GB2043639A - 3-optionally substituted methyl-2- penem derivatives - Google Patents

3-optionally substituted methyl-2- penem derivatives Download PDF

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GB2043639A
GB2043639A GB8005476A GB8005476A GB2043639A GB 2043639 A GB2043639 A GB 2043639A GB 8005476 A GB8005476 A GB 8005476A GB 8005476 A GB8005476 A GB 8005476A GB 2043639 A GB2043639 A GB 2043639A
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penem
general formula
carboxylic acid
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compound
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
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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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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

There are provided penem- carboxylic acids and esters of the general formula <IMAGE> In the formula, n=0 or 1; R''=H, lower alkyl, CCl3CH2-, p.nitrobenzyl, p.methoxybenzyl, phenyl, p.nitrophenyl or benzhydryl or a residue known to undergo metabolic activation in vivo and having favourable pharmacokinetic properties; Z=H, halogen, OH, NH2, NH2COO, SH or pyridinium or OR1, OCOR1, NHCOR1 or SR1 wherein R1=lower alkyl, aryl or a heterocyclic ring, each of which may be substituted or unsubstituted; R'=H, lower alkyl, lower alkoxy cycloalkyl or hydroxyalkyl (the hydroxy group of which is free or protected). Pharmaceutically acceptable salts of these compounds, which are antibacterial agents and beta -lactamase inhibitors, are included in the invention, as is a process for their preparation from penicillanic acid S-oxide esters.

Description

SPECIFICATION Antibacterial agents and ss-lactamase inhibitors Description The invention relates to ss-lactam containing compounds, to processfortheir preparation and to compositions containing them.
The invention provides penem-carboxylic acids and esters of the general formula (1)
wherein n isO or 1, R" represents a hydrogen atom, a loweralkyl group, a 2,2,2-trichloroethyl, benzyl, acetonyl, p.nitrobenzyl,p.methoxybenzyl, phenyl, p.nitrophenyl or benzylhydryl group, or a residue known to undergo metabolic activation "in vivo" and having favourable pharmacokinetic properties;Z represents a hydrogen or halogen atom, a hydroxy, amino, carbamoyloxy, mercapto or pyridinium group, or a group of the formula OR1, OCOR1, NHCORa and SR1 wherein R1 represents a lower alkyl group, an aryl group or a heterocyclic ring, each of which may be substituted or unsubstituted; and R' represents a hydrogen atom or a lower alkyl, lower alkoxy, cycloalkyl or hydroxyalkyl group, the alcoholic function of the hydroxyalkyl group being free or protected. The 6-substituent may have the a- or B-configuration. 6a-substitution is preferred.
Examples of residues which R" may represent, since they are known to undergo metabolic activation "in vivo" and have favourable pharmacokinetic properties, are acetoxy-methyl, pivaloyloxymethyl and phthalidyl groups and groups of the formulae -CH(CH3).OCOOC2H5 and -CH2NHCOR2 wherein R2 represents an alkyl group having from 1 to 5 carbon atoms or a cyloalkyl or aryl group.
When R1 represents a heterocyclic ring, it preferably represents a 5 or 6 membered heterocyclic ring, for example a 5-methyl-1 ,3,4-thiadiazol-2-yl, 1 -methyl-1 H-tetrnzol-5-yl, 1 ,2,3-triazol-5-yl or pyrazinyl group.
When R' represents a hydroxyalkyl group, the alcoholic function of which is protected, the protecting group is preferably a p.nitrobenzyloxycarbonyl or dimethyl-t.butyl-silyloxy group. Preferred hydroxyalkyl groups which R' may represent are lower hydroxyalkyl groups. Examples of values of R' are methyl, ethyl, methoxy, 1-hydroxy-ethyl and 1 -(p.nitrobenzyloxycarbonyloxy)-ethyl groups.
The compounds according to the invention possess a wide spectrum of antibacterial activity as well as a p-lactamase inhibiting activity. It should be pointed out that the stereochemistry at C5 of the compounds according to the invention, as well as that of all the intermediates of their preparation, is the same as in naturally occurring penicillins and cephalosporins.
Pharmaceutically acceptable salts of penem-carboxylic acids of the general formula (1 ) such as sodium, potassium, benzathin, procaine, and like salts usually formed with penicillins and cephalosporins, are also included within the scope of the invention.
The invention further provides a process for the preparation of compounds of the general formula (1) in which n, R' and R" are as above defined and Z has any of the meanings ascribed to it above except a mercapto or pyridinium group or a group of the formula SR1. The process is illustrated by the following reaction scheme, in which R', R", and n have the meanings ascribed to them above, R represents an alkyl group, X represents a group of the formula CH2Z' in which Z' has any of the meanings ascribed to Z above except a mercapto or pyridinium group or a group ofthe formula SR1, Y represents a hydrogen atom, a lower alkyl, cyano or alkoxycarbonyl group or a group of the formula CH2Z' in which Z' has the meaning ascribed to it above, and Ph represents a phenyl group.
The process comprises condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) with an acetylenic compound of the general formula XC CY, isomerising the resultant compound of the general formula (3) in basic conditions, converting the resultant azetidinone derivative of the general formula (4) into one of the general formula (11) by the steps of (a) ozonolysis of the 1 -substituent oftheformula
in solution at reduced temperature, (b) removal of the 1 -substituent of the formula
resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1 -unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO.COOR" by refluxing in a solvent, (d) chlorination of the 1 -substituent of the formula
introduced in step (c) by the action of a chlorinating agent.
(e) conversation of the 1 -substituent of the formula
introduced in step (d) into one of the formula
by reaction with triphenylphosphine, (f) reduction of the 4ss-(substituted vinylsulphinyl) group by the action of a reducing agent, and (g) ozonolysis of the double bond of the group of the formula
in solution at reduced temperature, the steps being carried out in the order (a), (b), (c), (d), (e), (f), (g) or (a), (f), (b), (c), (d), (e), (g) or (f), (a) and (g) simultaneously, (b), (c), (d), (e), step (f) being carried out in acidic conditions if carried out after step (e), and cyclising the compound of the general formula (11) by heating it in an inert solvent at from 50 Cto 1 40"C to obtain a compound of the general formula (1) in which n is 0, and optionally converting that compound to one of the general formula (1) in which n is 1 by oxidation.
The preparation of compounds of the general formula (1) in which n, Rand R" are as herein defined and Z represents a mercapto or pyridinium group our a group of the formula SR1 wherein R1 is as herein defined is carried out according to the above process with the additional step of converting the substituent X into a substituent of the formula Z wherein Z is as defined in this sentence.The additional step may be carried out at any stage in the above process after the condensation of the penicillanic acid S-oxide ester (2) with the acetylenic compound XC--CY, and is necessary because of the difficulty of condensing the penicillanic acid S-oxide ester (2) directly with an acetylenic compound HS-C=-CY, R1SC=CY or PY-C=-CY in which Py represents a pyridinium ion. This process is also within the scope of the invention.
The starting materials of the general formula (2) in which R' represents a hydrogen atom may be prepared from (5R)-6-aminopenicillanic acid following known procedures (see CIGNARELLA et al., Journal of Organic Chemistry, 27,2668 and EVRARD et al., Nature, 201,1124).
When R' represents a lower alkyl, cycloalkyl or hydroxyalkyl group, it can be introduced according to the procedure of Di Ninno et al., Journal of Organic Chemistry 42, 2960 (1977). When R' represents a lower alkoxy group, it may be introduced according to the procedures of Hauser et al., Helv. Chem. Acta, 50, 1327 (1967) and Giddings et al., Tetrahedron Letters, 11,995, (1978). Alternatively compounds of general formula (2) in which R' represents a hydrogen atom can be converted to compounds of the general formula (2) in which R' represents a lower alkyl, cycloalkyl or hydroxyalkyl group by introducing the substituent into the 6-position using a strong base, as illustrated in the following Examples.Compounds of the general formula (2) in which R' represents a lower alkyl, cycloalkyl or hydroxyalkyl group can also be prepared starting from a suitable ester or penicillanic acid S-oxide, as illustrated in the following Examples. The substitution at the 6-position is stereospecifically directed to the 6a-derivatives.
