for * v> = 1750 em ”^ (ys-lactam) and 1600 - 1650 cnf" ^ (wide, -COg “). The UV spectrum includes a at 258 nm (E 1105 ) and 305 nm (£ 12 ^).

EXAMPLE k-9

Sodium salt and potassium salt of the acid (R. 5R. 6S and. S. 5S. 6R) -6- (l'-hydroxy-l '~ propyl) -2 - methylpénème-3-carboxyliaue (isomer B).

Ha, H

y £> “· co2h (the R.3S. * 4-R and the S. 3RAS) -l-t'-Butvldiméthvlsilyl-3- (l'-formyloxv-l'-rroOvll - ^ - tritylthio ^ -azetidinone ( isomer B).

pH HCO H, Et.N pCHO

STr DMAP, Ac20 \ Ax.j __ ^ Tr

N. CH .Cl N

CT ^ SiMe 2 2 0 ^ \ ς.Μο.

2 SiMe ^

^ -Dimethylaminopyridine (DMAP) is prepared as described a) by H.C. Brown et al. Org. Synth. Collect.

Flight. 5, 977 (1973) and b) by Helmut Vorbruggen et al.

Angew. Chem. Int. Ed., 17, 569 (1978).

To a 0 ° solution of (l'R, 3S, * fR and l'S, 3R, * fS) - 1- t-butyldimethylsilyl-3- (l7-hydroxy-l'-propyl) - ^ - tritylthio- 2- azetidinone (isomer B), (3.612 g, 7 millimoles) in methylene chloride (50 ml), triethylamine is added (* f, * + 8 ml, 35 millimoles), formic acid (0.63 ml, [16.8 millimoles) and * f ~ dimethylaminopyridine (0.85 * 4 · g, 7 millimoles), then, drop by drop, acetic anhydride (7.1 * 4- g, 70 millimoles ). The clear yellow solution is stirred at - * f0 °. It is then poured onto a mixture of ice and 1 N hydrochloric acid with a pH of 6 and the layers are separated. The organic solution is washed with 1 M sodium bicarbonate and brine. It is dried over sodium sulfate and evaporated to dryness to obtain 3.8 g of a solid residue. This is treated with pentane and filtered to obtain 3.7 g (96.8 #) of a white solid with a m.p. 125 - 127 °. The IR spectrum (pure compound) includes signals for -O = 172 cm “1 (H - ^ C-) and 1750 cm“ 1 (ß-lactam). The 1 H NMR spectrum (CDCl 4) includes the following signals: 7.1 (H, s, H —— CX 6.8 - 7.7 (15H, m), M (H, m), _ M5 <* , J = 1.5), 3.7 (H, m, J = 1.5, J = 7). 1 "* f (2H. M). 0.95 f9H. al. 0.8 fiïï. t 1 and 0.1 nrrni (6Η} s).

Analysis for C ^^^ NO ^ SSi:

Calculated: C, 70, ^ 2; H, 7.20; N, $ 2.57.

Found: C, 70.20; H, 7.33; R, $ 2.73.

(R.3SAR and S. ^ R.lj ^ d-fl’-fformyloxy-l'-propvl) - ^ - tritylthio-2-azetidinone (isomer B).

OCHO OCHO

—S ΞΤΓ r »STr

1 HMPT ΊT

DD + NaN_ - * I

0 ^ "\ SiMe 1 °% h2 ° CT“ N \

Sodium azide (0.91 g, 1 ^ millimoles) is added to a cooled (ice bath) solution of the starting azeti-dinone (3.7 g, 6.77 millimoles) in hexamé-thylphosphorotriaraine (* + 0 ml) containing 10 $ of water. The mixture is stirred for 90 minutes at room temperature.

* It is poured onto 200 ml of Jea, ice-cold and an ether extraction is carried out (* f x ^ 0 ml). We dilute 1a. ethereal solution with petroleum ether and washed thoroughly with water and 1a. brine to remove hexamethylphosphoro-triamide. The organic phase is dried over sodium sulfate and evaporated to dryness to obtain 2.92 g ($ 100) of a thick colorless oil. The RM spectrum of (CDCl ^) includes the following signals c>: 8.1 (H, HC -, S), 7.1 - 7.7 U5H, m, STr), 5.23 (H, m, J = 7), 38 (H, d, J = 2.5),> +, 3 (H, -KH), 3.35 (H, dd, j. = 2.5, J = 7), 1, 75 (2H, m) and 1.0 ppm (3H, t).

_ (l'R ,, 3S, ifR et l? S.8R.ifS) -Wl'-Eormyloxy-l, -éthvl ') - l- (p-ni trobenzyl-2ll-hydroxv-2 "-acetate tritvlthio- 2- azetidinone (τη isomer.

OCHO 'OCHO

j ± STr 1 .STr | - | PNB GLYOXYLATE | [

^ \ H And ^ N / THF V 0 ^ V ^ X0H

CO PNB 2

Stirred for 18 hours, at room temperature, a mixture of 3- (l, -i, ormyloxy-l, -propyl) -if-tri-tylthio-2-azetidinone (isomer B), (2.9 g, 6.77 millimoles), p-nitrobenzyl glyoxylate (1.59 g, 7 millimoles), triethylamine (5 drops) and anhydrous sodium sulfate (5.0 g) in tetrahydrofuran (50 ml). The mixture is filtered and the filtrate is evaporated to dryness to obtain if, 33 g ($ 100) of an amorphous solid. The RM spectrum of (CDCip includes the following signals 6: 8.2 (2H, d), 7.1 - 7.8 (18ü, m), 5.2 (2H, d), if, 9 (H, m ), if, 65 and M [H, if, 65 (1 / 2H, s), if, 3 (1 / 2H, s)], if, 2 - if, 3 (H, d, 1 / 2H to if , 2, 1 / 2H at if, 3), 3.65 (H, m), l, if (2H, m) and 0.8 ppm (3H, t).

(the R. ^ ifR and the S. ^ R.ifS ^ -l-d'-gormyloxy-l ^ -propyD-l-CO- 'nitrobenzvl ~ 2ll-chloro-2ll-acetate) -if-tritvlthio-2- a, zetidinone (isomer B).

? CH0 OCHO

_f> STr ^ STr j Py / THF · - | —r cr "- * 1 '^ 00 soci2 / thf *

C02PNB C02PNB

A 1 M solution of thionyl chloride in tetrahydrofuran (8 ml, 8 mmol) is added dropwise to a cooled solution (salt and ice bath), of the above glyoxylate (b, 3 g, 6 , 77 millimoles) in dry tetrahydrofuran (30 ml) containing a 1 M solution of pyridine in tetrahydrofuran (8 ml, 8 millimoles). The resulting solid mixture is stirred a. the above temperature for 1 hour. Dilute it with benzene (30 ml) and continue stirring for 20 minutes. The mixture is filtered through Celite and charcoal, then the filtrate is evaporated to dryness to obtain * +, 1 g ($ 92) of an amorphous solid. The IR spectrum (pure compound) includes signals for V = 1720 cm-1 (H _2i5C-), 1750 cm “1 qm cix (-C- ~ 0PNB) and 1780 cm" 1 (ß -lactam). The MIR spectrum of 1 c H (CDClp) comprises the following signals o: 8.25 (2H, d),

0V

7.8 (H, s, H -lC-), 7 - 7.75 (17H, m), 5.25 (2H, d), i 5.0 (H, m), V, 6 (H, s), b, k (H, d), 3.7 (H, m), 1.6 (21%, m) and 0.9 ppm (3H, t).

(the R. ISAR and the S.! R.i + Sj-l- (l'-Bormvloxv-l'-propvl ') - l- (p-nitrobenzvl-2ll-triphénvlphosphora.nvlidene-2ll-acetate) - * -i ~ tritvlthio-2-azetidinone (isomer B).

OCHO ........ OCHO

03P dioxane

Cr lutidine 0 ^

CO PNB CO_PNB

* 2

The mixture is heated for 2 days at 100 ° in an oil bath, a mixture of the above chlorinated compound (* f, 0 g, 6.07 millimoles), triphenylphosphine (1.83 * + g, 7 millimoles) and lutidine (0.7 ^ -9 g, 7 millimoles) in dioxane (UO ml).

The mixture is cooled, diluted with ether and washed with 1 M sodium bicarbonate and brine. The organic phase is dried over sodium sulfate and filtered through celite and charcoal. The filtrate is evaporated to dryness to obtain an oil which is chromatographed on 200 g of silica (activity 1), which is eluted with benzene and a mixture of benzene and ether to collect 2.60 g (kôdu compound sought which is an amorphous solid.

The IR spectrum (pure compound) includes signals for i 0. 1 ”OmaV = 1720 cm" -1- (H —— C-C-) and 1750 - 1760 ckl

IilcLÂ.

(-CO ^ PNB and ß-lactam).

(the R. ^ SAR and the S. ^ R.ifS) -if-Acétvlthio-l- (l'-formvloxv - l'-nroryl ') - l- (u-nitrobenzvl-2 "-triΌhénvlphos · phoranylidene- 21, - a.cetate) -2-azetidinone (isomer B ').

OCHO OCHO; \ A, - ^ STr _ ^ SAg '* cJ — 1

CO PNB CO PNB

2

OCHO

Ογγ ““

”J

co2pnb

A hot (60 °) solution of 0.15 M silver nitrate in methanol (8.7 ml, 1.3 millimole) is added to a mixture of the above phosphorane (0.88 g, 1 millimole) and of pyridine (0.103 g, 1.3 millimole) in methanol (5 ml) which was heated to 60 °. The mixture is stirred at the tem- ηρΤ’Ρ + '.' ΠΤ’Ρ amhi anfo rionflant 1 K mï mitae û + - q Γ) ο nonflnrvh 9 Vl ΡΠ T * P S _

It is filtered and the solid is washed with cold methanol to isolate 0.53 g ($ 71) of the silver mercaptide which is a yellow solid which is used as it is. Acetyl chloride (79 mg, 1 millimole) in methylene chloride (5 ml) is added dropwise to a cooled mixture (ice bath) of the above mercaptide (0.53 g, 0, 71 millimole) and pyridine (79 mg, 1 millimole) in methylene chloride (10 ml). After 1 hour of stirring at 0 °, the mixture is filtered. The filtrate is washed carefully with cold 0.5 M hydrochloric acid, 0.5 M sodium bicarbonate and brine. The organic phase is dried over sodium sulfate and evaporated to dryness to collect 0.23 g (63%) of an oil. The IR spectrum (pure compound) includes signals for V = 1700 - 1760 cm ”1 q max (wide —C £ andß -lactam).

(R.SAR and S.S, 3RAS) -Acetylthio-3- (l'-hYdroxy-l'-1 propvl-1- (O-nitrobenzvl-2l, -triphenvlphosOhoranylidene-2n- a.cetate) -2-azetidinone (isomer B).

OCHO PH

, vLyslc vA. — s TT HCl / MeOH 1 |

èojnm C02PKB

At room temperature, 1.0 g (1.5 μmol) of the above formate is added to tetrahydrofuran (10 ml) of methanolic hydrochloric acid (10 ml, obtained from 2 ml of (concentrated hydrochloric acid which has been diluted to a total volume of 2 ml with methanol). The mixture is kept at 1a. room temperature for 30 minutes. It is made alkaline with 1 M sodium bicarbonate, relating to brine, then dried over sodium sulfate. The extract is evaporated to obtain 0.9 g of the crude desired compound. This is chromatographed on silica which is eluted with ether and a 1: 1 mixture of ether and ethyl acetate in order to obtain 0.6 g (62.5 $) of the compound sought pure which is an amorphous solid. The NMR spectrum of (CDCl 4) comprises the following signals S: 8.25 (2H, d), 7? 3 - 8.1 (17H, m, aromatic), 5.6 (H, m), 5? 2 (2H), ^, 9 (H), (H, m), 2.3 (3H, · SAc), 1.5 (2H, m) and 0.9 ppm (3H, t). (R, 1R.6S and S. 5S.6R) -6- (1'-Hvdroxy-l'-OroOVl) -2-methvlpénème-3-carboxvlate of u-nitrobenzvle (B isomer).

νΛ, _ P * h3 - ‘A /" "3

CO PNB CO PNB

2 c »

0.2 g (0.3 millimole) of the above phosphorane is heated to reflux in toluene ml) and 5 ml of toluene is distilled off. The resulting solution is heated at reflux for 6 hours. It is cooled and evaporated to dryness to collect 0.2 g of an oil.

This is chromatographed on silica which is eluted with ether to obtain 0.1 g ($ 87) of the desired compound which is a white solid having a m.p. of 133-135 ° (pentane). The H NMR spectrum (CDCl 4) includes the following signals: 8.3 (2H, d), 7.6 (2H, d), 5) 6 (H, d), 5) 35 (2H, d) , M5 (H, m), 3.8 (H, m), 2, k (3H, s, CH3), 2.2 (Π, 0H), 1.7 (2H, m) and 1.05 ppm (3H, t).

Salt, potassium and sodium salt of acirip f]? Rr 5fL 68 ^ et 1 * S. 5 S, 6R) - 6-g '-hydroxy-1' -propyl) -2-methylpéneme- 3-carboxvliaue (isomer B-).

OH Oh jX) - “· -1 0eQ-“.

C02PNB \ ° 2_ (Na + K)

Hydrogenation is carried out for 1+ hours, at an initial pressure of 3.37 kg per cm, of a mixture of the above ester (0.07 g, 0.185 mole), Celite palladium-plated at $ 30 (150 mg) and buffer solution (pH 7? ^ ml) in a mixture of tetrahydrofuran (15 ml), ether (25 ml) and deionized water (15 ml). The mixture is filtered through. Celite and we separate the phases. We wash 1a. aqueous phase with ethyl acetate, then lyophilized to obtain 91 mg of a solid. The IR spectrum (KBr) includes signals for ~ ^ max = 1780 cm 1 (^ 5 -lactam) and 1650 cm ”1 (wide, -C09). The spectrum U? (Ho0) includes Ov. at 255 nm (£ 983) and 300 nm (£ 1092).

-EXAMPLE 50.-

Acid (l'R, 5R, 6S and l'S, 5S, 6R) -6- (l'-hydroxy-2'-phenylethyl) - 2-methylpénème-3-carboxyliaue (isomer B).

h., jm OC— I> -CB, 3 ^ co2h

Trans - l - (, t-butyldimethylsilyl) -3-uhénvlacétvl - I <- tritYlthio-2-azétidlnnne.

—F ^ Tr I + LDA. + φΟΗ CO Et -? * · j N-SiM ^ o <J_N_SiMe2

A solution of lt-butyldimethylsilyl - ^ - tritylthio ^ -azetidinone (18.32 g, * f0 millimoles), in dry tetrahydrofuran (100 ml) in nitrogen atmosphere is added dropwise to a cooled solution (- 78 °) of lithium diisopropylamide (prepared in a nitrogen atmosphere at -78 ° by dropwise addition of 1.6 M n-butyllithium (101.25 ml, 162 millimoles) to diisopropylamine (22.95 ml, 162 millimoles) in dry tetrahydrofuran (150 ml) and by stirring at -78 ° for 30 minutes].

