SE449489B - BETA-LAKTAM ASSOCIATES WITH ANTIBACTERIAL AND BETA-LACTAM INHIBITIVE ACTIVITY - Google Patents

BETA-LAKTAM ASSOCIATES WITH ANTIBACTERIAL AND BETA-LACTAM INHIBITIVE ACTIVITY

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Publication number
SE449489B
SE449489B SE8001424A SE8001424A SE449489B SE 449489 B SE449489 B SE 449489B SE 8001424 A SE8001424 A SE 8001424A SE 8001424 A SE8001424 A SE 8001424A SE 449489 B SE449489 B SE 449489B
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methyl
hydroxyethyl
compound
nitrobenzyloxycarbonyloxyethyl
penem
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SE8001424A
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Swedish (sv)
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SE8001424L (en
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M Foglio
G Franceschi
C Scarafile
F Arcamone
A Sanfilippo
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Erba Farmitalia
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/568—Four-membered rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Description

449 489 Dessa föreningar besitter ett brett spektrum av antibakteri- ell verkan samt en beta-laktamashämmande verkan. Det skall observeras att stereokemin vid C5-atomen hos föreningarna enligt uppfinningen samt i alla under loppet av deras framställning bildade mellanprodukterna är densamma som i naturligt förekommande penicilliner och cefalosporiner. 449 489 These compounds possess a broad spectrum of antibacterial activity and a beta-lactamase inhibitory effect. It should be noted that the stereochemistry at the C5 atom of the compounds of the invention and in all the intermediates formed during their preparation is the same as in naturally occurring penicillins and cephalosporins.

Farmaceutiskt godtagbara salter av penemkarboxylsyror med den allmänna formeln (i), såsom natrium-, kalium-, bensatin¿,_ prokain- och liknande salter, som vanligtvis bildas med penicilliner och cefalosporiner faller likaledes inom ramen för föreliggande uppfinning.Pharmaceutically acceptable salts of penem carboxylic acids of general formula (i), such as sodium, potassium, benzatin, procaine and similar salts, which are usually formed with penicillins and cephalosporins, likewise fall within the scope of the present invention.

Uppfinningen hänför sig även till farmaceutiskt godtagbara sammansättningar, som innehåller dessa föreningar med formel I i blandning med vanliga bärare för oral och parenteral administrering.The invention also relates to pharmaceutically acceptable compositions containing these compounds of formula I in admixture with conventional carriers for oral and parenteral administration.

Följande schema visar framställning av föreningar med den allmänna formeln (I) enligt föreliggande uppfinning. 449 489 Q v ff *- Y (II) COOR OCR (III) (O) ~' RH! n n .i X R _-N a' o” ~- O H cooR H COORKIDI) n R|% RU l ...__ I .o ß N\H Y 0% N¥O - ' ' cooR _ (vn (ïl, 3:1 (xIII) RI! I n . \__1/'S\4H:X R \ ASYX fiw -N ° C/ . Y 0/ \H .COORII ll (VII) (XIV) l l 449 489 (VII) (XIV) i ' 4 (own 11"' RM \ (flïx off-SW Y O/“N H coon" " bóoR" " (VIII) (XV) o R" k R"' xhw \__rßs' w wc I' X R|||\ X *f 1[ +.___ -f *är r---N ,._.._.The following scheme illustrates the preparation of compounds of general formula (I) according to the present invention. 449 489 Q v ff * - Y (II) COOR OCR (III) (O) ~ 'RH! nn .i XR _-N a 'o ”~ - OH cooR H COORKIDI) n R |% RU l ...__ I .o ß N \ HY 0% N ¥ O -' 'cooR _ (vn (ïl, 3: 1 (xIII) RI! I n. \ __ 1 / 'S \ 4H: XR \ ASYX fi w -N ° C /. Y 0 / \ H .COORII ll (VII) (XIV) ll 449 489 (VII) ( XIV) i '4 (own 11 "' RM \ (fl ïx off-SW YO /“ NH coon "" bóoR "" (VIII) (XV) o R "k R" 'xhw \ __ rßs' w wc I' XR | || \ X * f 1 [+ .___ -f * is r --- N, ._.._.

C00R"" 0/ \|==PP113 (XI) (I) (XI) 449 489 När R"' är lägre hydroxialkyl kan gruppen R"' införas medelst förfarandet enligt Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1977). Å andra sidan kan föreningar med formeln (II) vari R"' är H överföras i föreningar med den allmänna formeln (II) vari R"' är lägre hydroxialkyl, varvid substituenten införes i ställ- ning 6 under användning av en stark bas, såsom áskàdliggöres i de följande exemplen.When R "is lower hydroxyalkyl, the group R" 'can be introduced by the method of Di Ninno et al., Journal of Organic Chemistry 42, 2960. (1977). Alternatively, compounds of formula (II) wherein R "'is H may be converted into compounds of general formula (II) wherein R"' is lower hydroxyalkyl, the substituent being introduced into position 6 using a strong base, such as is illustrated in the following examples.

Föreningar med formel (II) vari R"' är lägre hydroxialkyl kan även framställas utgående från en lämplig ester av penicillan- syra-S-oxid, såsom àskådliggöres i de följande exemplen. Sub- stitutionen i ställning 6 är inriktad stereospecifikt på 6 alfa~derivaten.Compounds of formula (II) wherein R "'is lower hydroxyalkyl may also be prepared from a suitable ester of penicillanic acid S-oxide, as illustrated in the following examples. The substitution in position 6 is stereospecifically directed to 6 alpha ~ derivatives.

Estern av penicillansyra~S-oxiden (II)(R är alkyl och R"' har den ovan angivna betydelsen) kan upphettas i ett inert lös- ningsmedel, sàsom bensen eller toluen, vanligtvis vid en temperatur av 70-l40°C, med ett lämpligt acetylenderivat med den allmänna formeln X'CsCY, vari X' är en grupp med formeln CH2Z' varvid Z' är hydroxi, amino, karbamoyloxi eller en grupp med formeln OCOR' och Y är väte, lägre alkyl, cyano eller en grupp med formeln COOR eller CH2Z', vari R och Z' har den ovan angivna betydelsen. När X' har en annan betydelse kan den medelst kända substitutionsreaktioner överföras i en grupp X varvid X utgör en grupp med formeln CHZZ vari Z har den ovan angivna betydelsen.The ester of the penicillanic acid-S-oxide (II) (R is alkyl and R "'has the meaning given above) can be heated in an inert solvent, such as benzene or toluene, usually at a temperature of 70-140 ° C, with a suitable acetylene derivative of the general formula X'CsCY, wherein X 'is a group of the formula CH2Z' wherein Z 'is hydroxy, amino, carbamoyloxy or a group of the formula OCOR' and Y is hydrogen, lower alkyl, cyano or a group of the formula COOR or CH 2 Z ', wherein R and Z' have the meaning given above. When X 'has another meaning, it can be transferred by means of known substitution reactions into a group X, where X constitutes a group of the formula CH 2 Z, wherein Z has the meaning given above.

Inneslutningsföreningen (III) kan med en bas isomeriseras till föreningen (IV) vilken på två olika sätt kan överföras i slut- föreningen (I). Enligt det första sättet kan föreningen (IV) selektivt ozoniseras vid isopropenyldubbelbindningen, varvid föreningen (V)(n=l) erhålles, som med lämpliga reduktionsme- del, sàsom fosfortribromid eller natriumjodid i acetylklorid, kan reduceras till föreningen (V)(n=noll), vilken därefter #31 449 489 under milda basiska betingelser eller på silikagel hydroly- seras till föreningen (VI)(n=noll)» Vid kondensation med en lämplig ester av glyoxylsyra erhålles föreningen (VII) (n=noll), som med ett kloreringsmedel, såsom tionylklorid eller pyridin, kan överföras i klorderivatet (VIII)(n=noll) och därefter till fosforanet (IX)(n=noll).The containment compound (III) can be isomerized with a base to the compound (IV) which can be transferred to the final compound (I) in two different ways. According to the first method, the compound (IV) can be selectively ozonized at the isopropenyl double bond, whereby the compound (V) (n = 1) is obtained, which with suitable reducing agents, such as phosphorus tribromide or sodium iodide in acetyl chloride, can be reduced to the compound (V) (n = zero), which is then hydrolysed to the compound (VI) (n = zero) under mild basic conditions or on silica gel. 'When condensed with a suitable ester of glyoxylic acid, the compound (VII) (n = zero) is obtained, which with a chlorinating agent, such as thionyl chloride or pyridine, can be converted into the chlorine derivative (VIII) (n = zero) and then to the phosphorane (IX) (n = zero).

Dessutom genomföres samma reaktionsföljd även utgående från den oväntade'föreningen (VI)(n=l), som är stabil, när Y-icke utgör någon stark avspaltbar grupp. När det rör sig om föreningar (IX)(n=noll) kan föreningen selektivt ozoniseras som fosfoniumsalt under sura betingelser, varvid föreningen (XI) erhålles, som på enkelt sätt cykliseras genom upphettning i ett inert lösningsmedel, såsom toluen, vid en temperatur av 50-l4Û°C till föreningen (I).In addition, the same reaction sequence is also carried out on the basis of the unexpected compound (VI) (n = 1), which is stable when Y-does not form a strong leaving group. In the case of compounds (IX) (n = zero), the compound can be selectively ozonized as the phosphonium salt under acidic conditions to give the compound (XI), which is easily cyclized by heating in an inert solvent such as toluene at a temperature of 50-164 ° C to the compound (I).

När det rör sig om föreningar (IX)(n=l) måste föreningen reduceras till föreningen (X) och därefter selektivt ozoniseras till föreningen (XI) som ger föreningen (I).In the case of compounds (IX) (n = 1), the compound must be reduced to the compound (X) and then selectively ozonized to the compound (XI) which gives the compound (I).

Enligt det andra sättet kan föreningen (IV) under de vanliga betingelserna reduceras till föreningen (XII), som ozoniseras vid båda dubbelbindningarna, varvid föreningen (XIII) och, efter hydrolys, föreningen (XIV) erhålles. Medelst samma förfarande som ovan beskrivits ger glyoxyleringen av förening (XIV) föreningen (XV), som kan överföras i klorderivatet (XVI) och därefter i fosforanen (XI), vilken utgör en gemensam mellanprodukt för båda förfaringssätten.According to the second method, the compound (IV) can be reduced under the usual conditions to the compound (XII), which is ozonized at both double bonds, whereby the compound (XIII) and, after hydrolysis, the compound (XIV) are obtained. By the same procedure as described above, the glyoxylation of compound (XIV) gives the compound (XV), which can be converted into the chlorine derivative (XVI) and then into the phosphorane (XI), which is a common intermediate for both processes.

När R"' är hydroxialkyl genomföres reaktionsföljden företrädesvis under skydd av den alkoholiska funktionen.When R "'is hydroxyalkyl, the reaction sequence is preferably carried out under the protection of the alcoholic function.

Föreningar med den allmänna formeln (I) vari R"" är väte kan erhållas genom hydrolys eller hydrogenolys av de motsvarande förestrade föreningarna. 449 489 Av följande tabell A framgår hur valet av substituenter påverkar aktiviteten gentemot bakterier. Det framgår sålunda tydligt att penem-derivaten enligt föreliggande uppfinning är mycket aktiva gentemot organismen Escherichia coli TEM, en gram-negativ stamalstrare av ett speciellt B-laktamas enzym som inaktivera: den testade förening som beskrives i DE 2.819.655, US 4.155.912 och EP 636.Compounds of general formula (I) wherein R "" is hydrogen can be obtained by hydrolysis or hydrogenolysis of the corresponding esterified compounds. 449 489 The following table A shows how the choice of substituents affects the activity towards bacteria. Thus, it is clear that the penem derivatives of the present invention are very active against the organism Escherichia coli TEM, a gram-negative progenitor of a particular β-lactamase enzyme which inactivates: the tested compound described in DE 2,819,655, US 4,155,912 and EP 636.

TABELL A '.' l) 2) 3) 4) R u_m,{/,f '//x L 111 _--u- -cum ,_, o (SR,6S)-2-acetoximetyl-611(R)hydroxietyl]-2-penem-3- -karboxylsyra (III, R=CH3CHOH, X = CH3CO0CH2 föreliggande uppfinning). (5R,6S)-2111-metyl-lfl-tetrazol-5-yl)-tiometyl7-6¿ï(R)- hydroxietylf-2-penem-3-karboxylsyra N“"N (111, a: cHBcHOH, x = n n\>_5'c"z N- » föreliggande upp- CH finning). 3 (5R,6S)-2-karbamoyloximetyl-611(R)hydroxietyl7-2-penem-3- -karboxylsyra (III, R=cn3cHoH, x = Hzncoocnz, föreliggande uppfinning). (5R,GS)-2-metyl-2-penem-3-karboxylsyra.TABLE A '.' l) 2) 3) 4) R u_m, {/, f '// x L 111 _-- u- -cum, _, o (SR, 6S) -2-acetoxymethyl-611 (R) hydroxyethyl] -2 -penem-3--carboxylic acid (III, R = CH 3 CHOH, X = CH 3 COOCH 2 present invention). (5R, 6S) -2111-methyl-1H-tetrazol-5-yl) -thiomethyl7-6β (R) -hydroxyethyl-2-penem-3-carboxylic acid N + N (111, a: cHBcHOH, x = nn \> _ 5'c "z N-» present invention). 3 (5R, 6S) -2-carbamoyloxymethyl-611 (R) hydroxyethyl7-2-penem-3-carboxylic acid (III, R = cn3cHoH, x = Hzncoocnz, present invention). (5R, GS) -2-methyl-2-penem-3-carboxylic acid.

(III, R = H, X = CH3, DE 2.819.655 exempel 5; US 4.155.912 exempel 5 och EP 636 exempel 6). 449 489 8 M.I.C. ng/ml _Stam Föreliggande uppfin. 1 2 3 -0 B) Staphy1ococc0s_a0reus Smlthn ' 0,00 0,01 0,00 1 b) " " 39/2* 0,03 0,015 0,03 4 C) Diplococcus pneumoniae ATCC6301 0,04 0,006 0,015 0,5 d) Streptococcus pyogenes C 203 0,00 0,015 0,03 0,5 C) "_- faecalls ATCC6057 2,8 -5,7 2 128 f)Escherich1a coli 1507 0,5 0,17 0,5 16 g) "_ _ -- IfM* 0,5 0,11 0,5 )12_a h) Klebsíella aerogenes 1082 E*' 1,4 0,35 0,7 128 1) H i" 1522 E 0,5 0,25 0,5 ' 16 j) Entcrnbacter cloacae P99* 5,7 2,8 2,8 32 _ I k) -- " 13212 0,5 ' 0,35 0,5 16 1) samonena :ypni Watson 0,5 0,125 0,5 ' 16 m) Proteus vulgaris X 20 1 0,125 1 )128 p) -- mirabilis 211009921 1 0,125 2 ' e 1,) cmsn-iaium perfringens 200611 0,5 0,25 0,25 ,. p) Bactetoides ffagílls ISM 75/42 0,7 0,25 0,5 - Anm. a-e och 0: Gram-positiva bakterier; f-n och p: Gram-negativa bakterier; o och p= anaeroba bakterier;*B-lactamasi framkallare.(III, R = H, X = CH 3, DE 2,819,655 Example 5; US 4,155,912 Example 5 and EP 636 Example 6). 449 489 8 M.I.C. ng / ml _Stam The present invention. 1 2 3 -0 B) Staphylococcus_a0reus Smlthn '0.00 0.01 0.00 1 b) "" 39/2 * 0.03 0.015 0.03 4 C) Diplococcus pneumoniae ATCC6301 0.04 0.006 0.015 0.5 d ) Streptococcus pyogenes C 203 0.00 0.015 0.03 0.5 C) "_- faecalls ATCC6057 2.8 -5.7 2 128 f) Escherich1a coli 1507 0.5 0.17 0.5 16 g)" _ _ - IfM * 0,5 0,11 0,5) 12_a h) Klebsíella aerogenes 1082 E * '1,4 0,35 0,7 128 1) H i "1522 E 0,5 0,25 0,5 '16 j) Entcrnbacter cloacae P99 * 5,7 2,8 2,8 32 _ I k) - "13212 0,5' 0,35 0,5 16 1) samonena: ypni Watson 0,5 0,125 0,5 '16 m) Proteus vulgaris X 20 1 0,125 1) 128 p) - mirabilis 211009921 1 0,125 2' e 1,) cmsn-iaium perfringens 200611 0,5 0,25 0,25,. p) Bactetoides ffagílls ISM 75/42 0.7 0.25 0.5 - Note. a-e and 0: Gram-positive bacteria; f-n and p: Gram-negative bacteria; o and p = anaerobic bacteria; * β-lactamase inducer.

