GB2151630A - The invention provides compounds of the formula i - Google Patents

The invention provides compounds of the formula i Download PDF

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GB2151630A
GB2151630A GB08500841A GB8500841A GB2151630A GB 2151630 A GB2151630 A GB 2151630A GB 08500841 A GB08500841 A GB 08500841A GB 8500841 A GB8500841 A GB 8500841A GB 2151630 A GB2151630 A GB 2151630A
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group
compound
formula
carried out
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GB2151630B (en
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Michael David Cooke
Barry Clive Ross
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Sanofi Aventis UK Holdings Ltd
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Hoechst UK Ltd
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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • C07D205/09—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a sulfur atom directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Description

1 GB 2 151 630A 1
SPECIFICATION
Antibacterial penem derivatives This invention relates to penem derivatives, to a process for their preparation, to pharmaceutical 5 preparations comprising them, and to intermediates for use in the preparation of substances having antibacterial activity and/or fl-lactamase inhibitory and/or inactivating activity.
The term---penem- is used herein to denote the following structure 1 6 2 0- 4 3 The present invention provides a compound of the general formula 1 E 2 0 S CODE in which R represents a hydrogen atom or a carboxyl esterifying group, R' represents a phenyl, naphthyl, thienyl, pyridyl, quinolyl or isoquinolyl group bonded at a ring carbon atom to the oxygen atom attached to the 2-position of the penem ring structure, a group R' being unsubstituted or substituted by one, two or three substituents, which may be the 30 same or different, selected from halogen a-toms and -OH, -NH2, -N02, -CN, NI- R 3 -, RIO-, R 3S_, R3-SO-, R3- S02-, R3-CO, RIO-CO-, R 3-CO -0-, HN-CO-, R3 R3 R3 R3 R3 '1-1, \11 35 N- IT-CO- N-t00-, N-CO-LT11- H R3 R31 R3 E R3 R3 40 N-CONE-, N-CO-0-, N-00-0-, N-CO-0-, RY / 1r/ R3t/ E m / 45 R 3_CO -NH-, NH,-CO-1\11---1-, W-SO-NH-, NHI-SO2-NH-, H,N-SO,-, R3 E3 R3EN R3 50 X-SO 2-NE-9 IT-SO 2-NH-, C = N-, N-SO 2-P RY H 2 K / R3t/ A 149 3 3' 3 55 H 2 N E R.' N N-, C = N-, C = S-, 17-SO 2 - 9 H 2 H a 2 N / R3n / H / 60 CF3, -SCF3, -SOCF3, -S02CF, and HO-CO- groups, in which R 3, R3' and R3" each represents an alkyl group having from 1 to 4 carbon atoms, R3, R 3' and R 3" being the same or different, and R 2 represents a hydrogen atom, or a hydroxyl group which may be protected by a hydroxyl 65 2 GB 2 151 630A 2 protecting group.
The invention also provides salts of a compound of formula 1, especially physiologically tolerable salts thereof.
The stereochemistry at positions 5, 6 and, when R 2 represents a hydroxyl group, at position 8, can be R or S independently (R and S being as defined by the Cahn- ingold-Prelog system of 5 nomenclature). The preferred stereochemistry at position 5 is R. When R' is a hydroxyl or protected hydroxyl group, the stereochemistry is preferably S at position 6 and R at position 8.
The invention further provides a process for the production of a compound of the general formula 1 or a salt thereof, which comprises reacting a compound of the general formula 11 R4 H3 - C' 15 12 R N SCOR5 7,J, -- K ', COOR 20 in which R, R' and R are as defined above R 4 represents a chlorine or bromine atom, and R5 represents an alkyl group having from 1 to 4 carbon atoms, or a phenyl group, with a base and, if desired, carrying out any one or more of the following steps in any desired order:
(a) converting an ester of formula 1 into the corresponding free acid, (b) converting a free acid of formula 1 into an ester thereof, (c) transesterifying a compound of formula 1, (d) converting a free acid or an ester of formula 1 into a salt, or a salt into the free acid, an ester, or another salt, (e) removing any protective groups present other than an esterifying group R, (f) converting a substituent of a group R' into another substituent of R'.
(9) converting a free hydroxy group R 2 into a hydroxy group protected by a group removable 35 physiologically, or converting a hydroxy group R 2 that is not removable physiologically into a hydroxy group protected by a group that is removable physiologically.
Protective groups for hydroxy groups are well known, and these and other protective groups are described below.
The term -lower- as used herein denotes a molecule, group or radical having up to 4 carbon 40 atoms. Unless stated otherwise, halogen atoms are fluorine, chlorine, bromine and iodine atoms.
The term -known- means in actual use in the art or described in the literature of the art.
R' may represent, for example, an unsubstituted phenyl group or a phenyl group substituted by a chlorine or fluorine atom or by a hydroxy, trifluoromethy], methyl, methoxy, acetoxy, nitro, cyano, amino, methylthio, methyisulphinyi, methyisulphonyl, methylcarbonylamino, methyisul- 45 phonylamino or methylaminocarbonylamino group, especially a cyano, hydroxy, acetoxy, methyl sulphinyl or methyisulphonyl group. R' may also represent a phenyl group substituted by more than one group, for example, by two or three methyl or methoxy groups. A heterocyclic group R' may also carry up to three substituents, for example, one or two methyl groups, preferably at ring carbon atoms.
It will be appreciated that the choice of substituents for R' may be subject to considerations of stereochemistry and also of possible interactions between the substituents themselves and other parts of a molecule in which R' is present, for example, R' may have 1, 2 or 3 substituents, but not more than one should be selected from (a) -OH and -NH2 groups and not more than one should be selected from (b) -CN, -N02, R 3-CO-, R30-CO-, R3-SO- and R 3 -S02- groups.
(Other substituents may, of course, be present on R' in addition to a group selected from (a) and/or a group selected from (b).) The expert will be aware of any restrictions on the choice of substituents, as such restrictions 60 are known in the art.
An esterified carboxyl group -COOR is, for example, an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryi, araliphatic, heterocyclic or heterocyclic-aliphatic alcohol having up to- 20 carbon atoms or is, for example, a silyl or stannyl ester.
GB 2 151 630A 3 An aliphatic group R is, for example a straight or branched chain substituted or unsubstituted alkyl, alkenyl or alkynyl group having up to 18 carbon atoms, preferably up to 8 carbon atoms, and especially up to 4 carbon atoms, for example, a methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, isobutyl, tert-butyl, r-pentyi, n-hexyi, allyl, or vinyl group.
An aliphatic group R, especially a methyl group, may be substituted by a cycloalkyl, aryl or 5 heterocyclic group, for example, a pyridyimethyl groups, or R may itself represent a cycloalky], aryl or heterocyclic group.
A cycloaliphatic group R may have up to 18 carbon atoms and is, for example, a cyclopentyl, cyclohexyl or adamantyl group. An aryl group R may have up to 12 carbon atoms and may have two or more fused rings. An aryl group R is, for example, an unsubstituted or substituted 10 phenyl group, and an unsubstituted or substituted aralkyl group is, for example, a benzyi, p nitrobenzyl or benzhydry] group.
A heterocyclic group R may have one or more, preferably one to three, heteroatoms, which may be the same or different, selected from oxygen, nitrogen and sulphur, and up to 14 atoms in total. A heterocyclic group is, for example, an oxygen-containing heterocyclic group, for 15 example, a tetrahydropyranyl or phthalidyl group.
A stannyl group R may have up to 24 carbon atoms, for example, R may represent a stannyl group having three substituents, which may be the same or different, selected from alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy and aralkoxy groups, for example, alkyl groups having up to 4 carbon atoms, for example, n-butyl groups, phenyl and benzyl groups, especially three 20 ri-butyl groups.
A silyl group R has three substituents on the silicon atom and preferably up to 24 carbon atoms in total. The three substituents may be the same or different, and selected from alky], alkenyi, cycloalkyl, aryl and aralkyl groups, preferably selected from alkyl groups having up to 4 carbon atoms and phenyl groups, especially selected from methyl, t-butyl and phenyl groups.
Preferred silyl groups are trimethyisily], d i phenyl- t-butylsi lyi, and d i methyl- t-b utylsi lyl groups.
Any group R that is capable of substitution may be substituted. Examples of substituents are halogen atoms; HO-, RIO-, R3-CO-, RIO-CO-, R'S-CO-, R3-CO-0-, R 3-CO-S-, H,N-CO-, H,N-CO-0-, F.3 R a3 j R3 _N R3 N-CO-Cl-, -NO 2' _CN' ' 3'. _CC_IZE_, R3_Co_N R3 R3_So_o R3_SO 2-P Ar A= AT fi. E',-, __1 11-, R3--- p31 9 R3 11 R'-S02-NH-, Ar, ArO-, ArO-CO-, ArS-CO, Ar-CO-0-, Ar-CO-S-, Ar-R 30_CO_' Ar-R 3S-CO -, Ar-R3-CO-O -, Ar-R 3-CO-S -, Ar-R30-, Ar-RIS-, in which R' and R3' are as defined above, and Ar denotes an aryl group, especially a phenyl group; aromatic and nonaromatic heterocyclic groups, for example, having one or more heteroatoms, for example, up to 3 heteroatoms, which may be the same or different, selected from nitrogen, oxygen and sulphur atoms, and preferably up to 14 atoms in total, and the corresponding heterocyclicoxy groups and heterocyclicthio groups. When R represents other than an aliphatic group, a further possible substituent is a lower alkyl group.
The group R may be removable by hydrolysis, by photolysis, by reduction or by enzyme action to give the free acid, or two or more methods may be used, for example, reduction followed by hydrolysis. A group R that may be removed readily without substantial degradation of the rest of the molecule is particularly useful as a carboxyl protecting group. Examples of esters that are readily split by reduction are aryimethyl esters, for example, benzyi, p-nitrobenzyi, 65 4 GB 2 151 630A 4 benzhydryl and trityl esters. Reduction of an ester, for example, an aryimethyl ester, may be carried out using hydrogen and a metal catalyst, for example, a noble metal, for example, platinum, palladium or rhodium, which catalyst may be supported, for example on charcoal or kieselguhr.
Alternatively, a p-nitrobenzyl ester may be converted to the free acid by a two-step method, with an initial reduction of the nitro group, followed by hydrolysis. The nitro group may be reduced by noble metal catalysed hydrogenation, for example, using platinum, or palladium on carbon, or by a metal reducing agent, for example, zinc in acetic acid. Other metal reducing agents are, for example, aluminium amalgam, and iron and ammonium chloride, see, for example, British Patent Specification No. 1,582,960. Reduction of the nitro group is followed 10 by hydrolysis which may occur in situ during reduction of the nitro group or which may be carried out subsequently by treatment with an acid or a base. An 0-nitrobenzyl ester may be converted to the free acid by photolysis.
A stannyl ester, for example, a tri-n-butyl stannyl ester, may be split readily by hydrolysis, for example, by solvolysis, for example, using water, an alcohol, a phenol or a carboxylic acid, for 15 example, acetic acid.
Certain ester groups may be split off by base hydrolysis, for example, acetyimethyl and acetoxymethyl ester groups.
There may be used an esterifying group that is removable under physiological conditions, that is to say, the esterifying group is split off in vivo to give the free acid or the carboxylate, for 20 example, an acyloxymethyl ester, e.g. an acetoxymethyl or pivaloyloxymethyl ester, an aminoal kanoyloxymethyl ester, for example, an L-glycyloxymethyl, Lvalyloxymethyl or L-leucyloxymethyl ester, or a phthalidyl ester, or an optionally substituted 2-aminoethyl ester, for example, a 2 cliethylaminoethyl or 2-(1-morpholino)-ethyl ester.
Preferred esters are the p-nitrobenzyi, phthalidyl, p iva loyloxy methyl, acetyimethyl and acetoxy- 25 methyl esters.
An ester of formula 1, or of any other free acid described herein, may be prepared by reaction with an alcohol, phenol or stannanol, or a reactive derivative thereof. The reaction is preferably carried out under mild conditions in order to prevent rupture of the ring or ring system, for example, under neutral or mild acidic or basic conditions, and at temperatures within the range 30 of from - 70' to + WC.
An alkyl, alkoxyalkyl or aralkyl ester may be prepared by reaction of an acid of formula 1 or any other free acid with the appropriate diazoalkane or diazoaralkane for example, diazomethane or diphenyidiazomethane. The reaction is preferably carried out in an ether, ester or halogenhy drocarbon as solvent, for example, in diethyl ether, ethyl acetate or d ich loro methane. In general, 35 temperatures below room temperature are preferred, for example, from - 15' to + 1 WC.
An ester derived from an alcohol may also be produced by reaction of a reactive derivative of the alcohol, for example, a halide, for example a chloride, bromide or iodide, or a hydrocarbon sulphonyl derivative, for example, a mesyl or tosyl ester, with a salt of an acid of formula 1 or another free acid described herein for example, an alkali or alkaline earth metal salt, for example, a lithium, sodium, potassium, calcium or barium salt or an amine salt, for example, a triethylammonium salt. This reaction is preferably carried out in a substituted sulphoride or amide solvent for example, in dimethyl sulphoxide, dimethylformamide or hexamethylphospho ramide or, alternatively, an ester may be prepared by reaction of the acid with the alcohol in the presence of a condensing agent, for example, dicyclohexylcarbodiimide.
A stannyl ester may be formed by reaction of a carboxylic acid of formula 1 or another free acid described herein, or a salt thereof with a reactive tetravalent tin compound, especially a trialkyl tin oxide.
The present invention also provides the salts of those compounds of formula 1 that have salt forming groups, especially the salts of free acids of formula 1 and the acid addition salts of compounds of formula 1 having a basic group. The salts are especially physiologically tolerable salts, for example, alkali metal and alkaline earth metal salts, for example, sodium, potassium, lithium, calcium and magnesium salts, ammonium salts and salts with an organic amine; also physiologically tolerable acid addition salts. These may be formed, with suitable inorganic and organic acids, for example, hydrochloric acid, sulphuric acid, organic carboxylic and organic sulphonic acids, for example, trifluoroacetic acid and p-toluene- sulphonic acid. Some com pounds of formula 1 which contain a basic centre may exist as Zwitterions; such salts are also part of this invention.
A salt of a free acid of formula 1 may be produced by reacting the free acid with the appropriate base in a solvent, preferably under conditions under which the salt precipitates. A 60 preferred base is potassium ethyl hexanoate.
A salt may be produced directly from an ester by splitting off the ester group under suitable reaction conditions, for example, catalytic reduction of an ester, for example, a P-nitrobenzyi ester, in an aqueous/organic solvent, for example, comprising water and ethyl acetate, dioxane, nr tetrahydrofuran, in the presence of a metal salt, especially a bicarbonate, for example, in an 65 GB 2 151 630A 5 equivalent amount or in a slight excess, yields a salt directly.
Compounds of the general formula 1 may be produced, for example, as shown in the reaction scheme below.
5 H Y H SR' ctl,- CH J3 14 CH3-CH C113-CE 12 h R, 2 0 R12 10 R _3 2 1 Ivg N 0 0 0j- CE 2 VI v IV COOR 15 CH- CH H SR6 CF13 M- H SR 6 20 2 OR 9COR5 S OR5(when R c / 1) 0 1 it M.
c c = c 1 "1,-, OR, 1 1,1 1 25 Vova coon OR XI 1 III H R4 Cd CE C-t - CIP3 SCOR5 R -9 SCOR 35 Os 0 c - C 1 1 OR COOR OR WOFL 40 XII CH3 - CIE2 A\ OR1 /L 0 COOR 1 in which R, W, R2, R4 and R5 are as defined above, R 2 represents a hydroxyl protecting group, R' is defined below, and Y represents a group that is capable of being replaced by a nucteophilic group and is especially an acyloxy group, a sulphonyl group, or a halogen atom. An acyloxy group is especially a lower alkylearbonyloxy group, in particular an acetoxy group. A halogen atom is especially a chlorine atom. A sulphonyl group is a group - SO,R in which R 7 60 represents an alkyl group having from 1 to 4 carbon atoms, or an aryl group, especially a phenyl group.
A compound of formula V1 in which R' represents a hydrogen atom may be prepared as described in Liebigs Annalen Chemie 1974, pp 539-560, Claus, Grimm and Prossel, DT-OS 1 906 401, UK Specification No. 2 013 674, Chem. Pharm. Pharm. Bull, 29 (7) 1854, or H.R.65
6 GB 2 151 630A 6 Pfaendier, J. Gosteli and R.B. Woodward, J.A.C.S. 102:6, 1980, 2039-2043, and certain compounds in which R2 represents a modified hydroxyi group may be prepared as described in Belgian Patent Specification No. 882 764 (R 2 represents a dim ethyl- t- butyisi lyfoxy group), and
E. P.A. 2210 (R 2 represens a p-nitrobenzyioxycarbonytoxy group).
A compound of formula VI may be converted into a compound of formula V by reaction with 5 a compound of formula VII W-S-R6 VIl in which R6 represents an alkyi group having from 1 to 8, preferably from 1 to 4 carbon atoms, 10 an alkenyl group having up to 4 carbon atoms, or a phenyl group, and W, represents a hydrogen atom or an alkali metal atom, especially a sodium or potassium atom. R6 preferably represents an allyl group or a straight chain, lower alkyl group, especially an ethyl group.
The reaction is generally carried out in a solvent, preferably a protic solvent, for example, water or an alcohol, or a non-protic, water-miscible solvent which is preferably polar, for example, dimethylformamide, dimethyl sulphoxide, tetrahydrofuran or dioxan. The reaction temperature is, for example, from - 20 to + 50, preferably from - 10 to + 2WC.
To obtain a compound of formula IV, a compound of formula V may be reacted, in the presence of a base, with a compound of formula Vill Y1CH2CO,R Vill in which R is as defined above and Y1 represents a group that is capable of being replaced by a nucleophilic group and is, for example, a halogen atom, preferably a bromine or iodine atom, or a modified hydroxy group, 25 preferably a sulphonyloxy group of the formula -OSO2R9 in which R9 represents a lower alkyl or -CF3 group, or a phenyl group which is unsubstituted or is substituted by a P-nitro, p-bromo or p-methyl group.
Y1 preferably represents a bromine or iodine atom or a methyisu 1 phonate, trifluoromethyisul phonate, tolyisulphonate or benzenesu]phonate group.
The base may be inorganic, organic or organometallic, for example, an alkali metal or alkaline 35 earth metal hydroxide, oxide, carbonate, bicarbonate or hydride, for example, sodium hydroxide, magnesium oxide, potassium carbonate, potassium bicarbonate or sodium hydride; a tertiary amine, for example, a trialkylarnine, for example, triethylamine, DABCO (diazabicyclo(2,2,2)oc tant), pyridine, or an alkyl-substituted or amino-substituted or dialkylamino-substituted pyridine, for example, N,N-dimethylaminopyridine, or collidine; a guanidine, for example, tetramethylgu- 40 anidine; DBN (diazabicyclo[4,3,0]non-5-ene) or DBU (diazabicyclo[5,4, 0]undec-7-ene); a poly meric base i.e. a base attached to an inert polymeric support e.g. H(inig's base (diisopropylethy lamine attached to e.g. polystyrene); a metallated amine, for example, a metallated alkyl or arylamine, for example, lithium diisopropylamide (LDA), lithium hexamethyidisilazide, lithium piperidicle, lithium 2,2,6, 6-tetra methyl pi peridid e, or a Grignard reagent, for example, methyl45 magnesium bromide. Preferred bases are, for example, potassium carbonate, sodium hydride, lithium diisopropylamide and triethylamine.
The reaction is generally carried out in an aprotic solvent or diluent, for example, a tertiary amide, for example, dimethylformamide, dimethylacetamide or hexamethylphosphoramide; a hydrocarbon, for example, benzene or toluene; or an ether, for example, diethyl ether, tetrahydrofuran or dioxane; a chlorinated hydrocarbon, for example, methylene chloride or chloroform; or acetonitrile, dimethyl sulphoxide, or sulpholane. Dimethylformamide and dimethylacetamide are preferred. A mixture of two or more solvents and/or diluents may be used.
The reaction may be carried out at a temperature generally within the range of from - 80C to + WC preferably from - 40 to + WC, and especially from - 20 to + 2WC.
From 1 to 1.5 njoles of compound VIII are preferably used per mole of compound V, especially from 1 to 1.1 moles of VIII per mole of V. The base is used in an amount for example, from 1 to 4 moles of base per mole of compound V.
The reaction is preferably carried out by dissolving compound V in a solvent, advantageously in dimethylformamide, with stirring, adding the base, adding the compound of formula VIII and 60 reacting at the desired temperature. The resulting compound of formula W may be worked up and isolated in the usual manner, for example, using chromatographic and/or crystallisation techniques, or the subsequent reaction may be carried out directly on the resulting reaction mixture after removal of any solvent that is not compatible with the subsequent reaction.
If R in formula W represents a carboxyl esterifying group, this group may be converted into 65 7 GB 2 151 630A another esterifying group R, for example, to introduce a group R that is more easily removable under desired conditions. This transesterification is generally carried out as follows: the ester of formula W is hydrolysed in known manner using, for example, acid or alkaline hydrolysis, preferably using an alkali metal hydroxide, especially sodium or potassium hydroxide. The ester of formula W, for example, a methyl ester, is preferably hydrolysed using an alkali metal hydroxide especially one mole thereof per mole of the ester of formula IV in a solvent, for example ethanol, methanol or water, or an aqueous-organic solvent, for example, tetrahydrofuran/water, ethanol/water, or acetonitrile/water.
The reaction mixture may then be acidified to give a solution of pH 1 to 5, preferably 2 to 4, and the free acid may then be isolated and, if desired, the free acid is then esterified with an 10 esterifying agent capable of introducing a different esterifying group R, for example with an alcohol ROH in the presence of an acid or another activating agent, for example, dicyclohexylcarbodiimide, or with an alkylating agent RY1 in which Y1 is as defined above. Alternatively, a salt may be isolated and esterified directly. Esterification methods are described above in relation to the compound of formula 1.
Transesterification may be carried out on compound IV as described above, or on any other intermediate or on the final product of formula 1.
A compound of formula IV may be converted into a compound of formula Ill by reaction, in the presence of a base, with a compound of formula IX S 11 Cl-C-OR' IX in which R' is as defined above, followed by reaction with an activated carboxylic acid derivative 25 which comprises the group R5, for example, a compound of formula X 0 11 R5-C-Cl X in which R5 is as defined above.
Some compounds of formula IX are known and some are new. New compounds may be prepared by processes analogous to those for the preparation of the known compounds. cf.
River & Schalch, Heiv. Chem. Acta, Vol 6, 1923, p.605, and Reich & Martin, Chern Berichte, 35 Vol 98, 1965 p.2063.
The reaction between compound IX and compound IV is carried out in the presence of a base, preferably having a pK,:_:-20, preferably a metallated amine, and examples of preferred bases are lithium diisopropylamide, lithium hexamethyidisilazide, lithium 6,6,2,2- tetramethylpiperidide, lithium cyclohexyl isopropylamide, and sodamide.