,. The mixture is stirred at -78 ° for 30 minutes and ethyl phenylacetate (15.66 g, 15.12 ml, 93.6 millimoles) is added to it in dry tetrahydrofuran (50 ml), then the mixture is stirred reaction at -78 ° for 2 hours. The reaction mixture is poured into a mixture of 1N hydrochloric acid and ice (pH 5 to 6) and the whole is extracted several times with ether. Wash 1a, ethereal solution with brine and dry, over sodium sulfate. It is evaporated at any time to obtain 33? 7 of a crude solid. This is dispersed in ether (10 ml) and triturated in pentane '(200 ml). The solid is collected by filtration and washed several times with pentane to collect 18.3 g (79.6%) of a white solid having a PF of 1 * 4-1 - 1 * 4-3 ° · The spectrum NMR of (CDCl ^) comprises the following signals S: 7.0 - 7.6 (20H, m), M (H, d), 3.7 (H, d), 3.53 (H, s), 3, ^ 3 (H, s), 1.5 (9H, s) and 0.3 ppm (6H, s).

1- (t-Butvldiméthvlsilvl-3- (1 '-hydroxv-2'-phenvl éthvl) -!) · - tritvlthio-2 ~ a.zetidinone (2 diastereoisomers transi.

OH

_ ♦ vA_> âIr J— K-saie2 J— N- ^ iMe2

The mixture is stirred for 18 hours at room temperature of 1a. tra.ns-l- (t-butyldimethylsilyl) -3-phenyl-acetyl-1f-tritylthio-2-a.zetidinone (28.8 g, 50 millimoles) and sodium borohydride (^ g, 0.25 mole) in tetrahydrofuran (200 ml). The reaction mixture is poured onto a mixture of ice and 1N hydrochloric acid and the whole is extracted with methylene chloride. Wash 1a. organic solution at 1a. brine and dried over sodium sulfate. It is evaporated to obtain 27.7 g of an amorphous solid. A fraction (23.0 g) of this solid is chromatographed on silica which is eluted with a mixture of hexane and ether to obtain 1 * -) -, * + g ($ 60) of a solid off-white which turns out to be a mixture of the isomers (the R, 3S, ^ and the S, 3R, HS) - and (the S, 3S, ^ R and the H ^ Rj ^ S) in the ratio of 1: 1 . The NMR spectrum of (CDCl 4) comprises the following signals S: 7 - 7.7 (20H, m), * f, 37 (1 / 2H, d), lf, 18 (1 / 2H, d), 3, 3 - 3.8 (H, m), 3Λ5 (1 / 2H, dd), 3.1 (1 / 2H, dd), 2.7 (2H, m), 0.87 (9H, d) and 0 , 25 PPm (6H, s).

} i l-ift-Butyldimethylsilvl ’) -λ- (1} -formvloxv-2 '-phenvléthvl) - * f- tritvlthio-2-azetidinone.

0H a

± (, H OCHO HCO

φνΛγυ5τγ φΟ <γ_ ^ 8τι ôCp-Y'511 QJ N ~ ^ | iMe2 O J —'N ~ 3 | _iMe2 N— | iMe2

isomer B isomer C

Triethylamine (15.93 ml, 125 millimoles), formic acid (2.2½ ml, 59.76 millimoles) and ^ -dimethylaminopyridine (3.0½ g, 2 ^ 9 millimoles) are added to a solution cooled to · Λθ ° of the above mixture of alcohols (1½} ½ g, 2½} 9 millimoles) in methylene chloride (250 ml). After 5 minutes of stirring, acetic anhydride (2.35 ml, 2 ^ 9 millimoles) is added dropwise. We shake it. clear solution at -UO ° for t 15 minutes a.At the end of which it becomes white and cloudy. The mixture is stored at Λθ ° for another ½5 minutes (total duration of 60 minutes). It is then poured onto a mixture of ice and 1N hydrochloric acid, then the layers are separated. The organic solution is washed thoroughly with cold 1 N hydrochloric acid, water, 1 M sodium bicarbonate and brine. It is dried over magnesium sulfate and evaporated to obtain 1 ^ 0 g of an amorphous solid. This is fractionated by means of high pressure liquid chromatography (Water Associates, System 500) to obtain 6.0 g of the B isomer having a PF of 172 - 173 ° and 6.0 g of the C isomer having a PF of 188 -I890. The total amount of pure compound is 12 g ($ 73.2). The C isomer has an RM spectrum of (CDCl ^) comprising the following S signals: 6.8 - 7.7 (21H, m), 5.05 (H, dt), .½ ^ 05 (0H, d) , 3.65 and 3.75 (H, two doublets), 2.7 - 2.9 (2H, d), 0.88 (9H, s) and 0.2 ppm (6H, s). Isomer B has a 1 H NMR spectrum (CDCl 4) comprising the following signals: 7.75 (H, s), 6.9 - 7.5 (20 H, m), 5-, 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- (1'-Formyloxy-2’-phenylethyl) -5 - tritylthto-2-azetidinone- (lrR., 3S.5-R and S "3R.5-S- enantiomers).

H OCHO

^ yr0CE0 STR KX / STr A-_p2 ^

isomer B

Sodium azide (1.3 g, 20 millimoles) is added to an ice-cooled solution of the above formate (5.9 g, 9.375 millimoles) in hexamethylphosphorotriamide containing 10 # d water (50 ml). The mixture is stirred at room temperature for 90 minutes. It is poured into 300 ml of ice water and the whole is extracted with ether (3 x 100 ml). The ethereal solution is washed thoroughly with • water and brine. It is dried over sodium sulfate and evaporated to obtain a solid residue. Petroleum ether is added thereto, then filtered to give 5-.5 g (92 #) of a white solid with a pH of 169-170%. The NMR spectrum of (CDCl 4) comprises the following signals 6: 7.9 (H, s), 7.1 - 7.6 (20H, m), 5.5- (H, m), 5-, 6 (H, NH), k, 2 (H, d), 3.3 (H, dd), 3.15 (H, s) and 3.0 (H, s).

Analysis for C ^ H ^ NO ^ S:

Calculated: C, 75.5-3; H, 5.51; .N, 2.8 * #.

Found: C, 75.05-; H, 5.65-; N, 2.78 #.

3-ClJ -Formvloxy-2? -phenylethvl ') - l- (p-nitrobenzvl-2 "-hvdroxy-211-

a.cetate) -if-tritvlthio-2-azetidinone (R.3S.ifR and S.lR.ifS

enantiomers).

H OCHO. H, OCHO

φ ^ V> STr Ψ \ Χ_ ^ STr

rf -► nT

./Bis's

CO GNP

at

We change at reflux for 2 hours in a device.

O

Reil of Dean & Stark containing 3 A molecular sieve, a suspension of glyoxylate. p-nitrobenzyl (2.37 g, 10.16 millimoles) in benzene, dry (100 ml). The above azetidinone (* +, 2 g, 8.537 millimoles) is then added and the heating is continued at reflux for 60 minutes.

The mixture is cooled to room temperature and triethylamine (0.12 ml, 0.85 millimole) is added thereto, then the new mixture is stirred at room temperature for 90 minutes. It is dried to dryness to obtain $ 100 of the desired compound, which is a mixture of two isomeric alcohols. The NMR spectrum of (CDCl 4) includes the following signals 6: 8.0 - 8.3 (2H, two doublets), 7.5 and 7.6 (H, two singlets), 7.0 - 7, * + (20H, m), 5.25 (2H, d), il ·, 9 (H, 0H), if, 25 and if, 35 (H,: two doublets), 3.5 - 5 (H, m, broad), 3.1 - 3.3 (H, m) and 2.9 ppm (2H, m).

λ- (1 * -Formyloxv ^ -nhenylethvl) -1- (ü ~ nitrol) enzyl-2, t-chloro-2'1-acetate) A-tritvlthio-2-azetidinone QUASAR and 1; S.3RAS. enantiomers) · H OCHO, H · ...> 0CH0

C02PNB C02PNB

A 1 M solution of pyridine in tetrahydrofuran (10 ml, 10 mmol) is added, then, dropwise, a 1 M solution of thionyl chloride in tetrahydrofuran (10 ml, 10 mmol) to a solution. cold (salt and ice bath) of the above glyoxylate (6.0 g, 8.537 millimoles) in dry tetrahydrofuran (30 ml). After 1 hour at 1a. above temperature, dilute >> the mixture with benzene (30 ml) and continue stirring in the fridge for 30 minutes. The mixture is filtered through Celite and charcoal and the drier filtrate is evaporated to give 6.0 g ($ 98) of an amorphous solid. The NMR spectrum of (CDCl 4) comprises the following signals S i 8.2 (2H, m), 7 - 7.7 (23H, m), 5.8 (H, s), 5.25 (2H, s ), 35 (H, d), 3.5 - M (H, m), 3.3 (H, m) and 2.9 ppm (2H, d).

3- (1 * -fformyloxy-23 - phenvlethvl) -1- (n-nitrobenzvl-2 ,, - triphenyl-phosohoranvlldène-2lt-a.céta.te,) - V-tritvlthio-2-azétidinone (l'-R .3SAR and 1S.3RAS enantiomers).

ΦνΧ_> Ka —S

CO PNB CO PNB

2

The mixture is heated at 110 ° (bath temperature) for 18 hours a mixture of the above chlorinated compound (6.0 g, 8.333 millimoles), triphenylphosphine (2, ^ 89 g, 9.5 millimoles) and lutidine (1 , 0165 gj 1.1 ml, 9.5 millimoles) in dioxane (50 ml) · The mixture is cooled and filtered through Celite, the filtrate is diluted with ethyl acetate and washed with cold 1 N hydrochloric acid, water, 1 M sodium bicarbonate and brine. The organic phase is dried over sodium sulfate and evaporated to give 8.0 g of a Crude product is chromatographed on silica which is eluted with a 1: 1 mixture of ether and hexane, then ether to obtain * f} 0 g (51 $) of the compound sought consisting of needles having a mp of 235-237 ° (decomposition) after crystallization in ether.The IR spectrum (layer) includes signals for = * 1720, 1750 cm-1.

* + - Acetylthio-3- (1 '-f ormyloxv-2' -hhenvlethyl) -1- (p-nitro-benzyl-211 -triphenyluhosphoranylidene-2tl- acetate) -2-azetidinone (R, 3S, l + R and S, 3RAS enantiomers).

H. OCHO H QcnQ H 0CH0

KX> STr * 0 <> S * g * nX_% SÂC

Ο ** - “γΡφ3

CO ^ NB CO ^ PNB C02PNB

A 0.15 M solution of silver nitrate in methanol (28 ml, k-, 2 millimoles) is added dropwise to a solution boiling at reflux of the above phosphorane (3.6 g, 3, 8 millimoles) and pyridine (0.33 g, * +, 2 millimoles) in methylene chloride (30 ml) and methanol (30 ml). The mixture is stirred at room temperature for 135 minutes. It is then concentrated to a small volume (about 10 ml), then cooled and filtered to isolate 2.3 g (77%) of the silver mercaptide which is a yellow solid. Acetyl chloride (0.27 g, 3.5 millimoles) in methylene chloride (5 µl) is added dropwise to a mixture of this mercaptide and pyridine (0.277 g, 3.5 millimoles) in ice-cold methylene chloride (20 ml). The mixture is stirred at room temperature for 3 hours. Filter it through Celite, wash the filtrate with cold 1N hydrochloric acid, water, 1H sodium bicarbonate and brine. We dry 1a. organic phase on magnesium substrate and evaporated to dryness to obtain 1.0 g ($ 89.8) of an amorphous solid. The 1 H NMR spectrum (CDCl 4) comprises the following signals 8: 8.2 (2H, d), 7.0 - 8.0 (23H, m), k, 5 - 5.7 M, m), 2 , 6 -! 3.3 (3H, m) and 2.3 ppm (2H, d ,. SAc).

Acetylthio-3- (1 '-hydroxy-2' -phenylethyl) -! - (p-nitrobenzyl- • S '^ triphenylphosphoranylidene-2 "-acetate) -2-azetidinone (R, 3S, * + R and S ^ Enantiomeric RAS).

H .. xOCHO. H ...> oh m> SAc _> SAc J — 1

CO ^ PNB ï ° 2PNB

A solution of the above phosphorane (1.8 g, 2.16 - 16 millimoles) in tetrahydrofuran (10 ml) is stirred for at hours at room temperature after adding 10 ml of a mixture of 1N hydrochloric acid and methanol. The mixture is concentrated to remove the methanol, then diluted with cold water and alkaline with 1 M sodium bicarbonate before extracting with chloroform. The chloroform solution is dried over magnesium sulfate and evaporated to give 1.65 g of an amorphous solid. This is chromatographed on silica which is eluted with a mixture of ether and ethyl acetate to obtain 1.30 g ($ 75) of the desired compound. The NMR spectrum of (CDCl ^) includes the following signals <5: 8.2 (2H, d), 6.7 - 8.0 (22H, m), * +, 0 - 6.0 (5H, m) , 2.5 - 3.5 (3H, m) and 2.2 ppm (3H, SAc).

6- (1’-Hydroxy-2’-phenylethvl) -2-methylüénème-3-carboxylate p-nitrobenzvle (the R.5R.6S and the S.5S.6R enantiomers).

H · ..> oh h. jPh

_ ^ SÂC

CO PNB CO PNB

ί 2 z

A solution of the above phosphorane (1.2 g, 1.67 millimole) in toluene (80 ml) is heated at reflux for 6 hours, distilling off 10 ml of distillate to remove humidity and low solvents. boiling point present. The mixture is evaporated to dryness and the crude product is chromatographed on silica. By elution from the column with ether, 0.65 g (89 ^) of the desired compound is obtained, which is an amorphous solid. The NMR spectrum of ^ H. (CDCl ^) includes the following signals 6: 8.2 (2H, d), 7.6 (2H, d), 5Λ (H, d), 5.2 - 5Λ (2H, d) , M - ^, 5 (H, m), 3.7 - M (H, dd), 3.0 (2H, d) and 2.3 ppm (3H, s).

6- (1 ’-hvdroxy-2’ -phenylethyl) -2-methylpenem-3-carboxylic acid (R, 5R-% 6S and S, 5S, 6R enantiomers).

gold, H 'OH

_r-S \ —T ^ SV_ - * J- ^ c *

OOjPNB c02H

Hydrogenated for 2k hours, under an initial pressure of 3.52 kg pa, r cm, a mixture of the p-nitro-benzyl ester (0.33 g, 0.75 millimole), of 0.05 M buffer solution (pH 7j 17, * + ml), tetrahydrofuran (30 ml), ether (30 ml), distilled water (60 ml) and Celite palladium at $ 30 (0.69 g). The mixture is filtered through Celite and washed 1a. organic layer with water. The mixture of aqueous phases is washed several times with ethyl acetate, then lyophilized for 18 hours to obtain the desired compound which is in the form of a yellow solid salt. Add a little water to the salt and acidify the mixture with cold 1 N hydrochloric acid, • then carry out an extraction with chloroform. The chloroform solution is dried over magnesium sulfate and evaporated to obtain a solid residue. Add ether to it and filter to collect 30 mg ($ 13.2) of a white solid with a m.p. 165 - 167 °. The IR spectrum (nujol) includes signals for λ) = 3580 cm "" *** (0H, acute), 1660 and I76O cm ***. The UV spectrum (methanol) includes at 310 nm (ε 5 ^ 90) and 2 $ k nm (ε ^ 880).

