NZ205246A - Beta-lactam derivatives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £05246 2 C 5 2 4 6 Priority Dale!:;;: J. .. (r. Compfeto Specification Filed: 'C?. class: . .Q.Q.V?.4pa:> . A:.

Publication Date: ..... P.O. Journal. No: . 1 ■ » ■■•••••••••! E5 DEC 1936 NO DRAWINGS NEW ZEALAND PATENTS ACT. 1953 No.: Date: COMPLETE SPECIFICATION g LACTAMS 59 We, F. HOFFMANN-la ROCHE & CO. AKTIENGESELLSCHAFT, of 124-Grenzacherstrasse, Basle, Switzerland, a Swiss Company, hereby declare the invention for whichXK( we pray that a patent may be granted to xas&c/us, and the method by which it is to be performed, to be particularly described in and by the following statement: - (followed by la) 205246 - lq- RAM 1410/IG8 The present invention is concerned with 3-lactams of the general formula © r2 r3 3~~2t .2 1„, * v in which R represents lower 2-alkenyl or 1-alkenyl or a group of the formula -CH2-CH(OR*)2 (a) -CH2-CHO (b) /•N ■r**\ -CO-CH(OH)9 ™""—c h 2 c h 2"™™ -CH=CH-R" (C) (d) (e) or -CHO (f) Mn/G.7.03 205246 2 - 4 9 wherein R signifies lower alkvl, R signifies a tertiary lower cycloali-phatic or aliphatic amino group and n signifies the number 0 or 1, and 2 wherein further R represents amino or a group convertible into amino and represents a lower organic group, 2 with the proviso that when R signifies amino R^- represents lower 2-alkenyl or 1-alkenyl or one of the groups (a), (c) and (d) .

The 3-lactams of general formula I are, owing to their particular protecting groups situated on the N^-atom, valuable intermediates for the especially ready manufacture of 3-lactams having antimicrobial properties, especially of N^-sulpho—azetidinones of the general formula R—NH R3 N / ii 'so3H wherein R represents an acyl group which is known, for example, from penicillin or cephalosporin chemistry; for example an acyl group of the general formula 205246 wherein R^ represents hydrogen, lower alkyl or carboxy-lower alkyl and R^ represents 10 a lower organic group (e.g. carbamoyl or carbamoyloxymethyl).

Intermediates of formula I which contain directly cleavable protecting groups are those of the general formula r2 r3 la 2 3 in which R and R have the above significance and R^° represents 1--alkenyl or group (c) above.

The remaining intermediates of formula I, i.e. those in which R^" has a significance other than R^, are pre-products which, as will be described in detail hereinafter, can be converted readily into the above compounds of formula la. 20524 6 Another sub-group of the novel intermediates of formula I are those in which R^ represents a group R^ which can be present at the beginning of the synthesis, i.e. compounds of the general formula R2 r3° -N lb in which R^" and R^ have the above significance and R30 represents styryl or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen, cyano, sulphaxnovl or lower alkylsulphonyl} lower cvcloalkyl, lower alkoxvcarbonyl, lower alkanoyl, lower alkanethiovl of a group of the , - , n 3 00 _301 general formula R or R R'O H ti—R6 R 7O \ H ,300 .301 wherein R^ and R7 each signify a lower 203246 hydrocarbon group which optionally contains oxygen and which is attached via a carbon atom , whereby these groups can also be joined with one another to form a ring including the carbon atom to which R^ is attached and the oxygen atom to which is attached.

The remaining intermediates of formula I, i.e. those in which R^ has a significance other than R^, can be 2 obtained from the compounds of formula lb, insofar as R represents a group convertible into amino, by transformation of the group R^°; especially by transformation of the group R^°^ or R"^^ or a lower alkoxycarbonyl group R^, for example as illustrated in Schemes r-III hereinafter.