The reaction is generally carried out in an aprotic solvent, for example, an oxygenated hydrocarbon, preferably an ether, for example, diethyl ether, tetrahydrofuran, dioxane, glyme br didlyme. The reaction temperature is, for example, from - 120 to + WC, preferably from - 78 to 20T.
The amount of base used is, for example, from 1 to 3 moles, calculated per mole of compound W, preferably from 1,5 to 2.5 moles of base. The compound of formula IX is preferably used in an amount of from 1 to 1.5 moles per mole of compound IV, preferably from 1 to 1.1 moles of compound IX.
The reaction is preferably carried out as follows: to a stirred solution of compound IV under an inert atmosphere is added the base and subsequently a solution of compound fX in the same or 50 a different solvent.
The activated acid derivative, preferably of formula X, is preferably added to the mixture resulting from the reaction of compounds IV and IX especially in an amount of from 1 to 2 moles calculated on compound IV. The reaction is preferably carried out at a temperaturr. of from - 80 to + 4WC, adding the compound of formula X to the reaction mixture at the temperature at which the reaction between compounds IV and IX took place, and then warming, or allowing the mixture to warm, to room temperature, if desired, heating the mixture to a temperature of up to 4WC.
The -SCOR1 group in the resulting compound of formula Ill may be cis or trans to the -COOR group. The isomers may be separated for the subsequent reaction, but this is not 60 generally necessary, and the isomeric mixture is generally used.
It is preferable to protect a free hydroxy group R' before the formation of compound Ill, to prevent the free hydroxy group from reacting with the compound of formula IX and/or with the activated carboxylic acid derivative. The protective group may be introduced into compound IV before its conversion into compound Ill, or it may be introduced at an earlier stage in the 65 8 GB 2 151 630A 8 reaction sequence eg. in compound V or V1 A compound of formula Ii may be produced from a compound of formula Ill directly by halogenation.
The halogenation is carried out with an agent capable of splitting a carbon-sulphur bond and introducing a halogen atom. Such agents are well known in the art and include, for example, 5 molecular chlorine, molecular bromine, sulphuryl chloride, sulphuryl bromide, t-butyihydrochlor ite and cyanogen chloride.
The reaction is generally carried out at a temperature within the range of from - 40 to + 2WC. The reaction is generally carried out in a solvent or diluent, that is non-protic and is inert under the reaction conditions, for example, an ether, a hydrocarbon or a halogenated hydrocarbon, for example, dioxane, benzene, chloroform or methylene chloride. A mixture of two or more solvents may be used. Examples of halogenating systems are: chlorine in chloroform and, especially, chlorine in benzene and t-butyihypochlorite in benzene. In the latter two cases, the temperature is preferably from 5 to 20', and especially from 5 to 1 O'C.
Generally 1 to 2 moles of chlorine, bromine or cyanogen bromide are used per mole of compound Ill. (cf. S. Kuko1ja J. Amer. Chem. Soc. (1971), 93 6267, and P. C. Cherry, C.E.
Newall and N.S. Watson, J.C.S. Chem. Comm. 1979 p. 663.) Before halogenation, however, it is preferable to remove the protective group R2 from a hydroxy group R 2 in a 3S-compound Ill, in order to obtain the most desired 5R stereochemistry in the final product. The protective group may be removed in any conventional manner (see below) to give compound Xl. Preferred hydroxy-protecting groups R,2 are those which are compatible with the synthesis of the compound of formula ill and which may be removed under reaction conditions in which the resulting compound X] is stable. Compound XI has been found to be stable in the presence of a proton source, for example, hydrogen chloride, aqueous hydrochloric acid or aqueous hydrofluoric acid. Accordingly, one type of preferred hydroxy protecting groups R2 are those which may be removed under acidic conditions. Such groups are a well known in the art and are, for example, tetra hyd ropyra nyl and tetrahydrofuranyl groups; acetal and ketal groups, for example, of formula - C -OWO R11 R12 in which W' and R 12, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, preferably a methyl group, or W' and R 12 together with the carbon atom to 35 which they are attached, represent a cycloalkyl ring having from 4 to 7 carbon atoms, or a tetra hydropyra nyl ring, and RIO represents a lower alkyl group, preferably a methyl or ethyl group; also silyl esters, for example, as described above in relation to R, for example, -SiRl3R 14 R 15 groups, in which W', R and R15, which may be the same or different, each represents a lower alkyl group or an aryl group, for example, triethyisilyl, t-butyidimethyisilyl and 40 methyidiphenyisilyl groups; and stannyl groups, for example, as describedabove in relation to R, for example, -SnR 16 RI7R18 groups, in which R16, R 17 and R18, which may be the same or different, each represents a lower alkyl group, for example, a tri-n- butylstannyl group. Preferred R 2 groups are tetra hyd ropyra ny], 2-methoxypro-2-yL trimethyisiiyl, triethylsilyl and, especially, t a butyidimethyisilyl groups.
Such groups may be removed by acid hydrolysis, for example, using moderately concentrated hydrochloric acid, eg. 6M HCI, eg. in tetrahydrofuran (cf. Belgian Patent Specification No. 881
012); t-Bu,NF in an acidic medium eg. in acetic acid (cf. Belgian Patent Specification No. 882
764): or aqueous hydrogen fluoride, eg. in the presence of acetonitrile (cf. J. Chem. Soc. Perkin 1, 1981, 2055).
The halogenation of compound XI to give compound Xii may be carried out substantially as described above. The halogenating agent is generally used in an amount of from 1 to 2 mole equivalents, calculated on the compound of formula X].
It has been found, surprisingly, that halogenation of a compound of formula X] that has 4R stereochemistry gives predominantly the corresponding 4S compound of formula XII, whereas 55 halogenation of the corresponding 4R compound of formula Ill having a protected hydroxy group R 2 gives predominantly the less desired 4R halogerated compound.
A compound of formula 1 is produced from a compound of formula 11 or XII by reaction with a base. The base must be capable of splitting the thiocarbonyl bond in a compound of formula 11 or formula XII and of bringing about ring closure. The base may be inorganic or organic, for example, ammonia, or an alkali metal, especially a sodium or potassium, carbonate, bicarbo nate, or hydroxide; a primary amine, for example, methylamine, ethylamine, aniline or benzylamine; an alkali metal alkoxide in the corresponding alcohol, for example, sodium methoxide in methanol; or a heterocyclic base, for example, having a pK. within the range of from 5 to 9, for example, imidazole or pyridine or a substituted pyridine, for example, an alkyl, 65 9 GB 2 151 630A 9 amino, or alkylamino-substituted pyridine, for example, 4-methyl-, or 4dimethylaminopyridine.
Imidazole is particularly preferred.
The reaction is generally carried out in a solvent or diluent, the choice of which is wide, provided that it is inert under the reaction conditions. Examples of solvents and diluents are oxygenated hydrocarbons, for example, alcohols, for example, having up to 4 carbon atoms, for 5 example, methanol and ethanol; ethers, for example having up to 4 carbon atoms, for example, diethyl ether, also tetrahydrofuran and dioxane; ketones, for example, having up to 4 carbon atoms, for example, acetone and methyl ethyl ketone; esters, for example, methyl acetate and ethyl acetate; and amides, for example, dimethylformamide and dimethylacetamide; also chlorinated hydrocarbons, for example, chloroform, methylene chloride and carbon tetrachloride; 10 aromatic hydrocarbons, for example, benzene and toluene; and other solvents for example, acetonitrile and nitromethane. A mixture of any two or more solvents may be used, and solvents are preferably used in admixture with water, preferably a water-miscible solvent in admixture with 5 to 20% (v/v) water.
The reaction is generally carried out at a temperature within the range of from 0 to 4WC, 15 preferably from 0 to 2WC.
It is preferable to esterify any free carboxyl group present in a compound of formula 11 or formula XII prior to conversion to a compound of formula 1. Although an ester group may be introduced immediately prior to this conversion, it is preferable to esterify the carboxyl group at an earlier stage in the preferred reaction sequence, for example, to esterify a free carboxyl group 20 in a compound of formula Ill, W or X11 to ensure that the carboxyl group does not take part in any of the subsequent reactions. An esterifying group may be transesterified to another ester group having more desirable properties for a particular stage of the reaction sequence.
Furthermore, it is advisable to protect any reactive moiety present in either R or R' so that such a moiety does not react with any of the reagents used in any subsequent reaction. Examples of moieties which may require protection are hydroxy, carboxy and amine moieties which may, for example react with the reagents used to convert a compound IV to a compound Ill. Groups suitable for protecting such reactive moieties are well known, as are methods for their removal. (cf. Protective Groups in Organic Chemistry, editor J.F.M McOmie, Plenum Press, 19 7 3). (The special considerations with regard to a free hydroxy group R 2 are given above.) Hydroxy-protecting groups are exemplified above.
Carboxy-protecting groups are, for example, as described above for R. Amino protecting groups are, for example, t-butyloxycarbonyl, benzyloxycarbonyl, p-nitrobenzyioxycarbonyi, p- n itrobenzenesu 1 phenyl and trityl groups.
Reactive moieties may be protected at any appropriate point in the reaction sequence, and the protective groups are preferably removed after the formation of the compound of formula 1, for example, if R in formula 1 represents an esterifying group, this may be removed in the usual manner, depending on the nature of the ester group, for example, by hydrolysis, reduction, or enzymatically, to yield the free acid. A free acid or an ester may be converted into a salt, 40 especially a physiologically tolerable salt, or a salt may be converted into another salt or the free acid or an ester. An ester may be transesterified, or a free acid converted into an ester, for example, to give an ester capable of removal under physiological conditions. Examples of such procedures are given above.
If R 2 in a compound of formula 1 represents a protected hydroxy group, the protecting group may be removed. Conversely, if R2 represents a free hydroxy group, this may be converted into a protected hydroxy group, especially one in which the protecting group is physiologically removable, for example, a group of the formula WICO- or R 20 in which W9 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms, especially a methyl, ethyl or t-butyl group, or represents a phenyl group or a phenoxyalkyl group in which the alkyl moiety is straight- chained or branched and has up to 4 carbon atoms, and is especially a methyl group; and RIO represents an alkanoyloxyme- 55 thy] group in which the alkane moiety is a straight or branched chain alkyl group having up to 4 carbon atoms, and is especially a methyl or t-butyl group. Preferred physiologically removable protecting groups for a hydroxy group R' are acetyl, propionyl, pivaloyl, benzoyi, phenoxyme thylcarbonyl, piva loyloxy methyl and acetoxymethyl groups. In a compound of formula 1, a hydroxy protecting group that is not removable under physiological conditions may be converted 60 into one that is removable under such conditions. An advantage of physiologically removable protecting groups is that they appear to increase the oral absorbability of the compounds of formula 1.
The invention also provides a modification of the process described above, wherein in a compound of formula 1, 11, Ill, XI or XII or in more than one of these compounds, a substituent 65 GB 2 151 630A 10 of a group R' is converted at an appropriate point in the reaction sequence into another substituent of W. A substituent of R' in compound Ill, for example, may be converted into another substituent of R' before the halogenation reaction to give compound 11, or the initial substituent of R' may be retained during the halogenation reaction, being converted into 5 another substituent of R' before the reaction of compound 11 to give compound 1.
The following are examples of interconversions of substituents of W: R3Sto R3SO_ R3S- or RISO- to R3SO,NO,- to NH,-, which may then be alkylated or acrylated, -CN to -CH,NH, -dittoN3 to NH.,-, -dittoHO- may be alkylated or acylated R3CO-O to HO-, which may then be alkylated or acylated Halogen to -SH, - SO,H, -SO,H or -CN, W' being as defined above.
The methods for carrying out such reactions are known in the art, for example, an alky[thio group may be oxidised, preferably with a carboxylic peracid, especially rr-chloroperbenzoic acid, to give the corresponding alkylsulphinyl or alkylsulphony; group; a nitro group may be reduced to an amino group by noble metal catalysed hydrogenation, for example, using platinum, or 10% palladium on carbon, c.f. M. Freifelder, Catalytic Hydrogenation in Organic Synthesis, Willey Interscience, 1978, page 26, and P.N. Rylander, Catalytic Hydrogenation over Platinum Metals, Academic Press, 1967, Chapter 111; an amino group may be alkylated with a conventional alkylating agent, for example, a lower alkyl halide, for example, methyl iodide, or acylated with, for example, an acid chloride or acid anhydride, for example, acetyl chloride or acetic anhydride, a cyano group may be converted into an amino group by reduction, for example, using a metal hydride; an azide group may be converted into an amino group by reduction, for example, using hydrogen sulphide or catalytic reduction; a hydroxy group may be alkylated or acylated as described above; and a halide, especially an iodide, may be treated with an organometallic compound, for example, an organolithium compound, especially tbutyllithium, the resulting complex being treated with sulphur, sulphur dioxide or cyanogen to give the 30 -SH, -SO,H or -CN group, respectively.
These modifications of the process of the invention are particularly useful for the production of a compound of formula 1 having a group R' bearing 1, 2 or 3 substituents, any one or more of which is potentially unstable or incompatible during any one or more of the stages of the reaction sequence described above. The conversion step is, accordingly, carried out after the 35 step in which the substituent is potentially unstable or incompatible.
It will be appreciated that although these modifications are particularly useful for the production of compounds of formula 1 having substituents on R' that are potentially unstable in the production process, it is not limited to such groups, and in a further modification of the process of the invention, a substituent of R' may be produced by conversion of another substituent that does not itself fall within the definition of a substituent of W, for example, an unsubstituted or substituted, preferably p-nitrosubstituted, benzyioxycarbonylamino group may be converted into a free amino group, for example, by noble metal catalysed hydrogenation, c.f.
M. Freifelder, loc. sit., page 111, P.N. Rylander, loc. cit., page 455, and C. Berse et al, J. Org.
Chem. 22, 805, 1957.
At each stage of the preferred reaction sequence, the desired compound may be isolated from the reaction mixture and, if desired, purified by appropriate techniques generally used for the purification of organic compounds, for example, chromatography or crystallisation.
As indicated above, various intermediates may be produced in the form of mixture of isomers of various kinds. Such a mixture may be separated or resolved at any stage, or the isomeric 50 mixture may be used per se for subsequent reactions. (in the case where a protective groups R 2 has been removed before halogenation, a resulting compound of formula XII is preferably separated into the 4R and 4S isomers (see below)).
All of the compounds that are provided by the invention may exist in any isomeric form, as discussed above, either as a pure isomer or as a mixture of any two or more isomers.
A compound of formula 1 may have the R- or S-stereochemistry independently at positions 5 and 6, and also at position 8 when R2 represents a hydroxy or protected hydroxy group. Further isomeric forms will occur when any substituent contains a chiral carbon atom. Any mixture of two or more isomeric forms may be resolved if desired, or a compound of formula 1 can be used in the form of the isomeric mixture. The preferred stereochemistry at position 5 in compound 1 60 is generally R, corresponding to that in naturally occurring penicillins and cephalosporins, at position 6 is S, and at position 8 is R.
If a 3S-compound of formula Ill in which R 2 represents a protected hydroxy group is converted into a compound Xl before halogenation, ie. if the protecting group is removed before halogenation, it has been found that the resulting compound of formula 1 is predominantly the 65 GB 2 151 630A 11 desired 5R, 6S isomer. The following reaction scheme illustrates the stereochemistry, R, R', R2, R4 and R5 being defined as above.
OR2 a c c 4R SOH 2 CE 3 0 COOR ",5001L5 11 H on "I CE3-0 '." 4R SCH2CE3 OR 1:"E 0 COOR 11 1 OE E OE 15 , 1 4 CE3 4:75 OR1 ORI 20 0/ COOR z SCOR5 1 ill Halogenation of the 4R compound of formula M gives predominantly the 4S compound of formula XII. The proportion 4S:4R compound XII depends on the halogenating agent used and the reaction conditions, but in general varies from 3:1 to amounts as high as 9A. The 4R and 4S isomers can be separated readily, for example, by chromatography. A compound of formula XI also has E/Z isomerism at the double bond, so the 4R and 4S isomers may be further separated into the individual E and Z isomers. This is not generally necessary, but the 4R and 30 4S isomers are preferably separated before conversion into a compound of formula 1. As can be seen from the reaction scheme, a 4S compound XII is converted by reaction with a base into a 5R compound 1. If, however, a 3S-compound of formula Ill having a protected hydroxy group R' is halogenated directly, the resulting compound 11 is 4R, and the resulting compound 1 is 5S.
As the preferred stereochemistry at position 5 is R, it will be appreciated that it is preferable to 35 deprotect before halogenation.
The compounds of formula 1 and salts thereof are fl-lactarnase inhibitors, and the compounds are generally stable to the action of fl-lactamases produced by gram- positive organisms, for example, by Staphylococcus aureus and gram negative organisms, for example, Enterobacter cloacae. They also possess antibacterial properties themselves and may be used in humans and 40 other animals, for example, to treat bacterial infections caused by gram- positive and gram negative bacteria, for example, Staphylococcus aureus, Streptococcus pyrogenes, Bacillus subtilis, E. coli, Pseudomonas aeruginosa, and Proteus morganii, some strains of which are pen ici 11 in-resistant.
The invention accordingly provides a pharmaceutical preparation which comprises a com- 45 pound of formula 1, or a physiologically tolerable salts thereof, or a mixture of two or more such substances as active ingredient, in admixture or conjunction with a pharmaceutical ly suitable carrier. The preparation may also comprise one or more other pharmaceutical ly active sub stances, for example, another antibacterial substance, especially one which has a 8-lactam ring.
The preparations may be in a form suitable for enteral or parenteral administration, for example, 50 for oral, intravenous, or intramuscular administration, for example, as tablets, capsules, syrups, or sterile injectable or infusible solutions. The preparations are advantageously in unit dosage form and preferably comprise from 10 to 2000 mg of the active ingredient. The daily dosage of the active ingredient is generally from 20 to 8000 mg, in divided doses, generally up to 4 doses.
The invention also provides the use of an active ingredient as defined above as a B-Iactamase inhibitor and/or as an antibacterial agent.
The invention further provides a pharmaceutical preparation which comprises an active ingredient as defined above, in unit dosage form.
The invention also provides a pharmaceutical preparation which comprises an active ingredi- 60 ent as defined above, or a physiologically tolerable salt thereof or a mixture of two or more such substances, and one or more further pharmaceutically active substances, for example, as described above and, for example, in unit dosage form.
Unit dosages are preferably as described above.
The following Table provides examples of compounds of the invention.
12 GB 2 151 630A 12 TABLE
CH3-CE Oal 5 P-2 0 CODE 10 R Ri 15 R -0 H 20 0 CE 25 30 E 05- 35 40 13 GB2151630A 13 Oil 5 E E OCE3 10 3 15 C? 3 20 l0 l-N 2 E OR 30 OC-E3 35 OUR, 0---3 E 05 40 14 - E.
H E3 CH3 OE 10 E3C 0"3 GB 2 151 630A 14 15 20 20 IL a -N C"3 25 CE -E3C 1; C]S 30 GB 2 151 630A 15 p RI R2 10 15 20 Els 25 OR 30- 30 STCE3 0 1. 35 3 16 GB 2 151 630A 16 R - Rl 2 11 C/ -1<. cli, A-i E 5 10 0 11 JF-k1_ C-OCE3 15 OF.
20 E -Cso 27CE3 E E. - --S02-CE3 OE 25 E3 35 E --01--,S02-CE3 W 17 GB 2 151 630A 17 R R R2 so 2-CR3 OR COOCE3 10 S l COOCE3 15 OR E -r3' R \--i 011 oil H 0COCE3 E 25 11 OCOCE 3 OR - 18 GB 2 151 630A 18 alternatively, for each of the above compounds R may represent Na 1, K I, Li or a pivaloyloxymethyl or phthalidyl group.
The stereochemistry at postion 5 is preferably R. When R7 represents a free or protected hydroxyl group, the stereochernistry at position 6 is preferably S, and at position 8 is preferably 5 R.
Furthermore, in each of the above compounds (salts and esters), in which W represents a hydroxy group, this group may be protected by an acetyl, propionyl, pivaloy], benzoyl, phenoxymethylearbonyl, pivaloyloxymethyl or acetoxymethyl group.
The present invention also provides compounds of the general formulae 11, Ill, IV, V, M and XII, and more especially provides the compounds specifically described in the Table, and in the 10 Examples given hereinafter.
The following Examples illustrate the invention. In them, temperatures are expressed in degrees Celsius, and T.L.C denotes thin layer chromatography, EXAMPLE 1 4-Allyithio-3-ethylazetidin-2-one.
To a stirred solution of 3.2 g of sodium hydroxide in 40 mi of water under an argon atmosphere was added 8 mi of allyl thiol (about 85% pure). After 20 minutes of further stirring, a solution of 12.5 g of 4-acetoxy-3ethylazetidin-2-one in 20 mI of water was added and the mixture was stirred for a further 15 minutes, and then extracted into dichloromethane. The organic extracts were washed with water, were dried over M9SO, and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a yellow oil (3.2 g).
(-CDC1-) 1,765 (f;,-lactam) -CM71 25 -1 3420 (YM) CM (CDC1 1. 01 (3R9, -t 9 J -7fiz CEL) 3 1.73 (2a, =9 CE-CH 3 =2 2.95 - 3.35 OR, =g SCE 2 =a -5-H) 4.43 (1H, di J 2.5a, 4-.7a-) 40 5.0 - 5.4 (2E5 m, ca C):2 5.6 - 6.3 (1111=9 CE=C) 45 6.77 flE, broad,}W) EXAMPLE 2 Methyl 2-(4-allytthio-3-ethylazetidin-2-on-l-yl)acetate.
To a vigorously stirred solution of 2.34 9 of 4-aiiyithio3-ethylazetidin2-one in 20 mI of dimethyiform?mide was added 1.37 mi of methyl bromoacetate and 4.16 g of finely ground pot - 4sCidm h%6ftte. After 18 hours, the mixture was poured intd; 75 mi of water, was extracted into ethyl acetate (5 X 20 mi) and the combined organic extracts were washed with water (6 X 15 mi), dried over M9SO, and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a yellow oil (3 g).
19 GB 2 151 630A 19 (CDCI) 1749 (ester) em 3 -1 1763 --=-' jo 4 (CDC1-) 1.05 (3ag tg j -tag M3 CS 2) 1.82 (2R, CE3CE2) 22 (3W-9 t cr =a 3-11) 3. _ 4.43 (SE9 z and AS Pattern, CE-0- PM-A c2CD-) 4.58 (1E, a, J 2av 4-E) 4.95 - 5.35 (2R, =? CE.C) 5.5 - 6.2 UE, =', CS.C) EXAMPLE 3 2-(4-Ailyithio-3-ethylazetidin-2-on-l-yl)acetic acid.
To a stirred solution of 3 g of methyl 2-(4-allyithio-3-ethylazetidin-2on-1 -yl)acetate in 10 mi of absolute ethanol was added dropwise a solution of 0.9 g of potassium hydroxide in a mixture 30 of 12 mi of ethanol and 1 mi of water. After 5 minutes, the mixture was poured into a mixture of 10 ml of dichloromethane and 20 m] of water. After acidification with 13 mi of 2M HCL the mixture was extracted with further dichloromethane; the dichloromethane extracts were ex tracted with saturated sodium bicarbonate solution. These aqueous extracts were acidified to pH 1.5 with 5M HCI and then extracted with dichloromethane. These organic extracts were 35 evaporated to dryness to afford the title compound as a white crystalline solid (2.56 g).