EXAMPLE £ L.-

Acid (VR.5R.6S and VS. 5S. 6R) -6- (2'.2'-dimethyl-l '. 3; -άΐοχο-lane-V -yl V2-methylpenene-3-carboxylic acid (C isomer) .

v>.

co2h A. Preparation of ¢ 1 ..> SIr Ö -._ xSTr / and <Τ ~ Ν \ /

/ six / V

i. (VR, 3S,! + R and VS ^ VS) and (VS, 3S, Vl and ^ »R, 3R, ifS) -l- (t-

Butyldimethylsilyl) -3- (2 ', 2; -dimethyl-1', 3 "-dioxolane-V-yl) -Vtritylthio-2-.azetidinone (isomer C and isomer B).

Ethyl 0- (2-Methoxy-2-propyl) glycolate ^

B <\ A —bMe ”y> vA

0And ïôcT Λ ^ 3 OMe At a temperature of 0 to 5 °, add phosphorus oxychloride (3 drops, 35 mg, 0.23 millimole) to a solution of ethyl glycolate, (1536 g, 0.150 mole , freshly distilled) and 2-methoxypropene (16, g, O) 0.216 mol, 35% titer)} in methylene chloride (150 ml) and the mixture is stirred at 0 - 5 ° for 15 minutes and at room temperature for 9 ° minutes. 30 drops of pyridine are added to the mixture, which is then stirred for minutes before evaporating the solvent. The residue is diluted with 150 ml of pentane and dried over potassium carbonate. After filtration, the solvent is removed to obtain 27.89 g (0.158 mol, $ 100, titer of $ 9 ^ 9) of the desired compound which is a colorless oil. The NMR spectrum of (CCl ^) includes the following signals 6: 1.25 C3H, t, J = 7 Hz, -CH2CH3), 1.28 (6H, s, Me2), 3.12 (3H, s, - 0CH3), 3.88 (2H, s, --OCH ^ O-), if, 10 (2H, q, J = 7 Hz, -ŒLCH-J. The IR spectrum (pure compound) includes —1 signals for Ό 1760 and 1735 cm (ester).

Dl 3.X

1) J. Meinwald et al. Tet. Lett., * F327 (1978).

2) M.S. Neman and M.C. Vander Zwan, J. Org. Chem., 38.5 2910 (1973).

HS AR and IR.ifS) -1- (t-Butvldimethvlsilvl) -3- (1'-keto-2 '- (2lt-methoxv-2ll-isoΌropyloχy) -l'-ethyl) -if-tritvlthio-2-h azetidinone.

_j ^ STr 1) LDA / THF_ ^ QL STr 21 χηι As / / X. OMe /

In a nitrogen atmosphere, n-butyl lithium (1.6 M in hexane, 9 ° ml, Ο, ΐΑ mole) is added to a stirred solution of diisopropylamine (18.5 ml, 0.13 ^ mole ) in tetrahydrofuran (if00 ml, freshly distilled on lithium aluminum hydride) at -78 °. After 30 minutes, a solution of 1- (t-butyldimethylsilyl) -if-tritylthio-2-azetidinone (50.0 g, 0.109 mol) in tetrahydrofuran (100 ml) is added dropwise over 10 minutes. mix for 5 minutes. To this pink solution is added ethyl 0- (2-methoxy-2-propyl) glycolate (23.9 ^ g, Ο, 136 mole) and the mixture is stirred for 60 minutes. After removing the dry ice bath, add a saturated solution of ammonium chloride (200 ml), then brine (100 ml). The aqueous phase is extracted with ether (3 x 100 ml). The combined organic extracts are washed with 1a. brine and dried over sodium sulfate, then evaporated to obtain 60.95 g (0.103 mole, crude yield 9 ^, $ 6) of the desired compound which is an orange oil. We use this gross product as is for the. next reaction. By chromatography on a column of silica (which is eluted with 2 $ of ethyl ether in benzene), a pure sample is obtained. The BMW spectrum of% (CDCl ^) includes the following signals <5: 0.30 (6H, s, Si-CH ^), 0.95 (9H, s, t-Bu), 1.12 (3H, s , CH3), 1.15 (3H, s, CH ^, 3.15 (3H, s, 0CH3), 3.57 (1H, A from Ab, Jgem = 17 Hz), 3.77 UH, d, » J = 1.6 Hz, H-3), 3.97 UH, B from AB, Jgem = 17 Hz), è-, 83 (1H, d, J = 1.6 Hz, Rb), 7.1 - 7.6 (15H, m, Hs ar.oma-tick). The IR spectrum (pure compound) includes signals for = 1750, 1725, 1710 cm-1 (C = 0). Thin layer chromatography indicates an Rf of 0.53 (benzene: ether * +: 1) and an Rf of 0.61 (hexane: ethyl acetate 2: 1).

(3SAR and 3R „* fS) -l- (t-Batyldimethylsilyl) -3-U’-hydroxy-2’-methoxyisopropvloxvéthvl) -Utritylthio-2-azetidinone (mixture of the I spines.

> C ~ \ -YSTr ^ u ^ wSTr

'x / V

Diluted with absolute ethanol (350 ml), a solution of 1- (t-but yldimethyl silyl) - 3- (1? - ce t o-2 '- (2 "-methoxy-2" -isopropyloxy) - l, -éthyl) -1f-tritylthio-2-azétidinone crude (60.95 g, 0.103 drown) in tetrahydro fur armed (100 ml) and to this solution is added at 0 °, sodium borohydride (* 4- , 88 g, 0.156 mole). The mixture is stirred at room temperature for 2 hours, then the reaction is stopped by the slow addition of 280 ml of brine. The mixture is extracted with ether (3 x 150 ml) and the extracts are washed with brine, then dried over sodium sulfate and evaporated to obtain a crude residue which is redissolved in methylene chloride ( 500 ml). The organic solution is dried over sodium sulfate and evaporated to give 57-1 g (96.6 millimoles, crude yield $ 9,358) of the crude target compound which is a yellow frothy substance. The NMR spectrum of (CDCl ^) includes the following δ signals: 0.17 (s, SiCH ^), 0.80, 0.87 (2s, Si-tBu), [1.22, 1.25 (2s, CH3), 3.03 (s, 0CÏÏ3), 32 (d, J = 2 Hz, H-il ·), 7.0 - 7.7 (n, H aromatics). The IR spectrum (pure compound) includes signals for * 0 = 3 * 4-60 cm ~ ^ (0H), 17 ^ 5 cm (C = 0), 1595 cm ^ (aromatic). Chromatography reveals Rf of 0, * f7 and 0, * + 2 (hexane: ethyl acetate 2: 1). The crude compound is used without further purification in the next stage.

(iHR. ^ S.mt and if'S. IRAS) and (k'S ^ SAlt and ih "R.3RAS) -lt-Butvldiméthvrlsilvl ') - 3- (2', 2'-dimethyl-l '" ν-άΐοχοΙηηθ-Λ '-νΙ1) -intritylthio ^ -azétidinone (isomer C and isomer B).

V ^ 'JL _ / ‘STr p-tsOH-h2o _ (^ ΤΓ" te J_] i, v ° Me J-h / / XoHa *> <,

/ X / X

P-toluenesulfonic acid monohydrate (200 11¾) and 2,2-dimethoxypropane (20 ml) are added at room temperature to a solution of (3S, 5-R and 5R, 5-S) -l- (t-butyldimethylsilyl) -3- (1'-hydroxy-2 '-methoxyisopropyloxyethyl) - 5 - tritylthio-2-azetidinone (mixture of diastereoisomers in 1', 57.1 g, 96.6 millimoles, compound crude) in methylene chloride (500 ml), then the mixture is stirred for 1 hour. It is washed with saturated sodium bicarbonate, then brine and dried over sodium sulfate, after which it is evaporated to obtain 5-9.65 g (88.8 millimoles, yield 91.9 $) of a mixture of the desired compounds (isomer B and isomer C) in the form of a yellowish frothy substance. This is purified by liquid chromatography under high pressure (silica gel, "Waters 5 °°, elution with a 9: 1 mixture of hexane and ethyl acetate) and by crystallization to obtain f 15-, 28 g (25.5 millimoles, $ 26.5) of the desired compound (isomer C) consisting of white crystals having a PF of 15-6 - 15-7 ° (pentane). The NMR spectrum of (CCl ^) includes the signals Following 6: 0.27 (6H, s, Si-CH ^), 0.95 (9H, s, Si-tBu, - 1.15 (6h, s, di-Me), 2.5 - 2.9 (1H, m, H-5- '), 2.97 (1H, t, J = 1.8 Hz, H-3), 3.25 - 3.9 (2H, m, H-5'), 5-, 27 (1H, d, J = 1.7 Hz, H-5-), 7.1 - 7.6 (15H, m, H aromatic). The IR spectrum (nujol) includes signals for = 1750 cm-1 (C = 0) and 1595 cm-1 (aromatic). Chromatography reveals an Rf of 0.5-5 (hexane: ethyl acetate 5-: 1). We also obtain 15-, 5 g (25.9 millimoles, $ 25.9) of the other desired compound (isomer B) consisting of white crystals having a PF of lMf - 15-5 ° (ether-pentane). The NMR spectrum of (CCl ^) includes the signals <$ next s: 0.02 (6H, s, Si-Me), 0.833 (9H, s, Si-tBu), 1.13, l, l8 (6H, 2s, di-Me), 2.5 - 2.8 ΠΗ. m. H-5- ’). λ. 3 - 5-.1 (2H. M. H-5 ’).

3, H-8 (ih, dd, J3 ^ = 1.5 Hz, J3 _ ^ = 5.0 Hz, H-3), 3.93 (1H, 8, ^ _3 = Hz, H-lf) 3 _ 7? Y (15H, m, aromatic H).

The IR spectrum (nujol) includes signals for = _ m3, x Ί 1650 cm (0 = 0) and I595 cm ”^ (aromatic). Chromatography reveals an Rf of 0.37 (hexane: ethyl acetate ^: 1). Analysis for C- ^ H ^ No ^ SSi:

Calculated: C, 70.80; H, 7.38; N, 2.50; S, $ 5.73.

Found: C, 70.23; H, 7.30; N, 2, ^ 1; S, $ 5.53 (isomer C).

0.70.52; H, 7.31; N, 2, ^ - 0; S, $ 5.05 (isomer B).

3. Preparation of penetration Csnmère C).

Xk? 3.3 $ Jtft.-Λ- (2 ’, 2’ -Diméthvl-1 ’, 3’-dioxola.ne- l ^ -yl) - ^. Tritylthio-2-a7.étidinone (Ç isomer).

_ ^ * STr -f ~ \ I Y NaN3 -j> STr ssæç * -► Xï ^ t

A solution of sodium azide (2.50 g, 38 A millimoles, 1.5 equivalent) in water (25.6 ml) is slowly added (over 20 minutes) at 0-5 ° to a solution. agitated with (V'R ^ S ^ R and VS, 3R, ^ S) -l- (t-butyldimethylsilyl ·) - 3- (2 ', 2'-dimethyl-l', 3'- dioxolane-Λ ' -yl) -! + - tritylthio-2-azetidinone (isomer C) (1 ^, 3 g, .25.6 millimoles) in hexamethylphosphorotriamide (230, ml). The mixture is stirred at room temperature for 2 hours, then poured into 25ΟΟ ml of cold water. The resulting white precipitate is collected which is washed with water and dried to obtain II, 26 g (25.3 millimoles, gross yield $ 98.8) of the desired compound which is a white solid. By crystallization from a mixture of methylene chloride and ether, the pure compound is obtained having a PF of 192-193 ° following signals 6: 1.33, 1.37 (6H, 2s, di-Me), 3, 27 (1H, t, J = 3 Hz, H-3), 3.8 - if, »f (3H, m, H-if 'and H-5'), if, ifO (1H, d, J = 3 Hz, H-if), if, if7 (1H, si, NH, after exchange with D ^ O) and 7.1-7.7 ppm (1H, m, aromatic H). The IR spectrum (nujol) includes signals for = 3220 cm 1 (HH), I76O cm “1 (C = 0) and 1950 cm” 1 (aromatics). Chromatography indicates an Rf of 0.31 (hexane: ethyl acetate 3: 2). (if'R.lS.ifR and VS. 8R AS ~) -8- (2 '.2'-Diméthvl-l'.8'-dioxolane-if'-vl) -l- (O-nitrohenzvl-2tl- hvdroxv-2ll-acetate) -if-tritvlthio- 2-azetidinone (mixture of spines in 211) (isomer C).

.STr ÇHO STX

v'N— ~ r co2pnb —f çfr— NH Et N / THF ^ rJ -— N _ ~ ΟΗ

3 Y

C02PNB

K

The mixture is refluxed for 2 hours, using a Dean & Stark trap, a suspension of hydrated p-nitrohenzyl glyoxylate (6.57 g, 28.95 millimoles, 1.15 equivalent) in benzene (500 ml). By evaporation of the solvent, p-nitrobenzyl glyoxylate is obtained in the form of an oil. A mixture of this oil and (if'R, 3S, ifR and if'S, 3R, ifS) -3- (2 ', 2'-dimethyl-l', 3'-dioxolane-if'-yl) are reacted Jt-tritylthio-2-azetidinone (isomer C) (11.2 g, 25.2 millimoles) in tetrahydro fur armed (350 ml, distilled on lithium aluminum hydride) with triethylamine (289 mg, 2.86 millimoles) at room temperature in a nitrogen atmosphere for 18 hours. After evaporation of the solvent, the residue is diluted with methylene chloride (200 ml) and the solution is washed successively with brine containing 1N hydrochloric acid (2.9 ml), sodium bicar- and it is evaporated after adding 30 ml of ether to obtain 17.2 g (26.3 millimoles, $ 100, titre of $ 95.8) of the research compound which is a white frothy material having Rf of 0, if0 and 0.30 (benzene: ether 3: 2). Each isomer is separated by liquid chromatography under high pressure (silica, elution with a benzene: ether mixture 3: 2) and is purified by crystallization from a mixture of methylene chloride and ether.

The I isomer has an Rf of 0.1 + 0 (benzene: ether 3: 2) and a P .F. from 153 - 15 ^ °. The NMR spectrum of λΉ. (CDClg) includes the following 6 signals: 1.20 (6H, s, di-Me), 3.1 (2H, m, H-3 and 0H), 3.5 - M (3H, m, HV and H -5 "), V, 55 (1H, d, J = 2 Hz, H-if), 5.12 (1H, si, H-2"), 5.30 (2H, s, OCS ^ Ar) and 7.1 - 8.3 ppm (19H, m, aromatic H).