The reaction sequence (a), (b), (c), (d), (e), (f), (g) is possible when Y is not a strong electron withdrawing group. Then the compound (6, n= 1) is surprisingly stable.
The reduction step (f) may be carried out using phosphorus tribromide or sodium iodide in acetyl chloride as reducing agent.
When R' represents a hydroxyalkyl group in the desired compound of the general formula (1), the reaction sequence is preferably carried out with the alcoholic function protected.
Compounds of the general formula (1) in which R" represents a hydrogen atom can be obtained by hydrolysis or hydrogenolylis of the corresponding esterified compounds.
Compounds of the general formula (1) in which n is 1 are readily prepared starting from compounds of the general formula (1) in which n is 0 following known oxidation processes. Peracids can be advantageously used; m.chloroperbenzoic acid and peracetic acid are preferred.
A series of tests was carried out in vitro to compare the activities of acetoxymethyl (5R)-2-acetoxymethyl2-penem-3-carboxylate (Laboratory code FCE/20077/B40/341), acetoxymethyl (5R)-2-(1 -methyl-1 H-tetrazol-5 yl-thio-methyl)-2-penem-3-carboxylate (compound A) and two reference compounds. The table below shows the results of the tests as MIC (minimal inhibitory concentration).
TABLE 1 MIC yglml Strains FCE/20077/ Compound Ampicillin Cefoxitin B40/341 A Staphylococcus aureus 209P 0.39 0.39 60.19 0.78 Staphylococcus aureus 153 1.56 0.78 1.56 0.78 Staphylococcus aureus PV2 0.39 0.78 60.19 0.78 Staphylococcus aureus Smith ATCC 13709 c0.19 0.39 s0.19 0.78 Streptococcus pyogenes ATCC 12384 3.12 0.78 3.12 1.56 Escherichia coli B 1.56 0.78 0.39 1.56 Escherichia coli V14 1.56 0.78 1.56 3.12 Escherichia coli V23 3.12 0.78 3.12 12.5 Enterobactersp. V19 12.5 > 100 > 100 12.5 Klebsiella pneumoniae ATCC 10031 - 3.12 50 0.78 Klebsiella sp.R2 25 - 50 12.5 ProteusvulgarisV15 3.12 6.25 1.56 0.78 ProteusmirabilisV15 0.39 0.78 60.19 0.78 Proteus mirabilis 525 3.12 0.78 0.39 1.56 Shigellaflexneri 0.39 0.39 60.19 0.78 Pseudomonasaeruginosa 3.12 0.39 25 6.25 Salmonellatyphimurium 1.56 0.78 0.78 3.12 Salmonella panamae F15 1.56 0.78 0.78 1.56 Salmonella Saint Paul F20 1.56 0.78 0.78 3.12 Salmonella derby F14 3.12 0.78 0.78 3.12 Salmonella montevideo F16 3.12 0.78 0.78 3.12 The following Examples illustrate the invention.
EXAMPLE 1 4ss-(1-acetoxymethyl-3-acetoxy- 1-propen ylsulphin yI)- 1-(1-methoxycarbonyl-2-methyl-allyl)-azetidin-2-one (3): R=CH3; R'=H,X=Y=CH2O.CO.CH3 A solution of 2.0 g of methyl penicillinate S-oxide and 2.8 g of butyndiol diacetate in 40 ml of toluene was refluxed for 24 hours. 1.4 g of the title compound was obtained after purification by column chromatography on silica gel eluting with 96:4 by volume dichloromethane:ethyl acetate.
PMR (CDCl3): 2.036 (s, CH3-C-), 2.15 and 2.20 6 (two s,2 CH3CO), 2.88 6 (dd, Jgem = 14Hz, Jvic cis = 4 Hz, C-3-Ha), 3.38 6 (dd, Jgem = 14Hz, Jvic trans = 2Hz, C-3-H0), 3.83 6 (s, CH30),
EXAMPLE 2 4(3-/ I-acetoxymeth yl-3-acetoxy- 1-pro pen ylsulphinyl)- 1-( 1-methoxycarbonyl-2-methyl- 1-propenyl)-azetidin2-one (4): R=CH3, R' =H, X=Y=CH2O.CO.CH3 1.7 g of the compound prepared in Example 1 were dissolved in 80 ml of dichloromethane. 0.5 ml of triethylamine were added and the solution was left for a few hours at room temperature. After evaporating off the solvent, the title compound was obtained in pure form in quantitative yield.
PMR (CDCl3): 2.13 (9H) and 2.32 (3H) 6 (two s,2 CH3CO and 2 CH3-C=), 2.925 (dd, Jgem=15Hz, Jvic cis = 5Hz, C-3-Ha), 3.385 (dd, Jgem=15Hz, Jvic trans = 2.5 Hz, C-3-HB), 6 (s, CH3O) 4.88 6 (d,
EXAMPLE 3 4ss-(1-acetoxymethyl-3-acetoxy- 1-propenylsulphinyl)- 1-methoxyoxalyl-azetidin-2-one (5): R=CH3, R'=H, X=Y=CH2O.CO.CH3,n=1 2.0 g of the compound prepared in Example 2 were dissolved in 150 ml of dichloromethane and, after cooling to -78 C, a flow of ozone in oxygen was bubbled through the solution until a slightly blue colour appeared. The solution was raised to room temperature, shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate.The resulting organic phase gave, after evaporation "in vacuo" of the solvent therefrom, 1.4 g of the title compound.
PMR (CDC13): 2.05 and 2.08 # (two 2CH3CO), 3.035 (dd, Jgem=17Hz, Jvic cis = 5.5Hz, C-3-Ha), 3.505 (dd,
IR (CH2Cl2): 1830 cm- ss-lactam C=O 1750 cm-' esters C=O 1715 cm-1 amide C=O EXAMPLE 4 4p-( 1-acetoxymethyl-3-acetoxy- 1-propen ylthio)- 1-methoxy-oxalyl-azetidin-2-one (5): R=CH3, R'=H, X=Y=CH2O.CO.CH3, n=O A solution of 1.4 g of the compound prepared in Example 3 in 10 ml of anhydrous dimethylformamide was cooled to -25 C and 0.9 ml of phosphorus tribromide were added.After 10 minutes the mixture was diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate. After drying the solution over anhydrous sodium sulphate and evaporating the solvent therefrom, 0.9 g of the title compound were obtained.
PMR (CDCl3): 2.07 b (s, 2CH3CO), 3.17 # (dd, Jgem = 19Hz, Jvic trans = 3.5Hz, C-3-Hp), 3.655 (dd, Jgem =
IR(CHCl3): 1815 cm- ss-lactam C=O 1745 cm-' esters C=O 1710 cm-' amide C=O EXAMPLE 5 4P-(l-acetoxymethyl-3-acetoxy- 1-pro pen ylthio)-azetidin-2-one (6): R'=H, X=Y=CH2O.CO.CH3, n=O 1.5 g of the compound prepared in Example 4 were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the methanolic solution evaporated to give 0.8 g of the title compound.
7.13 b (broad, N-H).
IR (CHCl3): 1770 cm-1 lS-lactam C=O 1740cm-1 esters C=O.
EXAMPLE 6 4B(1-acetoxymethyl-3-acetoxy- 1-propenylsulphinyl)-azetidin-2-one.
(6): R'=H, X=Y=CH2O.CO.CH3, n=1 0.800 g of the compound prepared in Example 3 were dissolved in 80 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the solvent was evaporated off. 0.5 g of the title compound were obtained.
7.235(5, NH).