(CDC1 1.42 (3Et tv J 7Rzi CE0 3 40 1.78 (2S, =g CH3M) =2 3.30 (3H, mg SCE2 and 3-E) 3.5 -.4.55 (.?Rl AB patte=, WCH.) 4.6o (1Hg aq J 2Ez, 4-E) 50 5. 0 5.4 (2111 =I CH -C) 2 5.56.3 (1E, Z, CE-C) 55 10.41 (1H, sy OB) EXAMPLE 4
4-Nitrobenzyi 2-(4-aliylthio-3-ethylazetidin-2-on- l-yl)acetate A mixture of 2.5 g of 2-(4-aiiyithio-3-ethylazetidin-2-on-l-yi)acetic acid, 8 mi of dimethylace- 60 tamide and 636 mg of anhydrous sodium carbonate was stirred under argon for 20 minutes, and then 2.59 g of 4-nitrobenzyl bromide were added. After 30 minutes further stirring, the mixture was partitioned between ethyl acetate and water. The organic layer was separated and was washed with saturated sodium bicarbonate, with water, with brine, was dried over M9S04, and was evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane- GB 2 151 630A 20 ethyl acetate mixtures, afforded the title compound as a pale yellow oil. (3.0 9) _) == (CDC1 1751(ester) c=71 5 (CDC1-) j 1755 (shoulaer, -lact=) c= 1.06 (3-;zg tl j 7a, CE_) 1.77 (2E, CE3%) 3.20 MIt SCR 2 = d 3-11) -1 4.50 (2E, AB pat-Lern, NC53) 4.58 (IE, d, J 2.55z, 4-H) 20 4.9 - 5.33 (2al =I c%-c) 5.30 (2E,stDCE2). 25 5.5 - 6.3 (1E, =9 CE-0 7.4 - 8.45 OR, zt -G-NO 2 30 EXAMPLE 5
4-Nitrobenzyl 2-(4-aliyithio-3-ethyl-azetidin-2-on-l-yl)-3-(4chforophenoxy)-3-trimethylac etyithiop- ropenate To a stirred solution of 1 g of 4-nitrobenzyl 2-(4-aiiyithio-3-ethyi- azetidin-2-on-l-yi)acetate in dry THF at - 78' under argon was added a solution of a mixture of 1.3 mi of hexamethyidisila zane and 6.2 mmol of r-butyllithium in dry THR The mixture was stirred for 30 minutes, and a solution of 0.63 9 of p-chlorophenyl chlorothionoformate in 5 mi of dry THF was added. The mixture was warmed to - 4WC, and after 30 minutes was then cooled to 78', and a solution of 0.50 mi of pivaloyl chloride in dry THF was added. The mixture was warmed to room temperature and after 30 minutes, acetic acid was added. The mixture was evaporated to dryness. The resulting oil was partitioned between ethyl acetate and water, the organic layer was separated, washed with water, with aqueous citric acid, with saturated sodium bicarbonate, with brine, and was then dried over M9S04 and evaporated to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures afforded the title compound (1.3 g, 76%) as a yellow oil.
V Mper (CDC13) 2.765 iS (CDC'3) 1.50 -.2.20 (2Es 0.851.30 (lat =I (c=) v3 31 CE24-CF5) 1 =9 'a CW 3) It 3.00 3.75 (3Er =9 SC-29 3--:-7) ho&jtr 4.80 5.5 (55r m, -9 CO.5CF--- 44 p G. a.
6.s - 8.3 (BE# ZIP 019 GB 2 151 630A 21 EXAMPLE 6 4-Nitrobenzyl 2-(4-chloro-3-ethyi-azetidin-2-on-l-yl)-3-(4chforophenoxy)-3-trimethylacety lthiopropenate To a solution of 1.3 g of 4-nitrobenzyl 2-(4-aiiyithio-3-ethyi-azetidin-2on-l-yi)-3-(4-chlorophenyi)-3-trimethylacetyithiopropenate in dichloromethane at - 20', was added a solution of 4.2 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Efution with hexane-ethyl acetate mixtures afforded 1.1 g of the title compound as a pale yellow oil (90% of the theoretical yield).
Ratio cis: trans = 1:2.5 by N M R MA(CDC13) 2.785. CM71 (CDC13) 0-BO 1.30 (22H, =p O(M.E) C R CrE 3 3 -2.--3 1.50 - 2.15 (2Hp =p 92CE-3) p 3.00 - 3.85 (IE, m. 37=) 9 5. 2 (2E, 00 C'J 22 5.80r 6.05 2dt JC415 4_=P Jt-"2= 1JEz, 25 4-E) r 6.8D - 8.20 (85p zt 19 EXAMPLE 7
4-Nitrobenzyl 3-(4-chlorophenoxy)-6-ethyl-7-oxo-4-thia-l-azabicyclo[3,2, 0]hept-2-ene-2-car boxyl- 35 ate To a stirred solution of 1.1 g of 4-nitrobenzyl 2-(4-chloro-3-ethyl- azetidin-2-on-l-yi)-3-(4- ch 1 orop he noxy)-3-tri methylacetylth io propen ate in dioxan-water (9:1 v/v) at 5'C was added 260mg of imidazole. After 30 minutes at 5'C the mixture was warmed to room temperature, and then partitioned between ethyl acetate and water. The organic layer was separated, was washed with water, with aqueous citric acid, with water, with saturated sodium bicarbonate, and with brine, and was then dried over MgSO,, and evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 720 mg of the title compound (82%) as a yellow oil.
Ratio cis:trans = 2:1 by NIVIR 22 GB 2 151 630A 22 - ?n (CDC1) 1.795 aj-1 a 3 (CMC13) 0.80 _ 1.40 (3St mt C:R2 5,ú=3) 5 1.70 - 2.4 (2EY zt E-2CE-5) t 3.50 - 4.10 (1Rp =p 65) p 10 5.25 (2E9 Ctr C02C1Y1 5.30p 5.65 (IE9 2C1r.7 4-lizt -T-." 1-5117.9 5-,a) 5 6. SO - 8.10 (aEr =p -@zi 1 -& H02) 20 EXAMPLE 8
Sodium 3-(4-chlorophenoxy)-6-ethyl-7-oxo-4-thia-l-azabicyclo[3,2,Olhept-2ene-2-car boxylate A mixture of a solution of 205 mg of 4-nitrobenzyl 3-(4-ch lorop hen oxy)- 6 -ethyl- 7-oxo-4-th ia- 1 azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 37.5 mg of sodium bicarbonate in water, and 10% palladium /charcoal was hydrogenated at 50 psi at 25' for 60 minutes. Then, the mixture was filtered through Celite, and then lyophilized to yield 83 mg of the title compound as a pale yellow crystalline solid (53%).
EXAMPLE 9
4-Nitrobenzyl 2-(4-ailylthio-3-ethylazetidin-2-on-l-yi)-3-phenoxy-3trimethylacetylthiopro penate To a stirred solution of 2.0 g of 4-nitrobenzyl 2-(4-allylth io-3- ethylazetidin-2-on- 1)-acetate in dry THF at - 78' under argon was added a solution of a mixture of 2.07 9 of lithium hexamethyidisilazane in dry THF. The mixture was stirred for 5 minutes, and a solution of 1.04 35 g of phenylchforothionoformate in 10 mi of dry TH F was added. The mixture was warmed to - 40', and after 30 minutes was then cooled to - 78', and a solution of 1. 01 mi of trimethylacetyl chloride was added. The mixture was warmed to room temperature and after 15 minutes, the mixture was evaporated in vacuo to dryness. The resulting oil was partitioned between ethyl acetate and water, the organic layer was separated, was washed with water, with 40 aqueous citric acid, with saturated sodium bicarbonate, with brine, was dried over M9S04 and evaporated to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures afforded the title compound (2.58 g, 80%) as a yellow oil.
23 max (CHIC1 1764 cia-i j (CD C13) GB 2 151 630A 23 m/e base peak 57.0708, C(CHI.
0.80 - 1.30 (I2E9 at C(CE-) -CE 5 3)l 1.55 - 2.15 (2SI, mr ZE2-CE-)v p 3.02 - 3..43 (33-1, =9 B-CE:12, 3-=--) 9 4.82, 4.9 5 (15.1 2d, -J... 3Ez. J.... 1.5azt 4-5),t 4098 - 5039 (45, =.. C2 =1 CO2C2) 5.40 - 6. D5 (ist =p CE-W t 6.78 - 8.2B (Slat =p.. 1 EXAMPLE 10
4-Nitrobenzyl 2-(4-chforo-3-ethyl-azefidin-2-on- l-yl)-3-phenoxy-3trimethylacetylthiopropenate 35 To a solution of 2.47 9 4-nitrobenzyl 2-(4-aliyithio-3-ethylazetidin-2-on- l-yi)-3-phenoxy-3- trim ethyl acetylth iopropen ate in dichloromethane at - 20' was added a solution of 8.4 mmol of chlorine in carbon tetrachloride. After 30 rainutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 1.782 9 of the title compound as a pale yellow foam 40 (78% of the theoretical yield).
(CECI 1784 =71 (CDC2) 0.80 - 1.42 (lat =g C(CE-) --C-=) 3 CE2 i.56 -..2.15 (2Ht my -E2CE3) 3.00 - 3.80 (nt =p 3-1)f 5.30 (2H Bi 00 5.71p 6.17 (IE9 2dt 4TA- 1. 55z 9 j 3Ezt Cie 6.66 - 8.37 (SIE? at EXAMPLE 11 4-Nitrobenzyl 6-ethyl- 7-oxo-3-phenoxy-4-thia- 1 -azabicyclo[3,2, Olhept-2-ene-2-carboxylate To a stirred solution of 0.416 g of 4-nitrobenzyl 2-(4-chloro-3- ethylazetidin-2-on-1 -yl)-3- 65 24 GB 2 151 630A phenoxy-3-trimethylacetyithiopropenate in dioxan-water (9:1 v/v) at W was added 104 mg of imidazole. After 30 minutes at 5' the mixture was warmed to room temperature, and then partitioned between ethyl acetate andwater. The organic layer was separated, was washed with water, with aqueous citric acid, with water, with saturated sodium bicarbonate, and with brine, was dried over M9S04, and then evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 216 mg of the title compound (67%) as a yellow foam.
1790 CM-19 1800 (eh) CM-1 10 (CDC1 3 0.50 - -1.42 (3--Jp inp p 1.56 - 2.20 (2H9 'n' 15 - 4.05 (ISt =p 6-E) r 5.35 (211, q, CO 2 C==2 20 5.369 5.75 (IS, 2d 1.5=, j 4. CiB 4=-z t 5-5) 9 25 7.00 - 8.29GEtzy' _'9'-ED2) - \ C.3) P EXAMPLE 12
Sodium 6-ethyl-3-phenoxy-7-oxo-4-thia-l-azabicyclo-[3,2,Olhept-2-ene-2carboxylate A mixture of a solution of 306 mg of 4-nitrobenzyl 6-ethyi-3-phenoxy-7- oxo-4-thia-lazabicyclo[3,2,0]hept-2ene-2-carboxylate in dioxan and 60 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25 for 60 minutes. The mixture 35 was then filtered through Celite, and lyophilised to yield 216 mg of the title compound as a pale yellow crystalline solid (96% of the theoretical yield).
EXAMPLE 13
3(S)- (1 (R)-Dimethyl(2-methylprop-2-yl)silyfoxyethyl) -4(R)ethyithioazetidin-2-one To a stirred solution of 2.03 g of sodium hydroxide in 70 mi of water at OC under an argon atmosphere was added 3.94 g of ethane thiol. After 30 minutes stirring, a solution of 12.6 g of 3(S)-{1(R)-dirnethyi(2-methylprop-2-yi)silyloxyethyi}-4-acetoxyazetidin-2on e in 200 mi of metha nol was added. The mixture was warmed to room temperature and, after 90 minutes, was partitioned between ethyl acetate and water. The aqueous layer was further washed with ethyl 45 acetate. The combined organic layers were back-washed with brine, dried over sodium sulphate, and evaporated to dryness. 6.9 g of the title product were obtained. Yield: 54% GB 2 151 630A 25 max (CDC1 3 1765 em-4 (CDC1 3 0.10 (6H,s) 0.90 GHYS) 1.26 0H9 di J = 6 Hz) 1.33 OH, ty J = 7 Hz) 10 2.68 (2Ht qp J = 7 Hz) 3.16 UR9m) 15 4.1-4.3 (1HP m) 4.85 (1H, d, J = 2 Hz) 20 6.78 UK, broad a).
25 EXAMPLE 14
Methyl 2-[3(S)- (1(R)-dimethyi(2-methylprop-2-yl)silyfoxyethyl)-4(R)ethylthio-azetidin-2-on - l-yila cetate To a stirred solution of 6.9 9 of 3(S)-{1(R)-dimethyi(2-methylprop-2- yi)silyloxyethyi)-4(R)ethylthio-azetidin-2-one in 150 mi of dry dimethylformamide was added 13. 15 9 of finely ground anhydrous potassium carbonate and 2.82 mi of methyl bromoacetate. After 24 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The aqueous layer was adjusted to pH2 by dropwise addition of dilute hydrochloric acid, and then backextracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulphate, and evaporated in vacuo to give an orange oil, which was chromatographed over silica gel. Elution with ethyl acetate/hexane mixtures afforded 6.37 g of the title compound as a pale yellow oil. Yield: 72%.
4 max (CDC1 3) 1749 (ester) and 1760 (p-lactam) em-1 (CD01 3) 0.06 (6HP S) 0.86 GHP 8) 1.3 (6H, m) 45 2.56 (2Hp q) J 6 Hz) 3.12 (1H9 ddq J 2 Hz and 4 Hz) 50 3.70 (3Ht 8) 3.93 (2H9 dd, J gem = 17 Ez) 55 4.3 (lfip m) 4.92 (1HO dp J = 2 Hz).
60 EXAMPLE 15
4-Nitrobenzyl 2-[3(S)- (1 (R)-dimethyl-(2-methylprop-2-yl)-silytoxyethyl) -4(R)-ethylthio-azetidin-2 on-l-yil-acetate To a solution of 6.37 g of methyl 2-[3 (S)- {1 (R)-d i methyl (2-methyl prop-2-yi)silyloxyethyi} -4(R)-65 26 GB 2 151 630A 26 ethyithio-azetidin-2-on-l-yi]acetate in 25 mi of 95% ethanol was added a solution of 1.16 g of potassium hydroxide in 25 mi of 95% ethanol. After 15 minutes, the mixture was evaporated in vacuo to dryness. The product was dissolved immediately in 25 mi of dimethylacetamide, and 4.24 g of solid 4-nitrobenzyl bromide were added with vigorous stirring. After 60 minutes, the mixture was partitioned between ethyl acetate and water. The separated aqueous layer was washed with further ethyl acetate; the combined organic layers were backwashed with water, then with brine, and were then dried over sodium sulphate and evaporated in vacuo to afford an orarge oil. Chromatography over silica gel, eluting with ethyl acetate/hexane mixtures afforded the title compound as a pale yellow, viscous oil. Yield: 6.18 g, 80%.
limax (CDC1 3) 1765 Zf (CDC1 3) (0-lactam) and 1755 (ester)cm-1 0.05 OH, s) 0.08 (3Ht a) - 0.88 (9HO S) 1.25 OHY to J = 7 fiz) 1.28 Mr do J = 6 Ez) (2E, qq J = 7 Hz) (1Ht dd# J = 2 Ez and 4 Hz) (2Ho ddp Jgem = 18 Ez) 4.1-4.3 URt m) 4.93 (1HO do J = 2Hz) EXAMPLE 16
4-Nitrobenzyl 2-[3(S)-(1(R)-dimethyl-(2-methylprop-2-yl)-silyloxyethyl)4(R)-ethylthio-aze tidin-2on-l-yll-3-(4-methytthiophenoxy)-3-trimethylacetylthio-propenate.
To a stirred solution of 2.0 g of 4-nitrobenzyi 2-[3(S)- {1 (R)-dimethyi(2-methylprop-2-yi)silyloxyethyi}-4(R)-ethyithio-azetidin-2-on-l-yi]-acetate and 1.123 9 of 4(mercaptomethyi)phenoxy 40 chlorothionoformate in dry tetrahydrofuran at 1 OWC under argon was added a solution of a rrixture of 2.35 m] of hexamethyidisilazine and 6.64mi of a 1.55 molar hexane solution of hutyllithium in dry tetra hydrofu ran. The mixture was stirred at - 100' for 30 minutes and at - 40' for 30 minutes, and 1.05 mi of trimethylacetyl chloride was added. The mixture was ailowed to warm to room temperature and was stirred for 2 hours. Acetic acid was then added 45 ;.nc: the mixture was partitioned between ethyl acetate and water. The organic layer was washed with citric acid, with water, with sodium bicarbonate, with brine, and was then dried over magnesium sulphate and evaporated to dryness. Chromatography over silica gel, eluting with hexane/ethyl acetate mixtures, afforded 2.06 g of the title compound as a yellow oil. Yield:
65%.
27 GB 2 151 630A 27 max (CH01 3) = 1764, em-' (CDC1 3 0.06 6E, 9) 0.80, 0.87 (9Hr 2s) 1.09 1.09 (9H, 2s) 1.23 (3Ht to J = 7 Hz) 10 1.26 OFL9 dg J = 6 Ez) 2.42 (3119 s) 15 2.64 (2H, qv J = 7 Hz) 3.20 (1H, ddg J = 2 Hz and 4 Hz) 20 4.00 - 4.40 (1H, m) 5.30 0Ho bs) 6.73 - 7.31 (4H, m) 25 7.35 8.28 RH, m) 30 EXAMPLE 17
4-Nitrobenzy] 2-[4(R)-ethylthio-3(S)- (1 (R)-hydroxyethyll -azetidin-2-on1 -yl]-3-(4-methylthiophe noxy)-3-trimethylacetylthio-propenate To a stirred solution of 2.06 g of 4-nitrobenzyl 2-[3(S)- {l (R)-dimethyi(2-methylprop-2- 35 yi)si lyl oxyethyl} -4(R)-ethyith io-azetid i n-2-on1 -yl]-3-(4- methylth iophenoxy)-3-tri methyl acetylth io propenate in tetrahydrofuran at room temperature was ad ' ded 2 mi of water and 22 mmol of concentrated hydrochloric acid. The mixture was stirred for 28 hours until T.L.C. analysis showed the reaction to be complete. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with sodium bicarbonate and brine, dried over MgSO, and 40 evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound (1.21 g, 70%) as a yellow foam. The product is isolated as a mixture of E and Z isomers, observed as double peaks in the nmr spectrum.
28 GB 2 151 630A 28 max (CHCl 3) (CDCI 3 1.02, 1.28 1.30 2t44 2.76 3.24 3.90 5.23 5.26 6.74 7. 27 1762 em-1 1.13 (9lit 2s) 3H9 tr J = 7 Hz) 3H9 do J = 6Hz) OHI C) 2H, ql J = 7 HZ) 1H, dd, J = 2 Hz and 4 Hz) - 4.38 (1H, m) (1Hr do J = 2 Hz) (2Hr a) - 7.20 (4H, - 8.23 (4H.
EXAMPLE 18
4-Nitrobenzyl 2-[4(S)-chforo-3(S)- ( 1 (R)-hydroxyethyl) -azetidin-2-on- 1 -yl]-3-(4-methylthiophenoxy)-3-trimethylacetylthio-propenate.
To a stirred solution of 1 g of 4-nitrobenzyl 2-[4(R)-ethyithio-3(S)- {1 (R)-hydroxyethyl} -azetidin2-o n- 1 -yl]-3-(4-methylth io ph e n oxy)-3tri methylacetylth io-prope n ate in dichloromethane at - 40 was added a solution of 1.6 mmol of chlorine in carbon tetrachloride. After 30 minutes the reaction was warmed to room temperature and evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound as a pale yellow foam (0.66 g, 68%).
max = 1783 c (CDC1 1.09 (9H, 2s) (3Ht do J 6Hz) (3Ht s) (1H9 dd, J 4Hz and 9Hz) - 4.58 (1HP m) 3.30 (2H, s) 6.039 6,17 (1H9 2dg C7 = 4HZ) 6.72 7.33 (411, m) 7,38e.32 Un. m) 1.069 1.40 2.44 3.52 3.98 E and Z isomers are sepalab!e by chromatography.
EXAMPLE 19
4-Nitrobenzyl 5(R), 6(S)- (1(R)-hydroxyethyl)-3-(4-methylthiophenoxy)-7oxo-4-thia-l-azabicy- 29 GB 2 151 630A 29 clo[3,2,0]hept-2-ene-2-carboxylate To a stirred solution of 0.342 g of 4-nitrobenzyl 2-[4(S)-chloro-3(S){1(R)-hydroxyethyi}azetidin-2-on-l-yl]-3-[4-methylthiophenoxy)-3trimethylacety[thio-propenate in dioxan-water (9:1 v/v) at + 5' was added 1. 12 mmol of imidazole. After 30 minutes at + 5' the reaction mixture was warmed to room temperature and partitioned between ethyl acetate and water. The organic. layer was washed with citric acid, with water, with saturated sodium bicarbonate and with brine, was dried over M9SO, and was then evaporated in vacuo to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound (0. 133 g, 49%) as a pale yellow foam.
Ymax (C11C1 3) 1786t 1790 (sh), 1797 (sh) =71 (CM31 3) 1.30 ORP do J 6Hz) 2.46 (3Ht 8) 3.68 (1E9 ddp J 1.5Hz and ISHz) 3.88 - 4.33 (1HP m) 5.29 (2119 q) 5.56 (1Hp d, J = 1.5fiz) 6.90 - 7..29 X4RY m) 7.31 - 8.20 (4HP m) EXAMPLE 20
4-Nitrobenzyl 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(4-methyisulphinylphenoxy)7-oxo-4-thio-l-azabicy clo[3,2, Olhept-2-ene-2-carboxylate To a stirred solution of 0.28 9 of 4-nitrobenzyl 5(R), 6(S)- {1 (R)- hydroxyethyl} -3-(4-methylthio- 35 phenoxy)-7-oxo-4-thia-l-azabicyclo[3,2,0]hept-2-en-2-carboxylate in ethyl acetate at - 78' was added a solution of 0.57 mmol of rn-chloroperoxybenzoic acid in ethyl acetate. After 30 minutes the reaction mixture was warmed to room temperature and washed with saturated sodium bicarbonate, with brine, dried over M9SO, and then evaporated to dryness. Chromatography over silica gel and elution with hexane-ethyl acetate mixtures afforded the title compound (0. 19 40 9, 66%) as a while foam.