The IR spectrum (nujol) includes signals for "Ό = ma.x 3370. cm-1 (0H), 1775 cm-1 (y3-lactam) and 17 ^ 5 cm-1 * (ester).

Analysis for C ^ gH ^ N ^ OgS:

Calculated: C, 66.0if; h, 5.23; N, if, $ 28.

Found: C, 65.85; H, 5.6if; N, if, $ 11.

Isomer II has an Rf of 0.30 (benzene: ether 3: 2) and a m.p. lif - 165 °. The 1 H NMR spectrum (CDClg) comprises the following signals 6: 1.17 (6H, s, di-Me), approximately 3.2 (2H, m, H-3 and 0H), 3Λ - Μ (3H, m, H-if5 and H-5 '), 57 (1H, d, J = 2 Hz, H-if), 5.23 (1H, if, -2 "), 5.27 (2H, s, - OCH ^ Ar) and 7.1 - 8.3 ppm (19H, m, Aromatic H). The IR spectrum (nujol) includes signals for =

lïlclX

33if0 cm ”'*' (0H), 1765 cm (^ -lactam) and 17if0 cm” · * "(ester). Analysis for CggHg ^ NgOgS:

Calculated: C, 66, Qif; H, 5.23; N, if, 28; S, if, $ 90. .

Found: C, 66.01; H, 5.3 * +; if, 28; S, if, 75% - * (VR, 3SAR and 3'S. ^ RAS) -3 - (- 2 ', 2'-bimethyl-l'.3'-dioxolane- ^ 7-yl) -l- (p- nitrobenzvl-2 "-chloro-2" -acetate) - ^ - tritylthio- 2-a, zetidinone (mixture of epimers in 2 ") (isomer O.

- | ^ Tr SOCl2-Pyr - | ^ STr THF Qj_i 1 C02PNB co2pnb

Pyridine (2.8 ^ ml, 35.1 millimoles) is added at -15 °, in a nitrogen atmosphere, and immediately thereafter thionyl chloride (2.20 mL, 30 µl millimoles, Company Anachemia). stirred solution of (3;, Η, 38, ^ and if'S, 3R, ^) - 3- (2 ', 2'- dimethyl-1J, 3 * -dioxolane - ^' yl) -! - (p-nitrobenzyl- 2 ,, - hydroxy-2,1'-acetate) -k-tritylthio-2-azétidi-none (isomer C) (17.13 g, 25.07 millimoles, mixture of epimers in 2 ") in tetrahydrofuran (250 The mixture is stirred for 20 minutes at -15 ° j and then the white precipitate is separated by filtration, after washing with benzene, the filtrate and the washing liquors are mixed, then they are concentrated. the residue in benzene (250 ml) and activated carbon is added to the solution, then the whole is filtered and the filtrate is evaporated to obtain 17.9 ^ g (26.65 millimoles, $ 100, title of 9 ^, 1 $) of the crude compound sought which is a white frothy material having an Rf of 0.76 (benzene: ether 3: 2) The NMR spectrum of (CDCl 4) includes the signa, ux δ following: 1.20 (6H, s di-Me), 3.17 (1H, m, H-3), 3Λ - 3.9 (3H, m, HV and ïï-5 '), M7, ^> 72 (1H, 2d, J = 2.5 Hz, H- ^ f), 5.30 (2H, s, 0CH2Ar), 5.83 (s, H-2 ”) and 7.1 - 8.3 ppm (19H, m, H: aromatics). The IR spectrum (pure compound) includes a signal for -O = ΙΠαΧ 1770 nm (fi-lafit.flmfi fit nfitfinl. We ntilifip ln nnnrhii t t.p.1 which without further purification in the next stage.

(è-'R. 3S, * fR and VS, 3R, lfS) -3- (2 ', 2; "Dimethyl-l *. 3' -dioxolane-i + '- vl) -l- (p-nitrobenzyl- 2ll-triphenylphosr) hora.nylidene-2tt-anetate ^ è-tritylthio ^ -azétidinone (isomer O.

V "" · ~ φ

J — N, C1 diox. IJ

Y

CO PNB T „

2 C02PNB

The mixture is heated at reflux in a nitrogen atmosphere, for IfO hours, a mixture of (VR, 3S, ^ R and VS, 3R, lfS) -3- (2 ', 2', dimethyl-1 ', 3, “dioxolane -l ^ · '-yl) -l- (p-nitrobenzyl-2 ,, - chloro-2 ,, - acetate) -1 + -tritylthio-2-azetidinone (isomer C) (17.87 g, 25) 0 millimoles, title of 9 ^, $ 1, mixture of epimers in 2 "), triphenylphosphine (7.27 g, 27.5 mil-i limoles) and 2,6-lutidine (3.19 ml, 27.5 millimoles) in dioxane (350 ml, distilled on lithium aluminum hydride). After evaporation of the solvent under vacuum, 29.5 gd are obtained; a dark oil which is purified by chromatography on a silica column (330 g, elution with 20 to 50 $ ether in benzene) to obtain 10.5 g of a yellowish solid. This is rinsed with ether to collect 7Λ9 g (8.33 millimoles, 33.3 $) of the desired compound in the form of yellowish crystals. The NMR spectrum of (CDCl 4) comprises the following signals 6: 1.07 (s,

di-Me) and 7.1 - 8.2 ppm (m, aromatic H). The IR spectrum

»1 (nujol) includes a signal for - \? = 1760 cm (C = 0).

IllaX

By crystallization from a mixture of methylene chloride and ether, an analytical sample is obtained having a m.p. of 231 - 232 °. Chromatography indicates an Rf of 0.17 (benzene; ether 1: 1).

Analysis for C ^ H ^ N ^ OyPS:

Calculated: C, 72.1 **; H, 5.27; N, 3.12, - S, $ 3.57.

Found: C, 72.18; H, 5Λ3; N, 2.98; S, 3, ^ 1 $.

f ^ R.lSAR et h'S ,, 3RAS ') - 3- (2'.2'-D.iméthvl-l'.3'-dioxolane-i +' - vl ') - l- (p-nitrobenzyl-2ll ~ triphenylphosphoranylidene-2tt-aoetate A) -2-azetidinone-t + -thiola.te silver (isomer Cl.

AgNO ^ -Pyr ^ A? Λ- “γ · ΡΦ3 * e0H 3

CO PNB CO PNB

2 2

A solution of (VR, 3S, ^ R and k 'S, 3R, IhS) - 3- (2J, 2', dimethyl-1 ', 3'-dioxolane-1 ^ -'- yl) -l- is evaporated. (p-nitrobenzyl-2 ,, - triphenylphosphoranylidene-2 "-acetate) -! + - tritylthio-2-azétidi-none (isomer C) (319 mg, 0.355 millimole) in methylene chloride (10 ml) to obtain a oily residue which is redissolved in hot methanol (8 ml, 60 °) To this solution is added at 60 ° a hot solution of silver nitrate in methanol (0.15 M, ^ 0, 0, 0.60 millimole), then pyridine (29 microliters, 0.36 millimole) The mixture is stirred at room temperature for 5 hours and at 0 ° for 1 hour, the precipitate is collected by filtration and filtered. wash with ice-cold methanol, then with cold ether, to obtain 255 mg (0.33 ** millimole, 9 ^, 1- $) of the desired compound which is a brownish solid. The IR spectrum (nujol): includes a signal for Ό = 1750 cm ”'1' (C = 0).

\ i (i + 'R, 3S, * + R and ^ -' S.lR.ifS) -! - ^, 2'-Dimethyl-1 ', V-dioxolane-V -yl) -1- (p-nitrobenzyl -2ll-triphenylühosphoranylidene-2tl-acéta.te) - ^ - a, cetylthio-2-azétidinone (isomer C).

fa fa f S9 CH ^ COCl / pyr ^ SAc <Λ- · γ * 3 '5Λ * 0ûy * 3

C02PN3 CO ^ NB

At a temperature of 0 to 5 ° j is added acetyl chloride (71 microliters, 1.2 * + millimole, 3.0 equivalents) to a solution of (VR, 3S, ^ R and 1fJS, 3R, Li- S) -3- (2 ', 2' - dimethyl-1 ', 3' -dioxolane- ^; yl) -1- (p-nitrobenzyl-2, r-triphenylphosphoranylidene-2 "-acetate-2-azetidinone-Îl · Silver thiolate (isomer C) (25 * + mg, 0.333 millimole) in methylene chloride (15 ml) containing * pyridine (100 microliters, 1.2b millimole, 3> 2 equivalents).

The mixture is stirred for ^ f0 minutes at 0 - 5 ° · After filtering the precipitate on. Celite, the filtrate is washed successively with brine containing 1N hydrochloric acid (1.25 ml), saturated sodium bicarbonate, then brine, after which it is dried over sodium sulfate and evaporate to obtain 200 mg of an oil which is crystallized from ether to collect 155 mg (0.222 millimole, 66.7%) of the desired compound which consists of white crystals. The NMR spectrum of (CDCl 4) comprises the following signals S: 1.23 (s, di-Me), 2.20, 2.33 (2s, -SAc) and 7.2 - 8.3 ppm (m, H aromatic). The IR spectrum (nujol) includes signals for ·> ί = 1750 cm-1 (y3-lactam and ester) and I69O cm-1 (thioester).

By crystallization from a mixture of methylene chloride. ". . . . 1 P 1! · -! -! I_ _____ P.F. from 177 - 1780. The Rf is 0.62 (ethyl acetate).

Analysis for ^ 37 ^ 35¾0 8 * ^:

Calculated: C, 63.60; H, 5.05; N, if, 01; S, h, 59%.

Found: C, 63.3 ^; H, 5.32; N, 3.83; S, if, $ 31 · (if'R „5R.6S and if 'S, if S. 6R) - 6- (2' .2 * -Dimethyl — 1 ', 3' -dioxolane— if'-yl) -2-N-methylpenen-3-carboxylate of p-nitrobenzyl (isomer C).

/ 1 BAG. ,; _,> S

ΓΓ Ρφ Δ J — Ν ^ / ° Η3

O * -Nv <^ 3 O

T „CO-PNB

CO ^ GNP 2

Is heated under reflux for 6 hours, in a nitrogen atmosphere, a suspension of (if'R, 3S, ifR and if'S, 3R, ifS) -3- (2 ', 2'-dimethyl-1', 3-dioxolane -if'-yl) -l- (p-nitrobenzyl-2 "-triphenyl-i phosphoranylidene-2" -acetate) -if-a.cetylthio-2 ~ azetidinone (isomer C) (ifi + 3 mg, 0.63½ millimole) in toluene (70 ml). By evaporation of the solveqt we obtain a white solid which is purified by chromatography on a column of silica (10 g, elution with 10 $ ether in benzene) to obtain 2if7 mg (0.587 millimole, 92.7 $) of sought compound which is a white solid. The NMR spectrum of (CDClg) includes the following signals 6: l, if2 (6H, s, di-Me), 2.38 (3H, s, 2-CHg), 3.8 - if, 5 (hE9 m, H-6, H-if 'and H-5 "), 5.02 - 5.25 - 5.33 - 5.57 (2H, type AB, -OCHgAr), 5.57 (1H, d, J = 1.8 Hz, H-5) and 7.52 - 7.67 - 8.12 - 8.27 ppm (ifH, A2'B2 ', Aromatic H). The IR spectrum (nujol) includes the signals for V = 1760 cm −1 (/ 3 -lactam) and 1700 cm ~ (ester). By crystallization from a mixture of methylene chloride and ether, a sample is prepared for years. l vti nim avant. 11η PF rln Ί 67 - 1 6P °. T, a “nantr a ΤΤΛ7- (ethanol) includes ^) 265 mil (£ l ^ f.OOO) and 31 * + mu îîlciX / / (£ The chromatography indicates an Rf of 0.62 (benzene: ether 1: 1).

Analysis for C19H20N2P7S:

Calculated: C, 5 ^, 28 $ H, i +, 79; N, 6.66; S, 7.6> 3%

Found: C, 5 ^, 15; H, 78; N, 6.5 ^; S, $ 7.65.

Acid Oh’K.tö.öS and VS, 5S.6m-6-f2’.2’-diTnéthvl-l'.V-dioxolane-V-vD-P-methylOénème-Vcarboxvliaue (C isomer).

Ôsp-r'N vm-c Î \ -> sv 0ΧΧ> -3 -> JÏV-3 C02P® Λθ2Η

A solution of (If- ^ R, 5Rj6S and VS, 5S, 6R) - 6- (2 ',' 2 * -dimethyl-l ', 3, -dioxolane-i ^ -yl) -2-methylpenem- is mixed. P-nitrobehzylè 3-ca.rboxylate (C isomer) (195 mg, 0, ^ 6 ^ - mil- * limole) in tetrahydrofuran (20 ml) with 1 * ether (20 ml), water ( 20 ml), sodium bicarbonate (39 mg, 0, ^ 6 millimole) and palladium on carbon at $ 10 (200 mg, Société

Engelhard). The mixture is hydrogenated for hours at room temperature under a pressure of 2. * 6 kg per cm.

After having separated the catalyst by means of Celite, the aqueous layer is washed with ethyl acetate (2 times), then it is saturated with sodium chloride and it is acidified with 1N hydrochloric acid ( 0. ^ 7 ml), then it is immediately extracted with ethyl acetate (3 x 20 ml). The extracts are washed at 1a. brine and dried over sodium sulfate, then evaporated to obtain 9 ^ mg of a yellowish solid which is rinsed with pentane to collect 89 mg (0.31 millimole, 67%) of the desired compound which is a yellowish solid with mp 132-133 °. Chromatography indicates f \ Λ. 1 Λ. / Λ /> I. - ". »Y-v« N 1-. Ί t ·.

of (CDCl ^) includes the following signals: 1.37? 1, ^ 3 (6H, 2s, di-Me), 2.36 (3H, s, 2-CH ^), 3 j9 - H ·, 6 (HH, m, H-6, HV and H-50 and 5.59 ppm (1H, d, J = 1.7 Hz, H-5).

The IR spectrum (nujol) includes signals for * 0 = 1760 cm ^ (/ ¾-lactarne) and 1660 cm (COgH). The UV spectrum (ethanol) includes \ 309 mu (£ 6300) and 263 mu ILcLX. / / (£ 3800).

EXAMPLE 52.-

Acid A'S, 5R, 6S and VR, 5S, 6R) -6- (2?, 2; -dimethyl-l7,3 * -dioxolane-V-yl) -2-methylpenem-3-ca.rboxylic (B isomer) .

\ o2h k A? S. ^ SAR and ^ R. ^ RASAV ^ A'-Umethyl-l'.V-dioxolane- H -’- yDA-tritylthio-B-azetidinone (B isomer).