IR (CHCl3): 1790 cm- ss-lactam C=O 1745 cm-' esters C=O EXAMPLE 7 4ss-acetylglyco/loylthio- 1-acetoxymethoxyoxalyl-azetidin-2-one.
(13): R=X=CH3O.CO.CH2, R'=H 0.8 g of 4p-( 1 -acetoxymethyl-3-acetoxy-1 -propenylthio)-1 -(1 -acetoxymethoxycarbonyl-2-methyl-1 propenyl)-azetidin-2-one were dissolved in 80 ml of dichloromethane and cooled to -78"C. A flow of ozone in oxygen was bubbled through the solution until a blue colour appeared. The solution, after shaking with an aqueous solution of sodium pyrosulphite, was dried over anhydrous sodium sulphate. The solvent was removed by evaporation to give 0.45 g of the title compound.
PMR (CDCl3): 2.10 and 2.135 (two 2CHsCO), 3.205 (dd, Jgem = 17Hz, Jvic trans = 3.5Hz, C3-Hss),3.77 6 (dd, Jgem = 17Hz, Jvic cis = 5.5Hz, C-3-Ha), 4.735 (s, -CO-CH2-OCO-),5.73 # (dd, Jvic=5.5 and 3.5Hz, C-4-H), 6 (s, COO-CH2-OCO).
EXAMPLE 8 4ss-acetylglycolloylthio-azetidin-2-one (14): R'=H, X=CH2O.CO.CH3 0.6 g of 4ss-acetylglycolloylthio-1 -methoxyoxalyl-azetidin-2-one were dissolved in 100 ml of methanol and a few grams of silica gel were added under stirring. After one hour the silica gel was filtered off and the resulting solution gave, after evaporation of the solvent therefrom, 0.35 g of the title compound.
PMR (CDCl3): 2.20 5 (s, CH3CO), 3.03 (dd, Jgem = 16Hz, Jvic trans = 2.5Hz, C3-Hss),3.50 5 (dd, Jgem = 16Hz, Jvic cis = 4.5Hz, C-3-Ha), 4.77 5 (s, -CO-CH2-OCO-), 5.32 6 (dd, Jvic = 4.5 and 2.5Hz, C-4-H),6.40# (broad s, NH).
EXAMPLE 9 4ss-(1-acetoxymethyl-3-acetoxy- 1-propen ylthio)- 1-( 1-acetoxymethoxycarbon yI- 1-h ydroxymethyl)-azetidin-2- one.
(7): R'=H,R"=X=Y=CH2O.CO.CH3,n=O 0.7 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate) were dissolved in 30 ml of benzene and the resulting solution was refluxed for 20 minutes through a Dean-Stark apparatus. After cooling to 50 -60 C,0.7 g of the compound prepared in Example5 dissolved in 10 ml of benzene were added and the resulting solution was refluxed for 2 hours. The title compound was obtained in almost quantitative yield and can be used as crude mixture for the next step. A pure sample was obtained by preparative TLC, for analytical purposes.
EXAMPLE 10 4ss-{1-acetoxymethyl-3-acetoxy- 1-propenylthio)- 1-(1-acetoxy-methoxycarbonyl- 1-chloromethyl)-azetidin-2one.
(8): R'=H, R"=X=Y=CH2O.CO.CH3,n=O 0.6 g of the compound prepared in Example 9 dissolved in 15 ml ml oftetrahydrofuran were cooled to 0 C.
0.115 ml of pyridine and 0.104 ml of thionyl chloride were added and the mixture was left under stirring for 10 minutes. The insoluble material was filtered off and the solution was evaporated "in vacuo" at room temperature to give the title compound in high yield. A sample was purified on preparative TLC for analytical purposes, but the crude mixture can be used without purification for the next step.
EXAMPLE 11 4ss-{1-acetoxymethyl-3-acetoxy- 1-propenylthio)- 1-(1-acetoxymethoxycarbonyl- 1triphenylphosphoranylidenem ethyl)-azetidin-2-one (9): R'=H, R"=X=Y=CH2O.CO.CH3, n=O A solution of 0.430 g of the compound prepared in Example 10 in 5 ml of tetrahydrofuran and 5 ml of dioxan containing 0.520 g of triphenylphosphine and 0.08 ml of pyridine was stirred overnight at 50 C. The resulting phosphorane was purified by column chromatography on silica gel eluting with 70:30 by volume dichloromethane:ethyl acetate. 0.400 g of the title compound was obtained.
EXAMPLE 12 4ss-acetylglycolloylthio- 1-(1-acetoxymethoxycarhonyl- 1-triphenylphosphoranylidenemethyl)-azetidin-2-one.
(11): R'=H,R"=X=CH2O.CO.CH3 0.7 g of the compound prepared in Example 11 were dissolved in 40 ml of dichloromethane and, after cooling to -20 C, 50 ml of a 10% solution of trifluoroacetic acid in dichloromethane were added. After a few minutes, a flow of ozone in oxygen was bubbled through the solution at -20 C until a slightly blue colour appeared. At this point, the reaction was stopped and a few drops of trimethylphosphite were added. The organic solution was washed with a saturated solution of sodium bicarbonate and dried over anhydrous sodium sulphate. The solvent was evaporated off to give 0.550 g ofthetitle compound.
PMR (CDCl3): 2.10 and 2.15 6 (two d, 2CH3CO), 4.72 6 (s, -CO-CHrOCO-), 5.645 (s, -COO-CH2-OCO), 7.1-8.0 5 (m, 3CsH5-).
EXAMPLE 13 acetoxymethyl (5R)-2-acetoxymethyl-2-penem-3-carboxylate.
(1) R'=H, R"=X=CH2O.CO.CH3,n=O 0.7 g of the compound prepared in Example 12 were dissolved in 30 ml of drytoluene and refluxed for 2 hours. The reaction mixture, consisting of the title compound and triphenylphosphine oxide, was purified by a short column chromatography on silica gel, eluting with 97:3 by volume dichloromethane:ethyl acetate, to give 0.250 g of the title compound.
PMR (CDCl3): 2.11 and 2.135 (twos, 2CH3CO), 3.495 (dd, Jgem = 16.5Hz, Jvictrans = 2Hz, (C-6-Hss),3.86 3.865 (dd, Jgem = 16.5Hz, Jvic cis = 3.8Hz, C-6-Hct), 5.12 and 5.45 6 (two d, Jgem = 15.5Hz, =C-CH2), 5.68 5 (dd, Jvic = 3.8 and 2Hz, C-5-H),5.87 5 (s, -COO-CH2-OCO-).
IR (CHCl3): 1800 cm-113-lactam C=O 1750-1725 cm-1 esters C=O U.V. (EtOH): imax325 nm.
MS: m/e 315.04108(M+) calculated for C12H13NO7S315.04127.
EXAMPLE 14 4ss-{1-acetoxymethyl-3-acetoxy- 1-propen ylthio)- 1-(1-p. -nitrobenzyloxycarbonyl- 1-hydroxymethyl)-azetidin- 2-one.
(7): R'=H, R"=p.NO2.C6H4.CH2, X=Y=CH2O.CH3, n=O The title compound was obtained following the procedure described in Example 9, using p-nitrobenzyl glyoxylate (freshly prepared by ozonolysis of p-nitrobenzyl fumarate) instead of acetoxymethyl glyoxylate.
Quantitative yield.
PMR (CDCl3): 2.1(s, 6H); 2.8-3.7 (m, 2H); 4.7-4.9 (m, 5H); 5.1-5.6 (m, 2H); 5.2 (m, 1H); 6.1 (m, 1H); 7.5-8.3 (m, 4H).
EXAMPLE 15 4ss( 1-acetoxymethyl-3-acetoxy- 1-propenylthio)- 1- (1-p. nitrobenzyloxycarbonyl- 1-chloromethyl)-azetidin-2 ona (8): R'=H, R"=p.NO2.C6H4.CH2, X=Y=CH2O.CO.CH3, n=O The title compound was obtained following the procedure described in Example 10, but using the compound prepared in Example 14 instead of that prepared in Example 9.