The term "lower alkenyl" signifies an olefinic hydrocarbon group which can be straight-chain or branched-chain and which contains up to 8, especially up to 4, carbon atoms such as, for example, vinyl, 2--propenyl (allyl), 1-propenyl, isopropenyl, 2-raethallyl, 1- or 2-butenyl, 1- or 2-hexenyl, 1- or 2-heptenvl, 1-or 2-octenyl etc. The term "lower alkyl" signifies, alone or in combinations such as "lower alkoxycarbonyl" or "lower alkylsulphonyl", a saturated hydrocarbon group which 'can be straight-chain or branched-chain and which contains up to 8, especially up to 4, carbon atoms such as, for example, methyl, ethyl, n-propvl, isopropvl, n--butyl, isobutyl, sec-butyl, t-butyl, n-pentvl, isopentyl, n-hexvl, n-heptyl, n-octyl etc. The term "lower alkoxy" t \ 15 OCT 1986 . \ 205246 - s - has an analogous significance. The term "lower cvcloalkyl" signifies an alicyclic saturated hydrocarbon containing 3-8 carbon atoms (e.g. cyclopropyl, cyclobutyl, cyclo-5 pentyl, cyclohexyl, cycloheptyl, cyclooctyl). The term "lower alkanoyl" signifies an aliphatic carboxylic acid group which contains up to 8 carbon atoms (e.g. acetoxy, propionyloxy, iscbutyryloxy). The term "lower alkanethioyl" has an analogous significance (e.g. thio-10 acetyl, thiopropionyl, thioiscbutyryl) . The term "halogen" represents all four halogens, especially chlorine and bromine.

The tertiary lower aliphatic or cycloaliphatic amino 15 group present in group (e) above is a 5- or 6- -membered ring which optionally contains an oxygen or sulphur atom and which can be optionally substituted by lower alkyl or lower alkoxy (e.g. morpnolino, pyrrolidino, piperidino, 4-methvlpiperidino); it can, however, also 20 be, for example, a di-lower alkylamino group (e.g. diethyl-amino) . 2 Groups R convertible into amino can be, for example, azido, phthalimido, (lower alkyl)-0C0-CH=C-(CH^)-NH- or 25 readily cleavable acylami no, i.e. Z-NH- in which Z represents a readily cleavable acyl group such as, for example, lower alkoxycarbonyl which is optionally halogen-substituted (e.g. t-butoxvcarbonvl or trichloroethoxycarbonyl), as well as benzyloxycarbonyl and benzhydrvl. /• f 150Cn986 •» •• i Q 205246 In the groups R300 or R® can signify, for example, lower alkyl, phenyl-lower alkyl, lower alkoxy--alkyl (e.g. lower alkoxymethyl) and R7 can signify lower 5 alkyl or phenyl-lower alkyl. These groups R^° or R^0^ can also represent a 5- or 6-membered O-heterocycle which © optionally contains a further oxygen atom not directly linked with the centre of chirality and which can be optionally substituted by lower alkyl, lower alkoxy, oxo or 300 spirocyclo-lower alkyl. Examples for group R are: <f h 0 v t-ch2o h h3 and examples for the group R301 are the optical antipodes thereof. 1 3 Preferred groups denoted by R -R are: R^": vinyl, 2-propenyl (allyl) , 1-propenyl, 2,2-di-methoxyethyl, 2, 2-diethoxyethyl, fonnylmethyl, dihydroxy-25 acetyl, 2-phenylthioethyl, 2-phenylsulphinylethyl, 2--morpholinovinyl, formyl. 2 R : amino, phthalimido, benzyloxycarbonylamino, t- 205246 - a - -butoxycarbonylamino, 2-methoxycarbonyl-l-methyl-viny1-amlno. a3: phenyl, styryl, p-cyanophenyl, p-sulphamoyl- phenyl, -alkoxycarbonyl and the group X [ (R)-2,2- Oh O O )L -dimethy1-1,3-dioxolan-4-yl] .

The compounds of formula I, insofar as R^ does not represent the group R3^ or R3^, can be present as race-mates, the substituents in the 3- and 4-position of the azetidine ring being either trans- or cis-positioned to one another. Each of these isomers can be present in 15 the optically uniform form. Where R3 represents the group R300 or R^0^", the compound is present in the optically uniform cis-form, i.e. as the compound of the formula Ic 12 6 7 wherein R , R , R and R have the above significance, or as the corresponding optical antipode thereof of the formula 2052 46 S'O H R? 6 pi" 12 6 7 wherein R , R , R and R have the above significance.

The 3-lactams of formula I can be manufactured in accordance with the invention by reacting a reactive derivative of a carboxylic acid of the general formula R20—CH2—COOH III in which R20 signifies azido, phthalimido or the group R0C0-CH=C(CH^)-NH- and R represents lower alkyl, in the presence of a base with a compound of the general formula h /r3° Y 205246 in which has the above significance and represents lower 2-alkenyl or group (a) or (d) above, if desired in a thus-obtained compound of the general formula R20 R30 in which R^, R2^ and R^ have the above significance, converting a lower 2-alkenyl group present as R^ into the corresponding 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R^ into the group (b) or (c) or transforming a group (d) present as R^ into the vinyl or formyl group, if desired transforming the group R20 in a resulting compound of the general formula 2 C 52 4 6 in which R^", R^® and R^° have the above significance, into the amino group, If desired reacting a thus-obtained compound of the general formula D30 X N I(3 V in which R^" and R^ have the above significance, with an agent yielding the group Z to give a compound of the general formula r30 2—NH.