'max (CHU 3) = 1790, 1797 =71 CS (CDC1 3) 1.35 (3E9 dr J = 6111z) 2.73 0HP 8) 3.81 (1H9 ddw J = 1.5Hz and 6Hz) 50 3.90 - 4.37 (1H, m) 5.31 (2H, q) 55 5.74 (1H9 dr i = l. 5H4 7.15 7.52 (4HP 60 7.55 8.27(4H, EXAMPLE 21
Sodium 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(4-methylsulphinylphenoxy)-7-oxo4-thia-l-azabicy - 65 GB 2 151 630A 30 1 clo[3,2, 01-hept-2-en-2-carboxylate A mixture of a solution of 6 5 mg of 4-nitrobenzyl 5(13), 6(S)-(1 (R)-hydroxyethyi)-3(4methyisulphinylphenoxy)-7-oxo-4-thia-l-azabicyclo[3,2, 0]hept-2-en-2carboxylate in dioxan, and I 1 1 mg sodium bicarbonate in water, and 10% palladium /charcoal was hydrogenated at 50 5 ii.s.i. until T.L.C. analysis indicated complete reaction. The mixture was filtered through Celite (Trade Mark) and Iyophifized to yield 42 mg of the title compound (83%) as a crystalline solid.
EXAMPLE 22 4-Nitrobenzyi 5(R), 6(S)-(1(R)-hydroxyethyi)-3-(4methyisulphonylphenoxy)-7-oxo-4-thia-l-azabi10 cyclo[3,2, Olhept'2-ene-2carboxylate 20 mg of the above compound were obtained by a procedure analogous to that described in F_-zarcip,'e 20 using 125 ing of 4nitrobenzy] 5(R), 6(S)- {1 (R)-hydroxyethyi)-3-(4-methyisulphinyipi-te.i-, Gxy)-7-oxo-4-thia-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate and 0.25 mmol "chloroper- oxybenzoic acid.
6(CDC1 3) 1.39 OR9 dr J = 6Hz) 2.97 UE, bs) 3.09 Ofit s) 3.86 (1Ht ddy J = 1.5Hz and 6Hz) 4.00 - 4.51 UE, m) 25 5.30 (2H9 q) 5.73 (1E9 dr J = 1.5Hz) 30 7.13 - 8.32 (Slit m) EXAMPLE 23
Sodium 5(R), 6(S)-(1(R)-hydroxyethyi)-3-(4-methyisuiphonylphenoxy)-7-oxo4-thia-l-azabicy - clo[3,2, 0]hept-2-ene-2-carboxylate 18 mg of the above compound were obtained from 20 mg of the corresponding 4-nitrobenzyl compound (see Example 22) by a procedure analogous to that described in Example 21, using 3.2 mg of sodium bicarbonate.
EXAMPLE 24
4-Nitrobenzyl 2-[3(S)- (1 (R)-dimethyi-(2-methylprop-2-yt)silyloxyethyl) 4(R)-ethytthioazetidin-2-on l-yil-3-phenoxy3-trimethylacetyithio propenoate 400 mg of the above compound were obtained, as a yellow oil, by a procedure analogous to 45 that described in Example 16, using 500 ing of the azetidinone starting material defined in Example 16, 200 mg of phenyl chlorothionoformate, 700 til of hexamethyidisilazane and 2 m] of ri-butyllithium, and 260 jul of trimethylacetyl chloride.
31 GB 2 151 630A 31 (S'(CDC1 3 0.01 (6E9 a) 0.80 0.90 GR 2s 1.09 1.06 (9H9 2s) 1.25 (6H, m) 2.7 (2H, q J = 7Hz) 10 3.20 UHy dd) 4.0 4 4.40 (1119 15 5.30 OH, bm) 6.8 - 7.5 GH. m) 20 7.5 - 8.4 (4Hg m) 25 EXAMPLE 25
4-Nitrobenzyl 2[3(S)- (1 (R)-hydroxyethyl) -4(R)-ethylthioazetidin-2-on- 1 -yll-3-phenoxy-3-trimethy facetylthiopropenoate 0. 19 g of the above compound were obtained from 0.390 g of the corresponding {1 (R) dimethyi-(2-methylprop-2-yi)-silyloxyethyi} compound (see Example 24) by a procedure analo- 30 gous to that described in Example 17, using 0.4 m] of water and 0.4 mi of concentrated hydrochloric acid.
6(CDC1 3 1.05t 1.10 (9H9 29) 35 1.35 (5E, m) 2.70 (2H9 qp J = 7Hz) 2.8 (1H,.broad) 40 3.30 (1Hp dd J = 2Hz + J 5HZ) 4.03 - 4.46 (1Hp 45 5.35 (3Ht m) 6.94 - 7.50 GE, m) 50 7.55 - 8.40 (4Ho m) EXAMPLE 26
4-Nitrobenzyl 2-[3(S)- (1 (R)-hydroxyethyl) -4(S)-chloroazetidin-2-on- lyil-3-phenoxy-3-trimethyla cetyl thiopropenoate To a stirred solution of 0. 114 9 of the 1 (R)-hydroxyethylazetid i none derivative defined in Example 25 in CDCI, at - 4WC was added a solution of 0.2mmol of chlorine in carbon tetrachloride and the solution was stirred for 1 hour. The reaction mixture was warmed to room 60 temperature and evaporated to dryness. The product was used unpurified in the following step.
32 GB 2 151 630A 32 IS(OC1 3 1.03y 1.06 OR9 2s) 1.40 0Ht m) 5 2.8 UR, broad) 3.50 (1H9 dd) 10 4.06 - 4.60 (1H. m) 5.30 (2H9 a) 6.13 (1H9 d J = Cz) 15 6.90 - 7.40 GH9 m) 7.40 - 8.35 (4Ht m) 20 EXAMPLE 27
4-Nitrobenzyl5(R), 6(S)-(1(R)-hydroxyethyll-3-phenoxy-7-oxo-4-thia-lazabicyclo[3,2,Ojhept-2- 25 en-2-carboxylate 0.044 g of the above compound were obtained by a procedure analogous to that described in Example 19, using the unpurified product of Example 26 and 0.22 mmol of imidazole.
30 S(WC1 3) 1.30t 1.40 (3Ht dp J = 6Hz) 2.0 (1H, broad) 35 3.76 UHt dd J = 1.5Hzand 6Hz) 3.96 - 4.43 (1H, m) 40 5.35 (2Hp q) 5.63 UE9 dt J = 1.5HZ) 7.10 - 7.40 (5HP 45 7.50 - 8.30 (4119 50 EXAMPLE 28
Sodium 5(R), 6(S)-(1(R)-hydroxyethyl)-3-phenoxy-7-oxo-4-thia-lazabicyclo[3,2,Olhept-2-en -2- carboxylate 0.0237 9 of the above compound were obtained from 0.031 g of the corresponding 4- 55 nitrobenzyl carboxylate (see Example 27) by a procedure analogous to that described in Example 21, using 0.0061 g of sodium bicarbonate.
EXAMPLE 29
4-Nitrobenzyl2[3(S)-(1(R)-dimethyl-(2-methylprop-2-yl)-silyloxyethyl)4(R)-e thyithioazetidin-2-onl-yll-3-(4-fluorophenoxy)-3-trimethylacetyithio propenoate 0.592 g of the above compound were obtained by a procedure analogous to that described in Example 16 using 0.5 9 of the azetidinone starting material defined in Example 16, 171 g] of jo fluorophenyl chlorothionoformate, 0.67 m] of hexamethyidisilazine and 1. 99 mi of n-butyl- lithium, and 261 jul of trimethylacetyl chloride.
33 GB 2 151 630A 33 v max (CDC1 3) 1763 =71 &(CDC1 3 0.06 (6Ht s) 0.759 0.80 (9H9 2s) 3 1.oo, 1.o6 GH. 213) 1.22 0HP tt J = 7HZ) 10 1.25 0HP t7J = 6Hz) 2.70 (2Ht q 7 J = 7HZ) 15 3.20 UHt ddo J = 2HZ and 4HZ) 4.00 4 4.40 (1H, m) 20 5.25 0H9 be) 6.8 4 8.2 (SE9 m) 25 EXAMPLE 30
4-Nitrobenzyl 2-[3-(S)- (1 (R)-hydroxyethyl) -4(R)-ethylthioazetidin-2-on1 -yll-3-(4-fluorophenoxy) 3-trimethylacetylthio-propenoate 380 mg of the above compound were obtained from 590rng of the corresponding {1 (R)dimethyi-(2-methylprop-2-yi)silyloxyethyi} compound (see Example 29) by a process analogous to that described in Example 17, using 1 m] of water and 1 mi of concentrated HCI.
Vmax (CDCI 3) 1761 em-1 (CDC1 3) 1.02o 1.10 (9Hp 2s) 1.20 4 1.30 (ISH9 m) 2.70 (2H9 qg J 7HZ) 2.8 UE, broad) 3.28 UE, ddp J 2Hz and 4HZ) 3.90 4 4.30 US, m) 5.22 (3Hr be) 6.85 8.20 (SE, m) EXAMPLE 31
4-Nitrobenzyi 2-[3(S)-(1(R)-hydroxyethyi)-4(S)-chloroazetidin-2-on-l-yll3-(4-fluorophenox y)-3-tri- methylacetylthio-propenoate To above compound was obtained by a procedure analogous to that described in Example 26, using 378 mg of the 1(R)-hyd roxyethylazetid i none derivative defined in Example 30, and a solution of 0.45 mmol of chlorine in 1.65 mi of carbon tetrachloride. The product was used in 60 the subsequent reaction without purification.
34 GB 2 151 630A 34 cg(=i 3 1.10t (9119 2s) 1.30 (311p t) 2.5 (IE, broad) 3.5 (1H9 dd J = 4Hz and 9Hz) 4.00 (1Ht m) 10 5.30 (2Ht s) 6.10 (1Ht m) 15 6.80 - 8.30 (8H, m) EXAMPLE 32 4-Nitrobenzyi RR). 6(S)-(1(R)-hydroxyethyi)-3-(4fluorophenoxy)-7-oxo-4-thia-l-azabicyclo[3,2,0 - lhept-2-en-2-carboxylate 67mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 0.622 mmol of the unpurified product of Example 31 and 42.3mg of 25 imidazole.
limax (CDC1 3) 1786t 1790 (sh) (CDC1 3) 1.32 My dw J = 6Hz) 2.0 (JE, broad) 3.70 (JEt dd J = 1.5Hz and 6Hz) 4.00 - 4.30 (1H, m) 5.30 (2E9 q) 5.56 (1Hp dp J = 1.5RZ) 6.90 - 8.30 (8E, m) EXAMPLE 33
Sodium 5(R), 6(S)-(1(R)-hydroxyethyi)-3-(4-fluorophenoxy)-7-oxo-4-thia-lazabicyclo[3,2,0]hept- 2-en-2-carboxylate 46.3 mg of the above compound were obtained from 67 mg of the corresponding 4- 50 nitrobenzyl carboxylate (see Example 32) by a procedure analogous to that described in Example 21 using 12.2 mg of sodium bicarbonate.
EXAMPLE 34
4-Nitrabenzyl 2-[3(S)-(1(R)-dimethyl-(2-methylprop-2-yl)-silyloxyethyl)4(R)-ethyithioazet idin-2- 55 on-l-yll-3-(4-chlarophenoxy)-3-trimethylacetylthio propenoate 600 mg of the above compound were obtained by a procedure analogous to that described in Example 16, using 500 mg of the azetidinone starting material defined in Example 16, 0.25 mt of p-chlorophenyl chlorothionoformate, 0.67 mi of hexamethyidisilazane and 1.99 m] of n-butyl- lithium, and 0. 195 mi of trichloroacetyl chloride.
GB 2 151 630A 35 -,.)max 1760 =71 6 (CD01 3 0.06 (6Ht 0) 5 0.8r 0._87p (9H 1 2s) 1.059 1.1Q (9Hp 2a) 1.20 - 1.40 (6H, m) 10 3.60 (2H, q,J=7liz) 3.20 (1H9 dd7J = 2Hz and 4Hz) 15 4.00 - 4.50 (1H, m) 5.20 (3Ht bs) 20 6.70 8.30 (8H9 25 EXAMPLE 35
4-Nitrobenzyl 2-[3(S)- (1 (R)-hydroxyethyl) -4(R)-ethylthioazetidin-2-on1 -yll-3-(4-chforophenoxy)-3trimethylacetyithio-propenoate 290 mg of the above compound were obtained from 600 mg of the corresponding {(1 R) dimethyi-(2-methylprop-2-yi)silyloxyethyi} compound (see Example 34) by a procedure analo- 30 gous to that described in Example 17 using 1 m] of water and 1 m] of concentrated HCL 1765 em-1 35 (CDC1 3) 1.05t 1.10 GH9 2s) 1.27 (6H, m) 2.70 (2H, q, J 7Hz) 40 2.8 (1H, broad) 3.20 (1H, dd, J 2Hz and 4H4 45 3.90 4 4.40 (1HP m) 5.25 (3Hp be) 50 6.80 4 8.20 (8H9 m) EXAMPLE 36 55
4-Nitrobenzyl 2-[3(S)-(1(R)-hydroxyethyl)-4(S)-chloroazetidin-2-on-l-yll3-(4-chlorophenox y)-3-tri- methylacetylthio-propenoate The above compound was obtained by a process analogous to that described in Example 26 using 290 mg of the 1(R)-hyd roxyethylazetid i none derivative defined in Example 35 and a solution of 0.45 mmol of chlorine in 1 mi of carbon tetrachloride. The product was used in the 60 next reaction without purification.
36 GB 2 151 630A 36 C(CDC1 3 1.05r 1.10 (9H9 2s) 1.40 0H9 dp J = 6Hz) 2.5 (1H, broad) 3.50 (1HO m) 4.00+4.50 (1H, m) 5.22 (2Ht a) 6.039 6.15 (1H9 2do -T = 4Hz) 6.8o 4 8.30 (8HP m) EXAMPLE 37 4-Nitrobenzyl 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(4chlorophenoxy)-7-oxo-4-thia-l-azabicyclo[3,2, Offiept-2-en-2-carboxylate 57 mg of the above compound were obtained by a procedure analogous to that described in Example 19, using 0.458 mmol of the unpurified product of Example 36, and 32 mg of 25 imidazole.
Yma.x 17879 1790 (sh) cm-1 (S(CD01 3 1.30 0Hp dp J = 6Hz) 2.0 (1H, broad) 3.60 (1Hp ddp J = 1.511z and 6H4 35 3.90 - 4.40 (1HP m) 5.22 (2H, q) 40 5.55 (1H9 dp J = 1.5HZ) 6.8o - 8.20 (8H9 m) 45 EXAMPLE 38
Sodium 5(R), 6(S)-(1(R)-hydroxyethyi)-3-(4-chlorophenoxy)-7-oxo-4-thia-lazabicyclo[3,2,0]hept- 2-en-2-carboxylate 43 mg of the above compound were obtained from 57 mg of the corresponding 4-nitrobenzyl 50 carboxylate (see Example 37) by a procedure analogous to that described in Example 21, using mg of sodium bicarbonate.
EXAMPLE 39
4-Nitrobenzyl 2-[3(S)-(1(R)-dimethyi-(2-methylprop-2-yl)-silyloxyethyl)4(R)-ethylthioazet idin-2- 55 on- l -yll-3-(4-cyanophenoxy)-3-trimethylacetylthio propenoate 1. 12 g of the above compound were obtained by a procedure analogous to that described in Example 16 using 1 g of the azetidinone starting material defined in Example 16, 0.63 g of jo cyanophenyl chlorothionoformate, 1.34 mi of hexamethyidisilazine and 3.98 m] of r)-buty]- lithium, and 0.52 m[ of trimethylacetyl chloride.
37 GB 2 151 630A 37 Ymax 1768 em-1 NPIR d^ (CDCJ 3 0.06 (6H9 a) 5 0.80. 0.87 (9Ht 2s).
1.05p 1.10 (9H9 2s) 10 1.20 (6Hp m) 2.70 (2Hp q;J'= 7HZ) 3.22 (1Ht ddg J = 2Hz and 4Hz) 15 3.90 - 4.40 (1H. m) 5.30 (3Hp bs) 20 6.88 - 8.30 (SH, m) 25 EXAMPLE 40
4-Nitrobenzyi 2-[3(S)- (1 (R)-hydroxyethyl) -4(R)-ethylthioazetidin-2-on1 -yll-3-(4-cyanophenoxy)-3 trimethylacetylthiopropenoate mg of the above compound were obtained from 325 mg of the corresponding {l (11) dimethyi-(2-rnethylprop-2-yl)-silyloxyethyi} compound (see Example 39) by a procedure analo gous to that described in Example 17, using 0.55 m] of water and 0.55 mi of concentrated hydrochloric acid.
'max 1765 cm-1 35 (CDC1 3 1.059 1.10 (9H9 2s) 1.30 (6H, m) 40 2.61 (2Hp q, J = 7Hz) 2.8 UR, broad) 45 3.16 (1H9 ddg J = 2Hz and 4liz) 3.91 - 4.50 UHt m) 5.30 0H9 bs) 6.90 - 8.3 (SH9 m).
EXAMPLE 41 4-Nitrobenzyl 2-[3(S)- (1 (R)-hydroxyethyi) -4(S)chloroazetidin-2-one- 1 -yll-3-(4-cyanophenoxy)-3trimethylacetylthiopropenoate The above compound was obtained by a process analogous to that described in Example 26 using 340 mg of the 1(R)-hydroxyethylazetidi none derivative defined in Example 40 and a solution of 0.676 mmol of chlorine in 0.81 mf of carbon tetrachloride. The product was used in - the next reaction without purification.
38 GB 2 151 630A 38 max 1785 em71 (CDCJ 3 1.069 1.09 (9H, 2s) 1.35 ORt dp J = 6Hz) 2.5 (1H, broad) 3.50 (1Hr dd?J = 4Hz and 9Hz) 10 3.95 - 4.40 (1Hr 5.35 (2Hp a) 15 6.039 6 0 179 (1Hp 2dp J = 4Hz) 6.90 8.4 (8H, m). 20 EXAMPLE 42 4-Nitrobenzyl 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(4cyanophenoxy)-7-oxo-4-thia-l-azabicy- clo[3,2,Olhept-2-en-2-carboxylate 89 mg of the above compound were obtained by a procedure analogous to that described in Example 19, using 350 mg of the unpurified product of Example 41 and 45 mg of imidazole.
( (CD01 3) 1.30 (3Hr d)J = ISEz) 30 2.55 UE, broad) 3.8 (1Hr dd.)J = 1.5Hz and 6Hz) 35 4.23 (1H, m) 5.25 (2Ht q) 5.70 UHyd>J = 1.5Hz) 40 7.15 - 8.20 (8HO 45 EXAMPLE 43 Potassium 5(R), 6(S)-(1(R)-hydroxyethyi)-3-(4-cyanophenoxy)-7oxo-4-thia-l-azabicyclo[3,2,0lhept-2-en-2-carboxylate 67 mg of the above compound were obtained from 1 0Orng of the corresponding 4- nitrobenzyl carboxylate (see Example 42) by a procedure analogous to that described in Example 50 21, using 21 mg of potassium bicarbonate.
T(D 2 0) 2.00 (311, d, J = 6Hz) 4.60 (1Hp dd) J = 1.5Hz and 6Hz) 4.81 UR9 m) 5.40 E20 (from D 20) 6.38 (1H, dp J - 1.5Hz) 7.8 - 84 (4H. m).
39 GB 2 151 630A 39 EXAMPLE 44
4-Nitrobenzyl 2-[3(S)-(1(R)-dimethyl-(2-methylprop-2-yl)-silyloxyethyl)4(R)-ethylthioazet idin-2- on- l -yl]-3-(4-tolyloxy)-3-trimethylacetylthio-propenoate 2.0 g of the above compound were obtained by a procedure analogous to that described in Example 16, using 2.0 g of 4-nitrobenzyl 2-[3(S)- {1 (R)-dimethyi-(2methyi-prop-2-yi)silyloxyethyi}-4(R)-ethyithio-azetidin-2-on-l-yi]acetate, 2.35 mi of bexamethyidisilazane, 0.873 9 of 4 tolyloxych loroth i onoform ate, 10.63 mmol of n-butyllithium, and 0.78 mi of trimethylacetyl chloride.
C(CDC1 3) 0.07 (6Ht a) 0.809 0.87 (9H9 2s) 1.09 1.10 (9H9 2s) 1.24 (3H ty J = 7Hz) 1.28 (311, d, J = 6Hz) 20 1.33 0HP 3) 2.75 (2H9 q# J = 7HZ) 25 3.20 (1H, dd, J = 2Hz and 4fiz) 3.90 - 4.36 (1R. m) 30 5.23 OFL, bs) 6.60 - 7.14 (411, 7.34 - 8.27 (4H, m).
EXAMPLE 45
4-Nitrobenzyl2-[3(S)-((R)-hydroxyethyl)-(-4(R)-ethytthioazetidin-2-on-lyl]-3 -(4-tolyloxy)-3-trime- 40 thylacetylthiopropenoate 258 mg of the above compound were obtained from 502 mg of the corresponding {l (R) dimethyi-(2-methylprop-2-yi)-silyloxyethyi} compound (see Example 44) by a procedure analo gous to that described in Example 17 using 5.5 mmoles of 6M HCI.
GB 2 151 630A 40 (CDC1 3 1.01, 1.09 GH, 2s) 1.30 (3119 t, J = 7Hz) 5 1.33 (3H9 do J = ISHz) 2.33 0HP 3) 10 2.64 (2E9 qt J = 7Hz) 3.22 (1H9 ddr J = 2Hz and 4Hz) 4.00 - 4.40 (1HW in) 15 5.22 (1H9 do J = 2Hz) 5.26 (2Hr 3) 20 6.73 - 7.18 (4Hr m) 7.32 - 8.20 (4Ht 25 EXAMPLE 46
4-Nitrobenzyi 2-[3(S)- (1 R-hydroxyethyl) -4(S)-chloroazetidin-2-on- 1 yl]-3-(4-tolyloxy)-3-trimethyl- 3-acetyithiopropenate The above compound was obtained by a process analogous to that described in Example 26 30 using 0.213 9 of the 1 (R)-hydroxyethylazetidinone derivative defined in Example 45 and a solution of 0.365 mmol chlorine in carbon tetrachloride. The product was used in the next reaction without purification.
(=1 3 1.06r 1.10 (9Ht 2s) 35 1.38 (3H# do J = 6Hz) 2.33 0HO S) 40 2.81 (1Ht bs) 3.60 (IH, dd, J - 4Hz, 9Hz) 45 4.02 - 4.47 (IH, m) 5.33 (2HO 8) 50 6.119 6.24 (1H9 2d# J 4Hz) 6.72 - 8.30 (8,qt MJ.