PMR (CDCl3)5 : 2.1(s, 6H); 2.8-3.7 (m, 2H); 4.7-4.9 (m, 4H); 5.2-5.4 (m, 1 H); 5.4 (m, 2H); 6.1-6.3 (m, 2H); 7.5-8.4 (m, 4H).
EXAMPLE 16 4P-(l-acetoxymethyl-3-acetoxy- 1-propenylthio)- 1-(1-p.nitrobenzyloxycarbonyl- 1 triphenylphosphoranylidenemethyl)-azetidin-2-one.
(9): R'=H, R"=p.NO2.C6H4.CH2, X=Y=CH2O.CO.CH3, n=O The title compound was obtained following the procedure described in Example 11, but using the compound prepared in Example 15 instead of that prepared in Example 10.
EXAMPLE 17 4ss-acetylglycolloylthio- 1-{1-,o nitrobenzyloxycarbonyl- 1-triphenylphosphoranylidenemethyl)-azetidin-2-one (11): R'=H, R"=p.NO2.C6H4.CH2,X=CH2O.CO.CH3 The title compound was obtained following the procedure described in Example 12, but using the compound prepared in Example 16 in place of that prepared in Example 11.
EXAMPLE 18 p.nitrobenzyl(5R)-2-acetoxymethyl-2-penem-3-carhoxylate.
(1) R'=H, R"=p.NO2.C6H4.CH2, X=CH2O.CO.CH3,n=O The title compound was obtained following the procedure described in Example 13, but using the compound prepared in Example 17 instead of that prepared in Example 12.
PMR (CDCl3) : 3.75 (1 H, dd, J = 2.3Hz, 16.8Hz, H-6a); 3.87(1 H, dd, J = 3.6Hz, 16.8Hz, H-6ss);5.14 (1 H, d, J = 15.8, =C-CH2O-); 5.50 (1 H, d, J = 15.8Hz, =C-CH2O); 5.71 (1 H, dd, J = 2.3Hz, 3.6Hz, H-5).
[a1D + 87 (c=1.2 CHCl3).
I.R. (CHCl3): 1800 (ss-lactam), 1750 and 1720 cm-1.
U.V. (EtOH): 265 (E11000) and 322 (E 7000) nm.
M.S.: m/e378(M*) M.p. 122 -123 C.
EXAMPLE 19 (5R)-2-acetoxymethyl-2-penem-3-carboxylic acid.
(1 ) R'=R"=H,X=CH2O.CO.CH3,n=O 200 mg of the compound prepared in Example 18 were dissolved in 12 ml of ethyl acetate. 8 ml of 0.2 M sodium bicarbonate solution and 400 mg of 10 percent palladium-on-charcoal were added and the resulting two phase mixture was shaken under hydrogen for 60 minutes. After filtering off the catalyst, the aqueous phase was acidified with 20 ml of 5 percent aqueous citric acid and extracted three times with dichloromethane. The organic layers were dried over anhydrous sodium sulphate and evaporated to give 60 mg of the title compound.
I.R. (CHCl3): 1790 (ss lactam), 1735 and 1700 cm-1.
U.V. (EtOH): 300 nm EXAMPLE 20 4ss-(1-hydroxymethyl-vinylsulphinyl)- 1-r1-methoxycarbonyl-2-methyl-allyl)-azetidin-2-one.
(3): R=CH3, R'=Y=H, X=CH2OH 4 g of methyl penicillanate S-oxide were dissolved in 15 ml of toluene and refluxed with 15 ml of propargyl alcohol for 8 hours. After evaporating off the solvent in vacuo, the residue was purified by short column chromatography on silica gel, eluting with dichloromethane:ethyl acetate (1:1 by volume). 2.8 g of the title compound were obtained.
PMR(CDCl3)6: 1.96 (bs, 3 H,C-CH3); 2.91 and 3.35 (dd, 2H, J = 2Hz, 5Hz, 15Hz, CO-,CH2-CH-S); 3.78 (s, 3 H, COOCH3); 4.36 (bs, 2 H, CH2OH,); 4.90-5.25 (m, 3 H, CH-COOCH3, C-C=CH2); 5.35 (m, 1 H, CH2-CH-S); 5.88 (s, 2 H, CH2=C-S).
EXAMPLE 21 4ss(1-hydroxymethyl-vinylsulphinyl)- 1-{1-methoxycarbonyl-2-methyl- 1-propenyl)-azetidin-2-one.
(4): R=CH3, R'=Y=H, X=CH2OH 3.0 g of the compound prepared in Example 20 were dissolved in 100 ml of dichloromethane and left at room temperature for a few hours. After evaporating the solvent from the solution, the residue consisted of the title compound in pure form. Quantitative yield.
PMR (CDCl3) 5 : 2.08 (s,3 H, =C-CH3); 2.18 (s,3 H, =C-CH3); 2.7-3.6 (m, J 2Hz, 16Hz, CO-CH2-CH-S); 3.78(s,3 H, COOCH3); 4.35 (s,2 H, CH2OH); 5.32 (ml 1 H, CH-S); 5.90 (bs, 2 H, =CH2).
EXAMPLE 22 4-(1-brnmomethyl-vinylthio)- 1-{1-methoxycarbonyl-2-methyl- 1-propenyl)-azetidin-2-one.
(12): R=CH3, R'=Y=H,X=CH2Br 1.8 g of the compound prepared in Example 21 were dissolved in 40 ml of dimethylformamide and cooled to -20 C. 0.7 ml of pyridine and 3.0 ml of phosphorus tribromide were added and the mixture was left for 15 minutes under stirring. Ethyl acetate was added and the organic layer was shaken with a saturated solution of sodium bicarbonate, washed with water and then dried over anhydrous sodium sulphate to give, after evaporating off the solvent, 1.6 g of the title compound.
EXAMPLE 23 4t3f1-(m ethyl- 1H-tetrazol-5-yl-thiomethyl)-vinylthio]- 1-(1-methoxycarbonyl-2-methyl- 1-propenyl)-azetidin-2
1.4 g of the compound prepared in Example 22 were dissolved in 25 ml oftetrahydrofuran and cooled to 0OC.0.8 g of 1-methyl-5-mercapto-tetrazole sodium salt were added and the mixture was left under stirring for three hours at room temperature. After filtering off the insoluble matter, the mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulphate and evaporated to dryness. The residue consisted of 2.0 g of the title compound in pure form.
PMR (CDCl3) #: 2.00 (s,3 H, =C-CH3); 2.22 (s,3 H, =C-CH3); 2.70-3.80 (m, 2 H, J = 2Hz, 5Hz, 15hz, CO-CH2-CH-S); 3.72 (s,3 H, COOCH3); 3.95(s,3 H, N,-Cll,3); 4.10 (s,2 H, CH2-S); 5.18 (bs, 1 H, S-C=CH); 5.36 (m, 1 H, CH2-CH-S); 5.57 (bs, 1 H, S-C=C-H).
EXAMPLE 24 4ss-[{1-methyl- 1-H-tetrazol-5-yl-thio)-acetylthio]- 1-meth oxyoxalyl-azetidin-2-one.
1.8 g ot the compound prepared in example 23 were dissolved In zuu mi ot dichioromethane and cooled to -78 C. A flow of ozonized oxygen was bubbled through the solution until a blue colour appeared. A few drops of trimethyiphosphite were added and the mixture was raised to room temperature. Removal of the solvent by evaporation gave 1.3 9 of the title compound.
PMR (CDCl3) #: 2.9-3.7 (m,2 H, COCH2CH S); 3.85 (s, 3 H, COOCH3); 3.98 (s, 3 H, N-CH3); 4.35 (s, 2 H, CH2S); 5.75 (m, 1 H, CH2CHS).