O- · ._ ^ STr Ö _> sTr JF], - =! * _—. ΓΤ o ^ W v .. / HMPT-H O QA-N \ kl> 2

/> <H

The desired compound is prepared (10.8 g, 2 * +, 3 millimoles, 9 ^, $ 1) having a PF of 155 ° (methylene chloride-ether) and an Rf of 0.2 * + (hexane-acetate d; ethyl 2: 1), operating as described in 1; example 51 concerning the G isomer starting from- -'δ, Ιδ, ^ ϊΙ and VR, 3R, iiS) -l- (t- hutyldimethylsilyl) -3- (2, 2; -dimethyl-1 '} S'-dioxolane-h'-yl) A-tritylthio-2-azetidinone (isomer B) (A, H- g, 25.8 millimoles) . The NMR spectrum of (CDC1-.) Includes the following signals 1,: 1.37? (6ÏÏ, 2s, di-Me), 3) ^ 3 (lHj dd, J3jf - 2.5 Hz, = 5 Hz, H-3), 3) 7 -½) 5 (Η-H, m, H- ^, H-5, NH), k, $ 0 (1H, d, J = 2.5 Hz, H-if) and 7.1 - 7) 6 ppm (15H, m, H aromatics). The IR spectrum (nujol) includes signals for '"'? = 3170 cm“ (NH) and 17 ^ 5 cm “1 (C = 0).

Analysis for C ^^ H ^ NO ^ S:

Calculated: C, 72.78; H, 6.11; N, 3.1 ^; S, 7.20%.

Found: C, 72.16; H, 6.11; N, 3.1½¾ s} 7.17%.

(VS.ISAR and VR, 3RAS) -l- (2'.2'-I> imethvl-l'.V-dioxolane-1f? -Vl ') - l- (p-nitrQt) enzvl-2,1- hvdroxv-2tI-acetate) -if-tritylthio- 2-azetidinone (mixture of epimers in 2 ") (isomer B).

gOp [œ 0¾

<Λ-Η-νη Ët ^ N / THF * oJ_] £, H

J co2pnb

Starting from (VS, 3S ^ R and VR, 3R ^ S) -3- (2>, 2 ', dimethyl-1', 3, -dioxolane-1f; yl) -if-tritylt] iio-2-azetidInone (isomer B) (10.8 g, 2 ^, 3 millimoles), as described in 1, is prepared as in example 51 with regard to the isomer C, the desired compound (15) 8 g, 2 ^, 1 millimoles, 99 , $ 3) which is a yellowish foamy substance with Rf of 0.29 and 0.22 (benzene: ether 1: 1). The 1 H NMR spectrum (CDCl 4) includes the following signals <$; 1.28, 1.3½ (2s, di-Me), 3, ½ - ^ ½ (m, H-3, HV, H-5 ', H-2 ", OH), ^ 39, ^ 53 (2d , J = 2 Hz, Ek), 5) 15) 5) 25 (2s, 0CH2Ar) and 7.1 - 8.3 ppm (m, aromatic H). The IR spectrum (pure compound) includes signals for ^ max = 3½ ^ cm "1 (wide, OH), 1760 cm-1 (C = 0), 1520, 1350 cm" 1 (N02).

(VS, 2SAR and lf'R, 3R.l + S) -3- (2'.2'-Dimethvl-l ', 3; -dioxolane-V-yl) -l- (u-nitrobenzyl- “2ll- chloro-2 "-acetate) - ^ - tritylthio- 2-azetidinone (mixture of e-pimers in 2") (isomer B).

7 ^ 9 y-o <^ "" rY‘3Tr s ° ci, -pyr | \ 2 -... ^ STr er-Νγ-0Η THP (y—

CO ^ NB CO ^ NB

Starting from (k * SjSSj ^ R and i + ^ R, 3ΙΙ, * 4-8) -3- (2;, 2 '- dimethyl-l ;, 3' -dioxolane-lf 'yl) -1- (p -nitrobenzyl-2M-hydroxy- 2 ,, - aeetate) -è ~ tritylthio-2-azetidinone (isomer B) (1 ^ -, 9 g> 22.8 millimoles, mixture of epimers in 2 "), prepared as described in Example 51 with respect to the C isomer, the desired compound (1 ^, 1 g, 20.9 millimoles, $ 919) which is a yellowish frothy substance having an Rf of 0.52 f (benzene: ether The NMR spectrum of H (CDCl 4) includes the following signals 1,: 1.30, 1.38 (6H, 2s, di-Me), 3Λ -k-, 5 (tH, m, H- 3, HV, H-5 '), k, 5? (1H, d, J = 3 Hz, Ek), 5.13 (s, H-2 "), 5.27 (s, 0CH2Ar) and 7, 1 - 8.3 ppm (19H, m, aromatic H). The IR spectrum (pure compound) includes a signal for = 1780 cm- ^ (/ 5 -lactam, ester).

(i + 'S., 3S „è-R and è-'R.3R.1fS) -3-C2'.2'-I) .imethyl-l', 3, -dioxolane-If'-yl) -l- ( u-nitrobenzyl - 2 "-triOhenylOhosOhoranylidene - 211- · acetate) -Li-Î-tritylthio-2-azetidinone (isomer B).

. m ÎVfSTr. ^ Yf "'0J — diox. 0 *

CO PNB CO PNB

2

Starting from (VS ^ Sj ^ R and 3'R, 3R, è-S) -3- (2 ', 2'-dimethyl-1', 3, -dioxolane-i + '-yl) -l- (p -nitrobenzyl-2 "-chloro-2" -acetate) -è ~ tritylthio-2-azetidinone (isomer B) (1 ^, 0 g, 20.8 millimoles, mixture of epimeres in 2 "), prepared as described in 1'example 51 with regard to the isomer C the sought compound (^, 6 ^ g, 5.16 millimoles, 2 * +, 8 $) having a'PF of 190 - 195 ° (decomposition, methylene chloride-ether The NMR spectrum of. (CDCl · ^) includes the following signals 1,: 1.12, 1.20, 1.27, 1.35 (^ s, di-Me) and 7.0 -.8.1 ppm (m, aromatic H). The IR spectrum (CHgCl ^) includes a signal for = 1750 cm-1 (A-lactam, ester).

UlciX y tographie indicates an Rf of 0.21 (benzene: ether 1: 1).

Analysis for C ^ H ^ N ^ PS:

Calculated: C, 72.1 ^; H, 5.27; N, 3.12; S, $ 3.57.

Found: C, 71.90; H, 5.57; N, 3.07; S, $ 3.56.

(VS.3S.è-R and è-'R.RR. ^) -3- (2 ', 2' ~ Dimethyl-l '. V-dioxolane-, V -vl) -l- (u-nitrobenzvl ~ 2tl-trir> hénylÎ) hosphoranvlidene-2tl-acetate) - 2-a.zétidinone-If “silver thiolate (isomer B).

tl / STr 0- 0J — Ν ^ .ΡΦ3 ΚβΟΗ J — v H 3 C02PNB co ^ pnb

Starting from (VS, 3S, ^ R and VR, 3R ^) - 3- (2 ^, 2 ^ -dimethyl-17,3? -Dioxolane-if7 -yl) -l- (p-nitrobenzyl-2 "- triphenylphosphora.nylidene-2 "-acetate) -If-tritylthio-2-azetidinone (isomer B) (1.00 g, 1.12 millimole), preparation is carried out as described in Example 51 with regard to the isomer C, the desired compound (580 mg, 0.760 millimole, $ 67.8) having a PF of 129-135 ° (decomposition). The IR spectrum

(nujol) includes a signal for s> max = 17 ^ 5 cm-1 (/ 3-lactam, ester).

(VS, 3S, Vl and * f'R, 3R, Vi) -3- (2 ', 2'-Mméthvl ~ l'. Λ'-dioxolane-V --yl) -l - (. P-nitΓobenzvl- 2lt-triΏhénvlphosphoranvlidène-2, l-acetate) -Vacétylthio-2-azétidinone (isomer BK

Ù ^ SAg ^ SAc "Ί Ç CR ^ COCl / pyr." | Ç "/ -ΗγϊΦ3

CO PNB CO PNB

2 2

Starting from (VS ^ S, 1® and VR, 3R, ^ - 3) -3- (25,2'-dimethyl-1 ', 3' -dioxola, ne-V -yl) -l- (p- nitrotienzyl-2 ,, - tripîié-nylphosphoranylidene-2 "-acetate) -2-a, zetidinone-silverthiolate (isomer B) (2, ^ 6 g, 3.22 millimoles), prepared as described in example 51 with regard to the isomer C, the desired compound which is collected in an amount of 2.2 g a.after purification by chromatography on a silica column (elution with 10 to 50% of acetate ethylene in methylene chloride). The NMR spectrum of (CDCl 4) includes the following signals S: 1.23, 1.27, 1.30 (3s, di-Me), 2.22, 2.33 (2s , Sic) and 7.3 - 8.3 ppm (m, H · aromatics) The IR spectrum (pure compound) includes signals for V = ÎUcLX.

-1 —1 1755 cm (/ î> -lactam, ester) and 1695 cm (thioester).

(VS.ÇR.éS and VR.BS.6RV6 ~ (2’.2’-Diméthvl-l'.V-dioxolane-

If’-vl) -2 "p-nitrobenzyl methvlüénème-3-carboxvlate (isomer B).

t3 :. S3AC

Jli ΡΦ3 - *

T CO GNP

co2pnb 2

Starting from A'S, 3S, lfR and> f'R, 3RAS) -3- (2 ', 2'-dimethyl-1', 3, -dioxolane-1 + '- yl) -l- (p-nitrobenzyl- 2 ,, - * tri-phenyphosphoranylidene-2 acetate) -1) - acetylthio-2-azetidinone (isomer B), (200 mg, 0.286 millimole), prepared as described in Example 51 in connection with isomer C, the desired compound (61 * mg, 0.15 millimole, $ 53) having a PF of 151 -152 ° (methylene chloride / ether) and an Rf of 0.67 (benzene: ether 1: 1). The RM spectrum of (CDCl ^) includes the following signals <5: 1.29, 1.38 (6H, 2s, di-Me), 2.30 (3H, s, 2-CH3), 3.6 - k , k AH, m, H-6, H-1 * ', H-5'), 5.00 - 5, 18 - 5.28 - 5A6 AH, qAB, -0CH2Ar), 5A7 (1H, d, J = 1.5 Hz, H-5) and 7, * + 2 - 7.55 - 8.05 - 8.15 ppm AH, A2'B2 ', Aromatic H). The IR spectrum (pure compound) includes signals for Ό = 1785 cm ^ (yP-lactam) and 1710 cm ^ (ester). The UV spectrum (ethanol) includes "^ max at 266 ψι (s 13-300) and 13A ipu (£ 9700).

ï Analysis for:

Calculated: C, 5 ^, 28; H, 795 N, 6.665 S, $ 7.63.

Found: C, 5 ^, 00; H, b, 75} N, 6.68; S, $ 7.61.

Acid A'S, 5R, 6S and ^ 'R.5S <6R) -6- (2'.2'-dimethyl-l'.3'-dioxolane-V-vl) -2-méthvlpénème-8-carboxvliaue (isomer B ).

v> - - ^ = ^ -

NC02PNB C02H

Starting from A'S, 5R, 6S and * f'R, 5S, 6R) -6- (2 ', 2'-. Dimethyl-1', 3'-dioxolane-1 + '- yl) -2-methylpenem- 3_carboxy-late of p-nitrobenzyl (isomer B) (79 mg, 0.19 millimole), the compound sought after, which is collected after crystallization from a mixture, is prepared as described in Example 51 with regard to isomer C methylene chloride and pen.ta.ne in an amount of 9 mg (0.032 millimole, $ 17), the Rf being 0.5 ^ (acetone: acetic acid 5: 0.5) · The 1 H NMR spectrum ( CDC13) includes the following signals 1: 1 ”35, 1, ^ (6H, 2s, di-Me), 2.37 (3H, s, 2-CEj), 3.6 -if, 5 (ifH, m, H ~ 6, H-if ", H-50 and 5.56 ppm (1H, si, H-5).

The IR spectrum (pure compound) includes a signal for Ό = 1785 cm (β-lactam). The UV spectrum (ethanol) includes Xmax at 307 mpL (ε 1 + 300) and 262 i ^ l (ε 3700).

EXAMPLE 53.- (lj.fi 1 5R6S and PS, 5S, 6RP6- (P-hydroxy-2; -methoxv-fflétb.oxy.-2; -éthvl) -2-methylioenem-3-ca.rboxvliaue ( isomer C ~).

Qh

COJ

2 f (l? Ro8S, ifR and 1,, S.PR.fiS) -P (P.2, -Dihydroxyethyl) -l - (p- nitrobenzyl-2 '' - triphenylhho sphor anylidene-2n-acetate) - fi-acetyltMo-2-a7.étidinone (Cl isomer

Ά. „9H

12 ··· | —tpa-h2o Ha ^ N — fSSc 0 <* - Ν '~ γ? Φ3 k

C02PNB C02PNB

A solution of (fi7R, 3S, ifR and Jf7S, 3R, i + S) -3- (2;, 27 - dimethyl-17,37-dioxolane-fi7 -yl is allowed to stand for 30 minutes at room temperature. ) -1- (p-nitrobenzyl- 2 ,, - triphenylphosphoranylidene-2 "-acetate) -Îf-acetylthio-2-azetidinone (isomer C) (fi? 2 mg, 0.676 millimole) in trifluoroaoetic acid (1, 0 ml) and Skin (0.1 ml).

The mixture is added dropwise to a cold solution of sodium bicarbonate (2.5 sec) in 15ea, u (50 ml) and extraction is carried out with methylene chloride (3 x 30 ml). The extracts are washed with "saturated sodium bicarbonate, then with brine and dried over sodium sulfate before evaporating to obtain * + 58 mg (0.695 millimole, $ 100, titer of $ 97? 3) of the desired crude compound which is a yellowish frothy substance. The H NMR spectrum (CDCl 4) comprises the following signals S: 2.20, 2.32 (2s,

SAc) and 7) 2 - 8.3 ppm (m, aromatic H). The IR spectrum

(pure compound) includes signals for ~ 0 = 3 ^ 20 cm "1 max (0H), 17 ^ 5 cm" 1 (/) - lactarne, ester) and 1690 cm ”1 (thioester).