55 EXAMPLE 47
4-Nitrobenzyl 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(4-tolyfoxy)-7-oxo-4-thial-azabicyclo[3,2,0]hept - 2-en-2-carboxylate 89 mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 3 mmol of the unpurified product of Example 46 and 49 mg of imidazole. 60 41 GB2151630A 41 i max (CEC1 3) 1788 =71 (CD01 3) 1.31 OR9 do J = 6Hz) 2.36 OHY s) 2.60 (1H9 bs) 3.68 (1HO ddg J = 1JEz, and 6Hz) 10 4.00 - 4.40 (1H, 5.33 (2H9 q) 15 5.57 (1E9 do J = 1.5Hz) 7.12 (411p S) 20 7.36 - 8.29 (4Ho 25 EXAMPLE 48
Sodium 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(4-tolyloxy)-7-oxo-4-thia-lazabicyclo[3,2,0]hept -2-en- 2-carboxylate 69 mg of the above compound were obtained from 150 mg of the corresponding 4- nitrobenzyl carboxylate (see Example 47) by a procedure analogous to that described in Example 30 21, using 0.33 mmol of sodium bicarbonate.
EXAMPLE 49
4(R)-Ailylthio-3(S)-[1 (R)- (dimethyl-(2-methylprop-2-yl)silyloxyJ ethyl]azetidin-2-one To a stirred solution of 1. 14 mi of allyl mercaptan (7 0%) and 0.4 9 of sodium hydroxide in 35 mi of water under an argon atmosphere was added a solution of 2.87 9 of 4- acetoxy-3(S) [1 (R)- {d i methyl-(2-methyl prop- 2-y1)si lyloxy) ethyl]-azetidin-2-one in 10 mi of methanol. After 30 minutes, the mixture was partitioned between dichloromethane and water. The separated organic layer was washed with water, dried over M9S04, evaporated to dryness, and then chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 1.8 g of the 40 title compound as white crystals.
14max (CDC1 3) 3420, 1767 em71 45 (:5"' (CDCJ 3) 0.05 (6E, e) 0.88 GHO 3) 1.20 OR9 d. J 6 Ez) 50 2.9 - 3.2 0HP m) 3.9 - 4.3 (1HP m) 55 4.84 (IEt d)i 394 2 Ez) 4.95 - 6.3 0H. m) 60 7.28 (1H, broad e).
EXAMPLE 50
42 GB 2 151 630A 42 Methyl 2-(4(R)-allytthia-3(S)-[1(R)(dimethyi(2-methylprop-2- yl)silyloxyI ethyl] azetidin-2-on-l-yi) acetate To a stirred solution of 1. 76 g of 4 (R)-aiiyithio-3-(S)-[1 (R){dimethyi-(2-methylprop-2yi)silyloxyjethyi]azetidin-2-one in 60 mi dry DIVIF was added 3.52 9 of finely ground K2C03 and 0.6 m] of methyl bromoacetate. After 18 hours, the mixture was filtered and then partitioned between ethyl acetate and water. The separated organic layer was washed with water and dried over M9S04. Evaporation in vacuo afforded a crude product which was chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 1.56 g of the title compound as a pale yellow oil.
Vmax CD01 3 1753, and 1768 =71 c' (CDC1 3 0.06 (6Hr 15 0.86 ORY 1.23 (3Ht d J 6.5 Hz) 3.2 (3Hr m) 20 3.70 (3H9 0) 3.6 - 4.3 OH, m) 25 4.87 (1Ht d J2 Hz) 4.9 - 6.3 OE, m). 30 EXAMPLE 51
4-Nitrobenzyi 2-(4(R)-aliylthio-3(S)-[1 (R)- (dimethyl-(2-methylprop-2yi)-silyloxy) ethyl]-azetidin-2 on-l-y1)acetate To a stirred solution of3.04 g of 85% pure KOH in 80 m[ of 95% ethanol was added a solution of 16 g methyl 2-(4(R)-aiiyithio-3(S)-[1 (R)- {dimethyi-(2methylprop-2-yi)silyloxyj ethyl] azetidin-2-on-l -yi) acetate. After 10 minutes the mixture was evaporated to about one fifth of its volume; 100 mi of dimethyl acetamide was added, followed by a solution of 9.25 g of 4 nitrobenzyl bromide in 50 mi dimethylacetamide. After 1 hour, the mixture was partitioned between 0.01 M HCl and ethyl acetate. The separated organic layers were washed with 0.01 M HCI, with water, with cold saturated NaHCO, and with brine, were dried and evaporated. The crude product was chromatographed over silica gel; elution with ethyl acetate-hexane mixtures afforded 19.5 g of the title compound.
4 5 -,j max (CDC1 3 1755 and 1769 em-1 45 G(MC1 3 0.07 and 0.09 (6Hr two singlets) 0.68 (glit S) 50 1.25 CH9 d J 6 Hz) 3.2 (3HP m) 55 3.7 - 4.5 (3HP m) 4.95 (1H9 d J 2 Ez) 4.9 - 6.3 OR, m) 60 7.5 - 8.35 (4H9 m).
43 GB 2 151 630A 43 EXAMPLE 52
4-Nitrobenzyi 2-[2(S)-(1(R)-dimethyi-(2-methylprop-2-yl)silyfoxyethyl)4(R)-allylthioazeti din-2-onl-yl]-3-(4-chforophenoxy-3-trimethylacetylthio-propenoate 670 mg of the above compound were obtained by a procedure analogous to that described in Example 16, using 1 9 of 4-nitrobenzyl 2-[3(S)- {1 (R)-d i methyl-(2-m ethyl prop-2-y1)si lyloxyethyl) - 5 4(R)-aiiylthioazetidin-2-on-l-yi] acetate, 0.32 mi of 4-chlorophenyl chlorothonoformate, 0.95 mi of hexamethyidisilazane and 2.28 mi of 1.6M n-butyllithium, and 0.4 m] of pivaloyl chloride; and 1.0 mi of glacial acetic acid.
Vmax (CDC1 3) 1733 and 1759 0M71 10 (CDC1 3) 0.04 (6St a) 0.83 (91Hr B) 15 1.03 and 1.06 (9H. two singlets) 1.23 0H9 d J- 7 Rz) 20 3,0 - 3.4 0HP 2) 4.0 - 4.3 (1HP m) 25 4.9 - 6.0 (6H9 m) 6.s - 84 (8HP m) 30 EXAMPLE 53
4-Nitrobenzyl 2-[3(S)- (1 (R)-dimethyl-(2-methylprop-2-yl)-silyloxyethyl) -4(R)-chloroazetidin-2-on- 1 yll-3-(4-chforophenoxy)-3-trimethylacetylthio-propenoate The above compound was obtained by a process analogous to that described in Example 26 35 using 73 mg of the corresponding 4(R)-a 1 lyith ioazetid i none derivative (see Example 51) and a solution of 1. 24 mmol of chlorine in 0. 12 mi of carbon tetrachloride.
%-4 ma 1788em-1 NDIR 6"(CDC1 3 0.06 (6Ht s) 0.909 0.91 (9Ht 2s) 1.059 1.10 (9119 2s) 1.40 0H9 do J = 6 Ez) 3.40 (1H, dd 1.5Hz a-nd 8Hz) 4.00 - 4.40 (1H, m) 5.40 (2Hg S) 6.1 (1H d J = 1.5HZ) 6.8 4 8.5 (8H, m).
EXAMPLE 54 4-Nitrobenzyl 5(S), 6(S)- (1 (R)-dimethyi-(2-methylprop-2yi)silyfoxyethyl) 3-(4-chlorophenoxy)- 765 oxo-4-thia-l-azabicyclo[3,2, Olhept-2-en-2-carboxylate 44 GB 2 151 630A 44 108 mg of the above compound were obtained by a procedure analogous to that described in Example 19, using 200 mg of the unpurified product of Examples 53 and 24.8 mg of imidazole.
V max 17929 1800 (sh) 5 (CDC1 3 0.06 (6Ht 0.90p 0.929 (9Hr 2s) 10 1.38 (3H9 dg J7liz) 3.80 - 4.8 (2H, m) 15 5.22 (2H, q) 5.65 (1H9 dp J 4Hz) 6.90 - 8.50 (8HP m). 20 EXAMPLE 55
4-Nitrobenzyi 5(S)-3(4-chlorophenoxy)-6(S)-[1(R)-hydroxyethyll-7-oxo-4thia-l-aza-bicyclo [3,2,0- 25 lhept-2-ene-2-carboxylate To a solution of 108 mg of 4-nitrobenzyi 5(S)-3-(4-chlorophenoxy)-6(S)- {1 (R){dimethy]-(2 methyl prop-2-y1)si lyfoxy} ethyl} -7-oxo-4-th ia- 1 -azab icyclo[3,2, 0]hept-2-ene-2-ca rboxylate in 54.9 jul acetic acid at room temperature was added 54 td of a 1 molar THF solution of tetrabutylammonium fluoride. After the mixture had been stirred for 16 hours, it was partitioned 30 between ethyl acetate and water; the organic layer was separated, was washed with water, with saturated Nal-IC03 solution, with brine, and was then dried over MgSO, and evaporated in vacuo. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 33 mg of the title compound.
35 lvmaz (CDC1 3 1790 and 1800 =71 (OCI 3 1.40 (3H9 dp J = 7 HZ) 40 2q25 (1H, broad) 3.86 (1H, dd j 4.Tiz.ane- loHz) 45 4.4 (1H, m) 5,30 (2H, ABI J 14Hz) 5.70 GE, dy J 4Rz) 50 6.s - 8,5 (8E, 55 EXAMPLE 56
* Sodium 5(R)-3-(4-methylthiophenoxy)-6(S)-(1R-hydroxyethyl)-7-oxo-4-thia-lazabicycl o[3,2,0- lhept-2-ene-2-carboxylate 63 mg of above compound were obtained by a procedure analogous to that described in Example 2 1, using 84 mg of the corresponding 4-nitrobenzyl carboxylate (see Example 19) and 60 13 mg of sodium bicarbonate.
EXAMPLE 57
4-Nitrobenzyl 2-[3-(S)-(1(R)-dimethyl (2-methylprop-2-yl)-silyloxyethyi)4(R)-ethy[thio-azetidin-2on-l-yll-3-(2-fluorophenoxy)-3-trimethylacetylthio-propenate GB 2 151 630A 45 840 mg of the above compound were obtained by a procedure analogous to that described in Example 16, using 1 9 of the azetidinone starting material, 486 mg of 2-fluorophenoxy chlorothionoformate, 1.18 mls of hexamethy(silazone and 5.32 mmol of n-butyllithium, and 0.525 mi of trichloroacetyl chloride.
S (CD01 3) 1.15 2.67 3.22 4.02 5.30 5.39 6.9o 1764 em-1 0.06 (6Hy 0.81, 0.87 GH, 2s) 0.97p 1.05 (9H9 2s) - 1.33 (6HP m) (2Hp q, J 7 Hz) (1H, ddp J 2 Hz and 4 Hz) - 4.40 (1H9 m) (2H9 S) (1H9 dg J = 2 Hz) 8.27 (8H, m) " EXAMPLE 58 4-Nitrobenzyl 2-[4(R)-ethylthio-3(S)- (1 (R)-hydroxyethyl) azetidin-2-on- 1 -yll-3-(2-fluorophenoxy)-3trimethylacety[thio-propenate 434 mg of the above compound were obtained from 830 mg of the corresponding (l (R)- 35 d i methyl-(2-methyl prop- 2-yl)-s i lyloxyethyl compound (see Example 57) by a procedure analo gous to that described in Example 17, using 0.85 m] of water and 0.85 m] of concentrated hydrochloric acid.
v max 1760 cm-1 (CDC1 3) 1.01p 1.09 (9.Ht 2s) 1.21 - 1.48 (6H, m) 2.65 (1.Ht bs) 2.68 (2H, q# J 7 Ez) 3.23 (1E, ddp J 2 Hz and 4 HZ) 4.02 - 4.40 (IHI m) 5.30 OH, bs) 6.95 - 8.26 (8Ht m) EXAMPLE 59
4-Nitrobenzy]2-[4(S)-chloro-3(S)-(1(R)-hydroxyethyl)azetidin-2-on-l-ylj-3(2 -fluorophenoxy)-3-tri- 60 methylacetyithio-propenate 233 mg of the above compound was prepared by a procedure analogous to that described in Example 26 using 434 mg of the l(R)-hydroxyethyl azetidinone derivative defined in Example 58 and 0.78 mmof of chlorine in 1.01 mls carbon tetrachloride.
GB 2 151 630A 46 46 Ymax 1780 cm-1 6 (CDC1 3 1.0, 1.04 GH, 2s) 5 1.20 1.55 (6Hr m) 2.52 (1H, be) 10 3.5.11 (1H, dd, J = 4 Hz and 9 Hz) 3.95 4.48 (1H, m) 15 5.21 (2Hr S) 5.989 6.10 (1Ht 2dp J = 4 Ez) 6.87 - 8.15 (8H, m) EXAMPLE 60
4-Nitrobenzyl5(R)-3-(2-fluorophenoxy)-6(S)-(1(R)-hydroxyethyl)-7-oxo-4thia-1 -azabicyclo[3,2,0- 25 lhept-2-ene-2-carboxylate 58 mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 233 mg of the product of Example 59 and 54 mg of imidazole.
Vmax 17909 1795 (eh) em-1 (.r(CDCJ 3 1.37 OR9 dg J = 6 Hz) 2.22 (!Hw be) 3.75 (1H9 ddg J = 1.5 Hz and 6 Hz) 4.05 - 4.50 UHt m) 40 5.34 (2H9 q) 5. 62 (1Hp dy J = 1.5 Hz) 7.04 - 7.33 (4H, m) 7.39 - 8.22 (4H. m) EXAMPLE 61
Potassium 5(R)-3-(2-fluorophenoxy)-6(S)-(1(R)-hydroxyethyi)-7-oxo-4-thia1-azabicyclo[ 3,2,0- lhept-2-ene-2-carboxylate 56 mg of the above compound were obtained by a procedure analogous to that described in Example 21, using 58 mg of the corresponding 4-nitrobenzy] carboxylate (see Example 60) and 55 13 mg of potassium bicarbonate.
EXAMPLE 62
4-Nitrobenzyl 2-[3(S) (1 (R)-dimethyl(2-methylprop-2-yl)-sityloxyethyl) 4(R)-ethylthioazetidin-2on-l-yl)-3-(3-fluorophenoxy)-3-trimethylecetylthio-propenate 0.974 g of the above compound were obtained by a procedure analogous to that described in Example 16, using 1.0 g of 4-nitrobenzyl 2-[3(S)-{1(R)dimethyl-(2-methylprop-2-yi)silyloxyethyl}-4(R)-ethyithioazetidin-2-on-lyi] acetate, 1.34 m] of hexamethyidisilazane, 0.6 g of 3fluorophenylchlorothionoformate, 6.38 mmol of n--butyllithium, and 0.53 m[ of trimethylacetyl chloride.
47 GB 2 151 630A 47 ^max (001 3 1763 =71 (5 (CDC1 3) 0.06 (6HP S) 0.75, 0.60 GE9 2s) - 1.059 1.10 GR9 2s) 1.22 (3Ht to J 7 Hz) 10 1.25 OR, t, J 6 fiz) 2.71 (2Hr q) 15 3.22 (1Hp cl d) 4.0 - 4.5 UHt m) 20 5.35 0H9 bs) 6.8 _) 8.2 (SH, m) 25 EXAMPLE 63 4-Nitrobenzyl 2-[3(S)-(1(R)-hydroxyethyl)-4(R)ethylthioazetidin-2-on-l-yll-3-(3-fluorophe noxy)-3trimethylacetyithiopropenate 0. 516 9 of the above compound were obtained from 0. 9 7 g of the corresponding (l (R)dimethyi-(2-methylprop-2-yl)silyloxyethyi} compound (see Example 62) by a procedure analogous to that described in Example 17 using 2 mi of concentrated hydrochloric acid, 2 m] of water and 20 mi of tetrahydrofuran.
35 IR max (CDC13) 1762 cm-1 (CDC1 3) 1.069 1.10 (9Ep 2e) 40 1.20 - 1.30 (6Ht m) 2.50 (1Hp b) 2.70 (2Hp q) 45 3.24 (1E9 dd) 3.91 --:\l 4.40 (1Ht m) 50 5.30 (3Ht bs) 6.70 - 8.20 (SE9 m). 55 EXAMPLE 64 4-Nitrobenzyl 2-[3(S)(1 (R)-hydroxyethyi) -4(S)- chloroazetidin-2-on- 1 -yl]-3-(3-fluorophenoxy)-3-trimethylacetyithio- propenate 405 mg of the above compound were obtained by a process analogous to that described in Example 26 using 516 mg of the 1 (R)-hydroxyethylazetidinone derivative defined in Example 63 and a solution of 0.912 mmol of chlorine in 1.2 mi of carbon tetrachloride. The product was used in the next reaction without purification.
48 GB 2 151 630A 48 Vmax (CDCJ 3 1782 cm-' j (CDCJ 3) 1.069 1.10 (9 El 2s) 5 1.35 (3Hr d 2.5 (1Hy b) 10 3.5 UE, dd J = 4 Hz and 9 Hz) 4.05 (1H, m) 5.30 (2Hr s) 15 6.10 (1Hg dy J = 4 Hz) 6.80 - 8.30 (8H9 m) 20 EXAMPLE 65
4-Nitrobenzyl 5(R), 6(S)- (1(R)-hydroxyethyl)-3-(3-fluorophenoxy)-7-oxo-4thia- 1-azabicyclo[3,2,0- 25]hept-2-ene-2-carboxylate 205 mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 400 mg of the unpurified product of Example 64 and 56.2 mg of imidazole.
Vmax (CD01 3) 1784 CM-1 1790 (eh) cm-1 30 (g(CDCJ 3) 1.32 (3H9 d) 1.90 (1H9 b) 35 3.70 UE, dd J = 1.5 E and 6 Ez) 4.00 - 4.30 (1Hr m) 40 5.30 (2H# q) 5.56 (1H9 dy J = 1.5 Ez) 45 6.90 - 8.30 (8H, im) EXAMPLE 66
Potassium 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(3-fluorophenoxy)-7-oxo-4-thial-azabicyclo[3,2,0 - 50 lhept-2-ene-2-carboxylate mg of the above compound were obtained from 200 mg of the corresponding 4 nitrobenzyl carboxylate (see Example 65) by a procedure analogous to that described in Example 21, using 43.4 mg of potassium bicarbonate.
EXAMPLE 67
Pivaloyloxymethyl 3-(3-fluorophenoxy)-6(S)-(1(R)-hydroxyethyl)-7-oxo-4thia-1-azabicy- clo[3,2, Offiept-2-ene-2-carboxylate To a solution of 100 mg of potassium 3-(3-fluorophenoxy)-6(S)- {1 (R)- hydroxyethyi} -7-oxo-4thia-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in 1 mi of dimethylformamide was added 98 gi 60 of pivaloyloxymethyl iodide and the mixture was stirred at room temperature for 90 minutes. The mixture was partitioned between ethyl acetate and water, the organic layer was washed with water and brine, dried over magnesium sulphate and evaporated in vacuo to dryness. Chromatography over silica gel and elution with hexaneethylacetate afforded 50 mg of the title 65 compound as a yellow oil.
49 GB 2 151 630A 49 .(CDC1 3 1.20 (9Hp s)t 1.34 0Hr dp J 6Hz), 5 2.41 UHt bs)t 3.75 (1Hr ddp J 1.5Hz, 6Ez), 10 4.27 (1HP m)t 5.67 UE9 s)t 5.86 (2H9 q)v 15 6.81---7.45 (4HP 20 EXAMPLE 68 4-Nitrobenzyl 2-[4-(R)-ethyithio-3(S)- (1 (R)-dimethyi-(2- methylprop-2-yl)silyoxyethyl) azetidin-2-onl-yll-3-(2-cyanophenoxy)-3- trimethylacetylthiopropenate 0.56 g of the above compound were obtained by a procedure analogous to that described in Example 16, using 1 g of 4-nitrobenzyl 2-[3(S)- {1 (R)dimethyi-(2-methylprop-2-yi)silyloxyethyi} 4(R)-ethytthioazetidin-2-on-lyi]acetate, 1.34 mf of hexamethyidisilazane, 0.63 g of 2-eyanophenyl chlorothionoformate, 6.38 mmol of n-butyllithium, and 0.53 mi of trimethylacetyl chloride.
max (CDC1 3 1765 em-' 30 (CDC1 3) 0.07.(6Hg e)t 0.809 0.87 (9fit 2s) 35 1.109 1.15 (9Ht 2s)q 1.23 OH t J = 7Hz), 40 1.26 OH d J = 6Hz), 2.62 (2E9 q) 3.25 UE9 dpd)g 45 4.0 - 4.5 (1H9 m) 5.40 (311 bs), 50 7.10 - 8.50 (SH, m).
55 EXAMPLE 69
4-Nitrobenzyi 2-[4(R)-ethyithio-3(S)- (1 (R)-hydroxyethyl) azetidin-2-on1 -yl]-3-(2-cyanophenoxy)-3 trimethylacetylthiopropenate 0.220 g of the above compound were obtained from 0. 560 9 of the corresponding {1 (R) dimethyi-(2-methylprop-2-yl)silyloxyethylj compound (see Example 68) by a procedure analo gous to that described in Example 17 using 1.5 mi of concentrated hydrochloric acid, 1.5 m[ of water and 20 mi of tetrahydrofuran.
GB 2 151 630A 50 V max (CDCI 3) 6 (CDC1 3) 1763 =71 1.o6, 1.10 GEt 2s)l 1.20 - 1.40 (6Hr m)p 2.50 (1Hr b), 2.80 (2Hs, q)t 3.24 (1H9 dd)t 4.0 4.40 UR, m), 5.40 (3flo bs)t 7.10 - 8.35 (8Hr m) EXAMPLE 70 4-Nitrobenzyl 2[4(S)-chloro-3(S)- (1 (R)-hydroxyethyl) - azetidin-2-on- 1 -yl]-3-(2-cyanophenoxy)-3-tri25 methylacetylthio- propenate 1 0Z g OT the above compound were obtained by a process analogous to that described in Example 26 using 190 mg of the 1 (R)-hyd roxyethylazetid i none derivative defined in Example 69 and a solution of 0.33 mmol of chlorine in 0.688 mi of carbon tetrachloride. The product was purified by chromatography over silica gel, eluting with ethyl acetate/hexane mixtures.
5(max (CDC1 3 IS (CDC1 3) 1785 1.079 1.13 (9Ht 23)p 1.40 OH# m),.
1.5 (1H9 b)t 3.50 (1Hp ddp)p 4.06 - 4.60 (1H, 5.40 (2fit sq) 6.25 (1Ht do J = 4Hz) 7.00 - 8.5 (8HP M)# EXAMPLE 71
4-Nitrobenzyl 5(R)-3-(2-cyanophenoxy)-6(S)-(1(R)-hydroxyethyl)-7-oxo-4thia-1-azabicyclo [3,2, Olhept-2-ene-2-carboxylate 80 mg of the above compound were obtained by a procedure analogous to that described in 55 Example 19 using 130 mg of the product of Example 70 and 18 mg of imidazole.
0 51 GB 2 151 630A 51 max (CH 3 cl 3) 1792 =71 (CDC1 3) 1.30 (3H cl), 5 3.71 (1H dd J = 1.5Hz and J = 6Hz)o 4.00 4.30 URP M)o 10 5.20 (2E9 q)p 5.65 (1H, do J = 1.5 Hz).