EXAMPLE 25 4(3-[( 1-methyl- 1-H-tetrazol-5-yl-thio)-acetylthio]-azetidin-2-one.
1.2 g of the compound prepared in Example 24 were dissolved in a 1:1 by volume ethyl acetate:methanol mixture and a few grams of silica gel were added under vigorous stirring. After one hour the insoluble matter was filtered off and the solution was evaporated in vacuo. The title compound was crystallized from methanol:diethyl ether: 0.6 g were obtained.
EXAMPLE 26 4ss-[01-methyl- 1-H-tetrazol-5-yl-thio)-acetylthio]- 1-( 1-acetoxymethoxycarbon yl- 1-hydroxymethyl)-azetidin-2one
1.5 g of the compound prepared in Example 25 were refluxed in 50 ml of benzene with 1.2 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate). The reaction was complete after 3 hours. The crude oil obtained after evaporating off the solvent can be used for the next step without further purification. A sample was purified on TLC for spectroscopic data.
PMR (CDCl3) #: 2.06 (s, 3 H); 2.7-3.8 (m, 2 H); 3.95 (s, 3 H); 4.30 (s, 2 H); 5.40 (s, 1 H); 5.50 (m, 1 H); 5.80 (s, 2 H).
EXAMPLE 27 4p-[(1-methyl- 1-H-tetrazol-5-yl-thio)-acetylthio]- 1-{1-acetoxymethoxycarbonyl- 1-chloromethyl)-azetidin-2
The oil obtained from the last preceding Example was dissolved in anhydrous tetrahydrofuran (20 ml) and treated at 0 C with equimolar amounts of pyridine and thionyl chloride until all starting material had disappeared. After filtering off the insoluble matter, the filtrate was used immediately for the next step.
EXAMPLE 28 4ss-[(1-m 1-methyl- 1-H-tetrazol-5- yl-thio)-acetylthio]- 1-(1-acetoxymethoxycarbonyl- 1triphenylphosphoranylidenemethyl)-azetidin-2-one.
10 the filtrate obtained in the last preceding Example were added 800 mg ottriphenylphosphine and 0.4 ml of pyridine. The resulting mixture was heated to 60 -70 C and maintained at that temperature for a few hours. The phosphorane was purified on silica gel eluting with dichloromethane:ethyl acetate (1:1 by volume).
EXAMPLE 29 acetoxymethyl (5R)-2-( 1-methyl- 1-H-tetrazol-5-yl-thio-meth yl)-2-penem-3-carboxylate
0.500 g of the compound prepared in Example 28 were dissolved in 30 ml of toluene. The solution was heated to 100 C and maintained at that temperature for two hours. The title compound was purified from triphenylphosphine oxide by short column chromatography on silica gel eluting with dichloromethane:ethyl acetate (8:2 by volume).
PMR (CDCl3) #: 2.15 (s,3 H, COCH3); 3.30-4.03 (m, J = 4Hz, 2Hz, -CH2-(6); 3.97(s,3 H, -NCH3); 4.56 (d, J = 14Hz, 1 H, HCH-S); 4.84 (d, J = 14Hz, 1 H, HCH-S), 5.65 (dd, J = 4Hz 2Hz, 1 H, H-5a); 5.88 (s,2 H, COOCH2O).
EXAMPLE 30 (5R)-2-(1-methyl- y/- l-H-tetrazol-5y/-thiometh ylJ-2-p en em3-carboxylic acid.
he title compound was prepared by catalytic reduction otp.nitrobenzyl (5R)-2-(1-methyl-1-H-tetrazol-5-yl- thiomethyl)-2-penem-3-carboxylate, obtained by a process substantially as described in Examples 20 to 29 but using p.nitrobenzyl glyoxylate instead of acetoxymethyl glyoxylate. The catalytic reduction was effected following the method described in Example 19.
I.R. (CHCl3): 1800 (ss lactam),1750 and 1720.
EXAMPLE 31 methyl 6a-( 1 '-h ydroxyeth yl)-peniclllinate-S-oxide.
A solution of methyl penicillinate S-oxide (2.3 g) 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 1.6 M solution of butyl lithium in hexane) dissolved in anhydrous tetrahydrofuran was added and the mixture left at -78 C for 10 minutes. 5 ml of acetaldehyde were then added and the mixture was stirred for 15 minutes.
The reaction was then quenched with a saturated aqueous solution of ammonium chloride, extracted with ethyl acetate, washed twice with water and dried over anhydrous sodium sulphate. After evaporating off the solvent the residue was shortly purified by column chromatography on silica gel eluting with dichloromethane:ethyl acetate (1 by volume). 1.5 g of the title compound were obtained consisting of a 2:3 mixture of epimers at the hydroxyl bearing carbon based on the PMR, being the new C6-C8 bond only in the a position because of the stereospecificity of the reaction in the used conditions.
PMR ICDCI3) 5:1.27 (s, 3 H, a-CH3); 1.40 (d, 3 H, J = 5.7Hz, CH3-CHOH) major isomer; 1.48 (d, 3 H, J = 5.7Hz, CH3-CHOH) minor isomer; 1.70 (s,3 H, ss-CH3); 3.4-3.8 (m, 1 H, H-6); 3.80 (s,3 H, COOCH3); 4.1-4.7 (ml 1 H, CHOH); 4.50 (s, 1 H, H-3); 4.98 (d, J = 1.9Hz, 1 H, H-5) minor isomer; 5.05 (d, J = 1.9Hz, 1 H, H-5) major isomer.
EXAMPLE 32 methyl 6-(1-hydroxyethyl)-3-penicillanate To a solution of 2.2 g of methyl penicillanate in 30 ml of anhydrous tetrahydrofuran, a slight excess of lithium diisopropylamide was added at -78 C under nitrogen. An excess of acetaldehyde was dropped in and the mixture was stirred for 5 minutes. The reaction was then quenched with a trace of acetic acid; the mixture was poured into water and extracted with dichloromethane. The organic layers were dried over anhydrous sodium sulphate and evaporated "in vacuo" to give 0.8 g of the title compound.
EXAMPLE 33 methyl 6-(1-p-nitrobenzyloxycarbonyloxyethyl)-3-peniclllanate.
1.2 g of methyl 6-(1-hydroxyethyl)-3-penicillanate, prepared as described in Example 32, were dissolved in 40 ml of tetrahydrofuran cooled to -78 C and treated with one equivalent of butyl lithium. 1.2 equivalents of p-nitrobenzyloxycarbonyl chloride were added to the mixture. After 30 minutes at -78 C, the reaction mixture was left at room temperature for 60 minutes, poured into water and extracted with dichloromethane. 1.4 g of the title compound were obtained after drying over anhydrous sodium sulphate and evaporating off the solvent.
EXAMPLE 34 methyl 6-( 1-p-nitrobenzyloxycarbon yloxyeth yl-3-p eniclllanate-S-oxide
1.8 g of methyl 6-[1-p-nitrobenzyloxycarbonyloxyethyl]-3-penicillanate, prepared as described in Example 33, were dissolved in 50 ml of dichloromethane and treated at OOC with 1.5 equivalents of mchloroperbenzoic acid. The organic phase was shaken with a saturated solution of sodium bicarbonate, extracted, dried over anhydrous sodium sulphate and evaporated: 1.4 g of the expected sulphoxide were obtained.
EXAMPLE 35 4P-(l-acetoxym eth yl-3acetoxy- 1-pro pen ylsulphinyl)-3-( 1-p-nitrobenzyloxycarbonyloxyethyl)- 1-( 1-methoxy- carbonyl-2-m eth yl-allyI)-azetidin-2-on e
Asolution of 2.0 g of the compound prepared in Example 34 and 2.4 g of butyndiol diacetate in 50 ml of toluene was refluxed for 24 hours. The trapped compound was then purified by silica gel column chromatography eluting with 9:1 by volume dichloromethane:ethyl acetate. 1.1 g of the title compound were obtained.