Uppfinningen âskádlíggöres närmare medelst följande exempel.The invention is further illustrated by the following examples.

Exemgel 1.Example 1.

Metyl-Gur(l'-hydroxietyl)-penicillanat-S-oxid.Methyl-Gur (1'-hydroxyethyl) -penicillanate S-oxide.

O . on 0 _ ll ' ' y H I? H S *_ 1,, Q: å S I CH 8 9,- __." i I; Q 5 I? 2' f-N - -N v3_ 0 f ”coocn3 07 4 H "'ffcoocu3 En lösning av 2,3 g metylpenicillinat~S-oxid i 50 ml vatten- fri tetrahydrofuran kyldes till -78°C. Litiumdiisopropylamid (färskt framställd ur 5 ml diisopropylamin och 20 ml av en l,6M BuLi-hexanlösníng), löst i vattenfri tetrahydrofuran, tillsattes och biananingen fick stå i 10 minuter via -7e°c. 5 ml acetaldehyd tillsattes efter hand och det hela omrördes 449 489 9 i 15 minuter. Därefter kyldes reaktionsblandningen med en mättad vattenhaltig NH4Cl-lösning, extraherades med etyl- acetat, tvättades två gånger med vatten och torkades över Na2SO4. Efter avdunstning av lösningsmedlet renades åter- stoden genom kort tids kolonnkromatografi pâ silikagel, varvid man eluerade med diklormetan-etylacetat (lzl). Utbyte 1,5 g. Den i rubriken angivna föreningen bestod av en 2:3- -blandning av epimerer vid den hydroxylgrupp som bar kol- atomen, med avseende på NMR, varvid den nya C6-C8-bindningen beroende på_reaktionens stereospecificitet under de använda betingelserna endast föreligger i a-ställning.O. on 0 _ ll '' y H I? HS * _ 1 ,, Q: å SI CH 8 9, - __. "I I; Q 5 I? 2 'fN - -N v3_ 0 f” coocn3 07 4 H "' ffcoocu3 A solution of 2,3 g of methylpenicillinate ~ S-oxide in 50 ml of anhydrous tetrahydrofuran was cooled to -78 ° C. Lithium diisopropylamide (freshly prepared from 5 ml of diisopropylamine and 20 ml of a 1,6M BuLi-hexane solution), dissolved in anhydrous tetrahydrofuran, was added and the mixture was allowed to stand for 10 minutes at -7 ° C. 5 ml of acetaldehyde was added gradually and the whole was stirred for 15 minutes. Then the reaction mixture was cooled with a saturated aqueous NH 4 Cl solution, extracted with ethyl acetate, washed twice with water and dried over Na 2 SO 4. After evaporation of the solvent, the residue was purified by short-term column chromatography on silica gel, eluting with dichloromethane-ethyl acetate (Izl). Yield 1.5 g. The title compound consisted of a 2: 3 mixture of epimers at the hydroxyl group bearing the carbon atom, with respect to NMR, the new C6-C8 bond depending on the stereospecificity of the reaction during the the conditions only exist in the a-position.

NMR (CDCl3): 1,27 J (S, 3H, Q-ÉE3), 1,40 J (d, 3H, J = 5,7 Hz, QÉ3-CHOH), huvudisømer, 1,48 J (d, 3H, J = 5,7 H2, CH3~CHOH), ringa isomer, 1,70 J (s, 3H,,ß-§§3), 3,4 - 3,8 J (m, lH, H-6), 3,8O1í (S, 3H, COOQÉ3), 4,1 - 4,7 J (m, lH, §fiOH), 4,50 J (s, lH, g-3), 4,98 J (d, J = 1,9 Hz, lH, §-5) ringa isomer, 5,05<{ (d, J = 1,9 Hz, lH, g-5) huvudisomer.NMR (CDCl 3): 1.27 J (S, 3H, Q-EE 3), 1.40 J (d, 3H, J = 5.7 Hz, QE 3 -CHOH), major isomers, 1.48 J (d, 3H , J = 5.7 H2, CH3-CHOH), minor isomer, 1.70 J (s, 3H, β-§§3), 3.4 - 3.8 J (m, 1H, H-6) , 3.8O1i (S, 3H, COOQÉ3), 4.1 - 4.7 J (m, 1H, §fi OH), 4.50 J (s, 1H, g-3), 4.98 J (d, J = 1.9 Hz, 1H, §-5) minor isomer, 5.05 <{(d, J = 1.9 Hz, 1H, g-5) major isomer.

Exemgel 2.Example 2.

Metyl-6-(1-hydroxietyl)-3-penicillanat. - ' oH 3 S J N -----> N h, ' O” I, 'fcoocn3 o H 'toocn3 Till en lösning av 2,2 g metylpenicillanat i 30 ml vattenfri tetrahydrofuran tillsattes ett litet överskott av litiumdi~ isopropylamid vid -78°C under kväve. Ett acetaldehydöver- skott tillsattes droppvis, blandningen omrördes 5 minuter, kyldes med en spàrmängd ättiksyra, hälldes i vatten och extra- herades med metylenklorid. De över Na2SO4 torkade och i vakuum indunstade organiska skikten gav 0,8 g av den i rubriken angivna föreningen. 449 489 10 Exemgel 3.Methyl 6- (1-hydroxyethyl) -3-penicillanate. To a solution of 2.2 g of methyl penicillanate in 30 ml of anhydrous tetrahydrofuran was added a small excess of lithium diisopropylamide at -78 ° C. ° C under nitrogen. An excess of acetaldehyde was added dropwise, the mixture was stirred for 5 minutes, cooled with a trace amount of acetic acid, poured into water and extracted with methylene chloride. The organic layers dried over Na 2 SO 4 and evaporated in vacuo gave 0.8 g of the title compound. 449 489 10 Example 3.

Metyl-6-(1-p-nitrobensyloxikarbonyloxietyl)-3-penicillanat.Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate.

OH ocozpms /k as /_ s “““__-*+ ó6”“'N Q, N-;1:š n COOCH 0 H 'coocn 1,2 g metyl-6-(l-hydroxietyl)-3-penicillanat löstes i 40 ml tetrahydrofüran, kyldes till -78°C och behandlades med-- l ekvivalent butyllitium. 1,2 ekvivalenter p~nitrobensyloxi- karbonylklorid sattes till den erhållna blandningen. Efter 30 minuter vid -78°C fick reaktionsblandningen stå 60 minuter vid rumstemperatur, hälldes i vatten och extraherades med metylenklorid. Man erhöll efter torkning över Na2SO4 och indunstning 1,4 g av den i rubriken angivna föreningen.OH ocozpms / k as / _ s ““ “__- * + ó6” “'NQ, N-; 1: š n COOCH 0 H' coocn 1.2 g methyl 6- (1-hydroxyethyl) -3-penicillanate was dissolved in 40 ml of tetrahydrofuran, cooled to -78 ° C and treated with 1 liter of butyllithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to the resulting mixture. After 30 minutes at -78 ° C, the reaction mixture was allowed to stand for 60 minutes at room temperature, poured into water and extracted with methylene chloride. After drying over Na 2 SO 4 and evaporation, 1.4 g of the title compound were obtained.

Exemgel 4.Exemgel 4.

Metyl-6-(l-p-nitrobensyloxikarbonyloxietyl)-3-penicillanat- -S-oxid. - o ocozsäms . 0C02PNB (q S S \ f ]< N 0,” -""_"'_"* f-N-f ,,_, O 1 COOCH3 Û HV 'CQQCH3 1,8 g metyl-6-(l-p-nitrobensyloxikarbonyloxietyl)-3-peni- cillanat löstes i 50 ml metylenklorid och behandlades vid O°C med 1,5 ekvivalenter m-klorperbensoesyra. Den organiska fasen skakades med mättad NaHCO3-lösning, extraherades, tor- kades över Na2SO4 och indunstades. Man erhöll 1,4 g av den förväntade sulfoxiden. 449 489 ll Exemgel -5. 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxikarbo- nyloxietyl)-l-(l-metoxikarbonyl-2-metyl-2-propenyl)-azetidin- -2~on~S-oxid. Û O ocozvuß H ' ocogpNB n s s /ïff Ûcocrä ----> N___._,9, Nj/tk ococn3 0 _ _ H 'coocn3 0 _ ~ H coocli3- En lösning av 2,0 g metyl-6-(l-p-nitrobensyloxikarbonyloxi- etyl)-3-penicillanat-S-oxid och 2,4 g butindioldiacetat i 50 ml toluen hölls i 24 timmar vid âterflöde. Inneslutnings- föreningen renades därefter medelst kolonnkromatografi, var- vid man eluerade med 9:1 diklormetan-etylacetat. Man erhöll 1,1 g av den i rubriken angivna föreningen.Methyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate-S-oxide. - o ocozsäms. CO 2 PNB (q SS \ f] <N 0, "-" "_" '_ "* fNf ,, _, O 1 COOCH3 Û HV' CQQCH3 1.8 g methyl-6- (1p-nitrobenzyloxycarbonyloxyethyl) -3-peni cillanate was dissolved in 50 ml of methylene chloride and treated at 0 DEG C. with 1.5 equivalents of m-chloroperbenzoic acid, the organic phase was shaken with saturated NaHCO3 solution, extracted, dried over Na2SO4 and evaporated to give 1.4 g of the expected sulfoxide 449 489 11 Exemgel -5,4β-vinylthio- (1,2-diacetoxymethyl) -3- (1p-nitrobenzyloxycarbonylloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidine- -2 ~ on ~ S-oxide. Û O ocozvuß H 'ocogpNB nss / ïff Ûcocrä ----> N ___._, 9, Nj / tk ococn3 0 _ _ H' coocn3 0 _ ~ H coocli3- A solution of 2 .0 g of methyl 6- (1p-nitrobenzyloxycarbonyloxyethyl) -3-penicillanate S-oxide and 2.4 g of butinediol diacetate in 50 ml of toluene were kept for 24 hours at reflux. The inclusion compound was then purified by column chromatography, whereby eluting with 9: 1 dichloromethane-ethyl acetate to give 1.1 g of the title compound.

Exemgel 6. 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxikarbo- nyloxietyl)-l-(metoxikarbonyl-2-metyl-1-propenyl)-azetidin- -2-on-S-oxid. 0 O øcozvms 1; _ - 0C02PNB ll s S .. (f, \U/\OCOCH3 fococrä _.Example 6.4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one S-oxide. 0 O øcozvms 1; _ - 0C02PNB ll s S .. (f, \ U / \ OCOCH3 fococrä _.

OCOCH '_""""“'> J OCOCH O/__1-: ,| \/ 3 _ of-rkí/ \ 3 lf WCOOCH3 CQ0Cu3 1,3 g 4ß-vinyltio-(l,2-diacetoximetyl)~3-(l-p-nitrobensyloxi- karbonyloxietyl)-l-(metoxikarbonyl-2-metyl-2-propenyl)-azeti- din-2-on-S-oxid löstes i 80 ml diklormetan. 0,3 ml trietyl- amin tillsattes och blandningen fick stå i 2 timmar vid rums- temperatur. Den rena, i rubriken angivna föreningen erhölls vid avdunstning av lösningsmedlet i kvantitativt utbyte. z-:a 449 489 12 Exemgel 7. 4ß-vinyltio~(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxikarbo- nyloxietyl)-1-metoxioxaloyl-azetidin-2-on-S-oxid. o I ' 0 ocozpnß || oeo2PNB|| Q§l_: COOCH3 coocu 3 En lösning av 1,1 g 4fiPvinyltio-(l,2-diacetoximetyl)-3-(1- -p-nitrobensyloxikarbonyloxietyl)-1-(metoxikarbonyl-2-metyl- -l-propenyl)-azetidin-2-on-S-oxid i 100 ml diklormetan kyldes till ~7s°c. ozøn 1 syre genomblåstes tills blåfärgning upp- trädde. Lösningen skakades med en vattenhaltig Na2S2O5-lös- ning och torkades över Na2SO4. Efter indunstning erhölls 0,5 g av den i rubriken angivna föreningen.OCOCH '_ "" "" “'> J OCOCH O / __ 1-:, | 1,3 g of 4-vinylthio- (1,2-diacetoxymethyl) -3- (1p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-2- propenyl) -acetidin-2-one-S-oxide was dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine was added and the mixture was allowed to stand for 2 hours at room temperature. The pure title compound was obtained by evaporation of the solvent in quantitative yield. 44- 489 12 Example 7. 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1-methoxyioxaloyl-azetidin-2-one S-oxide. o I '0 ocozpnß || oeo2PNB || Q§l_: COOCH3 coocu 3 A solution of 1.1 g of 4ox Pvinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) - azetidin-2-one-S-oxide in 100 ml of dichloromethane was cooled to 77 ° C. ozøn 1 oxygen was blown through until blue staining occurred. The solution was shaken with an aqueous Na 2 SO 2 solution and dried over Na 2 SO 4. After evaporation, 0.5 g of the title compound was obtained.

Exemgel §¿ 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxikarbo- nyloxietyl)-l-metoxioxaloyl-azetidin-2-on. 0 ocozvnß H OCQZPNBS ,*l\\___Tf”5*\\Ü/“\ococn3 //l\\r__Tß *\H:ï“ococH3 ----rå ¿L__N /A9 \v,ococn3 ¿r__N , ococn3 o 0 CÜOCH3 COOCH? En lösning av 0,8 g 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p- -nitrobensyloxikarbonyloxietyl)-l-metoxioxaloyl-azetidin-2- -on i l5 ml vattenfri dimetylformamid kyldes till -20°C och 0,6 ml fosfortribromid tillsattes. Reaktionsblandningen ut- späddes efter 10 minuter med etylacetat och tvättades två gånger med en NaHC03-lösning. Den över Na2SO4 torkade och indunstade organiska fasen gav 0,4 g av den reducerade före- ningen. s.\\ s ' -1* ü:::ococH3 “\Ü::ïococH3 -f---+ F__N\?¿\_ ococH3 N¿fiá0 0COCH3_ O _ 449 489 13 Exemgel 9. 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxikarbo- nyløxietyl)-azetidin-2-on. oco PNB oco PNB 2 2 S s fococns fococrä -i-*fi ococu N /0 ococn3 h N\ - 3 o Y _ . 0 H coocu3 1,2 g 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxi~ karbonyloxietyl)-l-metoxioxa1oyl-azetidin-2-on löstes i metanol och 2 g silikagel sattes till lösningen. Efter 60 minuter avfiltrerades det olösliga materialet och den orga- niska fasen indunstades. Kort tids kolonnkromatografi gav 0,4 g av den i rubriken angivna föreningen.Exemgel § 4ß-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxioxaloyl-azetidin-2-one. 0 ocozvnß H OCQZPNBS, * l \\ ___ Tf ”5 * \\ Ü /“ \ ococn3 // l \\ r__Tß * \ H: ï “ococH3 ---- rå ¿L__N / A9 \ v, ococn3 ¿r__N, ococn3 o 0 CÜOCH3 COOCH? A solution of 0.8 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1β-nitrobenzyloxycarbonyloxyethyl) -1-methoxioxaloyl-azetidin-2-one in 15 ml of anhydrous dimethylformamide was cooled to -20 ° C and 0.6 ml of phosphorus tribromide was added. The reaction mixture was diluted after 10 minutes with ethyl acetate and washed twice with a NaHCO 3 solution. The organic phase dried over Na2SO4 and evaporated gave 0.4 g of the reduced compound. s. \\ s' -1 * ü ::: ococH3 “\ Ü :: ïococH3 -f --- + F__N \? ¿\ _ ococH3 N¿ fi á0 0COCH3_ O _ 449 489 13 Exemgel 9. 4ß-vinyltio- ( 1,2-diacetoxymethyl) -3- (1p-nitrobenzyloxycarbonylloxyethyl) -azetidin-2-one. oco PNB oco PNB 2 2 S s fococns fococrä -i- * fi ococu N / 0 ococn3 h N \ - 3 o Y _. 0 g Coculum 1.2 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxy-carbonyloxyethyl) -1-methoxyioxaloyl-azetidin-2-one were dissolved in methanol and 2 g of silica gel were added to the solution. After 60 minutes, the insoluble matter was filtered off and the organic phase was evaporated. Brief column chromatography gave 0.4 g of the title compound.