6.90 - solo (8Hr My) 15 EXAMPLE 72
Potassium 5(R)-3-(2-cyanophenoxy)-6(S)-(1(R)-hydroxyethyl)-7-oxo-4-thia-lazabicyclo [3,2, Olhept-2-ene-carboxylate 62 mg of the above compound were obtained from 80 mg of the corresponding 4 nitrobenzylcarboxylate (see Example 71) by a procedure analogous to that described in Example 2 1, using 17.1 mg of potassium bicarbonate.
EXAMPLE 73
4-Nitrobenzyl 3-(3-acetoxyphenoxy)-2-[4(R)-ethylthio-3(S)- (1 (R)dimethyl-(2-methylprop-2-yl)silyfoxyethyl)-azetidin-2-on-l-yll-3-trimethylacetylthiopropenate 1.05 g of the above compound were obtained by a procedure analogous to that described in Example 16 using 1 g of 4-nitrobenzyl 2-[3(S)-{1(R)-dimethyi-(2- methylprop-2-yi)silyloxyethyi}4(R)-ethyithioazetidin-2-on-l-yi] acetate, 1.34 mi of hexamethyidisilazane, 0.98 9 of 3-acetoxy phenyl chlorothionoformate, 6.38 mmol of ri-butyllithium and 0.53 mi of trimethylacetylchlo ride.
Ymax (CD01 3 1760 cm-1 35 C(CDC1 3 0.06 (6H9 s)t 0.809 0.90 (9Hr 2s)p 40 1.05t 1.10 (9H9 2s), 1.22 0H9 to J = 7Hz), 45 1.25 OH d J 6Hz), 2.28 (3H,, S) 50 2.70 (2H, q), 3.30 (1H9 dd), 4.10 - 4.5 (1HP m) 55 5.36(3H9 bs)t 6.75 - 8.40 (8HP M) 60 EXAMPLE 74
4-Nitrobenzyl 3-(3-acetoxyphenoxy)-2-[4(R)-ethylthio-3S-(1(R)hydroxyethyl)-azetidin-2-on-l -yll- 3-trimethylthiopropenate(i) and 4-nitrobenzyl 2-[4(R)-ethylthio-3(S)-(1R- hydroxyethyl)azetidin-2-65 62 GB 2 151 630A 52 on-l-yl]-3-(3-hydroxyphenoxy)-3-trimethyI acetylthiopropenate (11) 88 mg of compound 1 above, and 110 mg of compound 11 were obtained from 400 g of the corresponding {1(R)-dimethyi-(2-methylprop-2- yi)silyloxyethyi} compound (see Example 73) by a procedure analogous to that described in Example 17 using 1 mi of concentrated hydrochloric acid, 1 m] of water and 10 mi of tetrahydrofuran. Compounds 1 and 11 were separated by column chromatography on silica gel, eiuting with ethyl acetate/hexane mixtures.
data for comDound (I) Y rn (CDC1 3) 1767 CM-1 10 (CD01 3) 1.079 1.13 OHy 2s)q 1.30 0HP t J = 7Hz)t 15 1.32 OH, d J = 6Hz)q 2.25 (1H bs)r 20 2.32 OH, 8)t 2.70 (2H9 q)g 25 3.28 UHt dd)p 3.90 - 440 (1HP M)v 5.30 0Hr be), 30 6.80 - 8.30 (8HP m).
35 data for compound (II) Ymax (CDCI 3) 1755 cm-1 40 (CD01 3) 1.051 1.12 OHy 2s)q 1.29 OHY t t J = 7a) 9 45 1.32 0H9 dp J =6Hz)j, 2.72 (2Hp q)p 2.85 (1Hr bs)p 50 3.26-(1Hg, dd)g 3.95 - 4.50 (1119 m) 55 5.35 (3Ht bs)p 6.40 - 8.30 (SH, m). 60 EXAMPLE 75
4-Nitrobenzyl 3-(3-acetoxyphenoxy)-2-[4(S)-chforo-3(S)-(1R-hydroxyethyl)azetidin-2-on-l-y ll-3- trimethylacetylthiopropenate 246 mg of the above compound were obtained by a process analogous to that described in Example 26 using 388 mg of the 3-(3-acetoxyphenoxy)- 1(Rhydroxyethylazetidinone derivative 165 53 GB2151630A 53 defined in Example 74 and a solution of 0.72mmol of chlorine in 1.49 mi of carbon tetrachloride. The product was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane mixtures.
Vmax (CD01 3) 1775 5 (CDC1 3) 1.079 1.13 (9H9 29)g 1.35 (3H, d)t 10 2.25 0Hr s)p 2.55 (1H9 bs), 15 3.50 (1H9 2.dd) 4.00 - 4.60 (1Ht 5.30 (2Hr e)g 20 6.15 (1H9 2d J = 4Ez).
6.80 - 8.30 (SH, m). 25 EXAMPLE 76 4-Nitrobenzyl 5(R)-3-(3-acetoxyphenoxy)-6(S)- (1 (R)- hydroxyethyl) - 7-oxo-4-thia- 1 -azabicy- clo[3,2,0]hept-2-ene-2-carboxylate mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 240rng of the ch loroazetid i none derivative defined in Example 75 and 31.6 mg of imidazole.
Ymax (CDC1 3) 1782 =71 1791 (sh) =71 35 (CDC1 3) 1.30 0H9 d)w 2.25 OH a) 40 2.60 (1Hp bs)p 3.71 UHt dd J = 1.5Hz and 6Hz), 45 3.90 - 4.40 (1H, m), 5.27 (2Hg q) 9 50 5.60 (IH, d J = 1.5 Hz), 6.80 - 8.20 (SH, m).
55 EXAMPLE 77
Potassium 5(R)-3-(3-acetoxyphenoxy)-6(S)-((1R)-hydroxyethyl)-7-oxo-4-thial-azabicyclo [3,2,0- lhept-2-ene-2-carboxylate 32 mg of the above compound were obtained from 115 mg of the corresponding 4 nitrobenzyl carboxylate (see Example 76) by a procedure analogous to that described in Example 21, using 23 mg of potassium bicarbonate.
54 GB 2 151 630A 54 -15 (D 20) 1.3 OH, d i 61Iz) 2.39 0H9 s) 3.95 (1H, dd J 1.5Hz and 6Hz) 4.30 OH, m) 4.80 (HOD) 5.70 (111, d J 1.511z) 7.10 - 7.5 (4H, m) EXAMPLE 78 20 4-Nitrobenzyi 2-[4(S)-chforo-3(S)-(1R-hydroxyethyllazetidin-2-on-l-ylj-3-(3-hydroxyphenox y)-3trimethylacetylthio-propenate 270 mg of the above compound were obtained by a process analogous to that described in Example 26 using 400 mg of the 3-(3-hydroxyphenoxy)-1 (R)hyd roxyethylazetid i none derivative 11 defined in Example 74 and a solution of 0.76mmol of chlorine in 1.6 mi of carbon tetrachloride. The product was purified by chromatography on silica gel, eluting with ethyl acetate/hexane mixtures.
Ymax (CD01 3) 1778 =71 (CDC1 3 1.01p 1.05 (9H9 2a) 30 1.35 (311p d)t 2.60 (1H vbs), 35 3.50 (1H9 dtd)p 4.00 - 4.50 (1H, m), 40 5.30 (2Ht S), 6.10 (1H, 2d J = 4Hz)r 45 6.40 - 8.30 (8Ht m)o EXAMPLE 79 4-Nitrobenzyi 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(3- hydroxyphenoxy)-7-oxo-4-thia-1-azabicyclo[3,2,Olhept-2-en-2-carboxylate mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 265 mg of the ch loroazetidi none derivative defined in Example 78 and 37.4 mg of imidazole.
GB 2 151 630A 55 ^Vmax (CDC1 3) 1780 em-' 1790 (Sh) em71 (CD01 3) 1.32 (3Hp d)g 3.10 (1H bs)p 3.80 (1H9 ddp J = 1.5 Hz, and 6 Ez), 10 4.00 - 4.40 (1H, m).
5.30 (2H q)g 5.70 (IH d J = 1.5 Hz). 15 6.40 8.20 (SH m), 8.70 (IH bs). 20 EXAMPLE 80 Potassium 5(R), 6(S)-(1(R)-hydroxyethyi)-3-(3-hydroxyphenoxy)7-oxo-4-thia-azabicyclo[3,2,025]hept-2-ene-2-carboxylate mg of the above compound were obtained from 98 mg of the corresponding 4- nitrobenzy] carboxylate (see Example 79) by a procedure analogous to that described in Example 21, using 21.3 mg of potassium bicarbonate.
EXAMPLE 81
4-Nitrobenzyl 3-(4-dimethylaminasulphonylphenoxy)-2-[4-(R)-ethylthio-3S(l (R)-dimethyl-(2-me thylprop-2-yl)silyloxyethyi) azetidin-2-on- 1 -yll-3- trimethylacetylthiopropenate 0.93 g of the above compound were obtained by a procedure analogous to that described in Example 16, using 1.3 9 of the azetidinone starting material defined in Example 16, 1.45 mi of hexamethyidisilazane, 1 g of 4-dimethylaminosulphonylphenyl chlorothionoformate, 6.88 mmol 35 of n-butyllithium, and 0.68 mi of tri methyl acetylch 1 orid e.
(5 CDC1 3 0.70 (6Ht s)r 40 0.819 0.90 ORs 2s)r 1.07t 1.15-(9Hp 2s)o 45 1.20 ORP to J = 7Hz), 1.30 OH d J = 6Ez), 50 2.75 (6H s)p 3. 27 (1E dd 1 J. 211z and 4Hz) 4.3 (1119 m), 55 5.3 OH, m), 7.2 - 8.35 (811, m) 60 EXAMPLE 82 4-Nitrobenzyl 3-(4-dimethylaminosulphonylphenoxy)-2-[4(R)ethylthio-3(S)-(1R-hydroxyethyl) az65 etidin-2-on-l-yll-3trimethylacetyithio propenate 56 GB 2 151 630A 56 0.57 9 of the above compound was obtained from 0.930 g of the corresponding {II(R)dimethyi-(2-methylprop-2-yl)silyloxyethyl} compound (see Example 81) by a procedure analogous to that described in Example 17 using 1.3 mi of concentrated hydrochloric acid, 1.25 mi of water and 5 m[ of tetrahydrofuran.
5 max (CD01 3 17289 1761 cm-1 (CDC1 3) 1.029 1.11 (9H9 2s)q 10 1.20 (3H9 t)l 1.25 (3H9 d)q 2.52 (1H9 bs)p 15 2.68 (6Hr s)p 2.80 (2H9 q), 20 3.24 (1H9 dd)v 4.0 4.40 UR9 m), 25 5.30 OH bs)t 7.10 - 8.30 (8R-m)t 4.10 - 4.50 (1H, m). 30 5.35 OR9 bs)t 761 8.4 (8H9 m). 35 EXAMPLE 83 40 4-Nitrobenzyl 2-[4(S)-chforo-3(S)- (1 (R)-hydroxyethyl) - azetidin-2-onl-yl]-3-(4-dimethylaminosulphonylphenoxy)-3- trimethylacetylthio-propenate 445 mg of the above compound were obtained by a process analogous to that described in Example 26 using 560 mg of the 1 (R)-hyd roxyethylazetid i none derivative defined in Example 82 and 1 mi of a 0.85 molar solution of chlorine in carbon tetrachloride. The product was purified by chromatography over silica gel, eluting with ethyl acetate/hexane mixtures.
57 GB 2 151 630A 57 Tmax (CD01 3 17839 1730 em-' 6 (CDC1 3 1.07t 1.12 (glit 2a) 5 1.40 OH, d) 2.50 (ing bs)g 10 2.75 (6H9 e) 3.60 (1Hp m) 15 4.05 - 4.50 (1Hr m) 5.35 (2Hr a)# 20 6.2 (1Hp do J = 4]iz) 7.1 - 8.3 (8H, m). 25 EXAMPLE 84
4-Nitrobenzyl5(R)-3-(4-dimethylaminosulphonylphenoxy)-6(S)-(1(R)hydroxyethy l)-7-oxo-4-thia1-azabicyclo[3,2,Olhept-2-ene-2-carboxylate 225 mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 445 mg of the chloroazetidinone derivative defined in Example 83 and 50 mg of imidazole.
max (CDC1 3 17899 1793 (sh) cm-1 (CDC1 3) 1.35 (3Ht dy J = 6Hz) 40 2.60 (1H9 be)g 2.83 (6Hp s)P 45 3.80 (1R dd J = 1.5Hz and J = 6Hz), 4.00 - 4.40 (1H, m), 5.30 (2Hp q# 2H9 AB, J gem 14Hz), 50 5.73 (1H9 dg J = 1.5Hz).
7.2 - 8.3 (SH, m), 55 EXAMPLE 85 Potassium 5(R)-3-(4-dimethylaminosulphonylphenoxy)-6(S)-(1(R)hydroxyethyl)-7-oxo-4-th ia-160 azabicyclo[3,2, Offiept-2-ene-2carboxylate 70.8 mg of the above compound were obtained from 112 mg of the corresponding 4nitrobenzyl carboxylate (see Example 84) by a procedure analogous to that described in Example 21, using 20.4 mg of potassium bicarbonate.
EXAMPLE 86
58 GB 2 151 630A 58 4-Nitrobenzyl 2-[3(S)- (1 (R)-dimethyl-(2-methylprop-2-yi)sityloxyethyi) 4(R)-ethytthioazetidin-2-on 1 -yil-3-(3-nitrophenoxy)-3-trimethylacetylthio-propenoate mg of the above compound were obtained, as a yellow oil, by a procedure analogous to that described in Example 16, using 2.0 g of the azetidinone starting material defined in Example 16, 1.3 g of 3-nitrophenyl chlorothionoformate, 2.2 mi of hexamethyidisilazane and 5 10.1 mmol of n-butyllithium, and 1.5 mi of trimethylacetyi chloride.
-im::1x(lbc,730, 1765 cm-1 6 (CD01 3) 0.06 (6H S)t 10 0.809 0.85 (9Hr 2s)p 1.00 (9HP S), 15 1.10 - 1.30 (6HP M)t 2.64 (2HO q, J = 7Ez), 20 3.19 (1R9 M)q 4.00 - 4.45 (1H9 M)r 25 5.25 (3Hp bs)t 7.00 - 8.10 (8HO m).
30 EXAMPLE 87
4-Nitrobenzyi 2-[3(S)-(1(R)-hydroxyethyl)-4(R)-ethylthioazetidin-2-on-lyi]-3-(3-nitrophen oxy)-3- trimethylacetyithio-propenoate 0. 7 5 5 g of the above compound were obtained f rom 1. 7 g of the corresponding {1 (R) dimethyi-(2-methylpro-2-yi)silyloxyethyi} compound (see Example 86) by a procedure analogous to that described in Example 17, using 1.7 m] of water and 1.7 m] of concentrated hydrochloric acid.
40,X CCDO, 3) 17309 1762 cm-1 (CD01 3) 1.06p 1.16(9H9 2s)q 1.20 - 1.38 (6H. m), 3.75 (2Hp q# J 7Hz).
3.29 (1H9 ddp J 2Hz and 4Hz), 3.98 - 4.4 0 (1Ht m), 5.27p 5.30 (3H9 2 bs,)y 7.25 - 8.18 (SHP m)o EXAMPLE 88 60 4-Nitrobenzyi 2-[3(S)- (1 (R)-hydroxyethyll -4(S)- chloroazetidin-2-on- 1 -yl]-3-(3-nitrophenoxy)-3-trimethylacetylthio- propenoate To a stirred solution of 0.755 g of the 1(R)-hydroxyethylazetid i none derivative defined in Example 87 in CDC13 at - 40C was added a solution of 1.3 mmol of chlorine in carbon tetrachloride and the solution was stirred for 1 hour. The reaction mixture was warmed to room temperature and evaporated to dryness. Chromatography over silica gel and elution with 59 GB 2 151 630A 59 hexane/ethyl acetate mixtures afforded 0.536 9 of the title compound.
V max (CDC1 3) 1729, 1784 =71 (CDC1 3 1.029 1.08 (9Hi 2s)v 1.15 OR, do J = 6Hz), 2.45 (1Hp bis)g 10 3.56 UR9 dd J = 4Hz and 9Hz).
3.90 - 4.57 URP m)v 15 5.34 (2Hg s)p 6.16 (1Hp do J = 4Hz), 20 7.40 - 8.33 (8H9 m).
EXAMPLE 89 4-Nitrobenzyl 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(3nitrophenoxy)-7-oxo-4-thia-l-azabicyclo [3,2, Olhept-2-en-2-carboxylate 0. 176 g of the above compound were obtained by a procedure analogous to that described in Example 19 using 0.299 g of the 4(S)-ch loroazeti d i none of Example 88 and 0.0668 g of 30 imidazole.
Y max CCDC1 3) 1712, 1789 cm-1 35 9 (CDC1 3) 1.32 (3H9 do J = 6Hz), 2.20 (1H bs)p 3.80 -.3.90 (IH, m)r 40 4.10 - 4.40 UK, m).
5.33 (2Hp q)l 5.72 (1H, do J = 1.5Hz). 45 7.48 - 8.25 (SHP m).
50 EXAMPLE 90
4-Nitrobenzyl 5(R), 3-(3-aminophenoxy)-6(S)-(1(R)-hydroxyethyl)-7-oxo-4thia-l-azabicyclo [3,2, 0]hept-2-en-2-carboxylate 1 A mixture of a solution of 0. 17 5 g of 4-n itrobenzy] 5 (R), 6 (S)- {1 (R)-hydroxyethyl} -3-(3 nitrophenoxy)-7-oxo-4-thia-l-azabicyclo [3,2, 0]hept-2-en-2-carboxyl ate in ethyl acetate and 25 55 mg of Adams catalyst (platinum dioxide) was hydrogenated at 50 p.s.i. for 105 mins. The mixture was filtered through Celite (Trade Mark) and evaporated to dryness. Chromatography over silica gel and elution with hexane/ethyl acetate mixtures afforded 75 mg of the title compound, as a yellow solid.
GB 2 151 630A 60 V max CeDel 3) 1778 cm-1 6((CD 3)2 CO) 1.30 (3H. m), 3.70 - 3.85 (1Hr m)# 3. 98 - 4.40 (1H9 m) 5.32 (2H9 q)i 5.70 (1H9 dg J = 1JEz).
6 -55 - 7.30 (4E. m), 7.55 - 8.16 (4Hr m).
EXAMPLE 9 1
Potassium 5(R). 3-(3-aminophenoxy)-6(S)-(1(R)-hydroxyethyl)-7-oxo-4-thial-azabicyclo [3,2, Olhept-2-en-2-carboxylate 59 mg of the title compound were obtained by a procedure analogous to that described in Example 21 using 66 mg of 4-nitrobenzyl 5(R), 3-(3-aminophenoxy)-6(S){1(R)-hydroxyethyl}-7oxo-4-thia-l-azabicyclo [3,2,Olhept-2-en-2carboxylate and 15 mg potassium hydrogen carbonate and 10% palladium /charcoal.
EXAMPLE 92 30 4-Nitrobenzyi 3-[4-(cyanomethyi)phenoxy]-2-[3(S)- (1 (R)dimethyi-(2-methylprop-2-yl)silyloxyethyll -4(R)-ethylthioazetidin-2-onyil-3-trimethylacetylthiopropenate 326 mg of the above compound were obtained by a procedure analogous to that described in Example 16, using 0.5 g of the azetidinone starting material defined in Example 16, 1.66 m] of ri-butyllithium, 0.59 mi of hexamethyidisilazane, 0.525 mi of trimethylacetyl chloride, and 0.269 g of 4-(cyanomethyi)phenyl chlorothionoformate.
max (CDC1 3 6 (CDC1 3) EXAMPLE 93
1762 cm-1 9 2240 cm-1 0.05 (6H. s), 0.79t 0.85 (9Hr 2s)q 1.039 1.07 (9H9 2a)# 1.21 (3Ht ti, J = 7HIZ), 1.25 (3fit dp J = 6Hz).
2.60 (2H9 qp J = 7Hz).
3.23 URt ddq J = 2Hz. 4Hz).
3.73 (2H9 s)v 3.97 5.25 6.85 - 4.44 (1HP m), (3H9 bs) - 8.25 (8HP m).
61 GB 2 151 630A 61 4-Nitrobenzyl 3-[4-(cyanomethyi)phenoxy]-2-(4(R)-ethy[thio-3(S)-{1(R)hydroxyethyll-azetid in-2- on-1 -yi]-3-trimethylacetyithiopropenate 159 mg of the above compound were obtained by a procedure analogous to that described in Example 17 using 348 mg of the corresponding {1 (R)-d i methyl-(2-m ethyl prop-2-y1)si lyl oxyethyl} compound (see Example 92), 0.5 mi of concentrated hydrochloric acid, and 0.5mi of water. 5 (CDC1 3) 1760p (CD01 3) 1.079 1.28 1.35 2.38 2.72 3.23 3.71 3.95 - 4.40 (1Hr M)p 5.27 Mr bs)g 6.86 8.23 (8119 m).
2240 =71 1.12 (9H, 2s)q 0Hr tt J = 7Hz).
CHq dt J = 6Hz). (1H9 bs)l, (2H, qg J = 7Hz), (1Ht ddp J = 2Hz + 4HZ)r (2HP S)? EXAMPLE 94 4-Nitrobenzyi 2-[4(S)-chloro-3(S) (1 (R)-hydroxyethyl) - azetidin-2-on- 1 -yl]-3-[4-(cyanomethyi)phe35 noxy]-3trimethylacetylthiopropenate mg of the above compound were obtained by aprocess analogous to that described in Example 26 using 100 mg of the 1 (R)-hyd roxyethylazetid i none derivative defined in Example 93 and 0.21 mi of a 0.85 molar solution of chlorine in carbon tetrachloride. The product was purified by chromatography over silica gel, eluting with ethyl acetate/hexane mixtures.
Ymax (CDC1 3) 1780 =719 2242 =71 6(CD01 3) 1.089 1.14 OR, 2a)t (3Hp dp J 6Hz).
2.40 (1H9 bs)p (1H9 ddy J 4Hz)r (2Hr S) 4.05 - 4.55 (1H, m), 55 5.32 (2Hr s)g 6.17 (1H, dy J = 4Hz) 60 6.89 - 8.28 (6Ht m).
EXAMPLE 95 65
62 GB 2 151 630A 62 4-Nitrobenzyi 5(R)-3-[4-(cyanomethyl)phenoxy]-6(S)-(1(R)-hydroxyethyi)-7oxo-4-thia-l-azab icyclo[3,2, Olhept-2-ene-2-carboxylate 61 mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 190 mg of the eh loroazetid i none derivative defined in Example 94 and 28 5 mg of imidazole.
(CDC1 3) 1785, 1795 (sh) and 2242 =71 (CDC1 3) 1.38 (3Hr do J = 6Hz). 10 2.39 (1H, bs)p 3.80 OR9 m)t 15 4.05 - 4.43 (IHP m)t 5.34 (2Hr q)v 20 5.68 (IHo do -T = 1.5Hz).