EXAMPLE 36 4p-(1-acetoxymethyl-3-acetoxy- 1-propenylsulphinyl)-3-(1-p-nitrobenzyloxycarhonyloxyethyl)- 1-(1- methoxycarbonyl-2-methyl- 1-propenyl)-azetidin-2-one
1.3 g of the compound prepared in Example 35 were dissolved in 80 ml of dichloromethane. 0.3 ml of triethylamine were added and the mixture was left at room temperature.for 2 hours. The title compound was obtained in pure form in quantitative yield by evaporating off the solvent.
EXAMPLE 37 4p-( 1-acetoxymethyl-3-acetoxy- 1-propenylsulphinyl)-3-(1-p-nitrobenzyloxycarhonyloxyethyl)- 1methoxyoxalyl-azetidin-2-one
A solution of 1.1 g of the compound prepared in Example 36 in 100 ml of dichloromethane was cooled to -78 C. Ozone in oxygen was then bubbled through the solution until a blue colour appeared. The solution was shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate.
0.5 g of the title compound were obtained after evaporation off of the solvent.
EXAMPLE 38 4P-(l-acetoxymethyl-3-acetoxy- 1-propen ylthio)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)- 1-methoxyoxalylazetidin-2-one.
A solution of 0.8 g of the compound prepared in Example 37 in 15 ml of anhydrous dimethylformamide was cooled to -20 C and 0.6 ml of phosphorus tribromide were added. The reaction mixture was diluted with ethyl acetate after 10 minutes and washed twice with a solution of sodium bicarbonate. The organic phase was dried over anhydrous sodium sulphate and the solvent was then evaporated off giving 0.4 g of the title compound.
EXAMPLE 39 4p-( 1-acetoxymethyl-3-acetoxy- 1-propenylthio)-3-( 1-p-nitrohenzyloxycarhon yloxyethyl)-azetidin-2-one
1.2 g of the compound prepared in Example 38 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: a short column chromatography afforded 0.4 g of the title compound.
EXAMPLE 40 4p-( 1-acetoxymethyl-3-acetoxy- 1-prop en ylthio)-3-( 1-p-nitrobenzyloxycarbon yloxyethyl)- 1-(1- acetoxymethoxy-carbonyl- 1-hydroxymeth yl)-azetidin-2-one.
0.6 g of the compound prepared in Example 39, dissolved in 30 ml of benzene, and 0.6 g of acetoxymethyl glyoxylate (freshly prepared by ozonolysis of diacetoxymethyl fumarate), were refluxed together. The reaction was completed after two hours. The condensation product can be used for the next step without further purification.
EXAMPLE 41 4P-(l-acetoxymethyl-3-acetoxy- 1-pro pen ylthio)-3-(1-p-nitrobenzyloxycarbon yloxyethyl)- 1-(1- acetoxymethoxycarbonyl- 1-chloromethyl)-azetidin-2-one.
0.5 g of the compound prepared in Example 40 were dissolved in 12 ml of anhydrous tetrahydrofuran and cooled to 0 C.1.1 Equivalents of pyridine and 1.1 equivalents of thionyl chloride were added and the mixture was left under stirring for 10 minutes. The insoluble matter was filtered off and the solvent was evaporated off at room temperature to give the title compound in nearly quantitative yield. The product can be used without further purification for the next step.
EXAMPLE 42 4p-( 1-acetoxymethyl-3-acetoxy- 1-pro pen ylthio)-3-(1-p-nitrobenzyloxycarbonyloxyethyl) 1 (acetoxymethoxycarbonyl- 1-triphen ylphosphoranylldenemethyl)-azetidin-2-one.
A solution of 0.760 g of the compound prepared in Example 41 in 10 ml oftetrahydrofuran and 10 ml of dioxan was stirred overnight at 500C with 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine. The phosphorane was purified by silica gel column chromatography, eluting with 70:30 by volume dichloromethane:ethyl acetate. 0.480 g of the title compound were obtained.
EXAMPLE 43 4p-acetylglycoloyfthio-3-(1-p-nitrobenzyloxycarbonyloxyethyl)- 1-r1-acetoxymethoxycarbonyl- 1 triphenylphosphoran ylidenemethyl)-azetidin-2-one.
0.45 g of the compound prepared in Example 42 were dissolved in 50 ml of dichloromethane and cooled to -20"C. 30 ml of trifluoroacetic acid dissolved in dichloromethane were added. After a few minutes ozone in oxygen was bubbled through the solution until a slightly blue colour appeared. The reaction was stopped and a few drops oftrimethylphosphite were added. The organic phase was washed with a saturated solution of sodium bicarbonate and dried over anhydrous sodium sulphate: 0.260 g of the title compound were obtained.
EXAMPLE 44 4p-(1-acetoxymeth yl-3-acetoxy- 1-prop en ylthio)-3-( 1-p-nitrohenzyloxycarbonyloxyethyl)- 1- (methoxycarbon yl-2-meth yl- 1-prop en yl)-azetidin-2-one.
1.5 g of the compound prepared in Example 36 were dissolved in 10 ml of anhydrous dimethylformamide and cooled to -20"C. 0.8 ml of phosphorus tribromide were added, and the mixture was stirred for 10 minutes. It was then diluted with ethyl acetate and washed twice with a saturated solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulphate and evaporation off of the solvent gave 1.1 g of the title compound.
EXAMPLE 45 4(i-acetWglycollo ylthio-3- (1-p-nftrohenzyloxycarhon yloxyethyl)- 1-methoxyoxalyl-azetidin-2-one.
1.4 g of the compound prepared in Example 44 in 120 ml of dichloromethane were cooled to -780C. Ozone in oxygen was bubbled through the solution until a blue colour appeared. The solution was shaken with an aqueous solution of sodium pyrosulphite and dried over anhydrous sodium sulphate. Evaporation off of the solvent gave 0.8 g of the title compound.
EXAMPLE 46 4-acetylg'lycoHo ylthio-3-( 1-p-nitrobenzylox ycarb on yloxyeth yl)-azetidin-2-one.
0.800 g of the compound prepared in Example 45 were dissolved in 50 ml of methanol and a few grams of silica gel were added. The mixture was left at room temperature for 60 minutes, and then the insoluble material was filtered off. The filtrate, after the solvent had been removed by evaporation, gave 0.300 g of the title compound.
EXAMPLE 47 4P-acetylglycolloylthio-3.(1-p-nitrobenzyloxycarbonyloxyethyl)- 1-acetoxymethoxycarbonyl- 1hydroxymethyl)-azetidin-2-one.
0.5 g of the compound prepared in Example 46 and 0.5 g of acetoxymethyl glyoxylate in 30 ml of benzene were refluxed until the reaction was complete (two hours). The title compound was obtained and can be used for the next step without further purification.
EXAMPLE 38 4p-acetylglycolloylthio-3-( 1-p-nitrobenzyloxycarbonyloxyethyl)- 1-01-acetoxymethoxycarbonyl- 1 chloromethylJ-azetidin-2-one.
0.35 g of the compound prepared in Example 47 were dissolved in 10 ml of anhydrous tetrahydrofuran at 0 C.1.1 Equivalents of pyridine and 1.1 equivalents of thionyl chloride were added and the mixture was stirred for 10 minutes. The precipitate was filtered off and the filtrate, after evaporation off of the solvent, gave the title compound in quantitative yield. The crude product was used as such for the next step.
EXAMPLE 49 4p-acetylglycolloylthio-3-( 1-p-nitrobenzyloxycarbonyloxyethyl)- 1-( 1-acetoxymethoxycarbonyl- 1 triphenylphosphoranylidenemethylJ-azetidin-2-one.
0.400 g of the compound prepared in Example 48 were dissolved in 20 ml of a 1:1 by volume mixture of tetrahydrofuran and dioxan; 2 equivalents of triphenylphosphine and 1.1 equivalents of pyridine were added and the mixture was stirred overnight at 50"C. The title compound was obtained and was purified by silica gel column chromatography, eluting with 70:30 by volume dichloromethane:ethyl acetate. 0.280 g of the phosphorane were obtained.