Exemgel 10. 4ß-vinyltio-(l,2-diacetoximetyl)-3-(1-p-nitrobensy1oxikarbo- nyloxietyl)-l-(l-acetoximetyloxikarbonyl-l-hydroximetyl)- -azetidin-2-on.Example 10. 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -1-azetidin-2-one.

PNB oco Que OCO2 1/Å\\z S S ._11 I ococH3 fococlä N ococu3 å N ococn3 ¿r*“ \\}1 O \ï»OH o COOCHZOCOCH3 0,6 g 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxi- karbonyloxietyl)-azetidin-2-on, löst i 30 ml bensen, och 0,6 g acetoximetylglyoxylat (färskt framställt genom ozonolys av diacetoximetylfumarat) hölls vid återflöde. Reaktionen var avslutad efter 2 timmar. Kondensationsprodukten kunde användas för det nästa steget utan ytterligare rening. 449 489 14 Exemgel ll. 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyloxikarbo- nyloxietyl)-l-(l-acetoximetyloxikarbonyl-l-klormetyl)-azeti- din-2-on. oco PNB ' i °C°2PNB 2 s - S I cocn3 fococxæ ----~> N\Å»-0H °C°CH3 N\l_,.fcl OCOCH3 o I ^ ° _. _cuocH2ococn3 coocuzoçocn3 0,5 g 4ß-vinyltio-(l,2-diacetoximetyl)-3-(1-p-nitrobensyloxi~ karbonyloxietyl)-l-(l-acetoximety1oxikarbonyl-l-hydroximetyl)- -azetidin-2-on löstes i 12 ml vattenfri tetrahydrofuran och kyldes till OOC. l,l ekvivalenter pyridin och l,l ekvivalen- ter tionylklorid tillsattes. Blandningen omrördes i 10 minuter. Det olösliga materialet avfiltrerades och lösningen indunstades vid rumstemperatur, varvid den i rubriken angivna föreningen erhölls i nästan kvantitativt utbyte. Produkten kunde användas för nästa steg utan ytterligare rening.PNB oco Que OCO2 1 / Å \\ z SS ._11 I ococH3 fococlä N ococu3 å N ococn3 ¿r * “\\} 1 O \ ï» OH o COOCHZOCOCH3 0.6 g 4ß-vinylthio- (1,2-diacetoxymethyl ) -3- (1β-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one, dissolved in 30 ml of benzene, and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) were kept at reflux. The reaction was complete after 2 hours. The condensation product could be used for the next step without further purification. 449 489 14 Exemgel ll. 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -acetidin-2-one. oco PNB 'i ° C ° 2PNB 2 s - S I cocn3 fococxæ ---- ~> N \ Å »-0H ° C ° CH3 N \ l _ ,. fcl OCOCH3 o I ^ ° _. 0.5 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxy-carbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one 12 ml of anhydrous tetrahydrofuran and cooled to 0 ° C. 1.1 equivalents of pyridine and 1.1 equivalents of thionyl chloride were added. The mixture was stirred for 10 minutes. The insoluble material was filtered off and the solution was evaporated at room temperature to give the title compound in almost quantitative yield. The product could be used for the next step without further purification.

Exemgel 12- 4ß-vinyltio*(l,2-diacetoximetyl)-3-(l~p-nitrobensyloxikarbo- nyloxietyl)-l-(acetoximetyloxikarbonyl~l-trifenylfosforanyli- denmetyl)-azetidin-2-on. ' oco 'ens I ÜÜÜ *WB 2 2 f I ococn3 ' cocu3 ----~> _ ococn ococH N 1 v 3 N f 3 O/"'_' \'.r/"C 0 coocuzococn3 COOCHZOCOCH3 En lösning av 0,760 g åßvinyltio-(1,2-diacetoximetyl)-3-(1- -p-nitrobensoyloxikarbonyloxietyl)-l-(l-acetoximetyloxikar- bonyl-l-hydroximetyl)-azetidin-2-on i 10 ml tetrahydrofuran och lO ml dioxan omrördes över natten vid 50°C med 2 ekviva- lenter trifenylfosfin och l,l ekvivalenter pyridin. Fos- foranen renades genom kolonnkromatografi på silikagel, varvid man eluerade med 70:30 diklormetan-etylacetat. Man erhöll 449 489 lá 0,480 g av den i rubriken angivna föreningen.Example gel 12- [4β-vinylthio * (1,2-diacetoxymethyl) -3- (1,2-p-nitrobenzyloxycarbonylloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one. 'oco' ens I ÜÜÜ * WB 2 2 f I ococn3 'cocu3 ---- ~> _ ococn ococH N 1 v 3 N f 3 O / "' _ '\'. r /" C 0 coocuzococn3 COOCHZOCOCH3 A solution of 0.760 g of acetonylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzoyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one in 10 ml of tetrahydrofuran and 10 ml of dioxane was stirred overnight at 50 ° C with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine. The phosphorus was purified by column chromatography on silica gel, eluting with 70:30 dichloromethane-ethyl acetate. 449,489 g of 0.480 g of the title compound were obtained.

Exemgel 13. 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxietyl)-1- -(l-acetoximetyloxikarbonyl-l-trifenylfosforanylidenmetyl)- -azetidin-2-on. 0CO PNB ' OC0 PNB 2 2 S //L\\ S Ü ' cocH3 - r -| ococfl I ococn "'_"""""'* 0 3 óf;N§fW§\/ 3 ' O N fsmä.Example Gel 13. 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- - (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one. 0CO PNB 'OC0 PNB 2 2 S // L \\ S Ü' cocH3 - r - | ococ fl I ococn "'_" "" ""' * 0 3 óf; N§fW§ \ / 3 'O N fsmä.

C00CH20C0CH3 CQQCHZOCOCH3 0,45 g 4ß-vinyltio-(l,2-diacetoximetyl)-3-(l-p-nitrobensyl- oxikarbonyloxietyl)-l-(acetoximetyloxikarbonyl-l-trifenyl- fosforanylidenmetyl)~azetidin-2-on löstes i 50 ml diklormetan och kyldes till -2000. 30 ml av en lösning av trifluorättik- syra i diklormetan tillsattes. Efter nâgra få minuter genom- blåstes ozon i syre tills lätt blåfärgning uppträdde. Reak- tionen avbröts och nâgra få droppar trimetylfosfit tillsattes.CO 45 CH 2 COCH 3 CQQCHZOCOCH 3 0.45 g of 4β-vinylthio- (1,2-diacetoxymethyl) -3- (1p-nitrobenzyloxycarbonyloxyethyl) -1- (acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -micloidimethane-2-dimethidin and cooled to -2000. 30 ml of a solution of trifluoroacetic acid in dichloromethane was added. After a few minutes, ozone was purged with oxygen until a slight blue color appeared. The reaction was stopped and a few drops of trimethyl phosphite were added.

Den organiska fasen tvättades med mättad NaHCO3-lösning och torkades över Na2S04. Man erhöll 0,260 g av den i rubriken angivna föreningen.The organic phase was washed with saturated NaHCO 3 solution and dried over Na 2 SO 4. 0.260 g of the title compound were obtained.

Exemgel 14. 4ß-vinyltio-(l,2-diacetoximety1)~3-(l-p-nitrobensyloxikarbo- nyloxietyl)~l-(metoxikarbonyl-2~metyl-l-propenyl)-azetidin- 3 -2-on.Example 14. 4β-Vinylthio- (1,2-diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonylloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-2-one.

O . oco2PNß ;| °C°2PNB S S . --_-§ __1,- ~__U:::ococH3 \\Ü:::ococn3 ococn ococn ,_N f 3 N\[/)\- 3 o \Tl\ 0 CUOCH3 “ coocn 1,5 g vinyltio-(l,2-diacetoximety1)-3-(1~p-nitrobensyloxi- karbonyloxietyl)~l-(metoxikarbonyl-2-metyl-1-propenyl)-azeti- din-2-on-S-oxid löstes i 10 ml vattenfri dimetylformamid och 449 489 16 kylaes till -2o°c. 0,8 ml fosforcribrømid tillsattes, bland- ningen omrördes i 10 minuter, utspäddes med etylacetat och tvättades två gånger med mättad NaHCO3-lösning. Det över Na2S04 torkade och indunstade organiska skiktet gav l,l g av den i rubriken angivna föreningen.O. oco2PNß; | ° C ° 2PNB S S. --_- § __1, - ~ __U ::: ococH3 \\ Ü ::: ococn3 ococn ococn, _N f 3 N \ [/) \ - 3 o \ Tl \ 0 CUOCH3 “coocn 1,5 g vinyltio- ( 1,2-Diacetoxymethyl) -3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -acetidin-2-one-S-oxide was dissolved in 10 ml of anhydrous dimethylformamide and 449,489 ° C is cooled to -2 ° C. 0.8 ml of phosphorus crybromide was added, the mixture was stirred for 10 minutes, diluted with ethyl acetate and washed twice with saturated NaHCO 3 solution. The organic layer, which was dried over Na2SO4 and evaporated, gave 1.1 g of the title compound.

Exemgel 15. 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxietyl)-l- -metoxioxalyl-azetidin-2-on.Example Gel 15. 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxioxalyl-azetidin-2-one.

OCOZPNB,-t - ' OCOZPNB " ¿5 ,S f \\Tíß\bcocn3 “'"I \\g//\bC0CH3 ----> f i* * 3 o' “Y COOCH3 _ COOCH 4 3 1,4 q 4AFvinylti0-(l,2-diacet0ximetyl)-3-(l-p-nitrobensyloxi- karbonyloxietyl)-l-(metoxikarbonyl-2-metyl-1-propenyl)-azeti~ ain-z-on i lzo m1 aiklormetan kyldes till -7a°c. ozon i syre genomblåstes tills en blåfärgning uppträdde. Lösningen ska- kades med vattenhaltig Na2S2O5-lösning och torkades över Na2SO4. vid indunstning erhölls 0,8 g av den i rubriken angivna föreningen.OCOZPNB, -t - 'OCOZPNB "¿5, S f \\ Tíß \ bcocn3"' "I \\ g // \ bC0CH3 ----> fi * * 3 o '“ Y COOCH3 _ COOCH 4 3 1,4 The 4A-vinylthio- (1,2-diacetoxymethyl) -3- (1β-nitrobenzyloxycarbonyloxyethyl) -1- (methoxycarbonyl-2-methyl-1-propenyl) -acetylamine-z-one in 20 ml of chloromethane was cooled to -7a ° c. ozone in oxygen was purged until a blue coloration occurred. The solution was shaken with aqueous Na 2 SO 2 O 5 solution and dried over Na 2 SO 4. evaporation gave 0.8 g of the title compound.

Exemgellß- 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxietyl)- -azetidin-2-on. oco PNB 0C02PNB 2 .Exemgellß-4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one. oco PNB 0C02PNB 2.

S S __]/ YOCOCHE; *OCOCH N o ----~> o 3 ___ 1 __ N ' i o Ü/o - o” N; COOCH3 0,800 g 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyl- oxietyl)-l~metoxioxalyl~azetidin-2-on löstes i 50 ml metanol och nâgra få g silikagel tillsattes. Blandningen fick stå i 60 minuter vid rumstemperatur, det olösliga materialet av- 449 489 17 filtrerades och filtratet gav efter indunstning 0,300 g av den i rubriken angivna föreningen.S S __] / YOCOCHE; * OCOCH N o ---- ~> o 3 ___ 1 __ N 'i o Ü / o - o ”N; COOCH3 0.800 g of 4β-acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxioxalyl-azetidin-2-one was dissolved in 50 ml of methanol and a few g of silica gel were added. The mixture was allowed to stand for 60 minutes at room temperature, the insoluble material was filtered off and the filtrate, after evaporation, gave 0.300 g of the title compound.

Exemgel 17. 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxietyl)-1- ~(l-acetoximetyloxikarbonyl-1-hydroximetyl)-azetidin-2-on.Example 17. 4β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- - (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one.

OCO PNB OCO PNB 2 2 S s I) WA ococ1i3 \[(\°C°CH3 - ---> -Nx ° N CÅ 04- > 'o ' 'V i coocn2ococ1¶3 0,5 g 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxi- etyl)-l-(l-acetoximetyloxikarbonyl-l-hydroximetyl)-azetidin- -2-on och 0,5 g acetoximetylglyoxylat i 30 ml bensen hölls vid återflöde tills reaktionen var avslutad (2 timmar). Den erhållna i rubriken angivna föreningen kunde användas för nästa steg utan ytterligare rening.OCO PNB OCO PNB 2 2 S s I) WA ococ1i3 \ [(\ ° C ° CH3 - ---> -Nx ° N CÅ 04-> 'o' 'V i coocn2ococ1¶3 0.5 g 4ß-acetylglycolylthio- 3- (1p-Nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one and 0.5 g of acetoxymethylglyoxylate in 30 ml of benzene were kept at reflux until the reaction was completed (2 hours). The title compound obtained could be used for the next step without further purification.

Exemgel 18. 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxietyl)- -1-(1-acetoximetyloxikarbonyl-l-klormetyl)-azetidin-2-on.Example 18. 18β-Acetylglycolylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one.

OCO PNB OCO PNB '~ 2 z s V S \r(\ .0cocx13 fií \g/\0cocr13 o *__Ü O/f-'Nïffll 0 *Nr-cl COOCHZOCOCH3 _ COOCHZOCOCH3 0,35 g 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxi- etyl)~l-(l-acetoximetyloxikarbonyl-1-hydroximetyl)-azetidin- -2-on löstes i 10 ml vattenfri tetrahydrofuran vid 0°C. l,l ekvivalenter pyridin och l,l ekvivalenter tionylklorid tillsattes. Blandningen omrördes i 10 minuter. Fällningen filtrerades och filtratet gav efter indunstning den i rubri- ken angivna föreningen i kvantitativt utbyte. Den råa pro- dukten användes som sådan för nästa steg. 449 489 l8 Exemgel 19. 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyloxietyl)-l- -(l-acetoximetyloxikarbonyl-l-trifenylfosforanylidenmetyl)- -azetidin-2-on.OCO PNB OCO PNB '~ 2 zs VS \ r (\ .0cocx13 fi í \ g / \ 0cocr13 o * __ Ü O / f-'Nïf fl l 0 * Nr-cl COOCHZOCOCH3 _ COOCHZOCOCH3 0.35 g 4ß-acetylglycolylthio-3- (lp -nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-hydroxymethyl) -azetidin-2-one was dissolved in 10 ml of anhydrous tetrahydrofuran at 0 ° C, 1,1 equivalents of pyridine and 1,1 equivalents of thionyl chloride were added. The precipitate was filtered off and the filtrate, after evaporation, gave the title compound in quantitative yield, the crude product being used as such for the next step. 449 489 18 Example 19 4β-acetylglycolylthio-3- (1β-nitrobenzyloxycarbonyloxyethyl) ) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one.