Chromatography shows an Rf of 0.16 (ethyl acetate). (l'R.lSAR et l'S, 8R, ^ H) -V (l'-Hydroxy-2'-iiiéthoxYméthoxv-l? -éthyl) -l- (p-nitroben2Yl-2ll-triühenylOhosphoranvlidène-2, t- a. acetate) -i + -a, cetylthio ~ 2-azetidinone (isomer C).

oh 9am

i ^ SAc XV Λ. ^ SRc -γ BrC ^ OCH ^ -dimethylaniline P | σ ^ -Ν · γΡφ3 ~ “Λ * 09- ^ γΡΦ3

CO PNB CO PNB

P 2

We add at 0 ° to 1a. N, N'-dimethylaniline (58.8 mg, "0, ^ 83 millimole, 5 drops), to a solution of (l'R, 3S, ^ R et l'S ^ Rj ^ Sj-d 'il', 2 ' -dihydroxyethyl) -l- (p-nitrobenzyl-2 '' - triphenylphosphoranylidene-2n-acetate) -I + -acetylthio-2-azetidinone (C isomer) (291 mg, 0, ^ 30 millimole, title of $ 97.3) and bromomethyl methyl ether (55.2 mg, 0.2 + 2 millimole, drops) in methylene chloride (8 ml), then the mixture is stirred for 20 hours at 1a. ambient temperature. An additional 2 drops of bromomethylmethyl ether and 2 drops of N, N’-dimethylaniline are added, followed by stirring for 1 hour. Ί ~ ____ ______ —L 1 Ä * 1 successively with 1N hydrochloric acid, saturated sodium bicarbonate and brine, after which it is dried over sodium sulfate and evaporated. The crude residue is purified by liquid chromatography under high pressure (silica eluted with ethyl acetate) to collect 31 mg (0.186 millimole, * + 2.2f0) of the desired compound which is an oil having an Rf of 0, 2 * + (ethyl acetate). The NMR spectrum of (CDCl 4) includes the following signals 6: 2.20, 2.32 (2s, SAC), 3.30 (s, 0CH3), * +, 52 (s, -0CH20-) and 7, if - 8.3 ppm (m, aromatic H). The IR spectrum (pure compound) includes signals for λ? = 3 * + 20 cm '(OH), 1755 cm- (si, JS -lactam and ester) and 1690 cm ”^ (thioester).

(R, 5R.6S and S.5S, 6R) -6- (1-Hvdroxv-2 ’-methoxvmethoxv-2’-ethyl) -2-methylpenem-3-carboxylate p-nitrobenzyl.

PH

J-ίγ *, - · ~ Τ ^. > CO.PNB 2

OH

CO PNB 2

A solution of (l'R, 3S, * + R and l'S, 3R, * + S) -3- (l'-hydroxy-2'-methoxymethoxy-1 'is heated at reflux for 8 hours in a nitrogen atmosphere. -ethyl) -1- (p-nitrobenzyl-2 "- triphenylphosphoranylidene-2n-acetate) -l + -acetylthiO” 2-azetidinone (isomer C) (167 mg, 0.238 millimole) in oily residue which is purified by high pressure liquid chromatography (silica eluted with ethyl acetate) to obtain 68 mg (0.16 millimole, $ 67) of the desired compound which is an oil having Rf of 0.61 (ethyl acetate) and 0.15 (benzene: ether 1: 1). The NMR spectrum of "bs (CDCl 4) includes the following signals S: 2.38 (3H, s-, 2-CH3), 3.35 (1H, if, OH), 3, kb (3H, s, 0GH3), 3.6 - 3.8 (2H, m, "H-2 '), 3.90 (1H, dd, J6_ ^ = 2 Hz, J6_p = k Hz, H-6), * f, l8 (1H, m, H-l '), V, 67 (2H, s, -OCHgO-), 5.03 - 5.27 - 5.38 - 5.62 (2H, qAB, 0CH2Ar), 5.65 (1H, d, J = 2 Hz, H-5) and 7.55 7.70 - 8, '15 - 8.30 ppm (ifH, A2'B2', H aromatic). The IR spectrum (pure compound) includes signals for Ό -3 ^ 50 cm “1 (O H), 1785 cm-1 (/ 3-lactam), 1710 cm-1 (ester) and 1520 cm-1 (NOg). The UV spectrum (ethanol) includes \ ax at 266 T (6 13000) and 313 τψ (& 9100).

Analysis for 8 ^: 1 Calculated: C, 50.9 ^; H, if, 75; N, $ 6.60.

Found: C, 51.13; H, if, 77; N, $ 6.36.

Acid (R., 5R.6S and S., 5S, 6R) -6- (1'-hydroxy-2 '-methoxy-methoxy-2'-ethyl) -2-methylpenem-3-ca.rboxylic (isomer VS).

9H OH

\ x> GNP

2 hours

A solution of (R, 5R, 6S and S, 5S, 6R) - 6- (l-hydroxy-2 '-methoxymethoxy-2' -ethyl) -2-methylpenem-3-carboxylate is mixed. nitrobenzyl (isomer C) (51 mg, 0.12 millimole) in tetrahydrofuran (10 ml) with ether (10 ml), water (10 ml), sodium bicarbonate (10 mg,

Engelhard). The hydrogenation is carried out at room temperature for 3 hours under a pressure of 2.25 kg per p cm. After filtration of the catalyst on Celite, the aqueous layer is separated and washed with ether (3 times), then saturated with sodium chloride. The aqueous phase is acidified to 0 ° with 0.1 N hydrochloric acid (1.2 ml), then it is immediately extracted with ethyl acetate (3 x 15 ml). The extracts are washed with brine, dried over sodium sulfate and evaporated to obtain 22 mg of a yellowish solid which is rinsed with a little ether to collect 20 mg (0.069 millimole, $ 58) of the desired compound which is a slightly yellow solid having a PF of 137-13δ ° (decomposition). The NMR spectrum of - (DMS0-dg) includes the following signals <5: 2.28 (3H, s, 2-CH3), 3.27 (3H, s, 0CH3), 3, lf9 (2H, d, J = 6.2 Hz, 2'-H), - 3.87 (1H, dd, J6_5 = 1.7 Hz, J6-1 = 3.3 Hz, 6-H), lf, 58 (2H, 's , -0CH20-) and 5.55 ppm (1H, d, J = 1.7 Hz, 5-H). The IR spectrum (KBr) includes signals for V = 31 + 10 cßf1 (0H), 1755 (93-lactam) and 1655 cm-m (C02H). The UV spectrum (ethanol) includes max at 308 nrp (ε 6800) and 262 mp.

. (ε 1 + 200).

EXAMPLE fl + .-

Acid (l'S, 5R-. 6S et l'R, 5S, 6R) -6- (l'-hvdroxv-2'-métbn-sr ^ r ~ méthoxy-2'-ethyl) -2-méthvlpénème-3-carboxvlique (i somere.

OH

^ rr> ·· Λο2η (l'SyRSy ^ R et l'R, 3RAS) -3- (l?, 2 '- »dihydroxyethyl) -! - (p-nitrobenzyl - 2lt-triphenylr) hosphoranvlidene-2' ' -acetate) -i + -acétvlthio-2-azétidinon0 (isomer B), i

* / - Q OH

V1 -.._> "<= ho .T bag I THF — H O '1 — r </ ~ Νγρφ3:"

H ™ 3 X2PNB

Starting from (VS, 3S, tàl and VR, 3R, ^ S) -3- (2J, 2} -dimethyl-1 ', 3; -dioxolane-lf'-yl) -1- (p-nitrobenzyl-2 !, - tri-phenylphosphoranylidene-2 ,, - acetate) -lf-acetylthio-2-azeti-dinone (isomer B) (1.03 g, 1, ^ 7 millimole), prepared as described in Example 53 a About isomer C, the desired compound (970 mg, l, è-7 millimole, $ 100) which> is a yellowish frothy material. The RM spectrum of (CDCl ^) includes the following signals 2,: 2.20, 2.32 (2s,

-SÂc) and 753 - 8.2 ppm (m, aromatic H). The IR spectrum

Ί (pure compound) includes signals for λ) __ = 3 ^ 10 cm “(OH), 1750 cm ^ (53 - lactam, ester) and 1690 cm 1 (thio-ester). Chromatography indicates an Rf of 0.16 (ethyl acetate).

(l'S.lSAR et l? R.3RAS) -3 "(l ~ hydroxy-2'-methoxymethoxy-l'-éthvl) -1- (p-nitrobenzvl- 2'r ~ tpiphenylphosOhoranylidene-211-acetate) -k ~ acetylthio-2-azetidinone (isomer B).

OH 0rr H ° T or?

I BrCH2OCH3 / dimethylaniline ‘j J

CH2C12 *

CO PNB CO PNB

Λ 2 From (l'S ^ Sj ^ R and l'R, 3R, è-S) -3- (l ', 2'-dihydroxyethyl) -1- (p-nitrobenzyl-2 "-triphenylpho sphor any-lidene -2 "-acetate) -5-acetylthio-2-azetidinone (isomer B) (* + 85 mg, 0.736 millimole), the compound sought (as described in example 53) is prepared (205) mg, 0.292 millimole, $ 3,936) which is an oil. The NMR spectrum of (CDCl 4) comprises the following signals S: 2.22, 2.33 (2s, SAc), 3.32 (s, OCH ^, **, 57 (s, -OCHgO-) and 7, 2 - 8.3 ppm (m, aromatic H). The IR spectrum (pure compound) includes signals for = 3 ^ 20 cm "1 (OH), 1755 cm 1 (ß -lactam, ester) and 1690 cm-1 (thioester) Chromatography indicates an Rf of 0.32 (ethyl acetate).

(p-nitrobenzyl) (5R, 6S and R, 5S. 6R) -6- (1'-hvdroxy-1'-methoxvmethoxv-2'-ethyl) -2-methylpenem-3-carboxvlate.

! Bag .

Il H toluene-Hg> | ^ —CH

0 ^ "Νψ Ψ3 Δ * co2pnb \: o2pnb From (l'S ^ Sj ^ -R and l'R, 3R, ipS) -3— (ls - hydroxy-2 '-methoxymethoxy-1'-ethyl) -1 - (p-nitrobenzyl-2u-triphenylphosphoranylidene ^ "- acetate) -H-acetylthio-2-azetidinone (isomer B) (205 mg, 0.292 millimole), and hydroquinone (10 mg, 0.09 millimole), on prepare as described in Example 53 with regard to the isomer C, the desired compound (38 mg, 0.090 millimole, $ 31) having a PF of 152-15% and an Rf of 0.23 (benzene: · ether 1: 1). The 1H NMR spectrum (CDCl 4) comprises the following signals 6: 2.37 (3H, s, 2-CH3), 3Λ0 (3H, s, 0CH3), 3Λ - 3.9 '(3H, m, ïï- 6, H-2 "), 15 (1H, m, H-l '), b, 67 (2H, s, -OCEÿ) -), 5.10 - 5.27 - 5.39 - 5.56 ( 2H, qAB, -OCHJlr), 5.67 (1H, d, J = 1.5 Hz, H-5) and 5.55 - 5.16 - 8.15 - 8.27 ppm (^ H, ^ 2 ^ 2 5 aromati (read) · The IR spectrum (CHgCLp) includes signals for -O = 3370 cm-1 (OH), 1785 cm-1 (ß -lactam) and 1700 cm-1 (ester). (tetrahydrofuran: ethanol 1: 1) includes A at 265 mu ÏÏ18.X / (ε 10i + 00) and 31½ mp. (ε 78ΟΟ).

Acid (S.5R "6S and R. 5S, 6R) -6- (1 * -hvdroxv-2 '-methoxy * · methoxy-2'-ethyl) -2-methylpenem-3-carboxylic (B isomer) .

OH OH

Hpnb Vh 2 From (1? S, 5H, 6S and l'R, 5S, 6R) -6- (l'-hydroxy-f 2i -methoxymethoxy-2'-ethyl) -2-methylpenem-3-carboxylate of p-nitrobenzyl (isomer B) (36 mg, 0.085 millimole), as described in example 53 is prepared with regard to isomer C, the desired compound (7.5 mg, 0.026 millimole, $ 30) which consists in yellowish crystals. The NMR spectrum of% (CDCl ^) includes the following signals S: 2.36 (3H, s, 2-CH3), 3.39 (3H, s, 0CH3), 3.6 - 3.9 (3H, m , H-6, H-2 '), i +, 15 (1H, m, H-l'), 66 (2H, s, 0CH20) and 5.67 ppm (1H, d, J = 1, ^ Hz, H-5). The IR spectrum (CH ^ Cl ^) includes signals for λ) = 1785 cm ^ (ß-lactam) and 1675 cm * "(C02H). The UV spectrum (ethanol) includes λ at 3Ο8 mu (£ 2900 ) and 263 mu (ε '2900).

ΙΙΙσ, Χ / / EXAMPLE 55.-

2-Benzimidovlaminométhvlpéneme-3-carboxvliaue acid.

COOH

A · \ _y-CH2 “^ ~ ^ ™ 2C02tia + + (C0C1) 2 CH2C12 (I)

V \ -CHp — jr — ïï- CH COCJ

XX

(II)

0.13 ml (1.5 millimole) of oxalyl chloride is added at room temperature to a suspension of 0.38 g (1.5 millimole) of 3-benzyl-1,2,2 * f-oxadiazole-5 -one-i + -sodium acetate (1) "^ in 10 ml of methylene chloride containing 2 drops of dimethylformamide, so that the mixture becomes effervescent. The reaction mixture is stirred for 1 hour at room temperature. the sodium chloride produced by the reaction is filtered off, then the filter cake is washed several times with a little methylene chloride, and the acid chloride (II) solution is used directly.

1. K. Taka.cs and K. Harsânyi, Ber. 103. 233Ο (1970 · B... / SAg (II) J —f B ch2ci2

çj, —H ^ 03 pyridine-C02PNB

(III)

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(IV)

A solution of 1.0 g (1.5 mmol) of compound (III) and 0.12 ml (15 mmol) of pyridine in 10 ml of methylene chloride is cooled to 0 ° C. in a nitrogen atmosphere. We add it all at once. chloride (acid (II) solution to the solution of compound (III) and the reaction mixture is stirred for 5 minutes, then at room temperature for 90 minutes, the reaction mixture deposits a thick precipitate. the precipitate is filtered and the filtrate is diluted with methylene chloride to a volume of 70 to 90 ml, the organic phase is then washed successively with 7 ml of 0.1 N hydrochloric acid, 80 ml of sodium bicarbonate 1% and 80 ml of water The organic phase is dried over magnesium sulfate, the solvent is removed under reduced pressure and the residual oil is chromatographed on silica gel (Mallinckrodt Silicar CC-7) which eluted with chloroform to obtain 0.! + g (30.5 $) of the compound (IV) which is an oil. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with the formula (IV).

C. (IV) s _ toluene _ 1 \ f / Λ \% if0 “8 '\ =)

C02PNB

(V)

A solution of 0.1 g (0.5 to 5 millimoles) of compound IV in 50 ml of toluene is heated at reflux for k hours. The solvent is removed under reduced pressure and the residue is chromatographed on silica gel (Mallinckrodt Silicar CC-7) which is eluted with% ethyl acetate in methylene chloride to obtain 0.15 g ($ 66 ) of compound V which is an oil which solidifies on standing. The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with formula V.

Analysis for G ^ H ^ gN ^ O ^ S:

Calculated: C, 55? 86; H, 3.67; N, $ 11.33.

Found: C, 56.17; H, 3.76; N, $ 11.23.

\ D. (V) P · _ àrw * cH ^ i, b ^ h2- (3

ÔOgH

A solution of 0.135 g (0.27 millimole) of compound V is added in è-0 ml of tetrahydrofuran and è-0 ml of anhydrous diethyl ether to a suspension of $ 10 palladium on carbon in è-0 ml of water , operating in a nitrogen atmosphere. The resulting mixture is hydrogenated in a Parr apparatus at room temperature for 210 minutes under

O

an initial hydrogen pressure of 3.66 kg per cm.