EXAMPLE 50 acetoxymethyl 15RJ-6-I I-p -nitrobenzyloxycarbon yloxyethy/l-2-acetoxymeth yl-2-pen em9-carb oxyla te
0.210 g of the compound prepared in Example 43 or Example 49 were dissolved in 7 ml oftoluene and the solution was refluxed for two hours. Purification by short column chromatography, eluting with 95:5 by volume dichloromethane:ethyl acetate, afforded 0.050 g of the title compound.
EXAMPLE 51 acetoxymethyl (5R)-6- ( 1-h ydrox ye th yl)-2-acetox ymeth yl-2-pen em-3-ca rb ox yla te.
(1): R'=CH3CH.OH, R"=X=CH2O.CO.CH3 0.060 g of the compound prepared in Example 50 were poured into a water:ethanol:dipotassium monohydrogen orthophosphate mixture and hydrogenolysed with 10% palladium-on-carbon. A quick purification by silica gel column chromatography gave 0.015 g of the title compound.
EXAMPLE 52 Operating as described in the previous Examples, but employing 5-methyl-2-mercapto-1,3,4-thiadiazole,5- mercapto-1,2,3-triazole or mercaptopyrazine instead of 1-methyl-1H-5-mercapto-tetrazole, (5R)-2-(5'-methyl 1 ',3',4'-thiadiazol-2'-yl-th iomethyl )-2-penem-3-carboxylic acid, (5R)-2-(1 ',2',3'-triazol-5-yl-thiomethyl)-2 penem-3-carboxylic acid, (5R)-2-(pyrazinyl-thiomethyl)-2-penem-3-carboxylic acid, (5R)-6-(1'-hydroxyethyl)- 2-(5"-methyl-1 ",3",4"-thiadiazol-2"-yl-thiomethyl )-2-penem-3-ca rboxyl ic acid, (5R)-6-(1'-hyd roxyethyl)-2- (1 ",2",3"-triazol-5"-yl-thiomethyl)-2-penem-3-carboxylic acid, (5R)-6-(1 '-hydroxyethyl)-2-(pyrazinyl- thiomethyl )-2-penem-3-carboxylic acid were prepared.
Operating as previously described, but reducing the methyl 6-(1 '-hydroxyethyl)-3-penicillinate following the widely known procedure, the corresponding 6-ethyl-derivatives were obtained.

Claims (27)

1. A penem-carboxylic acid or ester of the general formula (1) as herein defined or a pharmaceutically acceptable salt thereof.
2. A penem-carboxylic acid or ester according to claim 1 wherein R" represents an acetoxymethyl, pivaloyloxymethyl or phthalidyl group or a group of the formula -CH(CH3).OCOOC2Hs or -CH2NHCOR2 wherein R2 represents an alkyl group having from 1 to 5 carbon atoms or a cycloalkyl or aryl group.
3. A penem-carboxylic acid or ester according to claim 1 or claim 2 wherein Z represents a group of the formula ORa, OCOR1, NHCOR1 or SR1, wherein R1 represents a 5-methyl-1,3,4-thiadiazol-2-yl, 1-methyl-1 H tetrazol-5-yi,1,2,3-triazol-5-yi or pyrazinyl group.
4. A penem-carboxylic acid or ester according to any preceding claim wherein R' represents a methyl, ethyl, methoxy, l-hydroxyethyl, 1 -(p.nitrobenzyloxycarbonyloxy)-ethyl or 1 -(dimethyl-t.butylsilyloxy)-ethyl group.
5. (5R)-2-Acetoxymethyl-2-penem-3-carboxylic acid.
6. (5R)-2-Acetoxymethyl-6-ethyl-2-penem-3-carboxylic acid.
7. (SR)-2-Acetoxymethyl-6-( 1 '-hyd roxyethyl )-2-penem-3-carboxylic acid.
8. (5R)-2-(1'-Methyl-1'-H-tetrazol-5'-yl-thiomethyl)-2-penem-3-carboxylic acid.
9. (5R)-2-(1 '-Methyl-1 '-H-tetrazol-5'-yl-th iomethyl )-6-ethyl-2-penem-3-carboxylic acid.
10. (5R)-6-(1 '-Hydroxyethyl)-2-( 1 "-m ethyl "-methyl-1 "-H-tetrazol-5"-yl-thiomethyl )-2-penem-3-carboxylic acid.
11. (5R)-2-(5'-Methyl-1 ',3',4'-thiadiazol-2'-yl-thiomethyl )-2-penem-3-carboxylic acid.
12. (5R)-2-(5'-methyl-1',3',4'-thiadiazol-2'-yl-thiomethyl)-6-ethyl-2-penem-3-carboxylicacid.
13. (5R)-6-(1 '-Hydroxyethyl)-2-(5"-methyl-1 ",3",4"-thiadiazol-2"-yl-thiomethyl)-2-penem-3-carboxylic acid.
14. (5R)-2-(1 ',2',3'-Triazol-5'-yl-thiomethyl )-2-penem-3-carboxylic acid.
15. (5R)-2-(1 ',2',3'-Triazol-5'-yl-th iomethyl )-6-ethyl-2-penem-3-carboxylic acid.
16. (5R)-6-(1'-Hydroxyethyl)-2-(1",2",3"-triazol-5"-yl-thiomethyl)-2-penem-3-carboxylicacid.
17. (5R)-6-(1 '-Hydroxyethyl )-2-(pyrazinylthiomethyl )-2-penem-3-carboxylic acid.
18. (5R)-2-(Pyrazinyl-thiomethyl)-2-penem-3-carboxylic acid.
19. (5R)-2-(Pyrazinyl-thiomethyl-6-ethyl-2-penem-3-carboxylic acid.
20. A process for the preparation of a penem-carboxylic acid or ester of the general formula (1) in which n, R' and R" are as herein defined and Z represents a hydrogen or halogen atom, a hydroxy, amino or carbamoyloxy group, or a group of the formula OR1, OCOR1 or NHCOR, wherein R1 is as herein defined, the process comprising condensing, in an inert solvent at elevated temperature, a penicillanic acid S-oxide ester of the general formula (2) as herein defined with an acetylenic compound of the general formula XC CY as herein defined, isomerising the resultant compound of the general formula (3) in basic conditions, converting the resultant azetidinone derivative of the general formula (4) into one of the general formula (11) by the steps of (a) ozonolysis of the 1-substituent of the formula
in solution at reduced temperaturem (b) removal of the 1-substituentoftheformula
resulting from step (a) by mild alkaline hydrolysis or by the action of silica gel, (c) condensation of the 1-unsubstituted azetidinone resulting from step (b) with a glyoxylate of the formula CHO.COOR" as herein defined by refluxing in a solvent, (d) chlorination of the 1-substituent of the formula
introduced in step (c) by the action of a chlorinating agent, (e) conversion of the 1-substituent of the formula
by reaction with triphenylphosphine, (f) reduction of the 4ss-(substituted vinylsulphinyl) group by the action of a reducing agent, and (g) ozonolysis of the double bond of the group of the formula
in solution at reduced temperature, the steps being carried out in the order (a), (b), (c), (d), (e), (f), (g) or (a), (f), (b), (c), (d), (e), (g) or (f), (a) and (g) simultaneously, (b), (c), (d), (e), step (f) being carried out in acidic conditions if carried out after step (e), and cyclising the compound of the general formula (11) by heating it in an inert solvent at from 50"C to 140into obtain a compound of the general formula (1) in which n is 0, and optionally converting that compound to one of the general formula (1) in which n is 1 by oxidation.