I Ann nun ecozpszs S “"“2'*“” s- \\í/^\ococn3 f' \\¶/^\ococH 0 N 1 N /PPh of* w* 0 ß coocu2ococn3 coocn2ococH3 0,400 g 4ß-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyl- oxietyl)-l-(l-acetoximetyloxikarbony1-l-klormetyl)-azetidin- -2-on löstes i 20 ml av en 1:1-blandning av tetrahydrofuran och dioxan. 2 ekvivalenter trifenylfosfín och l,l ekvivalen- ter pyridin tillsattes och blandningen omrördes över natten vid SOOC. Den i rubriken angivna föreningen renades genom kolonnkromatografi på silikagel, varvid man eluerade med 70:30 diklormetan-etylacetat. 0,280 g av fosforanen erhölls.I Ann nun ecozpszs S “" “2 '*“ ”s- \\ í / ^ \ ococn3 f' \\ ¶ / ^ \ ococH 0 N 1 N / PPh of * w * 0 ß coocu2ococn3 coocn2ococH3 0,400 g 4ß-acetylglycolylthio -3- (1p-Nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-chloromethyl) -azetidin-2-one was dissolved in 20 ml of a 1: 1 mixture of tetrahydrofuran and dioxane, 2 equivalents of triphenylphosphine and 1 The equivalent of pyridine was added and the mixture was stirred overnight at 5 DEG C. The title compound was purified by column chromatography on silica gel, eluting with 70:30, dichloromethane-ethyl acetate to give 0.280 g of the phosphorane.

Exemgel 20. (5R)-acetoximetyl-6-(l-p-nitrobensyloxikarbonyloxietyl)-2- -acetoximetyl-2-penem-3-karboxylat. ocozvnß oc0zPNB S __ S\ \ \*E/^\ococn3" ”/L:í:jf' I ococn3__ . -----+ _ N /PP-h ' N 0/ \T' 3 . 0 coocH2ococu3 C00CH2ococH3 0,210 g 40-acetylglykolyltio-3-(l-p-nitrobensyloxikarbonyl- oxietyl)-l-(l-acetoximetyloxikarbonyl-l-trifenylfosforanyli- denmetyl)-azetidin-2Äon löstes i 7 ml toluen och lösningen hölls 2 timmar vid återflöde. Genom rening med hjälp av kort tids kolonnkromatografi, varvid man eluerade med 95:5 diklor- metan-etylacetat, erhölls 0,050 g av den i rubriken angivna föreningen. 449 489 19 Exemgel Zl. (5R)-acetoximetyl-6-(l-hydroxietyl)-2-acetoximetyl-2-penem-3- -karboxylat. oco ZPNB OH- _ 3 ,,J\\ /,S ~ ococn ""¶ I øco@u3 ________? I \H/^\\ 3 N r/ N \ o coocn2ococH3 0* CÛÛCHZOCOCH3 0,060 g 5R-acetoximetyl-6-(1-p-nitrobensyloxikarbonyloxietyl)- -2-acetoximetyl-2-penem-3-karboxylat hälldes i en blandning av vatten, etanol och KZHPO4 och hydrogenolyserades med 10 % Pd/C. En hastig rening genom kolonnkromatografi på silikagel gav 0,015 g av den i rubriken angivna föreningen.Example Gel 20. (5R) -Acetoxymethyl 6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate. ocozvnß oc0zPNB S __ S \ \ \ * E / ^ \ ococn3 "” / L: í: jf 'I ococn3__. ----- + _ N / PP-h' N 0 / \ T '3. 0 coocH2ococu3 C00CH2ococH3 0.210 g of 40-acetylglycolylthio-3- (1p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetoxymethyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2-one was dissolved in 7 ml of toluene and the solution was kept at reflux for 2 hours. by short-term column chromatography eluting with 95: 5 dichloromethane-ethyl acetate, 0.050 g of the title compound were obtained. 449,489 19 Example 44 (5R) -acetoxymethyl-6- (1-hydroxyethyl) -2- acetoxymethyl-2-penem-3-carboxylate. oco ZPNB OH- _ 3 ,, J \\ /, S ~ ococn "" ¶ I øco @ u3 ________? I \ H / ^ \\ 3 N r / N \ o C * OCHZOCOCH3 0.060 g of 5R-acetoxymethyl-6- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-acetoxymethyl-2-penem-3-carboxylate was poured into a mixture of water, ethanol and KZHPO4 and hydrogenated with 10% A rapid purification by column chromatography on silica gel gave 0.015 g of the title compound.

Vid arbete pà samma sätt som i de föregående exemplen, varvid man dock använde 5-metyl-2-tiol-1,3,4-tiadíazol, 5-tio1-l,2,3- -triazol eller tíolpyrazín i stället för'l-metyl-5-tioltetra- zol, erhölls (SR)-6-(l'-hydroxietyl)-2-/(5"-metyl-1",3",4"- -tiadiazol-2"-yl)-tíometyl/-2-penem-3-karboxylsyra, (5R)-6- -(l'-hydroxíetyl)-2-/(l“,2“,3"~triazol-5"-yl)-tiometyl/-2- -penem-3-karboxylsyra och (5R)~6-(1'-hydroxietyl)-2-(pyrazi- nyl)-tiometyl-2-penem-3-karboxylsyra. 449 489 Exemgel 22. 4ß-(l-hydroximetyl)-vinyltio-Baf(l-p-nitrobensyloxikarbonyl- oxietyl)-1-(l-metoxikarbonyl-2fmetyl-2-propenyl)-azetidin-2- -on-S-oxid. Reaktion (2) - (3). o OCOZPNB o - co2PNB u f H 5 \ou _\. /Sq/ ,_\ f | an. - x -a i áP-Nflx _ /i-N O \“ _ CH O X \ H C00 3 H coocn 3 En lösning av 2,6 g metyl-6-(1-p-nitrobensyloxikarbonyl-oxi- etyl)-3-penicillinat-S-oxid och 8 ml propargylalkohol i 20 ml toluen återflödesupphettades under kväve i 40 timmar. Efter avdunstning av lösningsmedlet renades den infângade förening- en genom silikagelkolonnkromatografi, eluering med (9:l) diklormetan-etylacetat, vilket gav 2,0 g av föreningen i rubriken. ' ExemEel23. 46-(l-hydroximetyl)-vinyltio-3af(l-p-nitrobensyloxikarbonyl- oxietyl)-l-(l-metoxikarbonyl-2-metyl-lfpropenyl)-azetidin-2- -on-S-oxid. Reaktion (3) - (4). oco PNB ^ 0 2 Q oco2PNB H I~~ w /I\_ S \ ~- | - Y J I 1 ---à I ,____N 0/ . . o / H COOCH3 coocfl 3 2,0 g 4B-(l-hydroximetyl)-vinyltio-3ar(l-p-nitrobensyloxi- karbonyloxietyl)-l-(l~metoxikarbonyl-2-metyl-2-propenyl)- azetidin-2-on-S-oxid, löst i 50 ml diklormetan lämnades vid rumstemperatur i närvaro av nâgra få droppar trietylamin i 12 É timmar. Efter avdunsning av lösningsmedlet utvanns den rena föreningen i rubriken i kvantitativt utbyte. 449 489 21 ExemEel 4ß-(l-brommetyl)-vinyltio-3a-(l-p-nitrobensyloxikarbonyl- oxietyl)-l-(l~metoxikarbonyl-2-metyl-l-propenyl)-azetidin- -2-on. Reaktion (4) - (5).When working in the same manner as in the previous examples, but using 5-methyl-2-thiol-1,3,4-thiadiazole, 5-thio1-1,2,3-triazole or thiolpyrazine instead of -methyl-5-thioltetrazole, obtained (SR) -6- (1'-hydroxyethyl) -2 - [(5 "-methyl-1", 3 ", 4" -thiadiazol-2 "-yl) - thiomethyl / -2-penem-3-carboxylic acid, (5R) -6- - (1'-hydroxyethyl) -2 - [(1 ", 2", 3 "-triazol-5" -yl) -thiomethyl / -2 - -Penem-3-carboxylic acid and (5R) -6- (1'-hydroxyethyl) -2- (pyrazinyl) -thiomethyl-2-penem-3-carboxylic acid 449 489 Example Gel 22. 4β- (1-hydroxymethyl ) -vinylthio-Baf (1p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetidin-2-one-S-oxide Reaction (2) - (3) OCOZPNB - co2PNB uf H 5 \ ou _ \. / Sq /, _ \ f | an. - x -ai áP-N fl x _ / iN O \ “_ CH OX \ H C00 3 H coocn 3 A solution of 2.6 g methyl 6- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -3-penicillinate S-oxide and 8 ml of propargyl alcohol in 20 ml of toluene were refluxed under nitrogen for 40 hours. After evaporation of the solvent, the trapped compound was purified to give by silica gel column chromatography, eluting with (9: 1) dichloromethane-ethyl acetate to give 2.0 g of the title compound. 'ExemEel23. 46- (1-hydroxymethyl) -vinylthio-3a (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one-S-oxide. Reaction (3) - (4). oco PNB ^ 0 2 Q oco2PNB H I ~~ w / I \ _ S \ ~ - | - Y J I 1 --- à I, ____ N 0 /. . o / H COOCH3 cooc fl 3 2.0 g of 4B- (1-hydroxymethyl) -vinylthio-3ar (1p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-2-propenyl) -azetinin-2-one S-oxide, dissolved in 50 ml of dichloromethane, was left at room temperature in the presence of a few drops of triethylamine for 12 hours. After evaporation of the solvent, the pure title compound was recovered in quantitative yield. 449 489 21 Example 4β- (1-Bromomethyl) -vinylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -azetidin-2-one. Reaction (4) - (5).

OCOZPNB R I ~ 050 PNB ,L_ ,,s5~\//*son /l_ 2 -. '_ || ~_ fas \[(\ Br d9”“" .T,f- _ oå“““'N-\f¿¿- __ COOCH3 COOCH3 2,0 g av den förening som framställdes i exempel 66 löstes i 50 ml dimetylformamid. Efter kylning vid -2000 tillsattes 0,7 ml pyridin och 3.2 ml PBr3 och reaktionsblandningen hölls un- der omröring i 15 minuter. Etylacetat sattes till blandningen och den organiska fasen skakades med en NaHCO3-mättad lösning, tvättades med vatten och torkades slutligen över Na2SO4.OCOZPNB R I ~ 050 PNB, L_ ,, s5 ~ \ // * son / l_ 2 -. '_ || ~ g phase \ [(\ Br d9 "" ".T, f- _ oå“ “'N- \ f¿¿- __ COOCH3 COOCH3 2.0 g of the compound prepared in Example 66 was dissolved in 50 ml of dimethylformamide After cooling to -2000, 0.7 ml of pyridine and 3.2 ml of PBr 3 were added and the reaction mixture was kept under stirring for 15 minutes Ethyl acetate was added to the mixture and the organic phase was shaken with a NaHCO 3 saturated solution, washed with water and finally dried over Na2SO4.

Efter avdunsning av lösningsmedlet erhölls 1,7 g av den rena föreningen i rubriken.After evaporation of the solvent, 1.7 g of the pure title compound were obtained.

ExemEel _ 25 - 4B-[l*(5-metyl-l~3,4-tiadiazol-2-yl)-tiometyl]-vinyltio-3a- ' (1-p-nitrobensyloxikarbonyloxietyl)-l-(l-metoxikarbonyl-2- ä -metyl-l-propenyh -azetidin-2-on . EXAMPLE 25 - 4B- [1- (5-Methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -vinylthio-3α- '(1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl- 2-methyl-1-propenyl-azetidin-2-one.

! OCOZPNB . OCOZPNB l_-]n I 1 I 1 CH 3 /~--..._J”'SY\B“~' )"“~~_\/“”S\\1^ S i . *f J* N Y* ”_ NY” 0 COOCH3 coocH3 1,8 g av den förening som framställdes i exempel 67 löstes i ; ,30 ml tetrahydrofuran. Den resulterande lösningen kyldes vid { o°c; 1,1 g s-mecyl-1,3,4-tiadiazo1~2-fiol-natriumsalt tiil- E sattes och blandningen hölls under omröring i 4 timmar. Efteri filtrering av de olösliga substanserna utspäddes den kvarva- i 1 l rande lösningen med etylacetat, tvättades med vatten, torka- 449 489 22 des över Na2SO4 och indunstades: 2 g av föreningen i rubriken erhölls.! OCOZPNB. OCOZPNB l _-] n I 1 I 1 CH 3 /~--..._J „'SY\B „~ ') "“ ~~ _ \ / “” S \\ 1 ^ S i. * F J * NY 1.8 g of the compound prepared in Example 67. Dissolve in 30 ml of tetrahydrofuran, the resulting solution was cooled to 0 DEG C., 1.1 g of s-mecyl-1.3. 4-Thiadiazol-2-fiol-sodium salt was added and the mixture was kept under stirring for 4 hours After filtration of the insolubles, the residual solution was diluted with ethyl acetate, washed with water, dried and dried. over Na 2 SO 4 and evaporated: 2 g of the title compound were obtained.

Exempel 26. _ 4ß-[l-(l,2,3-triazol-5-yl)-tiometyl]-vinyltio-3ur(l-p-nitro- bensyloxikarbonyloxietyl)-l-(l-metoxikarbonyl-2-metyl-l- pšopenyl)-azetidin-2-øn. ÛCOZPNB t S I OCOZPNB I šq }._____T/ Br /øs ïl/\S;Q1Å --> i H k - //°_ N\æ~ ' o 3 coocn O COOCH 3 Utgående från 2,5 g av den förening som framställdes i exem- pel 67 och med samma förfarande som i exempel 68 men med an- vändning av 1,2,3-triazol-5-tiolnatriumsalt, erhölls 2,2 g av föreningen i rubriken.Example 26- [4β- [1- (1,2,3-Triazol-5-yl) -thiomethyl] -vinylthio-3-urea (1β-nitro-benzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1- pšopenyl) -azetidin-2-øn. ÛCOZPNB t SI OCOZPNB I šq} ._____ T / Br / øs ïl / \ S; Q1Å -> i H k - // ° _ N \ æ ~ 'o 3 coocn O COOCH 3 Starting from 2.5 g of that compound prepared in Example 67 and using the same procedure as in Example 68 but using 1,2,3-triazole-5-thiol sodium salt, 2.2 g of the title compound were obtained.

Exempel 27. 4B-[l-(5-metyl-1,3,4-tiadiazol-2-yl)]~tioacetyltio~3ur(l-p- nitrobensyloxikarbonyloxietyl)-l-metoxi-oxaloyl-azetidin-2-on. _OCO2PNB r_fi ?CO2PNB S I N - | ' \ f\ 1 S S \ I' /~_'. w S S,\ Jay-K *ß Wu .f-K s '* CH N I L_N o/' Ü/f oó/ \|//'° COOCH3 _ COOQH3 2 g av den förening som framställdes 1 exempel 68 löstes i 250 ml diklormetan och kyldes vid -78°C. Ett flöde av ozonisef rat syre bubblades igenom lösningen tills en blå färg erhölls* som resultat. Några få droppar P(0CH3)3 sattes till lösningen och temperaturen för blandningen höjdes till rumstemperatur.Example 27. 4B- [1- (5-methyl-1,3,4-thiadiazol-2-yl)] -thioacetylthio-3-ur (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxy-oxaloyl-azetidin-2-one. _OCO2PNB r_ fi? CO2PNB S I N - | '\ f \ 1 S S \ I' / ~ _ '. w SS, \ Jay-K * ß Wu .fK s' * CH NI L_N o / 'Ü / f oó / \ | //' ° COOCH3 _ COOQH3 2 g of the compound prepared in Example 68 were dissolved in 250 ml of dichloromethane and cooled at -78 ° C. A stream of ozonated oxygen was bubbled through the solution until a blue color was obtained * as a result. A few drops of P (OCH 3) 3 were added to the solution and the temperature of the mixture was raised to room temperature.