7.09 - 7.40 (4HP m)p 7.43 - 8.31 (4Hr m). 25 EXAMPLE 96
Potassium 5(R)-3-[4-(cyanomethyl)phenoxy]-6(S)-(1(R)-hydroxyethyl)-7-oxo4-thia-l-azab icy- 30 clo[3,2, 0]hept-2-ene-2-carboxylate 13 mg of the above compound were obtained from 60 mg of the corresponding 4-nitrobenzyl carboxylate (see Example 95) by a procedure analogous to that described in Example 21 using 12.5 mg of potassium bicarbonate.
EXAMPLE 97
4-Nitrobenzyl 5(R), 6(S)- (1 (R)-acetoxyethyl) -3-(4-fluorophenoxy)- 7oxo-4-thia- 1 -azabicyclo[3,2, 0 lhept-2-ene-2-carboxylate To a stirred solution of 100 mg of 4-nitrobenzy] 3-(4-fluorophenoxy)-6(S)- {1 (R)-hydroxyethyi} 7-oxo-4-thia-l-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in 3 mi of tetrahydrofuran at OC was 40 added a solution of 3 mg of dimethylaminopyridine in 0.5 mi of acetic anhydride. After 30 minutes, the reaction mixture was warmed to room temperature, partitioned between ethyl acetate and water, the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulphate, and evaporated in vacuo to dryness. Chromatography over silica gel and elution with ethyl acetate-hexane mixtures afforded 74 mg of the title compound.
63 GB 2 151 630A 63 6(CDC1 3) 1.40 0H9 d. J=6Hz).
2.01 Mr s)t 3.80 UR9 dd. J=1.5Hzt 6Hz).
4.99 - 5.26 (1HP M)p 5.29 (211p q) v 10 5.51 UE9 d, J=1.5Hz).
6.87 - 7.23 (4H, m). 15 7.34 - 8.22 (4119 m).
20 EXAMPLE 98 4-Nitrobenzyl 5(R), 6(S)-(1(R)-benzoyloxyethyi)-3-(4cyanophenoxy)-7-oxo-4-thia-l-azabicyclo[3,2, Olhept-2-ene-2-carboxylate 70 mg of the above compound were obtained from the corresponding 1 (R)hydroxyethyl compound (defined in Example 42) by a procedure analogous to that described in Example 97, using 100 mg of the 1 (R)-hydroxyethyl compound, 1 mi of tetrahydrofuran, 1 mg of dimethylaminopyridine, 33 mg of benzoyl chloride and 18 mg of pyridine.
gS (CDC, 3 1.3 0HP d. J=6Hz) 30 3.95 (1Hp ddt J=1.5 and 6liz) 5.29 (3119 m) 35 5.6 (1Ht d. J=1.5Hz) 7.0 - 8.2 (13H9 m). 40 EXAMPLE 99 4-Nitrobenzyl 5(R), 6(S)-(1(R)-acetoxyethyl)-3-(4methyisulphinylphenoxy)-7-oxo-4-thia-l-azabicyclo[3,2, Olhept-2-ene-2carboxylate 71 mg of the above compound were obtained as an oil, from 100 mg of the corresponding 1 (R)-hydroxy compound (defined in Example 20) by a procedure analogous to that described in Example 97 using 25 gi of acetic anhydride, 1 mi of tetrahydrofuran, and 2 mg of dimethylaminopyridine.
6(CD01 3 1.36 (3119 d, J=6Hz) 2.02 0HP 8) 2.74 OR S) 3.85 (1Hr ddr J=1.5 and 6R4 5.3 (3Ht m) 5.8 (1Hr d J=1.5HZ) 7.0 - 8.3 (8Hr m).
64 GB 2 151 630A 64 EXAMPLE 100
4-Nitrobenzyl 5(R), 6(S)-(1(R)-(phenoxyacetoxy)ethyl)-3-(4methylsulphinylphenoxy)-7-oxo-4-thia- 1 -azabicyclo-[3,2, Olhept-2-ene-2-carboxylate 53 mg of the above compound were obtained from 170 mg of the corresponding 1 (R)- 5 hydroxyethyl compound (see Example 20) by a procedure analogous to that described in Example 97 using 86.2 mg of phenoxyacetyl chloride, 40 mg of pyridine and 1 mi of tetrahydrofuran.
0 (CDC1 3 1.35 0H9 d J=6Hz) 10 2.73 (3Hr 3) 3.96 (1H, dd J=1.5 and 6Hz) 15 4.4 (2-Hr m) 5.1 (2Hp m) 20 5.31 (2Hr m) 5.78 (IHy d J=1.5Hz) 25 7.0 - 8.3 (13HP m).
EXAMPLE 101
4-Nitrobenzyi5(R)-3-(2-fluorophenoxy)-6(S)-(1(R)pivaloyloxymethyloxyethyl)-7 -oxo-4-thia-l-aza- 30 bicyclo-[3,2, Olhept-2-ene-2-carboxylate To a stirred solution of 50 mg of the corresponding 1 (R)-hydroxyethyl compound (see Example 60) and 96 mg of pivaloyloxymethyl iodide in 1 mi of tetrahydrofuran was added portionwide 125 mg of silver oxide. The crude product was filtered, was evaporated in vacuo and then chromatographed on silica gel. Elution with ethyl acetate/hexane mixtures afforded the 35 title compound as an oil.
V = (CDC1 3) 1795 =71 cS(CDC1 3 - 1.20 (9Hr 40 1.38 OH d J=6Hz't 3.85 (1Ht dd J=1.5 and 6Hz) 45 4.5 (1E, m) 5.33 (2Ht m) 50 5.80 Mr bs) 7.15 - 8.25 (8H9 m).
EXAMPLE 102 Potassium 5(R), 6(S)-(1(R)-acetoxyethyll-3-(4-fluorophenoxy)7-oxo-4-thia-l-azabicyclo[3,2,0 lhept-2-ene-2-carboxylate 47 mg of the above salt were obtained from 74 mg of the corresponding 4- nitrobenzyl 60 carboxylate (see Example 97) by a procedure analogous to that described in Example 21, using 14 mg of potassium bicarbonate and 100 mg of 10% I'd on carbon.
EXAMPLE 103
66 Potassium 5(R), 6(S)-(1(R)-acetoxyethyl)-3-(4-methyisulphinylphenoxy)7-oxo-4-thia-l-azabicy - 65 GB 2 151 630A 65 clo[3,2, O)Ihept-2-ene-2-carboxylate 41 mg of the above salt were obtained by a procedure analogous to that described in Example 21 from 55 mg of the corresponding 4-nitrobenzyl carboxylate (see Example 99) using 10 mg of potassium bicarbonate and 50 mg of palladium on charcoal.
EXAMPLE 104 Potassium 3-(2-fluorophenoxy)-(5R), 6(S)-(1(R)pivaloyloxymethyloxyethyll-7-oxo-4-thia-l-azabicyclo[3,2, Olhept-2-ene-2carboxylate 13 mg of the above salt were obtained as a yellow, oily solid by a procedure analogous to that described in Example 2 1, using 15 mg of the corresponding 4- nitrobenzyl carboxylate (see 10 Example 101) 2.6 mg of potassium bicarbonate and 20 mg of 10% palladium on charcoal.
EXAMPLE 105 Potassium 5(R), 6(S)-(1(R)-benzoyloxyethyll-3-(4cyanophenoxy)-7oxo-4-thia-1-azabicyclo[3,2, Olhept-2-ene-2-carboxylate 48 mg of the above salt were obtained from 65 mg of the corresponding 4nitrobenzyl carboxylate (see Example 98) by a procedure analogous to that described in Example 21, using 11.4 mg of potassium bicarbonate.
EXAMPLE 106 Potassium 5(R), 6(S)-(1(R)(phenoxyacetoxy)ethyl)-3-(4methyisulphinylphenoxy)-7-oxo-4-thia-1 azabicyclo-[3,2, Olhept-2-ene-2carboxylate 34 mg of the above salt were obtained from 40 mg of the corresponding 4- nitrobenzyl carboxylate (see Example 100) by a procedure analogous to that described in Example 21 using 6.3 mg of potassium bicarbonate.
EXAMPLE 107
2-Methyloxycarbonyl-3-thienyl chlorothionotormate To a vigorously stirred solution of 20 g of methyl 3-hydroxythiophene-2- carboxylate and 15 mi of thiophosgene in alumina-dried chloroform at 0' was added dropwise a solution of 5.1 g of 30 sodium hydroxide in 50 mi of water. The mixture was then warmed to room temperature, was stirred for a further 105 minutes, and then partitioned. The organic layer was separated, was washed with ice-cold water, with brine and thoroughly dried over CaC12. Evaporation in vacuo afforded a yellow-orange oil which solidified on standing.
6(cDcl 3) 3.65 (3Hts) 6.95 (1Htd J=6 Ez) 7.055 (1Htd J=6 Ez).
EXAMPLE 108
4-Nitrobenzyi 2-[3(S)- 1 (R)-dimethyl(2-methylprop-2-yl)-silyfoxyethyl4(R)-ethylthio-azatidin-2-onl-yl]-3-(2-methyloxycarbonyl-3-thienyloxy)-3-trimethylacetylthiopropenate 580 mg of the above compound were obtained by a procedure analogous to that described in Example 16, using 1 g of the azetidinone starting material, 4.90 mg of 2- methyloxycarbonyi-3 thienyl chloroformate (see Example 107), 1.18 mi of hexamethyidisilazane and 5.32 mmol of nbutyllithium and 0.525 mi of trichforoacetyl chloride.
66 GB 2 151 630A 66 )rm= (CDC1 3) 1765 em:-' (CDCI 3) 0.06 (6H9 0.81, 0.87 GE9 2s) 0.98, 1.05 (9Hp 2s) 1-1-1.35 (6Hr m) 10 2.70 (2H9 q J=7HZ) 3.23 (1HI, dd.1=2Hz and 4Hz) 15 3.85 OH, a) 4.0-4.4 (1HP m) 20 5.3 (2Hp a) 5.40 (1H9 d 9, J=2HZ) 25 6.9---8.3 (6Hr m).
EXAMPLE 109
4-Nitrobenzyl 2-[4(R)-ethylthio-3(S)- (1 (R)-hydroxyethyi) -azetidin-2-on1 -yil-3-(2-methyloxycarbo nyi-3-thienyloxy)-3-trimethylacetyithiopropenate 290 mg of the above compound were obtained from 570 mg of the corresponding {1(R) dimethyi-(2-methylprop-2-yi)-silyloxyethyi} compound (see Example 108) by a procedure analo gous to that described in Example 17, using 0.5 m] of water and 0.5 mi of concentrated 35 hydrochloric acid.
Ymal (CDC1 3) & (CD01 3) 1760 =71 1.019 1.09 (9Ht 2s) 1.2-1.48 (ISHP m) 2.5 UHt be) 2.65 (2Hp q J=6HZ) 3.25 UR, dd J=2HZ and 4HZ) 50 3.85 OH,.5) 4.0-4.4 (1H, m) 55 5.3 (3Ht bs) 6.9-8.27 (6H, m).
60 EXAMPLE 110
4-Nitrobenzyl 2-[4(S)-chloro-3(S)-(1(R)-hydroxyethyl)-azetidin-2-on-l-yll3-(2-methyloxyca rbonyl- 3-thienyloxy)-3-trimethylacetylthiopropenate 145 mg of the above compound were prepared by a procedure analogous to that described in65 67 GB 2 151 630A 67 Example 26 using 290 mg of the 4-(R)-ethylthio azetidinone derivative defined in Example 109 and 0.49 mmol of chlorine in 1.5 mi carbon tetrachloride.
Vmax (CD01 3) 1780 em71 5 (CDC1 3) 1.09 1.04 GE9 2s) 1.2-1.6 (6H, m) 2.5 (1H9 be) 3.52 (1Hr dd J=4Hz and 7Hz) 3.85 0HP a) 15 3.95-4.5 (lfip m) 5.20 (2Hp s) 20 5.99 (1H9 d J=4Hz) 6.9-8.2 (BE, 25 EXAMPLE 111 4-Nitrobenzyl 5(R). 6(S)-(1(R)-hydroxyethyl)-3-(2methyloxycarbonyl-3-thienyloxy)-7-oxo-4-thia1-azabicyclo-[3,2,Olhept-2-ene-2-carboxylate 68 mg of the above compound were obtained by a procedure analogous to that described in Example 19 using 145 mg of the product of Example 110 and 16 mg of imidazole.
Vrnaz (CDC1 3 1793 em-1 35 6(CDC1 3 1.37 0H9 do.1=6HZ) 2.2 (1H9 be) 40 3.7 (4Hr 4.01-4.5 (1H, m) 5.34 (2HW q) 45 5.62 URP do J=1.5HZ) 6.91-8.2 (6HP m) - 50 EXAMPLE 112 Potassium 5(R), 6(S)-(1(R)-hydroxyethyl)-3-(2methyloxycarbonyl-3-thienyloxy)-7-oxo-4-thia-l 55 azabicyclo[3,2, Olhept2-ene-2-carboxylate 49 mg of the above compound were obtained by a procedure analogous to that described in Example 21, using 60 mg of the corresponding 4- nitrobenzyl carboxylate (see Example 111) and 11.8 mg of potassium bicarbonate.

Claims (39)

1. A compound of the general formula 1 68 GB 2 151 630A 68 E arr 3 - A -S k2 ORI 0. J C002 in which R represents a hydrogen atom or a carboxyl esterifying group, R' represents a phenyl, naphthyl, thieny], pyridy], quinoly] or isoquinoly] group bonded at a ring carbon atom to the oxygen atom attached to the 2-position of the penem ring structure, a group R' being unsubstituted or substituted by one, two or three substituents, which may be the same or different, selected from halogen atoms and -OH, -NH,, -NO,, -CN, -N3, R'-, R 30-, 15 R3S-, R3-SO-, R 3 -S02-, R3-CO-, R30-CO-, R 3- CO-0, H2N-CO-, R3 R3 p R 3\ 3 N-t "\I-C 0- 9 20 il/ R3 v RY / R3 R3 25 N-00-NH-9 LN-CO-NE-9 H-CO-0-9 H / 113 E / 30 R3 R3 N-00-0-t N-CO-0-1 R3_Co_NE_P 35 NH2-CO-NH-, R 3-SO,NH-, NH2-SO2-NH-, H2N-SO,-, 40 p3 R3 R3EN N-SO 2 -NE-t N-SO -1%7H- 9 pY 2 45 H."/ H1PN R3 11 2 9 p3Y p3pY N-SO 2 a = H-9 C = K-, 11 2 K H 2 X R3pY R3 0 = N-P N-S02-P 60 R3 E "I' -CF3, -SCF3, -SOCF3, -S02CF3. and HO-CO- groups, in which R3, R3' and R 3" each represents an alkyl group having from 1 to 4 carbon atoms, R3, RY' and R 3 being the same or 65 69 GB 2 151 630A 69 different, and R 2 represents a hydrogen atom, or a hydroxyl group which may be protected by a hydroxyl protecting group.
2. A compound as claimed in claim 1, wherein R' represents an unsubstituted phenyl group or a phenyl group substituted by a chlorine, fluorine, trifluoromethyl, methyl, methoxy, nitro, 5 cyano, amino, methylthio, methylcarbonylamino, methyisulphonylamino or methylaminocarbony lamino group, or a phenyl group substituted by two or three methyl or methoxy groups, or a heterocyclic group having one or two methyl substituents.
3. A compound as claimed in claim 1, wherein R' represents a phenyl group substituted by a hydroxy, acetoxy, methyisulphinyl or methyisulphonyl group.
4. A compound as claimed in any one of claims 1 to 3, wherein an esterified carboxyl group -COOR is an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heterocyclic or heterocyclic- aliphatic alcohol having up to 20 carbon atoms or is a silyl or stannyl ester.
5. A compound as claimed in claim 4, wherein a carboxyl esterifying group R is removable 15 by hydrolysis, by photolysis, by reduction or by enzyme action to give the free acid, or by any two or more of such methods.
6. A compound as claimed in claim 4 or claim 5, wherein R represents a pnitrobenzyi, phthalidyl, pivaloyloxymethyl, acetyimethyl or acetoxymethyl group.
7. A salt of a compound of formula 1 as claimed in any one of claims 1 to 3, in which R 20 represents a hydrogen atom.
8. A salt as claimed in claim 7, being a physiologically tolerable salt.
9. A process for the production of a compound of the general formula 1 as claimed in claim 1 or a salt thereof, which comprises reacting a compound of the general formula 11 25 R4 CE3 C-' 2 R 30 35 in which R, R' and R 2 are as defined in claim 1, R4 represents a chlorine or bromine atom, and R' represents an alkyl group having from 1 to 4 carbon atoms, or a phenyl group, with a base and, if desired, carrying out any one or more of the following steps in any desired 40 order; (a) converting an ester of formula 1 into the corresponding free acid, (b) converting a free acid of formula 1 into an ester thereof, (c) transesterifying a compound of formula 1, (d) converting a free acid or an ester of formula 1 into a salt, or a salt into the free acid, an 45 ester, or another salt, (e) removing any protective groups present other than an esterifying group R, (f) converting a substituent of a group R' into another substituent of W, (g) converting a free hydroxy group R2 into a hydroxy group protected by a group removable physiologically, or converting a hydroxy group R 2 that is not removable physiologically into a 50 hydroxy group protected by a group that is removable physiologically.
10. A process as claimed in claim 9, wherein the base is inorganic.
11. A process as claimed in claim 9, wherein the base is a primary amine, an alkali metal alkoxide in the corresponding alcohol, or a heterocyclic base having a pK, , within the range of from 5 to 9.
12. A process as claimed in claim 11, wherein the heterocyclic base is pyridine or a substituted pyridine.
13. A process as claimed in claim 11, wherein the heterocyclic base is imidazole.
14. A process as claimed in any one of claims 9 to 13, carried out in a mixture of a water miscible solvent and from 5 to 20% (v/v) of water.
15. A process as claimed in any one of claims 9 to 14, wherein a compound of formula 11 is produced by halogenating a compound of the general formula Ill GB 2 151 630A 70 6 E3 - 011'2 R2 0JIN 0 aC Irr 1 '-\'.1 COOR SCOR5 M in which R, R', R 2 and R' are as defined in claim 9 and R6 represents an alkyl group having from 1 to 8 carbon atoms, an alkenyl group having up to 15 4 carbon atoms, or a phenyl group.
16. A process as claimed in claim 15, wherein the halogenating agent is molecular chlorine, molecular bromine, sulphuryl chloride, sulphuryl bromide, t-butyihypochlorite, or cyanogen chloride.
17. A process as claimed in claim 15 or claim 16, wherein a compound of formula Ill is 20 produced by reacting, in the presence of a base, a compound of the general formula IV CE3 - C, "2 11 SRI rv 25 12 R 0 CH 1 2 COOR 30 in which R, R' and R6 are as defined in claim 15, with a compound of formula IX S 11 Cl-C-OR1 IX in which R' is as defined above, followed by reaction with an activated carboxylic acid derivative which comprises the group R5 as defined in claim 9.
18. A process as claimed in claim 17, wherein the base has a pK,,:-:-20.
19. A process as claimed in claim 17 or claim 18, wherein the activated acid derivative has the formula X 0 H R5-C-Cl X in which R 5 is as defined in claim 9.
20. A process as claimed in any one of claims 17 to 19, wherein a compound of formula IV 50 is produced by reacting a compound of formula V H 5 5 cH3 - CHi 12 X - NH V in which R 2 and R6 are as defined in claim 15, with a compound of formula V111 Y1CH2CO2R VIII in which R is as defined in claim 1 and Y' represents a group that is capable of being replaced 65 by a nucleophilic group.
71 GB 2 151 630A 71
21. A process as claimed in claim 20, wherein Y1 represents a halogen atom or a sulphonyloxy group of the formula -0so,Rg in which R9 represents a lower alkyl or -CF3 group, or a phenyl group which is unsubstituted or is substituted by a p-nitro, p-bromo or pmethyl group.
22. A process as claimed in claim 20 or claim 21, wherein a compound of formula V is produced by reacting a compound of formula VI CH 2 12 V1 in which R 2 is as defined in claim 1 and Y represents a group that is capable of being replaced by a nucleophilic group, with a compound of formula VII W-S-R 6 VII in which R 6 is as defined in claim 15 and W' represents a hydrogen atom or an alkali metal atom.
23. A process as claimed in 21 or claim 22, wherein Y represents an acyloxy group, a 25 sulphonyl group or a halogen atom.
24. A process as claimed in claim 23, wherein Y represents a lower alkylcarbonyloxy group, a chlorine atom or a group -S02R 7 in which R' represents an alkyl group having from 1 to 4 carbon atoms or an aryl group.
25. A process as claimed in any one of claims 15 to 24, wherein R 6 represents an allyl 30 group or an ethyl group.
26. A process as claimed in claim 9, wherein the compound of formula 11 has the formula X11 R4 35 CE3 CH 1 X11 OH 0 N,,-rICOR5 40 COOR 'OR' in which R, W, R 4 and R5 are as defined in claim 9.
27. A process as claimed in claim 26, wherein a compound of formula X11 is produced by - 45 halogenating a compound of formula XI sill 0 CE3 - CH -!Nf 50 W1 N\ -'sCOR5 xi 0 C z-- W r OR' 55 16.
in which R, R, R5 and R' are as defined in claim 15.
28. A process as claimed in claim 27, wherein the halogenating agent is as defined in claim
29. A process as claimed in claim 27 or claim 28, wherein a compound of formula X] is produced by removing a protecting group R2 , from a compound of formula Ill as defined in claim 15, wherein R2 represents a hydroxyl protecting group R 2
30. A process as claimed in claim 29, wherein a hydroxy protecting group R2. is removable 65 under acidic conditions.
72 GB 2 151 630A 72
31. A process as claimed in claim 30, wherein R2 represents a tetrahydropyranyl or a tetrahydrofuranyl group; an acetal or ketal group; a silyl ester group or a stannyl group.
32. A process as claimed in claim 31, wherein an acetal or ketal group has the formula - C -OR10 W' R 12 in which W' and R 12, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, or W' and R12 together with the carbon atom to which they are attached, 10 represent a cycloalkyl ring having from 4 to 7 carbon atoms, or a tetra hyd ropyra nyl ring, and R10 represents a lower aikyl group.
33. A process as claimed in claim 31, wherein a silyl ester has the formula -SiR 13 R 14 R's in which R13, R14 and R15, which may be the same or different, each represents a lower alkyl group or an aryl group and a stannyl group has the formula -SnRI6RI1R18 in which W6, W and R18, 15 which may be the same or different, each represents a lower alkyl group.
34. A process as claimed in claim 31, wherein R2 , is a tetrahydropyranyl, 2-methoxyprop-2yL trimethylsilyl, triethylsilyl or t-butyidimethyisily] group.
35. A process as claimed in any one of claims 30 to 34, wherein a group 112. is removed using moderately concentrated hydrochloric acid in tetrahydrofuran, t- butylammonium fluoride in 20 an acidic medium, or aqueous hydrogen fluoride.
36. A process as claimed in any one of claims 26 to 35, wherein a compound of formula XI having 3SAR-stereochemistry is halogenated, and the resulting mixture of 4S and 4R isomers of compound XII is treated with a base to give a mixture of 5R and 5S isomers of compound 1.