21. A process for the preparation of a penem-carboxylic acid or ester of the general formula (1) in which n, R' and R" are as herein defined and Z represents a mercapto or pyridinium group or a group of the formula SR1 wherein R1 is as herein defined, the process being according to claim 20 and further comprising substituting converting the substituent X into a substituent of the formula CH2Z wherein Z is as defined in this claim by a substitution reaction carried out at any stage in the process according to claim 20 after the condensation of the penicillanic acid S-oxide ester of the general formula (2) with the acetylenic compound of the general formula XCCY.
22. A compound having the general formula (9) as herein defined.
23. A compound having the general formula (14) as defined herein.
24. A compound having the general formula (6) as defined herein.
25. A compound having the general formula (4) as defined herein.
26. A compound having the general formula (3) as defined herein.
27. A pharmaceutical composition comprising a penem-carboxylic acid or ester of the general formula (1) as herein defined or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.
GB8005476A 1979-02-24 1980-02-19 3-optionally substituted methyl-2-penem derivatives Expired GB2043639B (en)

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MX9203121A MX9203121A (en) 1979-02-24 1992-06-22 ANTIBACTERIAL AGENTS AND BETA-LACTAMA INHIBITORS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.

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GB7932591 1979-09-20

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DE3245270A1 (en) * 1981-12-11 1983-06-23 Farmitalia Carlo Erba S.p.A., 20159 Milano METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE PENEMAS
GB2133010A (en) * 1983-01-06 1984-07-18 Erba Farmitalia Penem Esters
US4577016A (en) * 1982-04-08 1986-03-18 Farmitalia Carlo Erba S.P.A. Process for the preparation of penem derivatives
US4616007A (en) * 1982-11-16 1986-10-07 Ciba-Geigy Corporation Heterocyclthio compounds, process for their manufacture, pharmaceutical preparations that contain these compounds, and the the use of the latter
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
GB2206578A (en) * 1987-07-07 1989-01-11 Erba Carlo Spa Process for preparing penems
US4965260A (en) * 1987-02-11 1990-10-23 Ciba-Geigy Corporation Bicyclic beta-lactam carboxylic acids
US5364768A (en) * 1987-07-07 1994-11-15 Farmitalia Carlo Erba S.R.L. Process for the preparation of penems
EP1216984A1 (en) * 2000-12-21 2002-06-26 Beacon Laboratories, Inc. Novel acetyloxymethyl esters and methods for using same
US6770759B2 (en) 1997-12-29 2004-08-03 Research Corporation Technologies, Inc. Penicillanic acid derivative compounds and methods of making
US6906054B2 (en) 1999-04-15 2005-06-14 Research Corporation Technologies, Inc. Compositions for inhibiting beta-lactamase
US6916801B2 (en) 2001-07-24 2005-07-12 Alamx, Llc 7-Alkylidene-3-substituted-3-cephem-4-carboxylates as β-lactamase inhibitors
US7022691B2 (en) 2002-04-04 2006-04-04 John D. Buynak Inhibitors of serine and metallo-β-lactamases

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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
DE3277696D1 (en) * 1981-07-15 1987-12-23 Sumitomo Pharma Carboxylic beta-lactam compounds and the preparation thereof
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
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
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

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LU77306A1 (en) * 1977-05-09 1979-01-18
AU3796278A (en) * 1977-07-13 1980-01-17 Glaxo Group Ltd Penams and azetidinones
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
JPS54117459A (en) * 1978-01-20 1979-09-12 Glaxo Group Ltd Novel lactam compound
EP0003960B1 (en) * 1978-02-02 1983-06-29 Ciba-Geigy Ag 6-substituted thia-aza-compounds, their preparation and pharmaceutical compositions containing them
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

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3245270A1 (en) * 1981-12-11 1983-06-23 Farmitalia Carlo Erba S.p.A., 20159 Milano METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE PENEMAS
US4577016A (en) * 1982-04-08 1986-03-18 Farmitalia Carlo Erba S.P.A. Process for the preparation of penem derivatives
US4729990A (en) * 1982-04-08 1988-03-08 Farmitalia Carlo Erba S.P.A. Substituted penem derivatives
US4616007A (en) * 1982-11-16 1986-10-07 Ciba-Geigy Corporation Heterocyclthio compounds, process for their manufacture, pharmaceutical preparations that contain these compounds, and the the use of the latter
GB2133010A (en) * 1983-01-06 1984-07-18 Erba Farmitalia Penem Esters
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
US4965260A (en) * 1987-02-11 1990-10-23 Ciba-Geigy Corporation Bicyclic beta-lactam carboxylic acids
GB2206578B (en) * 1987-07-07 1991-07-03 Erba Carlo Spa Process for the preparation of penems
GB2206578A (en) * 1987-07-07 1989-01-11 Erba Carlo Spa Process for preparing penems
US5364768A (en) * 1987-07-07 1994-11-15 Farmitalia Carlo Erba S.R.L. Process for the preparation of penems
US6770759B2 (en) 1997-12-29 2004-08-03 Research Corporation Technologies, Inc. Penicillanic acid derivative compounds and methods of making
US7125986B2 (en) 1997-12-29 2006-10-24 Southern Methodist University Foundation For Research Penicillanic acid derivative compounds and methods of making
US6906054B2 (en) 1999-04-15 2005-06-14 Research Corporation Technologies, Inc. Compositions for inhibiting beta-lactamase
EP1216984A1 (en) * 2000-12-21 2002-06-26 Beacon Laboratories, Inc. Novel acetyloxymethyl esters and methods for using same
US6699902B2 (en) 2000-12-21 2004-03-02 Beacon Laboratories, Inc. Acetyloxymethyl esters and methods for using the same
US6720445B2 (en) 2000-12-21 2004-04-13 Beacon Laboratories, Inc. Acetyloxymethyl esters and methods for using the same
US6916801B2 (en) 2001-07-24 2005-07-12 Alamx, Llc 7-Alkylidene-3-substituted-3-cephem-4-carboxylates as β-lactamase inhibitors
US7488724B2 (en) 2001-07-24 2009-02-10 Southern Methodist University Foundation For Research 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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CH654831A5 (en) 1986-03-14
CA1154010A (en) 1983-09-20
NL8001012A (en) 1980-08-26
HK74487A (en) 1987-10-23
FI800493A (en) 1980-08-25
ES8200685A1 (en) 1981-11-16
UA6041A1 (en) 1994-12-29
AU535080B2 (en) 1984-03-01
GR73623B (en) 1984-03-26
LU82192A1 (en) 1980-06-06
AT368506B (en) 1982-10-25
PT70849A (en) 1980-03-01
CH651570A5 (en) 1985-09-30
FR2449690B1 (en) 1986-06-13
IT1193922B (en) 1988-08-31
NO161000B (en) 1989-03-13
NL192265B (en) 1996-12-02
FI75163B (en) 1988-01-29
IE49407B1 (en) 1985-10-02
ES488886A0 (en) 1981-11-16
HU182664B (en) 1984-02-28
IE800338L (en) 1980-08-24
DK159448C (en) 1991-03-04
CA1212665B (en) 1986-10-14
AU5567080A (en) 1980-09-11
SE8001424L (en) 1980-08-25
GB2043639B (en) 1983-07-20
DK77580A (en) 1980-08-25
NO161000C (en) 1989-06-21
FR2449690A1 (en) 1980-09-19
ATA91980A (en) 1982-02-15
SE449489B (en) 1987-05-04
NO800501L (en) 1980-08-25
DK159448B (en) 1990-10-15
CS226010B2 (en) 1984-03-19
ES8107224A1 (en) 1981-10-01
YU42964B (en) 1989-02-28
IT8020021A1 (en) 1981-08-19
NL192265C (en) 1997-04-03
YU46180A (en) 1983-02-28
ES495977A0 (en) 1981-10-01
NZ192949A (en) 1984-03-16
FI75163C (en) 1988-05-09
DE3006273A1 (en) 1980-09-04
IT8020021A0 (en) 1980-02-19

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Effective date: 20000218