Blandningen indunstades vilket gav 1,5 g av föreningen i rubriken. 449 489 ExemE el 28 . 4B-[l-(l,2,3-triazol-5-yl)]-tioacetyltio-3a-(l-p-nitrobensyl- oxikarbonyloxietyl)-l-metoxi-oxaloyl-azetidin-2-on.The mixture was evaporated to give 1.5 g of the title compound. 449 489 ExemE el 28. 4B- [1- (1,2,3-triazol-5-yl)] - thioacetylthio-3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxy-oxaloyl-azetidin-2-one.

Reaktion (12) - (13). oco PNB *P1 °C°2PNB Ä__\ ¿S\ïi/\s/h\ïp ' /tnx 95. \ L] Ûf/“NY/L "ö «f"“\~.=<> Utgående från 1,6 g av den förening som framställdes i exempel 25 och med samma förfarande som i exempel 27 erhölls l,l g av föreningen i rubriken. I Exemgel 29. 4ß-Il-(5-metyl-1,3,4~tiadiazol-2-yl)]-tioacetyltio-3a-(l-p- nitrobensyloxikarbonyloxietyl)-azetidin-2-on.Reaction (12) - (13). oco PNB * P1 ° C ° 2PNB Ä __ \ ¿S \ ïi / \ s / h \ ïp '/ tnx 95. \ L] Ûf / “NY / L" ö «f" “\ ~. = <> Starting from 1 6.6 g of the compound prepared in Example 25 and by the same procedure as in Example 27, 1.1 g of the title compound were obtained. In Example Gel 29. 4β-II- (5-methyl-1,3,4-thiadiazol-2-yl)] - thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one.

Reaktion (13) - (14).Reaction (13) - (14).

, Iocozprqß lïl- ti! ocozPNß N__N L »S .regim L. S ll i J O 3 __? \l/\S s CHB- N _* o O' \1::.O COOCH J_N O *H 3 1,5 g av den förening som framställdes i exempel 27 löstes i lzl-blandning av metanol och etylacetat. Några få gram silika- gel tillsattes och blandningen hölls vid rumstemperatur vid kraftig omröring. Efter filtrering av silikagelet indunstades filtratet vilket gav en olja som kromatograferades på silika-_ gel med diklormetan:etylacetat (8:2), vilket gav 0,9 g av den rena föreningen i rubriken. 449 489 ExemEel3Û-_ 4ß-[l-(l,2,3-triazol-5-yl)]-tioacetyltio-3a-(l-p-nitrobensyl- qxikarbonyloxietyl)-azetidin-2-on. Reaktion (13) - (l4)., Iocozprqß lïl- ti! ocozPNß N__N L »S .regim L. S ll i J O 3 __? CHO- N _ * o O '\ 1 ::. O COOCH J_N O * H 3 1.5 g of the compound prepared in Example 27 were dissolved in a 1zl mixture of methanol and ethyl acetate. A few grams of silica gel were added and the mixture was kept at room temperature with vigorous stirring. After filtration of the silica gel, the filtrate was evaporated to give an oil which was chromatographed on silica gel with dichloromethane: ethyl acetate (8: 2) to give 0.9 g of the title compound. 449 489 Example 3β-4β- [1- (1,2,3-triazol-5-yl)] -thioacetylthio-3α- (1-p-nitrobenzyl-oxycarbonyloxyethyl) -azetidin-2-one. Reaction (13) - (14).

OCO PNB ___ 2 -___ /L få sl /ï ÉCOZPNB I” ' \\____f F ~\“~ ßsmís Z\N”N __§ ° å* 1 0 »Ä 0 \-O / \ _ Ü- O H -COOCH3 Utgående från l,l g av den förening som framställdes i exem- pel 28 och med samma förfarande som i exempel 29 erhölls 0,6 g av föreningen i rubriken.OCO PNB ___ 2 -___ / L få sl / ï ÉCOZPNB I ”'\\ ____ f F ~ \“ ~ ßsmís Z \ N ”N __§ ° å * 1 0» Ä 0 \ -O / \ _ Ü- OH - COOCH 3 Starting from 1.1 g of the compound prepared in Example 28 and using the same procedure as in Example 29, 0.6 g of the title compound were obtained.

Exem2el3l. 4ß-[l-(5-metyl-1,3,4-tiadiazol-2-yl)]-tioacetyltio-3a-(l-p- nitrobensyloxikarbonyloxietyl)-l-(l-acetonyloxikarbOnyl~lf gzdroximetyl)acetidin-2-on. Reaktion (14) - (15).Exem2el3l. 4- [1- (5-methyl-1,3,4-thiadiazol-2-yl)] -thioacetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1H-hydroxymethyl) acetidin-2-one. Reaction (14) - (15).

N-N OCOZPNB J. . EC ZPNB lik Å _" - 5'7|/\S \S/\CH .x-ï/as S S C33 o 1 Ef - N å; / \ - // 0 »FCH 0 H - COOCHZCOCHB 0,9 g_av den förening som framställdes i exempel29 löstes 1 40 ml bensen; 0,6 g acetonylglyoxylat tillsattes och den resul- terande lösningen âterflödades i 3 timmar. Efter avdunstning av lösningsmedlet användes den råa oljan för följande steg utan vidare rening.N-N OCOZPNB J.. EC ZPNB lik Å _ "- 5'7 | / \ S \ S / \ CH .x-ï / as SS C33 o 1 Ef - N å; / \ - // 0» FCH 0 H - COOCHZCOCHB 0,9 g_av the compound prepared in Example 29 was dissolved in 40 ml of benzene, 0.6 g of acetonyl glyoxylate was added and the resulting solution was refluxed for 3 hours After evaporation of the solvent, the crude oil was used for the following steps without further purification.

Exemgel 32. g 4ß-[l-(l,2,3-triazol-5-yl)]-tioacetyltio-3a~(l-p-nitrobensyl-_ oxikarbonyloxietyl)-1-(l-acetonyloxikarbonyl-l-hydroximetyl)- azetidin-2-on. Reaktion (14) - (15) 449 489 25 OCOZPNB . - à i: ° H ° H 0 \\1w~oH I COOCH2COCH3 Utgående från 0,6 g av den förening som framställdes i exempel 30och med_samma förfarande som i exempel3l erhölls 0f7-g av föreningen i rubriken.Example gel 32. g 4β- [1- (1,2,3-triazol-5-yl)] -thioacetylthio-3α- (1p-nitrobenzyl-oxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) -acetidine -2-on. Reaction (14) - (15) 449 489 25 OCOZPNB. Starting from 0.6 g of the compound prepared in Example 30 and using the same procedure as in Example 31, 0f7-g of the title compound was obtained.

ExemBel33. 4B-[l-(5-metyl~l,3,4-tiadiazol-2-yl)]-tioacetyltio-3d-(l-p- nitrobensyloxikarbonyloxietyl)-l-(l-acetonyloxikarbonyl-l- klorometyl)-azetidin-2-on. Reaktion (15) - (l6).ExemBel33. 4B- [1- (5-methyl-1,3,4-thiadiazol-2-yl)] - thioacetylthio-3d- (1p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) -azetidin-2- on. Reaction (15) - (16).

OCOZPNB TCOZPNB ñq-N _ - \ /\ / \ fJ\ \ \,_______I ' ' o 3 o --> N f* N //"_' 0 NW OH _ O \|-~ (31 coocn2cocH3 C00CH2C0CH3 Den råa olja som erhölls i exempel 31_löstes i vattenfri tetrahydrofuran (30 ml) och kyldes vid 0°C. Ekvimolära mäng- der av pyridin och tionylklorid sattes till lösningen tills utgângsmaterialet försvann. Efter filtrering av det olösliga materialet användes filtratet omedelbart för nästa steg.OCOZPNB TCOZPNB ñq-N _ - \ / \ / \ fJ \ \ \, _______ I '' o 3 o -> N f * N // "_ '0 NW OH _ O \ | - ~ (31 coocn2cocH3 C00CH2C0CH3 The raw oil obtained in Example 31 was dissolved in anhydrous tetrahydrofuran (30 ml) and cooled at 0 DEG C. Equimolar amounts of pyridine and thionyl chloride were added to the solution until the starting material disappeared.After filtration of the insoluble material, the filtrate was used immediately for the next step.

ExemEel34" 45-[l~(l,2,3-triazol-5-yl)]~tioacetyltio-3a-(l-p-nitrobensyl- oxikarbonyloxietyl)-l-(l-acetonyloxikarbonyl-l-klorometyl)- azetidin-2-on. Reaktion (15) - (16).Example 34 "45- [1- (1,2,3-Triazol-5-yl)] -thioacetylthio-3α- (1p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) -acetidin-2- on. Reaction (15) - (16).

J AW. fw". ~__\ \/\ S »IIIN \\\ Síïfl O 449 489 26 -- oc ocozpns N o2PNB I J p i? *r 4S\,|/\s “IJ \\ sfs NfN n* O H a-m i, Q/r__'\@ÛH I /r_fN COOCHZCOCH3 \ C OöçH2COCH3 Utgående från 0,7 g av den förening som framställdes i exempel 32_ech med samma förfarande som beskrevs i exempel 31 erhölls det råa klorderivatet. Produkten användes för nästa steg utan ytterligare rening.J AW. fw ". ~ __ \ \ / \ S» IIIN \\\ Síï fl O 449 489 26 - oc ocozpns N o2PNB IJ pi? * r 4S \, | / \ s “IJ \\ sfs NfN n * OH am i, The crude chlorine derivative was obtained starting from 0.7 g of the compound prepared in Example 32 by the same procedure as described in Example 31. The product was used for the next step without further purification. ../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../../ ..

ExemEel_35. _ 4ß-[l-(5-metyl-l,3,4-tiadiazol-2-yl)]-tioacetyltio-3ar(l-p- nitrobensyloxikarbonyloxietyl)-l-(l-acetonyloxikarbonyl-l- trifenylfosforanylidenmetyl)-azetidin-2-on. Reaktion (16)-(ll).ExemEel_35. 4β- [1- (5-methyl-1,3,4-thiadiazol-2-yl)] - thioacetylthio-3ar (1p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-triphenylphosphoranylidenemethyl) -azetidin-2- on. Reaction (16) - (ll).

OCO PNB "_" 2 w s W Ä i i 1 -_~. \ /\ \-CH \ sf S \ 3 \,~\ l/ S / N ï""9 / N 0/' \fCl . 0' \,æm5 I i l coocu coca 2 3 coocH2cocH3 oco2PN5 Den råa produkt som erhölls i exempel 33 löstes i 20 ml tetra- hydrofuran; 700 mg trifenylfosfin och 0,35 ml pyridin tillsat- tes och den resulterande lösningen värmdes under kväve vid 70°C under nâgra få timmar. Fosforanen i rubriken renades på silikagel genom eluering med diklormetan:etylacetat (lzl).OCO PNB "_" 2 w s W Ä i i 1 -_ ~. \ / \ \ -CH \ sf S \ 3 \, ~ \ l / S / N ï "" 9 / N 0 / '\ fCl. The crude product obtained in Example 33 was dissolved in 20 ml of tetrahydrofuran; 700 mg of triphenylphosphine and 0.35 ml of pyridine were added and the resulting solution was heated under nitrogen at 70 ° C for a few hours. The title phosphorane was purified on silica gel eluting with dichloromethane: ethyl acetate (Izl).

Man erhöll 0,6 g av föreningen i rubriken.0.6 g of the title compound was obtained.

Exemgel 36. _ 4ß-[l-(l,2,3-triazol-5-yl)]~tioacetyltio-3a-(l-p-nitrobensyl- oxikarbonyloxietyl)-1-(l-acetonyloxikarbonyloxietyl-l-trifeny1- fosforanylidenmetyl)-azetidin-2-on. Reaktion (16) - (17). ä OCO2PNB N"“' N i ïJ. 449 489 27 Jocozpnß jcozeus ' _ "\_ S /\S /\ N N \\ S /\S N *N “ \xl l \ 71 I 0 I 1.: 0 H /, N “ --9 ¿Å___N o \\«c1 o \Iá 92113 COOCHZCOCHB COOCHZCOCH3 Utgående från det råa klorderivat som erhölls i exempel 34 och med samma förfarande som âskâdliggjordes i exempel 35 erhölls 0,É5 g av föreningen i rubriken.Example Gel 36. - 4β- [1- (1,2,3-Triazol-5-yl)] -thioacetylthio-3α- (1β-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyloxyethyl-1-triphenyl) phosphoranylidenemethyl) - azetidin-2-one. Reaction (16) - (17). ä OCO2PNB N "“ 'N i ïJ. 449 489 27 Jocozpnß jcozeus' _ "\ _ S / \ S / \ NN \\ S / \ SN * N“ \ xl l \ 71 I 0 I 1 .: 0 H / 92113 COOCHZCOCHB COOCHZCOCH3 Starting from the crude chlorine derivative obtained in Example 34 and using the same procedure as illustrated in Example 35, 0.5 g of the title compound was obtained.

Exemgel 37. _ (SR)-acetonyl-2-[(S-metyl-l,3,4-tiadiazol-2-yl)-tiometyl]-6a- (l~p-nitrobensyloxikarbonyloxietyl)-2-penem-3-karboxylat.Example Gel 37. (SR) -acetonyl-2 - [(S-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -6α- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-penem-3- carboxylate.

Reaktion (ll) - (1). i F Sw S slcflj 3 ' COQCH2C0CH OCOZPNB 3 COOCHZCOCH3 0,6 g av den förening som framställdes i exempel 35 löstes 1 50 ml toluen och âterflödades under kväve i tre timmar. Före- ningen i rubriken renades genom kort kolonnkromatografi på silikagel under eluering med diklormetanzetylacetat (8:2).Reaction (ll) - (1). COGCH2COCH OCOZPNB 3 COOCHZCOCH3 0.6 g of the compound prepared in Example 35 was dissolved in 50 ml of toluene and refluxed under nitrogen for three hours. The title compound was purified by short column chromatography on silica gel eluting with dichloromethane ethyl acetate (8: 2).

Man erhöll 0,25 g av föreningen i rubriken.0.25 g of the title compound was obtained.

I.R.: 1795, 1750, 1720.I.R .: 1795, 1750, 1720.

Exempel 38.Example 38.

(SR)-acetonyl-2-[(l,2,3-triazol-5-yl)-tiometyl]-6or(l-p- nitrobensvloxikarbonyloxietyl)-2:penem-3-karboxylat.(SR) -acetonyl-2 - [(1,2,3-triazol-5-yl) -thiomethyl] -6or (1-p-nitrobenzyloxycarbonyloxyethyl) -2: penem-3-carboxylate.

Reaktion (ll) - (1). 449 489 28 7 o \; PPh l 3 f coocnzcocn coocnzcocaa _ 3 Utgående från 0,45 g av den förening som framställdes i exem- pel 36ocn'med samma förfarande som visades i exempel37 'er- hölls 0,180 g av föreningen i rubriken.Reaction (ll) - (1). 449 489 28 7 o \; Starting from 0.45 g of the compound prepared in Example 36ocn 'using the same procedure shown in Example 37', 0.180 g of the title compound was obtained.

I.R.: 1795, 1750, 1720.I.R .: 1795, 1750, 1720.

Exemgel 39. _ (5R)-acetonyl-2-[(5-metyl-1,3,4-tiadiazol-2-yl)-tiometyl]-6a- (l-hydroxietyl)-2-penem-3-karboxylat. Reaktion (l).Example Gel 39. (5R) -Acetonyl-2 - [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -6α- (1-hydroxyethyl) -2-penem-3-carboxylate. Reaction (l).