37. A process as claimed in any one of claims 26 to 35, wherein a compound of formula XI 25 having 4R-stereochemistry is halogenated, the resulting mixture of 4S and 4R isomers is separated and the 4S-isomer is treated with a base to give predominantly the 5R isomer of formula 1.
38. A process as claimed in any one of claims 29 to 37, wherein a compound of formula Ill is produced by a process as claimed in any one of claims 17 to 25.
39. A compound of formula Ill as claimed in claim 4, whenever produced by a position as claimed in any one of claims 5 to 13 or claim 31.
Printed in the United Kingdom for Her Majesty's Stationery Office, Dd 8818935. 1985. 4235. Published at The Patent Office, 25 Southampton Buildings, London. WC2A 1 AY, from which copies may be obtained.
39. A process as claimed in any one of claims 9 to 38, wherein any free carboxyl group in a compound of formula 11, Ill, IV, XI or XII is esterified.
40. A process as claimed in any one of claims 9 to 39, wherein a carboxyl esterifying group R in a compound of formula It, Ill, W, XI or XII is converted into another carboxyl esterifying group R.
41. A modification of a process as claimed in any one of claims 9 to 40, wherein in a compound of formula 11, Ill, XI or XII or in more than one of these compounds, a substituent of a group R' is converted into another substituent of W.
42. A process as claimed in claim 9(f) or claim 41 wherein one or more of the following interconversions is or are carried out: R 3S_ to R 3SO_ R 3S_ to R 3SO_ to R 3SO,_ N02- to NI-12-, which is then optionally alkylated or acylated, -CN- to--CH,NH2, -ditto- -N, to NH,, ditto- HO- is alkylated or acylated R 3CO_O_ to 1-10-, which is then optionally alkylated or acrylated, Halogen to -SH, -S021-1, -S03N or -CH, R 3 being as defined in claim 1.
43. A modification of a process as claimed in any one of claims 9 to 42, wherein a 50 substituent of R' is produced by conversion of another substituent that does not itself fall within the definition of R1.
44. A process as claimed in claim 9, carried out substantially as described in any one of Examples 7, 8, 11, 12, 19 to 23, 27, 28, 32, 33, 37, 38, 42, 43, 47, 48, 54 to 56, 60, 61, 65, 66, 67, 71, 72, 76, 77, 79, 80, 84, 85, 89 to 91, 95 to 106, and 112 herein.
45. A process as claimed in claim 15, carried out substantially as described in any one of Examples 6, 10 and 53.
46. A process as claimed in claim 17, carried out substantially as described in any one of Examples 5, 9, 16, 24, 29, 34, 39, 44, 52, 57, 62, 68, 73, 81, 86, 92 and 108 herein.
47. A process as claimed in claim 20, carried out substantially as described in any one of Examples 2, 14 and 50 herein.
48. A process as claimed in claim 22, carried out substantially as described in any one of Examples 1, 13 and 49 herein.
49. A process as claimed in claim 26, carried out substantially as described in any one of Examples 19, 27, 32, 37, 42, 47, 60, 65, 71, 76, 79, 84, 89, 95 and 111 herein.
73 GB 2 151 630A 73 50. A process as claimed in claim 27, carried out substantially as described in any one of Examples 18, 26, 31, 36, 41, 46, 59, 64, 70, 75, 78, 83, 88, 94 and 110 herein.
51. A process as claimed in claim 29, carried out substantially as described in any one of Examples 17, 25, 30, 35, 40, 45, 58, 63, 69, 74, 82, 87, 93 and 109 herein.
52. A process as claimed in claim 40, carried out substantially as described in any one of Examples 2 to 4, 15 or 51 herein.
53. A compound as claimed in clairn 1, or a salt thereof, whenever pMuced by a process as claimed in any one of claims 9 to 52.
54. A compound of formula 1 or a salt thereof as claimed in any one of claims 1 to 8 or claim 53, having R-stereochemistry at position 5.
55. A compound of the general formula 1 or a salt thereof, as claimed in any one of claims 1 to 8, claim 53 or claim 54, wherein R2 represents a free hydroxy group or a protected hydroxy group.
56. A compound as claimed in claim 55, having S-stereochemistry at position 6.
57. A compound as claimed in claim 55 or claim 56, having Rstereochemistry at position 15 8.
58. A compound of the general formula 1 or a salt thereof, as claimed in any one of claims 1 to 8 or claim 55, wherein R2 represents a free hydroxy group or a protected hydroxy group, having R-stereochemistry at position 5, S-stereochemistry at position 6 and R-stereochemistry at position 8.
59. A compound of the general formula 1 or a salt thereof, as claimed in any one of claims 1 to 8 and 53 to 58, wherein R 2 represents a hydroxy group that is physiologically removable.
60. A compound as claimed in claim 59, wherein a physiologically removable protecting group has the formula R19CO- or R20_ in which R19 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms, a phenyl group, or a phenoxyalkyl group in which the alkyl moiety is straight chained or branched and has up to 4 carbon atoms; and R 20 represents an alkanoyloxy- 30 methyl group in which the alkane moiety is a straight or branched chain alkyl group having up to 4 carbon atoms.
61. A compound as claimed in claim 60, wherein a group R19 is a methyl, ethyl or t-butyl group, or a phenoxymethyl group, and a group R 20 is an acetoxymethyl or piva loyloxy methyl group.
62. A compound of formula 1 as claimed in claim 1 or a salt thereof, substantially as described in the Table herein.
63. A compound of formula 1 as claimed in claim 1 or a salt thereof, substantially as described in any one of Examples 7, 8, 11, 12, 19 to 23, 27, 28, 32, 33, 37, 38, 42, 43, 47, 48, 54 to 56, 60, 61, 65, 66, 71, 72, 76, 77, 79, 80, 84, 85, 89 to 91, 95 to 106, and 112.
64. A pharmaceutical preparation which comprises a compound of formula 1 as claimed in any one of claims 1 to 6 or 53 to 63, or a physiologically tolerable salt thereof or a mixture of two or more of such substances as active ingredient, in admixture or conjunction with a pharmaceutical ly suitable carrier.
65. A pharmaceutical preparation as claimed in claim 64, which also comprises one or more other pharmaceutical ly active substances..
66. A pharmaceutical preparation as claimed in claim 65, wherein the other substance is an antibacterial substance.
67. A pharmaceutical preparation as claimed in claim 66, wherein the antibacterial substance has a P-lactam ring.
68. A pharmaceutical preparation as claimed in any one of claims 64 to 67, in unit dosage form.
69. A pharmaceutical preparation which comprises an active ingredient as defined in claim 64 in unit dosage form.
70. A pharmaceutical preparation which comprises an active ingredient as defined in claim 64 and one or more further active substances as defined in any one of claims 65 to 67.
71. A pharmaceutical preparation as claimed in claim 70, in unit dosage form.
72. A pharmaceutical preparation as claimed in any one of claims 68, 69 and 71, which comprises from 10 to 2000 mg of the active ingredient per unit dose.
73. A pharmaceutical preparation as claimed in any one of claims 64 to 72, in a form suitable for oral administration.
74. A pharmaceutical preparation as claimed in claim 73, wherein the active ingredient is a compound as claimed in any one of claims 59 to 63.
75. A compound of the general formula 11 74 GB 2 151 630A 74 R4 CE3 - C-' 12 5 0 COOR R 10 in which R, R', R 2, R 4 and R5 are as defined in claim 9. 76. A compound of the general formula Ill 11 SK, cH 3 - 12 RC11 0;[::., "C.C".COR COOR Ort' M in which R, W, R2, R5, and R 6 are as defined in claim 15.
CLAIMS New claims or amendments to claims filed on Superseded claims all New or amended claims:- A compound of the general formula 11 E4 30 CE Ca.
12 IT a SCOR5 35 in which R represents a hydrogen atom or a carboxyl esterifying group, R' represents a phenyl, naphthyl, thienyl, pyridy], quinolyl or isoquinolyl group bonded at a 40 ring carbon atom to the oxygen atom attached to the 2-position of the penem ring structure, a group R' being unsubstituted or substituted by one, two or three substituents, which may be the same or different, selected from halogen atoms and -OH, -NH, -N02, -CN, - N, R 3_, R 30-, R3S-, R 3_SO-, R 3 -SO, R 3-CO-, R 30-CO, R 3-CO-0-, H2NCO-, R 3 R R 3 3 \,co ET co H R 1:1 50 R 3 T-CO-1,1.H-, 1/ H R 3 1. ccl-i-lIH- T-CC-O-, 3./ R R J R 3 !-CO-0-, R CO---.ti-, R 3 117.1 2-CO-'-,7H-, R 3 -SO 2_ 1,-,-1 2-SC 2!-.n-, H 2 S 0 2-' R 3 Y.1,_ S 0 2 IM-, M-SO -MH_ 3 /-" 2 H R11-50 - ' 7 R 3 IR 31 1 C 20 3,, R 3 R 1-1, 1--- H --2 p 3 H-17 \1 2 \C C IT 2 IT / C = r_ F 1111;, T-SO 2' -CF, -SCF, -SOCIF,, -S02CF3 and HO-CO- groups, in which R', R and R311 each represents an alkyl group having from 1 to 4 carbon atoms, R3, IRV and R3t, being the same or different, R2 represents a hydrogen atom, or a hydroxyl group which may be protected by a hydroxyl protecting group, R 4 represents a chlorine or bromine atom, and R5 represents an alkyl group having from 1 to 4 carbon atoms, or a phenyl group.
2. A process for the production of a compond of formula 11 as claimed in claim 1, which 30 comprises halogenating a compound of formula Ill GB2151630A 75 SR CH,_ CT1 2- 12 N ROCC OR' SCCR- in which R, W, R2 and R5 are as defined in claim 1, and R 6 represents an alkyl group having 40 from 1 to 8 carbon atoms, an alkenyl group having up to 4 carbon atoms, and a phenyl group.
3. A process as claimed in claim 2, wherein the halogenating agent is molecular chlorine, molecular bromine, sulphuryl chloride, sulphuryl bromide, t- butyihypochlorite, and cyanogen chloride.
4. A compound of the general formula Ill ú1 CH 3_ CH, I- - SCOR ROOC OR 1 in which R, R', R5 and R 6 are as defined in claim 2.
5. A process for the production of a compound of formula Ill as claimed in claim 4, which 55 comprises reacting, in the presence of a base, a compound of the general formula IV 76 GB2151630A 76 E SR6 3 Ca12r R 0 C3 1 2 0001R 17 in which R, R' and R 6 are as defined in claim 2, with a compound of formula IX S 11 Cl- C-OR' IX in which R' is as defined above, followed by reaction with an activated carbodylic acid derivative which comprises the group R5 as defined in claim 1.
6. A process as claimed in claim 5, wherein the base has a pK.>_-20.
7. A process as claimed in claim 5 or claim 6, wherein the activated acid derivative has the 20 formula X 0 11 R5- C-Cl X in which R5 is as defined in claim 1.
8. A process as claimed in any one of claims 5 to 7, wherein a compound of formula IV is produced by reacting a compound of formula V H SR6 j2 CH3 CH27 -NE V in which R 2 and R6 are as defined in claim 2, with a compound of formula Vill Y1-CH2COIR Vill in which R is as defined in claim 1 and Y1 represents a group that is capable of being replaced by a nucleophilic group.
9. A process as claimed in claim 8, wherein Y' represents a halogen atom or a sulphonyloxy 45 group of the formula -OSO2R9 in which R9 represents a lower alkyl or -CF, group, or a phenyl group which is unsubstituted or 50 is substituted by a p-nitro, p-bromo or p- methyl group.
10. A process as claimed in claim 8 or claim 9, wherein a compound of formula V is produced by reacting a compound of formula V1 T 55 CE2 - CH 12 V1 NE 60 in which R 2 is as defined in claim 1 and Y represents a group that is capable of being replaced by a nucleophilic group, with a compound of formula V11 W-S-R6 V11 77 GB2151630A 77 in which R6 is as defined in claim2 and R' represents a hydrogen atom or an alkali metal atom.
11. A process as claimed in 9 or claim 10 wherein Y represents an acyloxy group, a sulphonyl group or a halogen atom.
12. A process as claimed in claim 11 wherein Y represents a lower alkylc#rbonyloxy group, a chlorine atom or a group -S02R 7 in which R7 represents an alkyl group having from 1 to 4 5 carbon atoms or an aryl group.
13. A process as claimed in any one of claims 4 to 12, wherein R' represents an allyl group or an ethyl group.
14. A compound as claimed in claim 1, which has the formula XII R4 10 CE3 - CS 1 X11 COR5 15 0 1 "1- 1 COOR OR in which R, W, R 4 and R 5 are as defined in claim 1.
15. A process for producing a compound as claimed in claim 14 which comprises 20 halogenating a compound of formula XI SR6 CH3 - CH U= N SCOR5 25 1 OR1 COOP.
in which R, R', R 5 and R6 are as defined in claim 2.
16. A process as claimed in claim 15, wherein the halogenating agent is as defined in claim 3.
17. A process as claimed in claim 15 or claim 16, wherein a compound of formula X] is produced by removing a protecting group R2 from a compound of formula Ill as defined in claim 35 2, wherein R' represents a hydroxyl protecting group R'.
18. A process as claimed in claim 17, wherein a hydroxy protecting group R 2 is removable a under acidic conditions.
19. A process as claimed in claim 18, wherein R2 represents a tetra hyd ropyra nyl or a tetrahydrofuranyl group; an acetal or ketal group; a silyl ester group or a stannyl group.
20. A process as claimed in claim 19, wherein an acetal or ketal group has the formula 40 - C -OR' W' R 12 12 in which W' and R, which may be the same or different, each represents a hydrogen atom or a lower alkyl group, or R' I and R12 together with the carbon atom to which they are attached, represent a cycloalkyl ring having from 4 to 7 carbon atoms, or a tetrahydropyranyl ring, and R10 represents a lower alkyl group.
2 1. A process as claimed in claim 19, wherein a silyl ester has the formula -SiR 1 -M 14 W' in 50 which W', W' and R15, which may be the same or different, each represents a lower alkyl group or an aryl group and a stannyl group has the formula -SnR"R'7R111 in which W6, R 17 and R", which may be the same or different, each represents a lower alkyl group.
22. A process as claimed in claim 19, wherein R2 is a tetrahydropyranyl, 2-methoxyprop-2 a yL trimethylsilyl, triethylsilyl or t-butyidimethyisilyl group.
23. A process as claimed in any one of claims 18 to 22, wherein a group R 2 is removed a using moderately concentrated hydrochloric acid in tetrahydrofuran, t- butylammonium fluoride in an acidic medium, or aqueous hydrogen fluoride.
24. A process as claimed in claim 2, wherein a compound of formula Ill is produced by a process as claimed in any one of claims 4 to 23.
25. A process as claimed in claim 2 or any one of claims 4 to 23, wherein any free carboxyl group in a compound of formula 11, Ill, IV, XI or XIII is esterified.
26. A process as claimed in claim 2 or any one of claims 4 to esterifying group R carboxyl esterifying group R.
23 wherein a carboxyl in a compound of formula 11, Ill, IV, X] or XII is converted into another 78 GB 2 151 630A 78 27. A modification of a process as claimed in claim 28, any one of claims 4 to 23, wherein in a compound of formula It, Ill, XI or X11 or in more than one of these compounds, a substituent of a group R' is converted into another substituent of W.
28. A process as claimed in claim 27, wherein one or more of the following interconversions is or are carried out: R 3S_ to R 3SOR 3S_ to R'SO- to R3S02N02- to NH,-, which is then optionally alkylated or acrylated, -CN to -CH2NH2, -ditto- -N3 to -NH2 -ditto- 1-10- is alkylated or acylated R3CO-0- to HO-, which is then optionally alkylated or acylated, Halogen to -SH, -SO,H, -S03N or -CN, R3 being as defined in claim 1.
29. A modification of a process as claimed in claim 2 or any one of claims 9 and 4 to 23, 15 wherein a substituent of R' is produced by conversion of another substituent that does not itself fall within the definition of W.
30. A process as claimed in claim 2, carried out substantially as described in any one of Examples 6, 10 and 53.
31. A process as claimed in claim 5, carried out substantially as described in any one of 20 Examples 5, 9, 16, 24, 29, 34, 44, 52, 57, 62, 68, 73, 81, 86, 92 and 108 herein.
32. A process as claimed in claim 8, carried out substantially as described in any one of Examples 2, 14 and 50 herein.
33. A process as claimed in claim 10, carried out substantially as described in any one of Examples 1, 13 and 49 herein.
34. A process as claimed in claim 14, carried out substantially as described in any one of Examples 19, 27, 32, 37, 42, 47, 60, 65, 71, 76, 79, 84, 89, 95 and 111 herein.
35. A process as claimed in claim 15, carried out substantially as described in any one of Examples 18, 26, 31, 36, 41, 46, 59, 64, 70, 75, 78, 83, 88, 94 and 110 herein.
36. A process as claimed in claim 17, carried out substantially as described in any one of Examples 17, 25, 30, 35, 40, 45, 58, 63, 69, 74, 82, 87, 93 and 109 herein.
37. A process as claimed in claim 26, carried out substantially as described in any one of Examples 2 to 4, 15 or 51 herein.
38. A compound as claimed in claim 1, whenever produced by a process as claimed in claim 2 or claim 30.
GB08500841A 1981-07-08 1985-01-14 The invention provides compounds of the formula i Expired GB2151630B (en)

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GB2161161A (en) * 1984-06-29 1986-01-08 Hoechst Uk Ltd Antibacterial 7-oxo-4-thia-1-azabicyclo/o.3 2 0/-hept-2-ene derivatives
GB2197864A (en) * 1984-06-29 1988-06-02 Hoechst Uk Ltd 7-oxo-4-thia-1-azabicyclo(3,2,0)hept-2-ene derivatives
GB2197865A (en) * 1984-06-29 1988-06-02 Hoechst Uk Ltd Azetidinone derivatives

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DE3274982D1 (en) * 1981-07-08 1987-02-12 Hoechst Uk Ltd Antibacterial penem derivatives
ES8504203A1 (en) * 1982-07-08 1985-04-01 Hoechst Uk Ltd Antibacterial penem derivatives.
US4595539A (en) * 1983-06-10 1986-06-17 Pfizer Inc. Preparation of penem derivatives and azetidinone intermediates
US4725678A (en) * 1983-06-10 1988-02-16 Pfizer Inc. Azetidinone intermediates for the preparation of penem derivatives
US4619783A (en) * 1983-06-10 1986-10-28 Pfizer Inc. Process and intermediates for the preparation of penem derivatives
GB2164334B (en) * 1984-09-10 1988-08-03 Hoechst Uk Ltd Antibacterial 7-oxo-4-thia-1-azabicyclo 3,2,0 hept-2-ene derivativess
GB8605549D0 (en) * 1986-03-06 1986-04-09 Erba Farmitalia Penem derivatives
DE3618813A1 (en) * 1986-06-04 1987-12-10 Hoechst Ag PHARMACEUTICAL PREPARATION FOR TREATING BACTERIAL INFECTIONS
GB2195627A (en) * 1986-08-12 1988-04-13 Hoechst Uk Ltd Penem derivatives
AT392903B (en) * 1987-10-08 1991-07-10 Hoechst Ag Pharmaceutical preparation containing a cephalosporin and a penem antibiotic
US5075439A (en) * 1990-08-17 1991-12-24 Pfizer Inc. Processes for (3S,4R)-3-[1(R)-t-butyl-dimethylsilyloxy)-ethyl]-4-[1-oxo-3-thiolanylthio(thiocarbonyl)thio]azetidin-2-ones and intermediates therefor

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US4168314A (en) * 1977-11-17 1979-09-18 Merck & Co., Inc. 6-(1'-Hydroxyethyl)-2-aminoethylthio-pen-2-em-3-carboxylic acid
JPS5625110A (en) * 1978-12-18 1981-03-10 Bristol Myers Co Antibacterial
US4293555A (en) * 1979-04-17 1981-10-06 Merck & Co., Inc. 6- and 6,6-Disubstituted-2-substituted-oxapen-2-em-3-carboxylic acids
JPS56115788A (en) * 1980-02-19 1981-09-11 Sankyo Co Ltd Azetidinone derivative and its preparation
ATE21105T1 (en) * 1980-11-06 1986-08-15 Hoechst Uk Ltd 7-OXO-4-THIA-1-AZA(3.2.0)HEPTANE AND 7-OXO-4-THIA-1-AZA-(3.2.0)HEPT-2-EN DERIVATIVES.
US4347183A (en) * 1981-02-02 1982-08-31 Schering Corporation Process for the synthesis of penems and carbapenems

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Publication number Priority date Publication date Assignee Title
GB2161161A (en) * 1984-06-29 1986-01-08 Hoechst Uk Ltd Antibacterial 7-oxo-4-thia-1-azabicyclo/o.3 2 0/-hept-2-ene derivatives
GB2197864A (en) * 1984-06-29 1988-06-02 Hoechst Uk Ltd 7-oxo-4-thia-1-azabicyclo(3,2,0)hept-2-ene derivatives
GB2197865A (en) * 1984-06-29 1988-06-02 Hoechst Uk Ltd Azetidinone derivatives
GB2197864B (en) * 1984-06-29 1989-05-17 Hoechst Uk Ltd Antibacterial 7-oxo-4-thia-1-azabicyclo(3.2.0)-hept-2-ene derivatives
GB2197865B (en) * 1984-06-29 1989-05-17 Hoechst Uk Ltd Azetidinone derivatives
GB2161161B (en) * 1984-06-29 1989-05-24 Hoechst Uk Ltd Antibacterial 7-oxo-4-thia-1-azabicyclo/o.3 2 0/-hept-2-ene derivatives

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PT75197A (en) 1982-08-01
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IL66245A0 (en) 1982-11-30
EP0069377A2 (en) 1983-01-12
GB8500841D0 (en) 1985-02-20
KR840000557A (en) 1984-02-25
AU7097487A (en) 1987-08-27
IE821641L (en) 1983-01-08
GB2151630B (en) 1986-02-12
GB2102798A (en) 1983-02-09
GB2102798B (en) 1985-12-11
DE3278689D1 (en) 1988-07-28
FI77661B (en) 1988-12-30
ES8305366A1 (en) 1983-04-01
KR890001885B1 (en) 1989-05-29
FI77661C (en) 1989-04-10
ES513672A0 (en) 1983-04-01
AU8570282A (en) 1983-01-13
ES8308567A1 (en) 1983-09-16
FI822401L (en) 1983-01-09
EP0069377A3 (en) 1983-04-13
AU7097287A (en) 1987-08-27
FI822401A0 (en) 1982-07-06
IE54585B1 (en) 1989-12-06
EP0069377B1 (en) 1988-06-22
PT75197B (en) 1985-01-07
CA1225392A (en) 1987-08-11
GR75500B (en) 1984-07-24
ES8402309A1 (en) 1984-01-16
US4772692A (en) 1988-09-20
IL66245A (en) 1988-05-31
ES516863A0 (en) 1984-01-16

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