The absorption of hydrogen induces a pressure drop of 2, 0.32 kg per cm. The catalyst is filtered off and the filter cake is washed thoroughly with water. Additional diethyl ether is added to the filtrate, then the phases are separated. The aqueous phase is extracted 3 times with diethyl ether. The aqueous phase is then concentrated to dryness under reduced pressure. By liquid chromatography under high pressure of the residue, we obtain 50 mg ($ 58) of the desired peneme which decomposes from 156 to 173 ° · The infrared spectrum and the nuclear magnetic resonance spectrum are compatible with 1a. formula V.

Analysis for .1.5Η ^ 0:

Calculated: C, 52.31; H, 5.27; N, 12.20%.

Found: C, 51.65; H, 5.95; N, $ 12.31 EXAMPLE 56, -

2-DhenyliïiiidoylaminométhvlOénème-3-carboxylic acid.

COOH

The desired compound is obtained by operating as • in Example 55, but by means of an equimolar amount of sodium 3-phenyl-1,2,5-oxadiazol-5-one-5-one-5-aceta.te instead of 3-benzyl-1,2,5-oxadiazol-5-one-5-a sodium acetate. Biological results.

Compounds representative of the invention are subjected to antibiotic potency tests in vitro against different microorganisms. The samples of the indicated compounds, after dissolution in water and dilution with nutritive broth, appear to have the minimum inhibitory concentrations indicated below, in micrograms per ml, with respect to the specified microorganisms, such as indicates nno inpnhfi + .inn nAnriani. nnp night h cui vani. la • honVmi rmo \ 0 H vO ro c \ | ο O rH tp \ ^ | c »r» # ·>

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Compounds representative of the invention are also subjected to in vivo tests on mice, which reveal that with respect to the organisms mentioned below, the DP ^ q (dose of compound, in mg per kg, necessary for protect 50% of treated mice against an otherwise lethal infection by a microorganism) have the following values.

S. aureus A9537

Compound Number of organ- Number of ad- Route of ad- DP ^ q nisms ministerial administrations 5 S.aureus tion (mg / kg pa: A 9537 administr; _ __ _ _ ^ __ tion)

Example. - ^ 0 7.8 x 10 5 2 IM. 0.12

Example? 36 6.6 x 10 '2 IM 7.7

Example - 38 8.6 x 10 '2 IM 1.0

Example ^ * 56 8 x 105 2. IM 5

Example ^ 39 8 x 10 '2 IM 0.0¼

After intramuscular administration of a representative compound of the invention, it is noted in 1a. mice the following blood levels.

Blood level in 1a. mice in micrograms per ml after intramuscular administration of a dose of è-0 mg per kg of body weight (average ._for 6 smiles if_

Compound Number of minutes after administration 10 20 30 ¼5 60 90 120 Example è-0 Mt, 7 3 ** Λ 23.7 17.6 9.8 3.6 1

Claims (10)