OCO 2PNs_ ' fr* I ' O” N -N l I' .,\ . S\/*S/\S “Cris \\\ pßsï/“SLSÅCHB I___N_:IL __* /GÅ / ~ _/ 0 Cwcflzcocfis 0 coocnzcocxx s s 3 0,450 g av den förening som framställdes i exempel37 löstes i 25 ml acetonitril innehållande nâgra få droppar etanol och hydrerades över 10% Pd på kol (400 mg). Katalysatorn avlägsna- des genom filtrering och filtratet kromatograferades pâ sili- kagel under eluering med diklormetan:etylacetat (7:3), vilket gav 0,18 g av föreningen i rubriken.OCO 2PNs_ 'fr * I' O ”N -N l I '., \. S \ / * S / \ S “Cris \\\ pßsï /“ SLSÅCHB I ___ N_: IL __ * / GÅ / ~ _ / 0 Cwc fl zcoc fi s 0 coocnzcocxx ss 3 0.450 g of the compound prepared in Example 37 was dissolved in 25 ml of acetonitrile containing some few drops of ethanol and hydrogenated above 10% Pd on carbon (400 mg). The catalyst was removed by filtration and the filtrate was chromatographed on silica gel eluting with dichloromethane: ethyl acetate (7: 3) to give 0.18 g of the title compound.

I.R.: 3605, 1795, l745, 1720.I.R .: 3605, 1795, 1745, 1720.

Exemgel 40.Example 40.

(SR)-acetonyl-2-[(l,2,3-triazol-5-yl)-tiometyl]-6a-(l-hydroxi- etyl)-2-penem-3-karbošylat. Reaktion (1). 449 489 29 *_ on - jcozvuß . i B /L _ »s \/\ S If' *X As g \S IV /J____N 1! H --9 ~' ____n - | H / coocnzcocnj _ 077* \ “ COOCHZCOCH3 l o Utgående frân 0,380 g av den förening som framställdes i exempel384~öch med samma förfarande scm i exempel 39 erhölls 0,12 g av föreningen i rubriken.(SR) -acetonyl-2 - [(1,2,3-triazol-5-yl) -thiomethyl] -6a- (1-hydroxyethyl) -2-penem-3-carbosylate. Reaction (1). 449 489 29 * _ on - jcozvuß. i B / L _ »s \ / \ S If '* X As g \ S IV / J ____ N 1! H --9 ~ '____n - | Starting from 0.380 g of the compound prepared in Example 384 and by the same procedure as in Example 39, 0.12 g of the title compound was obtained.

I.R.: 3610, 1795, 1750, 1720.I.R .: 3610, 1795, 1750, 1720.

Exemgel 4l¿ (SR)-2[(5-metyl-1,3,4~tiadiazol-2-yl)-tiometyl]-6d-(l-hydroxi- etyl)-2-penem-3-karboxylsyra. Reaktion (1).Exemgel 41 (SR) -2 [(5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl] -6d- (1-hydroxyethyl) -2-penem-3-carboxylic acid. Reaction (1).

/ --\ COOCH2COCH3 .O COOH En lösning av 0,200 g av den förening som framställdes i exem- pel 39 i acetonitril (30 ml) innehållande nâgra få droppar vatten kylaes vid o°c; s m1 av en 0,1 N Nam-lösning till- sattes under kväve och lösningen cmrördes i 10 minuter. Den alkaliska blandningen extraherades tvâ gånger med metylen- klorid, surgjordes med en 10% citronsyravattenlösning och extraherades återigen tvâ gånger med metylenklorid. De före- nade organsika faserna torkades över Na2SO4 och indunstades vilket gav 0,110 g av föreningen i rubriken.COOH - COCH 3 .O COOH A solution of 0.200 g of the compound prepared in Example 39 in acetonitrile (30 ml) containing a few drops of water is cooled at 0 ° C; s m1 of a 0.1 N Nam solution was added under nitrogen and the solution was stirred for 10 minutes. The alkaline mixture was extracted twice with methylene chloride, acidified with a 10% aqueous citric acid solution and extracted again twice with methylene chloride. The combined organic phases were dried over Na 2 SO 4 and evaporated to give 0.110 g of the title compound.

I.R.: 3500, 1795, 1665.I.R .: 3500, 1795, 1665.

Exemgel 42.Example 42.

(SR)-2-[(l,2,3-triazol-5-yl)-tiometyl]-6a-(l-hydroxietyl)-2- Benem-3-karboxylsvra. Reaktion (1). 449 489 30 CH OH N I - fä J Ü .' AK ß' s\/\S/ IÄÄ x* /s\ßs E, \_ I -_à .1 . ! / N / coon 0 'coocflzcocu3 o Utgående från 0,25 g av den förening som framställdes i._ exempel 4Û och med samma förfarande som visades i exempel 41 erhölls 0,135 g av föreningen i rubriken.(SR) -2 - [(1,2,3-triazol-5-yl) -thiomethyl] -6a- (1-hydroxyethyl) -2-Benem-3-carboxylic acid. Reaction (1). 449 489 30 CH OH N I - fä J Ü. ' AK ß's \ / \ S / IÄÄ x * / s \ ßs E, \ _ I -_à .1. ! Starting from 0.25 g of the compound prepared in Example 4Û and using the same procedure shown in Example 41, 0.135 g of the title compound was obtained.

I.R.: 3480, 1795, 1660.I.R .: 3480, 1795, 1660.

Exemgel 43. 46-(l-karbamoyloximetyl)-vinyltio-3o-(l-p-nitrobensyloxi- karbonyloxietyl)~l-(l-metoxikarbonyl-2-metyl-l-propenyl)- azetidin-2-on-S-oxid. Reaktion (4) - (5).Example Gel 43. 46- (1-Carbamoyloxymethyl) -vinylthio-3- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -acetidin-2-one S-oxide. Reaction (4) - (5).

' OCOZPNB O - ' OQO PNB \“~ \ ou ___) J ficouaz / v 3 coocn3 2,2 g av den förening som framställdes i exempel 23 löstes i 30 ml acetonitril och kyldes vid OOC. Därefter tillsattes 2 0,8 ml klorsulfonylisocyanat under kväve och blandningen om- rördes i 2 timmar. Reaktionsblandningen hälldes ned i en mättad NaHC03-lösning, omrördes under några få minuter och extraherades därefter med etylacetat. Efter torkning över Na2S04 gav avdunstning av lösningsmedlet 1,5 g av föreningen i rubriken. 449 489 Exempel 44. 4ß-(l-karbamoyloximetyl)-vinyltio-3a-(l-p-nitrofensyloxi- karbonyloxietyl)-l-(l-metoxikarbonyl-2-mety1-lfproenyl)- azetidin-Zfon. Reaktion (4) - (l2).2.2 g of the compound prepared in Example 23 was dissolved in 30 ml of acetonitrile and cooled at 0 DEG C. OCOZPNB O - OQO PNB O2. Then 0.8 ml of chlorosulfonyl isocyanate was added under nitrogen and the mixture was stirred for 2 hours. The reaction mixture was poured into a saturated NaHCO 3 solution, stirred for a few minutes and then extracted with ethyl acetate. After drying over Na 2 SO 4, evaporation of the solvent gave 1.5 g of the title compound. 449 489 Example 44. 4β- (1-Carbamoyloxymethyl) -vinylthio-3α- (1-p-nitrophenyloxycarbonyloxyethyl) -1- (1-methoxycarbonyl-2-methyl-1-propenyl) -acetidine-Zfon. Reaction (4) - (l2).

OCOZPNB ? OCO2PNB L 1 . ~_~ 4øgS\\1//-OCONH2 ~\_ ¿S\\{/^\ QCQNHñ ~ ä \ ___» l /i l .OCOZPNB? OCO2PNB L 1. ~ _ ~ 4øgS \\ 1 // - OCONH2 ~ \ _ ¿S \\ {/ ^ \ QCQNHñ ~ ä \ ___ »l / i l.

O \ o \ coocn coocx3 3 Utgående från l,7 g av den förening som framställdes i exempel 43 och med samma förfarande som i exempel 24 erhölls 1,4 g av föreningen i rubriken.Starting from 1.7 g of the compound prepared in Example 43 and using the same procedure as in Example 24, 1.4 g of the title compound were obtained.

ExemQel_45, 4ß-(1-karbamoyloxi)-acetyltio-3a-(l-p-nitrobensyloxikarbonyl- oxietyl)-l-metoxioxaloyl-azetidin-2-on. Reaktion (12) ~ (13). ocozpue l3?°2PNB _ J'~ _ ' - 'I \_ ocoNH . \ s \/ ocomzz .___/Å 2 L " .--+ Å o ' \“<;__ 07%; \T::0 0 coocn 3 coocn Utgående från 2,2 g av den förening som framställdes i exempel 44 och med samma förfarande som åskådliggjordes i exempel 27 erhölls 1,4 g av föreningen i rubriken.Example 45, 4β- (1-Carbamoyloxy) -acetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-methoxioxaloyl-azetidin-2-one. Reaction (12) ~ (13). ocozpue l3? ° 2PNB _ J '~ _' - 'I \ _ ocoNH. \ s \ / ocomzz .___ / Å 2 L ".-- + Å o '\“ <; __ 07%; \ T :: 0 0 coocn 3 coocn Starting from 2.2 g of the compound prepared in Example 44 and by the same procedure as illustrated in Example 27, 1.4 g of the title compound were obtained.

Exemgel 45- 4ß-(l-karbamoyloxi)-acetyltio-3a-(1-p-nitrobensyloxikarbonyl- oxietyl)-azetidin-2-on. Reaktion (13) - (14). 449 489 OCÛ2PNB OCO2PNB »_ (__-T //_-“\ 0 H CCO CH3 Utgående från 1,4 g av den förening som framställdes i exempel 45 och med samma förfarande som visades i exempel 29 erhölls 0,9 g av föreningen i rubriken.Example 45-4β- (1-Carbamoyloxy) -acetylthio-3α- (1-p-nitrobenzyloxycarbonyloxyethyl) -azetidin-2-one. Reaction (13) - (14). 449 489 OCÛ2PNB OCO2PNB »_ (__- T // _-“ \ 0 H CCO CH3 Starting from 1.4 g of the compound prepared in Example 45 and using the same procedure shown in Example 29, 0.9 g of the compound was obtained in the title.

Exemgel 47. 46-(l-karbamoyloxi)-acetyltio-3a~(l-p-nitrobensylóxikarbonyl~ oxietyl)-l(l-acetonyloxikarbonyl-l-hydroximetyl)-azetidin-2- :gg¿ Reaktion (14) - (15). ocozPms cozmß \ O L N äwflfl 49 \\H 0 C0OCH2COCH3 O Utgående från 0,9 g av den förening søm framställdes i exem- pel 46 och 0,6 g acetonylglyoxylat och med samma förfarande som i exempel 31 erhölls den råa karbinolamiden.Example 47. 46- (1-Carbamoyloxy) -acetylthio-3α- (1-p-nitrobenzyloxycarbonyl-oxyethyl) -1- (1-acetonyloxycarbonyl-1-hydroxymethyl) -azetidine-2-yl: Reaction (14) - (15). The starting material from 0.9 g of the compound which was prepared in Example 46 and 0.6 g of acetonyl glyoxylate and by the same procedure as in Example 31 the crude carbinolamide was obtained.

Exemgel åå- 4B-(l-karbamoyloxi)-ace;yltio-3u-(l-p-nitrobensyloxikarbonyl- oxietyl)-1-(l-acetonyloxikarbonyl-l-klorometyl)~azetidin-2- :2g¿ Reaktion (15) - (16). /ß Sfißocomaz . o , _ ' s _ acomr JK 5 fi|/\ocom¶2 X jS\/\ u o 449 489 33 ocozpma ~ ' - /IOCOZPNB \ s ' S \ Axïß SW QCONf-lz - _ OCONIÉ: o 7 ] ß o __'N '/___N\ 0/ \,~» on _ o IW c1 coocazcoca3 ~ C°°CH2°°CH3 Utgående från den råa produkt som erhölls i exempel47 och med samma förfarande som i exempel33 erhölls det råa klor- derivatetl' ExemEel êfi. 45-(l-karbamoyloxi)-acetyltio-3a-(l-p-nitrobensyloxikarbonyl- oxietyl)-l-(l-acetonyloxikarbonyl-l-trifenylfosforanyliden-_ metyl~l)~azetidin-2-on. Reaktion (16) - (ll). ocozpnn 9002M11; t ' /X o\1 x _ S foconnz __ j; s\"/\oc *H2 - f I I o o __N N --> l._.._ / f/ o/ wfcl 0 \I=1>Pn3 COOCHZCOCH3 COOCHZCOCHS Utgående från den råa produkt som erhölls i exempel48 och med samma förfarande som i exempel 35 erhölls 0,40 g av fos- foranen.Example gel α-4β- (1-carbamoyloxy) -acetyl-3H- (1β-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-chloromethyl) -acetidine-2-: 2g Reaction (15) - ( 16). / ß S fi ßocomaz. o, _'s _ acomr JK 5 fi | / \ ocom¶2 X jS \ / \ uo 449 489 33 ocozpma ~ '- / IOCOZPNB \ s' S \ Axïß SW QCONf-lz - _ OCONIÉ: o 7] ß o __ 'N' / ___ N \ 0 / \, ~ »on _ o IW c1 coocazcoca3 ~ C °° CH2 °° CH3 Starting from the crude product obtained in Example 47 and using the same procedure as in Example 33, the crude chlorine derivative was obtained. ExemEel ê fi. 45- (1-carbamoyloxy) -acetylthio-3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1- (1-acetonyloxycarbonyl-1-triphenylphosphoranylidene-methyl-1) -acetidin-2-one. Reaction (16) - (ll). ocozpnn 9002M11; t '/ X o \ 1 x _ S foconnz __ j; s \ "/ \ oc * H2 - f II oo __N N -> l ._.._ / f / o / wfcl 0 \ I = 1> Pn3 COOCHZCOCH3 COOCHZCOCHS Starting from the crude product obtained in Example48 and with the same procedure as in Example 35, 0.40 g of the phosphane was obtained.

Ešemgel 5Û; (SR)-acetonyl-2-karbamgyloximetyl-6a-(l-p-nitrobensyloxi- karbonyloxietyl)-2-penem-3~karboxylat. Reaktion (ll) - (l). ' co P ocozpma 2 NB /L /._ S /\ocomz2 \_ J;ø5 \7(f\\OC0NH2 ~.____T/3 \\ ___.- O -ê | // N á N COOCHZCOf-'H ä 0 \\= Ppha O 3 i coocn coca 2 3 _ I i 449 489 Utgående från 0,4 g av den förening som framställdes i exempel 49 och med samma förfarande som i exempel 3% erhölls 0,11 q av föreningen i rubriken.Ešemgel 5Û; (SR) -acetonyl-2-carbamgyloxymethyl-6α- (1-p-nitrobenzyloxycarbonyloxyethyl) -2-penem-3-carboxylate. Reaction (ll) - (l). 'co P ocozpma 2 NB / L /._ S / \ ocomz2 \ _ J; ø5 \ 7 (f \\ OC0NH2 ~ .____ T / 3 \\ ___.- O -ê | // N á N COOCHZCOf-'H starting from 0.4 g of the compound prepared in Example 49 and using the same procedure as in Example 3%, 0.11 q of the title compound was obtained. .

Exempel 5ln (SR)-acetonyl-2-karbamoyloximety1-6a-(1-hydroxietyl)-2- -penem-3-karboxxlat. Reaktion (1). ooo PNB f OH 2 »k - /'~._ g S\]/\ oconná \_ 1 \ I | I N ;__N i f/ ø f* coocazcodu 0 coocH2cocH3 Utgående från 0,35 g av den förening som framställdes i exempel 59 och med samma förfarande som i exempel39 erhölls 0,11 g av föreningen i rubriken.Example 5ln (SR) -acetonyl-2-carbamoyloxymethyl-6α- (1-hydroxyethyl) -2--penem-3-carboxylate. Reaction (1). ooo PNB f OH 2 »k - /'~._ g S \] / \ oconná \ _ 1 \ I | Starting from 0.35 g of the compound prepared in Example 59 and using the same procedure as in Example 39, 0.11 g of the title compound was obtained.

Exempel 52.Example 52.