1.- Compound of formula: ÏQ- o \ C02Z where Z represents a hydrogen atom or an easy-to-remove esterifying protective radical, X represents (a) a radical of formula: (i) -OR, where R represents an atom of hydrogen, (ii) -COR ^, where R ^ represents a hydrogen atom or a hydroxyl, optionally substituted (lower) alkyl or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the radical alkyl of 1 or more being chosen from halo, hydroxyl, oxo, carboxyl, carbalkoxy (lower), carbamoyl, alkoxy • (lower), amino, alkyl (lower) amino, dialkyl (lower) -amino, alkanoyl ( amino or phenyl or heterocyclic radicals optionally substituted and the substituents carried by phenyl or heterocyclic radicals 1 in number or more being chosen from hydroxyl radicals., ... ... alkoxy (lower), halo, alkyl (lower), halo-alkyl (lower), met hanesuifonyl, oxo, lower alkyl-thio, amino, lower alkyl amino, dialkyl (lower) amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower) , o "(iii) -OCOR, where R represents an amino radical, cc alkyl (lower) amino, dialkyl (lower) amino or optionally substituted (lower) alkyl whose substituents are as defined under (ii), or (b ) a substituted aliphatic (lower), cycloaliphatic (lower) or cycloaliphatic (lower) -aliphatic (lower) radical or a substituted phenyl, phenylalkyl (lower), heterocyclic, heterocycloalkyl (lower) or heterocyclothioalkyl (lower) radical substituted on the ring, substituents of the above aliphatic, cycloaliphatic, phenyl or heterocyclic radicals being R-, (i) of the radicals -G - KRgR ^ or -E = C- where R ^ represents a hydrogen atom or an (lower) alkyl radical or phenyl and R2 and R ^ each represent independence ent a hydrogen atom or an alkyl (lower), phenyl or benzyl radical, (ii) radicals -OR ^, where R ^ represents an amino radiocal, amino (lower) amino, dialkyl (lower) amino, alkyl (lower) substituted or alkenyl (lower) or phenyl, phenylalkyl (lower), heterocyclic or heterocycloalkyl (lower) optionally substituted on the .cycle, the substituents carried by the alkyl, phenyl and heterocyclic radicals being as defined in (a) ( ii), (iii) radicals -0 ((^) OR ^, where n represents an integer from 1 to 6 and Rr represents an optionally substituted (lower) alkyl or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the alkyl, phenyl or heterocyclic radicals being as defined under (a) (ii), (iv) of the radicals -OCOR ^ 5, where represents an amino, alkyl (lower) amino, dialkyl (lower) amino or Rr radical , with the restriction that R 'cannot represent an (lower) alkyl radical no n substituted, (v) the radical -OSO ^ H, (vi) the radical 0ÎIToP (OH) 2, (vii) of the radicals -0S02Rr, where R ^ is as defined under Cb) (iii), (viii) of radicals ^ ToP (ORe) (OR), where Re represents an (lower) alkyl radical and Rr is as defined under (b) (iii), (ix) of the radicals “^ (0) R ^ ', where n represents O, 1 or 2 and R ^ is as defined in (b) (ii) or represents, in the case where n = 0, a radical R ^ R = C-RR ^ R ^, where R ^ _ represents an atom d hydrogen or an alkyl radical (lower) and R ^ and R ^ each independently represent a hydrogen atom or an alkyl radical (lower), with the restriction that R ^ cannot represent an unsubstituted phenyl radical, (x) des radicals -COR ^, where R ^ represents an aminoalkyl radical (lower) j alkyl {lower) aminoalkyle- '(lower), dialkyl (lower) aminoalkyl (lower), “NHNH2, -RR1yRR18, -RHOR ^, -SR- ^ y, -0 (CH2) n ~ A-Re or -RReRg, where R ^, R1q and Rg each represent an (lower) alkyl radical and R- ^ represents a hydrogen atom or an (lower) alkyl radical, A represents 0, S, RH or NOEL and n and R are as defined under (b) (iii) and (b) (viii), O o (xi) of the radicals -P0 (0Rw ) 2, where Rw represents a hydrogen atom or an (lower) alkyl radical, (xii) of the radicals -RHR ^, where R ^ represents an optionally substituted phenyl radical, optionally substituted heterocyclic, -GH = RH, -SO ^ H, -OH, alkoxy (lower), amino, alkyl (lower) amino, dialkyl (lower) -amino, -HHCOCH ^, -CS2CH3, -S02CH3, -S02 -O, -S02HH2, S = CRHCH3 , si-RH- ^}, RH = C-HRyRg, where Ry and Rq each independently represent an alkyl radical i (lower), phenyl or phenylalkyl (lower), HH = G-Rg, where represents a radieax av i phenylalkyl (lower), or 0 = CR ^, where R ^ represents an aminoalkyl radical (lower), ~ RH9, alkyl (lower) friend 1- "V 0 dialkyl (lower) amino, -Rïï-v ^ y, - RH-C ^ —R- ^ q, ° û represents an optionally substituted (lower) or phenyl or heterocyclic alkyl radical, the substituents carried by the phenyl and heterocyclic radicals being as defined under (a) (ii), -RH- C ^ - RH2, alkoxy (lower), -OCH2 - ^>, -0CH2 - ^^ - R02 or -0 (CÏÏ2) 2Si (C (xiii) of the radicals -S ~ C - R. ^ "where R- ^ represents an (lower) alkyl radical carrying an amino, (lower) amino or dialkyl (lower) amino radical, (xiv) of the radicals -IR ^ .R ^, where R ^ represents a rt cal alkyl (lower) and represents - an alkyl radical (lower), alkoxy (lower), heterocyclic, amino or 0 = CR ^, where R ^ is as defined under (b) (xii), or taken together ^ with the nitrogen atom, R ^. and R ^ represent a radical / Vb "yO o with the restriction that when R ^ represents an amino radical or -0ï2 CH2RH2, R ^ represents a methyl radical and also the restriction that R ^ and R ^. cannot both represent (lower) alkyl radicals, (xv) -RR ^ 'R ^' radicals, where R .. 'represents an (lower) alkoxy radical and R ^. * represents a (lower) alkyl radical, heterocyclic, aminoalkyl. (lower), alkyl (lower) aminoalkyl (lower), dialkyl (lower) aminoalkyl (lower) or 0 = C-ùL, where R ^ is as defined in (b) (xii), or your taken together with the nitrogen atom, R- 'and Rv' represent a D * - radical L · ^. -H | y ^ o Θ (xvi) of the radicals -IfiELR E, where B,, Em and E 1 m η l7 mn each independently represent an alkyl radical (lower) or taken together with the nitrogen atom, represent a radical -ÎT . 7, (xvii) of the radicals -R = CH-R, where R represents JL> iL an alkyl (lower) or phenyl or heterocyclic radical f optionally substituted on the ring, the substituents carried by the phenyl or heterocyclic radicals being as defined under (a) (ii), (xviii) of the radicals -N ^ CRR, where R represents xyy an alkyl (lower) or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the phenyl and heterocyclic radicals being such that defined under (a) (ii), and R is 'as defined JL under (b) (xvii), (xix) of the radicals = IT-R, where R represents a P r' hydroxyl, alkoxy (lower) radical, amino, dialkyl- (lower) amino or -KH- \ /, (xx) radicals -C - ^^ 2 ^ n ^ l5 ^ l6 'n represents an integer from 1 to 6 and R- ^ and R - ^ each independently represent a hydrogen atom or an alkyl radical (lower), and Y represents a hydrogen atom or a radical chosen from “(a) aliphatic radicals (lower), cycloaliphatic (lower) or cycloaliphatic (lower) -aliphatic "(lower) optionally substituted, the substituents carried to the number of 1. or more being chosen from hydroxyl, alkoxy (lower), phenyl-oxy optionally substituted, optionally heterocycloxy substituted, optionally substituted (lower) thio alkyl, optionally substituted phenylthio, optionally substituted hetero-rocyclothio, mercapto, amino, amino (lower) amino, dialkyl (lower) amino, alkanoyl- (lower) oxy, alkanoyl (lower) amino, phenyl optionally substituted, heterocyclic optionally substituted, carboxyl, carbalkoxy (lower), carbamoyl, H-alkyl- (lower) carbamoyl, N, Ν-dialkyl (lower) carbamoyl, f halo, cyano, oxo, thioxo, -SO ^ H, - OSO ^ H, -S02-alkyl (lower), alkyl (lower) sulfinyl, nitro, phosphono and —-OP (OR) (0R), where E and R are as defined above, erer _ the substituents carried by the alkyl radical (lower r) thio 1 or more being chosen from halo, hydroxyl, alkoxy (lower), amino, .alkanoyl- (lower) amino and phenyl or heterocyclic radicals optionally substituted, the substituents carried by the phenyl or heterocyclic radicals ci- above numbering 1 or more being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), halogenoalkyl (lower), methanesulfonyl, alkyl (lower) thio, amino, 'alkanoyl (lower) amino, alkanoyl ( lower) oxy, carbûxy, carboxyalkyle (lower), sulfo and sulfoalkyle (lower), (b) the radicals -0Rs, where Rs represents an alkyl radical (lower) or alkanoyl (lower) optionally substituted or a phenyl or heterocyclic radical optionally substituted , the substituents carried by the alkyl and alkanoyl radicals numbering 1. or more being chosen from the halo, hydroxyl, alkoxy (lower), alkyl (lower) amino, dialkyl (lower) radicals - amino, amino, oxo, alkanoyl (lower) amino and phenyl or heterocyclic optionally substituted and the substituents carried by the phenyl or heterocyclic radicals numbering 1 or more being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower) radicals ), halo-alkyl (lower), methanesulf.onyl, alkyl (lower) thio, alkyl (lower) amino, dialkyl (lower) amino, amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy , carboxyalkyl (lower), sulfo and sulfoalkyl (lower), (c) the radicals -S (0) R, where n represents 0, 1 or 2 Ώ. s and R is as defined above, 1 (d) halo radicals, and (e) optionally substituted phenyl or heterocyclic radicals whose substituents 1 or more in number are chosen from hydroxyl, alkoxy (lower) radicals , halo, alkyl (lower), haloalkyl (lower), methane sulf ony1e, alkyl (lower) thio, amino, alkyl (lower) amino, dialkyl (lower) amino, alkanoyl- (lower) amino, alkanoyl (lower) oxy , carboxyl, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), and its pharmaceutically acceptable salts, with the restriction that when X represents a hydrogen atom, X does not represent a radical -C ^ OCH ^ ILjOCH ^. 2.- Compound according to claim 1 in the formula of which Y represents a hydrogen atom. 3 · - Compound according to Claim 1, in the formula in which X represents a C 1 -C 4 alkyl radical optionally carrying a hydrosyl radical. Compound according to Claim 1, in the formula in which Y represents an a-hydroxyethyl radical. 5 · - Compound according to claims là1 * in the formula of which X represents: (a) a radical 0 -yO (J where n represents an integer from 1 to 6; (h) a radical - (Cïïg) ïffiDH where n represents an integer from 1 to 6; (c) a radical - (CH ^) HiCO-alkyl) ,, where n represents an integer from 1 to 6 and whose alkyl radicals are C1 "C6; ml (d) a radical - (CHp) HE-C-alkyl where n represents an integer I - It integer from 1 to 6 and whose alkyl radical is C - ^ - Cg; (e) a radical where n represents an integer from 1 to 6; (f) a radical - (CH ^ oÔkcH ^ llI ^ R5 where n and m each independently represent 1 or 2 and and RB each independently represent a hydrogen atom or an (lower) alkyl radical, or jjh "(g ) a radical - (CH ^^ MC-R. where n represents an integer from 1 to 6 and R ° represents an alkyl radical in C ^ -C ^, phenyl or - (CH ^).-O where m represents 1 or 2. 6.- Intermediate compound chosen from the compounds, of formula: ai ï _ / s-- <-N, P (Q) 3 M 0 co7r "Δ X where Y represents a hydrogen atom or a radical chosen from (a ) the aliphatic (lower cycloaliphatic (lower) or cycloaliphatic (lower-aliphatic (lower)) radicals optionally substituted, the substituents brought to the number of 1 or more being chosen from hydroxyl, alkoxy (lower), phenyl-oxy optionally substituted, optionally heterocycloxy radicals substituted, optionally substituted (lower) thio alkyl, optionally substituted phenylthio, optionally substituted hetero-rocyclothio, mercapto, arnino, K- lower alkyl amino, dialkyl (lower) amino, alkanoyl- (lower) oxy, alkanoyl (lower) amino , optionally substituted phenyl, optionally substituted heterocyclics, carboxyl, carbalkoxy (lower), carbamoyl, N-alkyl- (lower) carbamoyl, N, N-dialkyl (lower) carbamoyl, halo, cyano, oxo, thioxo, -S O ^ H, -OSO ^ H, -SO ^ -alkyl (lower), alkyl (lower) sulfinyl, nitro, phosphono and —OP (ORp) (OR), where R and R are as defined above, the substituents carried by the alkyl radical (lower) thio numbering 1 or more being chosen from the halo, hydroxyl, alkoxy (lower), amino, r.alkanoyl- (lower) amino and phenyl or heterocyclic radicals optionally substituted, the substituents carried by the above phenyl or heterocyclic radicals, numbering 1 or more being chosen from hydroxyl and alkoxy radicals (inf- • p-ï απτρΛ - haï. allrvl a (î nférn enrs'l. ΙΊπτΙ a ftnfé— rieurs), methanesulfonyl, lower (alkyl) thio, amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower ), (h) -OR radicals, where Rß represents an optionally substituted (lower) or alkanoyl (lower) radical or an optionally substituted phenyl or heterocyclic radical, the substituents carried by the alkyl and alkanoyl radicals being 1 or more being chosen from halo, hydroxyl, alkoxy (lower), alkyl (lower) amino, dialkyl (lower) -amino, amino, oxo, alkanoyl (lower) amino and phenyl or heterocyclic radicals optionally substituted and the substituents carried by the phenyl radicals or heterocyclic 1 or more in number being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), halo-alkyl (lower), methanesulfonyl, lower (thio) alkyl, i (lower) alkyl radicals no, dialkyl (lower) amino, amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), (c) radicals -S (0) R, where n represents 0, 1 or 2 JjL S and Eg is as defined above, (d) halo radicals, and / (e) optionally substituted phenyl or heterocyclic radicals whose substituents 1 or more in number are chosen from hydroxyl radicals, alkoxy (lower), halo, alkyl (lower), haloalkyl (lower), tallow methane, alkyl (lower) thio, amino, alkyl (lower) amino, dialkyl (lower) amino, alkanoyl- (lower) amino , alkanoyl (lower) oxy, carboxyl, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), Q represents a phenyl radical. or alkyl (lower), E "represents an easily removable ester radical, x represents 1 or 2, M represents Gu (ll), Fb (lI) or Hg (ll) when x represents 2 or Ag (l) when x represents 1, and of formula: Y ^ SHgCOOCH ΎΥ C02R "where Y, Q and E" are as defined above. 7 · - Intermediate compound of formula: γτγ * -τ JN P (Q) q O 3 C02R "^ where Y represents a hydrogen atom or a radical chosen from (a) aliphatic (lower), cycloaliphatic (lower) radicals or cycloaliphatic (lower) -alipha-: ticks (lower) optionally substituted, the substituents numbering 1 or more being chosen from hydroxyl, alkoxy (lower), phenyl-oxy optionally substituted, heterocycloxy optionally substituted, alkyl (lower ) optionally substituted thio, optionally substituted phenylthio, optionally substituted heterocyclothio, mercapto, amino, alkyl (lower) amino, dialkyl (lower) amino, alkanoyl- (lower) oxy, alkanoyl (lower) amino, phenyl optionally substituted, heterocyclic substituted, carboxyl, carbalkoxy (lower), carbamoyl, ÜT-alkyl- (η rvP ΰτη * ûnn ιΛύ uKamnvl o TT TT — An a Ί VttT (-î-nP ^ -n-î dut »lr» a τ »Ηαττ» η- * τΊ o halo, cyano, oxo, thiox o, -SO ^ H, -OSO ^ H, -SO ^ -alkyl (lower), lower alkyl, sulfinyl, nitro, phosphono and 0 —OP (OR) (0Η ^), where Rq and R ^ are such that defined above, the substituents carried by the alkyl radical (Lower) thïO-in number of 1 or more being chosen from the halogeno, hydroxyl, alkoxy (lower), amino, alkanoyl- (lower) amino and phenyl radicals or optionally substituted heterocyclics, the substituents carried by the above phenyl or heterocyclic radicals 1 in number or more being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), haloalkyl (lower), methanesulfonyl, alkyl ( lower) thio, amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), (b) -0Rs radicals, where Rfi represents an alkyl radical (lower) or optionally substituted (lower) alkanoyl or an optionally substituted phenyl or heterocyclic radical, the substituents carried by the alkyl and alkanoyl radicals in number of 1 or more being chosen from the halo, hydroxyl, alkoxy (lower), alkyl (lower) amino, dialkyl (lower) -amino, amino, oxo, alkanoyl (lower) radicals amino and phenyl or heterocyclic optionally substituted and the substituents carried by the phenyl or heterocyclic radicals 1 in number or more being chosen from hydroxyl radicals,. alkoxy (lower), halo, alkyl (lower), haloalkyl (lower), methanesulfonyl, alkyl (lower) thio, alkyl (lower) amino, dialkyl (lower) amino, amino, alkanoyl (lower) amino, alkanoyl (lower) oxy , carboxy, carboxyalkyle (lower), sulfo and sulfoalkyle (lower), (c) radicals -S (OVR, where n represents 0, 1 or 2 .Tl s „and Rs is as defined above, (d) halo radicals, and / / (e) optionally substituted phenyl or heterocyclic radicals the substituents of which are 1 or more in number are chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), haloalkyl (lower) radicals , tallow methane, alkyl (lower) thio, amino, alkyl (lower) amino, dialkyl (lower) amino, alkanoyl - (lower) amino, alkanoyl (lower) oxy, carboxyl, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), Q represents a phenyl or alkyl radical (lower), E "represents a radical is er easy to eliminate, and 0 * T represents a radical (C ^ H ^^ C- or -CX, where X represents (a) a radical of formula: (i) -0E, where E represents a hydrogen atom, aa (ii) -COE ^, where represents a hydrogen atom or a hydroxyl, optionally substituted (lower) alkyl or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the alkyl radical. of .1 or more being chosen from halo, hydroxyl, oxo, carboxyl, carbalkoxy. (lower), earbamoyl, alkoxy_____ (lower), amino, alkyl (lower) amino, dialkyl (lower) -amino, alkanoyl (lower) amino or phenyl or heterocyclic optionally substituted and the substituents carried by phenyl or heterocyclic radicals 1 in number or more being chosen from hydroxyl, alkoxy (lower), halo, alkyl (lower), halo-alkyl (lower) radicals , methanesulfonyl, oxo, lower alkyl-thio, amino, alkyl (i amino), dialkyl (lower) amino, alkanoyl (lower) amino, alkanoyl (lower) oxy, carboxy, carboxyalkyl (lower), sulfo and sulfoalkyl (lower), or (iii) -0C0E, where E represents an amino radical, alkyl (lower) amino, dialkyl (lower) amino or optionally substituted alkyl (lower), the substituents of which are as defined under (ii), or (b) an aliphatic (lower), cycloaliphatic (lower) or cycloaliphatic (lower) radical substituted aliphatic (lower) or phenyl, phenylalkyl (lower), heterocyclic, heterocycloalkyl (lower) or heterocyclothioalkyl (lower) substituted on the ring, the substituents of the above aliphatic, cycloaliphatic, phenyl or heterocyclic radicals being (i) radicals -C -NR ^ R ^ or -K = C —- MR ^ R ^, where R ^ represents a hydrogen atom or a (lower) or phenyl alkyl radical and R ^ and R · ^ each independently represent an atom hydrogen or an alkyl radical (lower ), phenyl or benzyl, (ii) radicals -0Rd, where Rd represents an amino, alkyl (lower) amino, dialkyl (lower) amino, substituted (lower) alkyl or alkenyl (lower) or "phenyl, phenylalkyl (lower), heterocyclic or heterocycloalkyl (lower) optionally substituted on the ring, the substituents carried by the alkyl, phenyl and heterocyclic radicals being as defined in (a) (ii), (iii) radicals -OÎCHg) OR, where n represents an integer from 1 to 6 and R ^ represents an optionally substituted (lower) alkyl or phenyl or heterocyclic radical optionally substituted on the ring, the substituents carried by the alkyl, phenyl or heterocyclic radicals being as defined under (a) (ii), (iv) radicals -OCOR ^ ', where R> represents an amino, alkyl (lower) amino, dialkyl (lower) amino or Rr radical, with the restriction that-R; ne .-. can represent an unsubstituted (lower) alkyl radical, (v) the radical -OSO ^ H, (vi) ie radical ° ίΐθΡ (ΟΗ) 2, (vii) of the radicals -0S02Rr, where Rr is such that defined under (b) (iii), 0? --- (viii) of the radicals - OP (QR) (OR), where R represents C 1 · c has an (lower) alkyl radical and R ^ is as defined under (b) (iii), (ix) of the radicals -S (0) nRd, where n represents 0, 1 or 2 and Rd is as defined under (b) (ii) or represents, in case n = 0 , a radical R ^ = C-ER, J8, where R ^ represents a hydrogen atom or an alkyl radical (lower) and R ^ and Rg each independently represent a hydrogen atom or an alkyl radical (lower), with the restriction that Rd cannot represent an unsubstituted phenyl radical, (x) of the radicals -C0Rf, where Rf represents an aminoalkyl radical (lower), alkyl (lower) aminoalkyl-! (lower), dialkyl (lower) aminoalkyl (lower), -HNH2, -ER17ERi8, -EH0Ri9, -S-Ri7, -0 (GH2) II-A-Re or -NR R, where In, R- · q and each represents a radical egl / 7 ± ô e alkyl (lower) and R ^ g represents a hydrogen atom or an alkyl radical (lower), A represents 0, S, EH or ECH-, and n and R_ are such that defined under (b) (iii) and (b) (viii) JS! (xi) radicals -P0 (0R) „, where R represents a WC, W hydrogen atom or an (lower) alkyl radical, (xii) radicals -EHR ^, where R ^ represents an optionally substituted phenyl radical ' , heterocyclic optionally substituted, -0ïï = HH, -SO ^ H, -OH, alkoxy (lower), amino, alkyl (lower) amino, dialkyl (lower) -amino, -EHCOCH- ,, -GSpCÏÏ., -S0pCH- ., -SO, -S0PEHP, I »i 0 ι '-' S = cm2, S = CEHCH3, S = C-Eïï- ^ 3» M = C-ER7R8, 'WHERE R? and Rg each independently represent an (lower) alkyl, phenyl or phenylalkyl (lower) radical, EH = C-Rn, where B. £ represents an (lower) alkyl, phenyl or phenylalkyl (lower) radical, or 0 = C-JL , where R ^ represents an aminoalkyl radical (lower), -Mïï0, alkyl (lower) amino, dialkyl (lower) amino, —R- ^ q, ®io represents an alkyl radical (lower) or phenyl or heterocyclic optionally substituted, substituents carried by the phenyl and heterocyclic radicals being as defined under (a) (ii), -RH-C ^ - RH2, alkoxy (lower), -OGH2- £ ^, -0Cïï2 - ^^ ~ ITO2 or -0 ( CH2) 2Si (CH3) 3, (xiii) of the radicals -SC R ^, where Rq represents an alkyl radical (lower) carrying an amino radical, alkyl (lower) amino or dialkyl (lower) amino, (xiv) radicals - NR.R, where R. represents unradi- J ^ J cal (lower) alkyl and R ^ .- represents an alkyl (lower), alkoxy (lower), heterocyclic, amino radical or 0 = CR ^, where R ^ is as defined under (b) (xii), or taken together ^ with the nitrogen atom, R ^. and R ^ represent a radical 0 0 with the restriction that when R ^. represents an amino radical or -CH2CH2NÏÏ2, R ^ represents a methyl radical and also the restriction that R .. and R ^ cannot both represent (lower) alkyl radicals, (xv) radicals -RR.'R, ', where R. 'represents ü ^ ü an alkoxy radical (lower) and R ^.' represents an alkyl (lower), heterocyclic, aminoalkyl (lower), alkyl (lower) aminoalkyl (lower), i dialkyl (lower) aminoalkyl ( lower) or 0 = G-31, where IL is as defined under (b) (xii) or yours taken together with the nitrogen atom, Ej 1 and E ^. ' represent a radical - (o 0 © (xvi) of the radicals -NR-jE ^ R ^ or Rp. Em and Rn each independently represent an alkyl radical (lower) or taken together with the nitrogen atom, represent a radical. , 8. An intermediate compound according to claim 7, in the formula of which X represents a hydrogen atom or an ethyl or α-hydroxyethyl radical and T represents a -C-X radical. ► 9-- An intermediate compound according to claim 7, in the formula of which Y represents a hydrogen atom or an a-hydroxyethyl radical and T represents an a radical. -C-X where X represents: (a) a radical ^ vO <y where n represents an integer from 1 to 6; (h) a radical - (CÏ ^ ^^ NHOH where n represents an integer from 1 to 6; (c) a radical - (CH ^) P0 (0-alkyl) 2 where n represents an integer from 1 to 6 and in which the alkyl radicals are in ° l "° 6; m" IN (d) a radical - (CEL) KH-C -alkyl or n. represents a name - c * Tl ber integer from 1 to 6 and in which the alkyl radical is in Cp-Ogî (e) a radical - (CHo where n represents an integer of 1 ao; 0 d (f) a radical - (CH9) OC (CHp) HeAÎ where n and m represent 4-. m AB ✓ each independently 1 or 2 and R and R each independently represent a hydrogen atom or an (lower) alkyl radical "or. Il" (g) a radical - (C ^^ ÏJHC-R where n represents a number integer from 1 to 6 and Rc represents an alkyl radical in - C ^, phenyl or - (GH,>) m ~ o where m represents 1 or 2. 10. Pharmaceutical composition, characterized in that it comprises as active constituent a compound according to any one of claims 1 to 5 or one of its pharmaceutically acceptable salts or physiologically hydrolysable esters, in addition to a pharmaceutically acceptable carrier or diluent> . 11. Method for combating bacterial infections, characterized in that the infected host is administered, in an amount sufficient to combat the infection, a com-. pharmaceutical position according to claim 10. 12. Process for the preparation of a compound according to any one of claims 1 to 5, characterized in that a compound of formula is cyclized: fi fl — CX D "JNP (Q) 3 ο 3 C02R" where Q represents a phenyl or alkyl radical (lower), 11 T? T * ATïT> PHATvhA a TvirH cal pr-Hpt farnle to be eliminated and X and Y are as defined above, in an inert organic solvent at a temperature ranging from just above room temperature up to the reflux temperature of the solvent, the ester radical which is easy to remove and possibly other protective radicals is removed according to conventional techniques and, in the case where Y represents a hydrogen atom and if the thing is desired, the product is converted into any other desired product in the formula of which Y does not represent a hydrogen atom by reacting this product with an appropriate electrophilic reagent in an inert solvent in the presence of a strong haze.! · - i