(SR)-2(karbamoyloximetyl)-6ar(l-hydroxietyl)-2-penem-3- karboxylsyra. Reaktion (1). i /S.\”/\ocoNH2 W V ocomz: N '_'_> /L- -ff \ N 0 I coocu2coc1a3 cf/ COOH Utgående från 0,ll g av den förening som framställdes i exempá 51 och med samma förfarande som i exempel 41 erhölls 0,060 g av föreningen i rubriken.(SR) -2 (carbamoyloxymethyl) -6ar (1-hydroxyethyl) -2-penem-3-carboxylic acid. Reaction (1). i /S.\"/\ocoNH2 WV ocomz: N '_'_> / L- -ff \ N 0 I coocu2coc1a3 cf / COOH Starting from 0,1 g of the compound prepared in exempá 51 and using the same procedure as in Example 41, 0.060 g of the title compound were obtained.

I.R.: 3400-3500, 1795, 1700-1650. 449 489 35 ExemEel53- (a) 4B-acetylglykolyltio-3a-[l-p-nitrobensyloxikarbonyloxi- etyl]-l-[l-acetonyloxikarbonyl-l-hydroximetyl]-azetidin~2- gg; Reaktion (14) - (15). oco2PNB -_jC02PNB I ,. S --%_ ,¿as\ïf/”f\.oCoCH3 *\“/”«\\ococH3 . _ O o /____N r--N NJ OH / \\ o H 0 4 coocn2cocn3 En lösning av 1,04 g 4ß-acetylglykolyltio-3a-[l-p-nitrobenyl- oxikarbonyloxietyl]~azetidin-2-on, framställd enligt exempel 16, och 1,8 g acetonylglyoxylat i 20 ml bensen âterflödades i 4 timmar. Avdunstning av lösningsmedlet gav den råa före- ningen i rubriken vilken användes för det följande steget utan ytterligare rening. (b) 45-acetylglycolyltio-3ar[l-p-nitrobensyloxikarbonyloxi- etyl]-l-[l-acetonyloxikarbonyl-1-klorometyl]-azetidin-2-on.I.R .: 3400-3500, 1795, 1700-1650. Example 53 - (a) 4B-Acetylglycolylthio-3a- [1-p-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetonyloxycarbonyl-1-hydroxymethyl] -azetidine-2-ug; Reaction (14) - (15). oco2PNB -_jC02PNB I,. S -% _, ¿as \ ïf / ”f \ .oCoCH3 * \“ / ”« \\ ococH3. A solution of 1.04 g of 4β-acetylglycolylthio-3α- [1β-nitrobenyloxycarbonyloxyethyl] -acetidin-2-one, prepared according to Example 16 , and 1.8 g of acetonyl glyoxylate in 20 ml of benzene were refluxed for 4 hours. Evaporation of the solvent gave the crude compound of the title which was used for the next step without further purification. (b) 45-Acetylglycolylthio-3ar [1-p-nitrobenzyloxycarbonyloxyethyl] -1- [1-acetonyloxycarbonyl-1-chloromethyl] -azetidin-2-one.

Reaktion (15) - (16).Reaction (15) - (16).

FCOZPNB ' - ïC°2PNB ._.,l ' I -ï 'al A lí_____f¿âsïi/\ 1, ÖCOCH3 - \ 0 --> 0 ó7""'N ffflofl Ö' N ~J“C1 o \Ä 0 \1 cøocH2cocn3 . ' - C00cH2cocH3 Den råa karbinolamid som erhölls från steg (a) löstes i 20 ml! vattenfri tetrahydrofuran och kyldes vid OOC. Ekvimolära mängf der pyridin och tionylklorid tillsattes tills allt utgângs- ; material försvann. Fällningen filtrerades; indunstning av å filtratet gav den råa föreningen i rubriken som användes för 4 449 489 36 det följande steget utan ytterligare rening. (c) 4B-acetylglykolyltio-3a-(l-p-nitrobensyloxikarbonyloxif etyl)-1-Lacetonyloxikarbonyl-l-trifenylfosforanylidenmetyl]- azetidin~2-on. Reaktion (l6) - (ll). oco2PNB , l °C°2PNB - 'I 'Ö ísï 2 S-\\,,f\\ ' lr/”\\ococH3 ll ococH3 _ O _ ' O I :à .á N . . 6/ N\\r,HCl Q- \T=PPh3 I coocH2cocH3 coocn cocn 2 3 Det råa klorderivatet löses i 100 ml metylenklorid; 1,5 g trifenylfosfin och 10 g silikagel tillsattes och lösningsmed- let avdunstades under vakuum. Det fasta materialet lämnades över natten vid rumstemperatur, hälldes ned i en kolonnkroma- tograf och eluerades med l:l metylenetylacetat, vilket gav 1,5 g av föreningen i rubriken. (d) (SR)-acetonyl-6a-[l-p-nitrobensyloxikarbonyloxietyl]-2- acetoximetyl-2-penem-3-karbogylat. Reaktion (ll) ~ (l). ocozpus ' -_ïco2PNn É ococfls ”zírß S ï \ococn3 ' ____9 / N coocfl cocn 0 . 2 3 coocH2cocn3 1,5 g 4ß-acetylglykolti0-3-Il-p-nitrobensyloxikarbonyloxi- etyl]-l-[acetonyloxikarbonyl-l-trifenylfosforanylidenmetyl]- -azetidin-2-on löstes i 50 ml toluen och âterflödades i tre timmar. Avdunstning av lösningsmedlet gav en olja som renades: genom kort kolonnkromatografi på silikagel med eluering med 449 489 37 (9:l) diklormetan-etylacetat. Man erhöll 0,51 g av föreningen i rubriken Erytrq PM (CDC13): 1,45 (0,0 = 5,5 Hz, 311, 0513011) 2,07 (s, 311, ococH3) 2,15 (s, 311, 000513) 4,02 (00, J = 2,0, 4,0 Hz, 1H,1z-s) 31,73 (s, 211, ggzoo) 5,0 - 5,11 (m, lmçío) 5,12, 5,20 (00, J = 15,5 Hz, zu, _c_11__,ooo) 5,22 (s, 211, ægizph) 7,4 - 3,5 (m, 411, 3110102) 111 (c11c13) 1725'cm“1 C=0 omättade estrar, ketoner, 1750 sm* c=o estfaf 1800 sm* C=0 ß-lsktam Treo 1=1v1R (CDC13)= 1,45 (<1, J = 5,0 Hz, an, 930m 2,08 (s, 311, 60033) 2,19 (s, an, ooc_1_13) 's,ss(<1<1,.1 = 2,0, 7,0 Hz, 111,1¿-_s_> 4,77 (s, 211, 93,00) 5,0 - 5,4 (m, 111, gg) 5,1s,s,42(0,.1 = 15,0 Hz, c_u_2000) 5,25 (s, 211, 9112101) 5,66 (d, J = 2,0 Hz, m, ¿a_-_5_) 7,4 - 0,5 (m, 411, 331102) 449 489 38 m (cHc13) 1725 cm“1 C=0 omättade estrar, ketoner 1150 m* ç=o estrar 1800 cm'1 Ö=0 B-laktam Egemgel 5í¿, (SR)-acetónjl-6a-[l-hydroxietyl]-2-acetoximetyl-2-penem>3- -karboxglat. Reaktion (l).FCOZPNB '- ïC ° 2PNB ._., L' I -ï 'al A lí _____ f¿âsïi / \ 1, ÖCOCH3 - \ 0 -> 0 ó7 ""' N ff fl o fl Ö 'N ~ J “C1 o \ Ä 0 \ 1 cøocH2cocn3. The crude carbinolamide obtained from step (a) was dissolved in 20 ml! anhydrous tetrahydrofuran and cooled to 0 ° C. Equimolar amounts of pyridine and thionyl chloride were added until all starting; material disappeared. The precipitate was filtered; evaporation of the filtrate gave the crude title compound used for 4,449,489 36 the following step without further purification. (c) 4B-Acetylglycolylthio-3a- (1-p-nitrobenzyloxycarbonyloxyethyl) -1-Lacetonyloxycarbonyl-1-triphenylphosphoranylidenemethyl] -acetidin-2-one. Reaction (l6) - (ll). oco2PNB, l ° C ° 2PNB - 'I' Ö ísï 2 S - \\ ,, f \\ 'lr / ”\\ ococH3 ll ococH3 _ O _' O I: à .á N. . 6 / N \\ r, HCl Q- \ T = PPh3 I coocH2cocH3 coocn cocn 2 3 The crude chlorine derivative is dissolved in 100 ml of methylene chloride; 1.5 g of triphenylphosphine and 10 g of silica gel were added and the solvent was evaporated in vacuo. The solid was left overnight at room temperature, poured into a column chromatograph and eluted with 1: 1 methylene ethyl acetate to give 1.5 g of the title compound. (d) (SR) -acetonyl-6α- [1-p-nitrobenzyloxycarbonyloxyethyl] -2-acetoxymethyl-2-penem-3-carbogylate. Reaction (ll) ~ (l). ocozpus '-_ïco2PNn É ococ fl s ”zírß S ï \ ococn3' ____9 / N cooc fl cocn 0. 1.5 g of 4β-acetylglycoltiol-3-yl-p-nitrobenzyloxycarbonyloxyethyl] -1- [acetonyloxycarbonyl-1-triphenylphosphoranylidenemethyl] -azetidin-2-one was dissolved in 50 ml of toluene and refluxed for three hours. Evaporation of the solvent gave an oil which was purified: by short column chromatography on silica gel eluting with 449 489 37 (9: 1) dichloromethane-ethyl acetate. 0.51 g of the title compound Erythq PM (CDCl 3) was obtained: 1.45 (0.0 = 5.5 Hz, 311, 0513011) 2.07 (s, 311, ococH 3) 2.15 (s, 311 , 000513) 4.02 (00, J = 2.0, 4.0 Hz, 1H, 1z-s) 31.73 (s, 211, ggzoo) 5.0 - 5.11 (m, lmçío) 5, 12, 5.20 (00, J = 15.5 Hz, zu, _c_11 __, ooo) 5.22 (s, 211, ægizph) 7.4 - 3.5 (m, 411, 3110102) 111 (c11c13) 1725 cm cm 1 C = 0 unsaturated esters, ketones, 1750 sm * c = o estfaf 1800 sm * C = 0 ß-lsktam Treo 1 = 1v1R (CDCl3) = 1.45 (<1, J = 5.0 Hz, an, 930m 2.08 (s, 311, 60033) 2.19 (s, an, ooc_1_13)'s, ss (<1 <1, .1 = 2.0, 7.0 Hz, 111.1¿- _s_> 4.77 (s, 211, 93.00) 5.0 - 5.4 (m, 111, gg) 5.1s, s, 42 (0, .1 = 15.0 Hz, c_u_2000) 5, (S, 211, 9112101) 5.66 (d, J = 2.0 Hz, m, ¿a _-_ 5_) 7.4 - 0.5 (m, 411, 331102) 449 489 38 m (cHc13) 1725 cm -1 C = 0 unsaturated esters, ketones 1150 m * ç = o esters 1800 cm -1 Ö = 0 β-lactam Egemgel 5i¿, (SR) -acetonyl-6α- [1-hydroxyethyl] -2-acetoxymethyl-2 -penem> 3- -carbox-smooth Reaction (l).

' H _lïIäPNB #_i -,_ ßs\/\OC0CH3 'i ococa3 1 I; -~> I í- í-\ 2 3 04 "- N coocH2cocH3- o coocfl coca 0,51 g (SR)-acetonyl-6a-[l-p-nitrobensyloxikarbonyloxietyl]- -2-acetoximetyl-2-penem-3-karboxylat framställd enligt exem- pel 53 löstes i 60 ml av en (l:l) acetonitril: (95%) etanol- blandning. 0,46 g 10% Pd/C tillsattes och blandningen omrördes under väteatomosfär i en timme. Efter filtrering av katalysa-1 torn indunstades filtratet och föreningen i rubriken renades genom silikagelkolonnkromatografi varvid man eluerade med (8:2) diklormetan-etylacetat, vilket gav 0,20 g ren produkt.'H _lïIäPNB #_i -, _ ßs \ / \ OC0CH3' i ococa3 1 I; 0.54 g of (SR) -acetonyl-6α- [1β-nitrobenzyloxycarbonyloxyethyl] -2-acetoxymethyl-2-penem-3-carboxylate prepared according to Example 53 was dissolved in 60 ml of an (1: 1) acetonitrile: (95%) ethanol mixture, 0.46 g of 10% Pd / C was added and the mixture was stirred under a hydrogen atmosphere for one hour. In the tower, the filtrate was evaporated and the title compound was purified by silica gel column chromatography eluting with (8: 2) dichloromethane-ethyl acetate to give 0.20 g of pure product.

EIXÉZIOW Pam (cøc13) = Trgo Pm (CDC13)= 449 489 1,30 (e, J _= s,s11-.=, 311, gagn) 2,09 (s, 311, 000113) 2,20 (s, 311, mig 3,00 (_00, J = 2,0, 4,011z, 111,1_1_-¿) 4,22 (dq, J = 6,0, 4,011z, 11-1, glom 4,72 (s, 211, gzoo) 5,12, 5,42 (d, J =1s',s11z, 211, ggzooo) 5,58 (d, J = 2,0 Hz, m, H-s) 1,32 (d, J = 6,5 Hz, an, c113c11) 2,10 (s, 311, oooc_11,) 2,20 (s,311,oog11_,) 3,06 (bs, 1.11, gg) I 3,74(0<1, .1 = 2,0, 2,0 Hz, _1011, gi) 4,23 (m, 111, 931011) 'A 0,77 (s, 211, 911,00) 5,12, 5,33 (<1, .1 = 13,0 115211, 9312000) 5,63 (0,0 = 2,0 Hz, m, 11-3) 449 489 40 ExemEel_55 (SR)-2-acetoximetyl-6a~(l-hydroxietyl)-2-penem-3-karboxylat- natriumsalt. Reaktion (l).EIXÉZIOW Pam (cøc13) = Trgo Pm (CDC13) = 449 489 1.30 (e, J _ = s, s11 -. =, 311, gagn) 2.09 (s, 311, 000113) 2.20 (s, 311, mig 3.00 (_00, J = 2.0, 4.011z, 111.1_1_-¿) 4.22 (dq, J = 6.0, 4.011z, 11-1, glom 4.72 (s, 211, gzoo) 5.12, 5.42 (d, J = 1s', s11z, 211, ggzooo) 5.58 (d, J = 2.0 Hz, m, Hs) 1.32 (d, J = 6.5 Hz, an, c113c11) 2.10 (s, 311, oooc_11,) 2.20 (s, 311, oog11_,) 3.06 (bs, 1.11, gg) I 3.74 (0 <1, .1 = 2.0, 2.0 Hz, _1011, gi) 4.23 (m, 111, 931011) 'A 0.77 (s, 211, 911.00) 5.12, 5.33 (<1 , .1 = 13.0 115211, 9312000) 5.63 (0.0 = 2.0 Hz, m, 11-3) 449 489 40 Example 55 (SR) -2-acetoxymethyl-6α- (1-hydroxyethyl) - 2-Penem-3-carboxylate sodium salt Reaction (1).

OH 1 j” --'-. s 4. S ' \ococn3 'if °C°CH3 N I I N i of - _ - \ ' “ i “~ cooNa COOCHZCOCHB 0,21 g (5R)-acetonyl-6a-[l-hydroxietyl]-2-acetoximetyl-2- penem-3-karboxylat framställd enligt exempel 54 löstes i 20 ml acetonitril och 3 ml vatten. Reaktionsblandningen kyldes vid OOC under kväve och 7,4 ml av en 0,lN Na0H-vattenlösning tillsattes långsamt inom 30 minuter. Efter avdunstning av acetonitril under vakuum extraherades återstoden tvâ gånger med kallt etylacetat. En C18 omvänd faskromatografi (eluering med vatten) av den koncentrerade vattenfasen gav 0,054 g ren förening som anges i rubriken. ål-'lëlfß PMR (Dzmsomxz: 1,34 (d,_ J = 6,3 Hz, an, gflJcx-x) 2,14 (s, aH, ooogrjß) 4,u1 (m, 1H,¿-_s_) 4,22 (m, 1H, çgou) 5,10, 5,44 (a, .J = 14.11 m, zu, 912000) 5,63 (d, J = 1.0 Hz, m, gi) U.V. (etanol 95%): Ånmx 262 nm (E.2000), 308 nm (E.2520) [a]D = 128 (C=0,92, H20) 449 489 41 2529 min (Dzoh 1,31 (d, J = 8,5 Hz, 33, än” 2,19 (s, an, ooogay, 3,92 (du, J =1,s, 7,11 Hz,1H,g-_s_) 4,21, (m, m, ggofl) 5,10, 5,44 (d, J =14¿0 Hz, ZH, CHZOCO) 5,67 (d, J =1.s Hz,,1H, H-s) U.V. (etanol 95%): Åmax 262 nm ( ¿34l0), 308 nm (g;4340) Exemgel 55.OH 1 j ”--'-. s 4. S '\ ococn3' if ° C ° CH3 NIIN i of - _ - \ '“i“ ~ cooNa COOCHZCOCHB 0.21 g (5R) -acetonyl-6a- [1-hydroxyethyl] -2-acetoxymethyl-2 penem-3-carboxylate prepared according to Example 54 was dissolved in 20 ml of acetonitrile and 3 ml of water. The reaction mixture was cooled at 0 ° C under nitrogen and 7.4 ml of a 0.1 N NaOH aqueous solution was added slowly over 30 minutes. After evaporation of acetonitrile in vacuo, the residue was extracted twice with cold ethyl acetate. A C18 reverse phase chromatography (elution with water) of the concentrated aqueous phase gave 0.054 g of the title compound. ål-'lëlfß PMR (Dzmsomxz: 1.34 (d, _ J = 6.3 Hz, an, g fl Jcx-x) 2.14 (s, aH, ooogrjß) 4, u1 (m, 1H, ¿-_s_) 4.22 (m, 1H, δgou) 5.10, 5.44 (a, .J = 14.11 m, zu, 912000) 5.63 (d, J = 1.0 Hz, m, gi) UV (ethanol 95% ): Λ max 262 nm (E.2000), 308 nm (E.2520) [α] D = 128 (C = 0.92, H 2 O) 449 489 41 2529 min (D 2 O 1.31 (d, J = 8, 5 Hz, 33, än ”2.19 (s, an, ooogay, 3.92 (du, J = 1, s, 7.11 Hz, 1H, g-_s_) 4.21, (m, m, ggo fl ) 5.10, 5.44 (d, J = 14 ° Hz, ZH, CH 2 OCO) 5.67 (d, J = 1.s Hz, 1H, Hs) UV (ethanol 95%): λmax 262 nm (Δ 3410), 308 nm (g; 4340) Exemgel 55.

Natrium(5R,6S)-6-[l(R)hydroxietyl]-2-I(l-metyl-l,2,3,4-tetr- azol-5-yl)~tiomefiyl]fßgnem-3-karboxylat.Sodium (5R, 6S) -6- [1 (R) hydroxyethyl] -2-1 (1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl] phosphine-3-carboxylate.

Utgående från 2,5 g av den förening som framställdes i exem- pel 24 och med samma förfarande som beskrevs i exemplen 25, 22 29, 31, 33, 35, 37 och 39 men med användning av l-metyl- -l,2,3,4-tetrazol-5-tiolnatriumsalt i stället för 5-metyl- -1,3,4-tiadiazol-2-tiolnatriumsalt och behandling av den resulterande föreningen såsom beskrevs i exempel 55 erhölls 0,13 g av föreningen i rubriken. uv (Hào) 315 mn ih max . sam (D20) 6 ppm 1,28 (SH, d, J=6,3 Hz) 3,87 (m, ad, J=1,4 ocn6,3 Hz) 4,10 (an, s) ' 4,19 (m, m) 4,40 (ZH, ABq, J=16,0 Hz, separation av inre linjer= 13 Hz) 5,59 (m, u, J=1.4 Hz)Starting from 2.5 g of the compound prepared in Example 24 and using the same procedure as described in Examples 25, 22, 29, 31, 33, 35, 37 and 39 but using 1-methyl-1,2 , 3,4-tetrazole-5-thiol sodium salt instead of 5-methyl-1,3,3-thiadiazole-2-thiol sodium salt and treatment of the resulting compound as described in Example 55, 0.13 g of the title compound was obtained. uv (Hào) 315 mn ih max. sam (D 2 O) δ ppm 1.28 (SH, d, J = 6.3 Hz) 3.87 (m, ad, J = 1.4 ocn6.3 Hz) 4.10 (an, s) '4, 19 (m, m) 4.40 (ZH, ABq, J = 16.0 Hz, separation of inner lines = 13 Hz) 5.59 (m, u, J = 1.4 Hz)

Claims (4)

449 489 lll PATENTKRAV449 489 lll PATENT REQUIREMENTS 1. Förening med den allmänna formeln R"' 5 / cnzz I I I! /""_" \\ 0 CæRIIII vari C5 har §-konfiguration, R"" är väte, lägre alkyl-, 2,2,2- -trikloretyl-, bensyl-, p-nitrobensyl-, p~metoxibensyl-, fenyl-, p-nitrofenyl-, benshydryl-, acetoximetyl-, pivaloyloáimetyl- eller ftalidylgrupp eller en grupp med formeln -?H-OCOOCZHS eller -CH2-NHCOR“"' CH3 vari R"“' är alkyl med l-5 kolatomer, Z är karbamoyloxi, en pyridïniumgrupp eller en grupp med formeln OCOR' eller SR" vari R' är lägre alkyl och R" är en 5-metyl-1,3,4-tiadiazol-2- -yl-, l-metyl-tetrazol-5-yl, l,2{3-tríazol-5-yl- eller pyrazinylgrupp, øch R"' är 1-hydroxietyl, l-(p-nitrobensyloxi~ karbonyloxi)-etyl eller 1-(dimetyl-tert.-butylsilyloxi)-etyl eller ett farmaceutiskt godtagbart salt därav.A compound of the general formula R "'5 / cnzz III! /" "_" \\ 0 CæRIIII wherein C5 has a § configuration, R "" is hydrogen, lower alkyl, 2,2,2- -trichloroethyl- , benzyl, p-nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloimethyl or phthalidyl group or a group of the formula -? H-OCOOCZHS or -CH 2 -NHCOR CH 3 wherein R "" 'is alkyl of 1-5 carbon atoms, Z is carbamoyloxy, a pyridinium group or a group of the formula OCOR' or SR "wherein R 'is lower alkyl and R" is a 5-methyl-1,3,4 -thiadiazol-2-yl-, 1-methyl-tetrazol-5-yl, 1,2 {3-triazol-5-yl or pyrazinyl group, and R "'is 1-hydroxyethyl, 1- (p-nitrobenzyloxy) carbonyloxy) -ethyl or 1- (dimethyl-tert-butylsilyloxy) -ethyl or a pharmaceutically acceptable salt thereof. 2. Förening enligt patentkravet l, k ä n n e t e c k n a d därav, att R"' är l-hydroxietyl.A compound according to claim 1, characterized in that R "'is 1-hydroxyethyl. 3. Förening enligt patentkravet l, k ä n n e t e c k n a d av att den utgöres av (SR)-2-acetoximetyl-6-(1'-hydroxietyl)-2-penem-3-karboxylsyra, (5R)~6-/1'-hydroxiety§F2-Û1“-metyl-l"-H-tetrazol-5"-yl)-tio- metyl]-2-penem-3-karboxylsyra, (SR)-6-X1'-hydroxietylf-2-[T5"-metyl-1",3“,4"-tiadiazol-2"-yl)- -tiometyl7-2-penem-3-karboxylsyra, i) 449 489 43 (SR)-6[1'-hydroxíety§L27fl',2",3"-triazol-5"-yl)~tiometyl7-2- -penem-3-karboxylsyra, (SR)-6-11'-hydroxiety§Ä21[byrazinyl)-tiometyl7-2-penem-3-karb- oxylsyra.Compound according to Claim 1, characterized in that it consists of (SR) -2-acetoxymethyl-6- (1'-hydroxyethyl) -2-penem-3-carboxylic acid, (5R) -6 / 1'- Hydroxyethyl [2- [2,1-methyl-1 "-H-tetrazol-5" -yl) -thiomethyl] -2-penem-3-carboxylic acid, (SR) -6-X1'-hydroxyethyl-2- [T5 "-methyl-1", 3 ", 4" -thiadiazol-2 "-yl) -thiomethyl7-2-penem-3-carboxylic acid, i) 449 489 43 (SR) -6 [1'-hydroxyethyl] L27fl ' , 2 ", 3" -triazol-5 "-yl) -thiomethyl7-2- -penem-3-carboxylic acid, (SR) -6-11'-hydroxyethyl [21-byrazinyl) -thiomethyl7-2-penem-3- carboxylic acid. 4. Förening med den allmänna formeln RI I I 5 S / L N \\ O J Cæ HN vari C5 har R-konfiguration, R"" är väte, lägre alkyl-, 2,2,2- -trikloretyl-, bensyl-, p-nitrobensyl-, p-metoxibensyl-, fenyl-, p-nitrofenyl-, benshydryl-, acetoximetyl-, pivaloyloximetyl- eller ftalidylgrupp eller en grupp med formeln -CH-OCOOCZHS eller -CH2-NHC0R"“' 'aa vari R""' är alkyl med 1-5 kolatomer, Z är karbamoyloxí, en pyridiniumgrupp eller en grupp med formeln OCOR' eller SR" vari R' är lägre alkyl och R" är en 5-metyl-l,3,4-tiadiazol-2- -yl-, l-metyl-tetrazol-5-yl, l,2,3-triazol-5-yl- eller pyrazínylgrupp, och R"' är l-hydroxietyl, l-(p-nitrobensyloxi- karbonyloxi)-etyl eller l-(dímetyl-tert.-butylsilyloxi)-etyl eller ett farmaceutiskt godtagbart salt därav för användning i farmaceutiska kompositioner i blandning med ett farmaceutiskt godtagbart utspädningsmedel eller bärare.A compound of the general formula R 1 II C 5 H / LN \\ OJ Cæ HN wherein C 5 has the R-configuration, R nitrobenzyl, p-methoxybenzyl, phenyl, p-nitrophenyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formula -CH-OCOOCZHS or -CH 2 -NHCO is alkyl of 1-5 carbon atoms, Z is carbamoyloxy, a pyridinium group or a group of the formula OCOR 'or SR "wherein R' is lower alkyl and R" is a 5-methyl-1,3,4-thiadiazole-2- yl, 1-methyl-tetrazol-5-yl, 1,2,3-triazol-5-yl or pyrazinyl group, and R "'is 1-hydroxyethyl, 1- (p-nitrobenzyloxycarbonyloxy) -ethyl or 1 - (dimethyl-tert-butylsilyloxy) -ethyl or a pharmaceutically acceptable salt thereof for use in pharmaceutical compositions in admixture with a pharmaceutically acceptable diluent or carrier.
SE8001424A 1979-02-24 1980-02-22 BETA-LAKTAM ASSOCIATES WITH ANTIBACTERIAL AND BETA-LACTAM INHIBITIVE ACTIVITY SE449489B (en)

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Families Citing this family (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5625110A (en) * 1978-12-18 1981-03-10 Bristol Myers Co Antibacterial
DE3121510A1 (en) * 1980-07-04 1982-06-16 Farmitalia Carlo Erba S.p.A., 20159 Milano 6-Alkyl-2-subst. penems and process for their preparation
JPS588084A (en) * 1981-07-08 1983-01-18 Takeda Chem Ind Ltd (6r)-substituted-(5r)-penem-3-carboxylic acid derivative and its preparation
US4742052A (en) * 1981-07-15 1988-05-03 Sumitomo Pharmaceuticals Company, Limited Antibacterial β-lactam compounds
US4508649A (en) * 1981-12-11 1985-04-02 Farmitalia Carlo Erba Process for preparing optically active penems
NO831160L (en) * 1982-04-08 1983-10-10 Erba Farmitalia PREPARATION OF SUBSTITUTED PENEM DERIVATIVES
PH21930A (en) * 1982-11-16 1988-04-08 Ciba Geigy Ag 6-hydroxy-lower alkylpenem compounds,pharmaceutical composition containing same and method of use thereof
EP0112283B1 (en) * 1982-11-16 1987-08-12 Ciba-Geigy Ag Heterocyclyl-thio compounds, process for their preparation, pharmaceutical compositions containing them and their use
GB8300295D0 (en) * 1983-01-06 1983-02-09 Erba Farmitalia Penem esters
JPS59152387A (en) * 1983-02-10 1984-08-31 Shionogi & Co Ltd Novel penem compound
GB8321677D0 (en) * 1983-08-11 1983-09-14 Erba Farmitalia Preparation of penems
US4656165A (en) * 1983-09-02 1987-04-07 Ciba-Geigy Corporation Aminomethyl penem compounds
US4711886A (en) * 1984-07-02 1987-12-08 Merck & Co., Inc. β-lactam derivatives as anti-inflammatory and antidegenerative agents
US4761408A (en) * 1984-11-02 1988-08-02 Ciba-Geigy Corporation Crystalline aminomethyl compound
DE3882730D1 (en) * 1987-02-11 1993-09-09 Ciba Geigy Ag BICYCLIC BETA LACTAM CARBON ACIDS.
GB2206578B (en) * 1987-07-07 1991-07-03 Erba Carlo Spa Process for the preparation of penems
US5364768A (en) * 1987-07-07 1994-11-15 Farmitalia Carlo Erba S.R.L. Process for the preparation of penems
IT1286558B1 (en) * 1996-02-27 1998-07-15 Menarini Farma Ind PROCESS FOR THE PREPARATION OF 2-HALOGENOMETHYL-PENEMS AND THEIR USE FOR THE PREPARATION OF ANTIBACTERIAL PENEMS
CA2282461C (en) 1997-12-29 2004-04-20 John D. Buynak 2-.beta.-substituted-6-alkylidene penicillanic acid derivatives as .beta.-lactamase inhibitors
US6407091B1 (en) 1999-04-15 2002-06-18 Research Corporation Technologies, Inc. β-lactamase inhibiting compounds
US6720445B2 (en) 2000-12-21 2004-04-13 Beacon Laboratories, Inc. Acetyloxymethyl esters and methods for using the same
CA2454413A1 (en) 2001-07-24 2003-03-13 Alamx, L.L.C. 7-alkylidene-3-substituted-3-cephem-4-carboxylates as beta-lactamase inhibitors
US7022691B2 (en) 2002-04-04 2006-04-04 John D. Buynak Inhibitors of serine and metallo-β-lactamases

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Publication number Priority date Publication date Assignee Title
LU77306A1 (en) * 1977-05-09 1979-01-18
EP0000636A1 (en) * 1977-07-13 1979-02-07 Glaxo Group Limited Penem compounds, processes for their preparation, their use in pharmaceutical compositions and azetidinones used in their preparation
US4168314A (en) * 1977-11-17 1979-09-18 Merck & Co., Inc. 6-(1'-Hydroxyethyl)-2-aminoethylthio-pen-2-em-3-carboxylic acid
US4155912A (en) * 1977-12-14 1979-05-22 Bristol-Myers Company 2-Methylpenem-3-carboxylic acid antibiotics
EP0003415A3 (en) * 1978-01-20 1979-08-22 Glaxo Group Limited Beta-lactam compounds, processes for their preparation,compositions containing them and intermediates of use in their preparation
EP0042026B1 (en) * 1978-02-02 1986-01-08 Ciba-Geigy Ag 3,4-disubstituted azetidin-2-on compounds and process for their preparation
JPS5559193A (en) * 1978-09-20 1980-05-02 Glaxo Group Ltd Bblactam compound
JPS5625110A (en) * 1978-12-18 1981-03-10 Bristol Myers Co Antibacterial
EP0013067A1 (en) * 1978-12-22 1980-07-09 Beecham Group Plc Bicyclic beta-lactam antibacterial agents, their use in pharmaceutical compositions, processes for their preparation and intermediates for use in such processes

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