S> N Ih in which R^" and R^^ have the above significance and 2 represents a readily cleavable acyl group, and, if desired, in a resulting compound of the general formula 205246 © Z—NH^ R^° . I Ih1 c N11 l1 30 in which R -, R and Z have the above significance, converting a lower 2-alkenyl group present as R11 into the 10 corresponding 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R11 into the group (b) or (c) or transforming a group (d) present as R11 into the vinyl or forniyl group,"and, if desired,' subsequently further transforming the group R"^ within the meaning of The reaction of a reactive derivative of a carboxylic acid of formula III with a compound of formula IV or the optical antipode thereof is a cycloaddition which is familiar to a person skilled in the art. Suitable reactive carboxylic acid derivatives are, for example, the cor-20 responding carboxylic acid halides, especially the carboxylic acid chlorides, the corresponding carboxylic acid anhydrides and mixed anhydrides (e.g. with trifluoroacetic acid, mesitylenesulphonic acid and the like), the corresponding carboxylic acid imidazolides and the like.

The reaction is conveniently carried out in the presence of a base, for example a tertiary amine such as triethylamine, and in an inert organic solvent, especially an ether such as tetrahyarofuran, diethyl ether, t-butyl methyl ether, dioxan, ethylene glycol dimethyl ether or the like, a r oj OCT 1986 2052 4 e halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane or the like, acetonitrile, dimethylfonnamide or the like. This cycloaddition is 5 carried out in a temperature range of about -30°C to about 50 °C.

In the aforementioned reaction there are obtained compounds of formula le above which, insofar as does not represent the group or R^01, are present in racemic form, the substituents in the 3- and 4-position of the azetidine ring being either trans- or cis-positioned to one another. Where R^ represents the group R300 or R^01, there is obtained a compound in the optically uniform cis-form, IS i.e. a compound of the general formula or le 1 le 2 wherein R11, R^°, R^ and R7 have the above significance.

The compounds of formula IV or their optical antipodes used as starting materials can be prepared by reacting m 2 0 52 4 6 .J an aldehyde of the general formula R30—CHO wherein R30 has the above significance, with an amine of the general formula R11—NH2 VI e wherein R11 has the above significance.

This reaction is preferably carried out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane and the like or in a hydrocarbon such as benzene, toluene and the like. The water formed during the reaction is preferably removed continuously, for example by azeotropic distillation or by working in the presence of a water-removmq 20 agent (e.g. in the presence of a suitable molecular sieve) or in the presence of a conventional drying agent such as potassium carbonate, magnesium sulphate and the like. When the water formed is removed azeotropically the reaction is carried out at the boiling point of the chosen solvent and 25 when a water-removing agent is used the reaction is <***S \ ' preferably carried out at room temperature.

The N-protecting groups R11 present in the resulting 205246 compound of formula le are not cleavable per se, but can be converted as follows into cleavable protecting groups R10 (see formula la above): I. R11: lower 2-alkenyl »R10: lower 1-alkenyl, e.g. -ch2-ch=ch2 *-ch=ch-ch3 .

This isomerizatlon is advantageously carried out using an isoroerization catalyst, for example a palladium dihalide such as palladium dichloride, a tris-(triphenylphosphine)--rhodium (I) halide such as the corresponding chloride or palladium-carbon and a protonic acid such as hydrochloric acid or phosphoric acid. The isomerization is advantageously carried out in an inert organic solvent such as ethanol, methylene chloride or mixtures thereof with water and at a temperature between about 50°C and the boiling point of the reaction mixture.

II. R11: -CH2-CH=CH2 ► R1: group (b) -ch2-cho »■ 1 in » R~ : group (e) R : group (f) »-CH=CH-R9 »-CH0 The above transformation of the allyl group R11 into the group (b) and the reaction (e) * (f) is preferably carried out by ozonolysis, i.e. by treatment with ozone gas in an inert organic solvent, for exanple in an alkanol containing up to 8 carbon atons such as methanol or in a chlorinated hydrocarbon such 205246 as methylene chloride or chloroform, and at a temperature between about -30°C and 0°C. The ozonide formed is decomposed in the usual manner, for example by treatment with dimethylsulphide or triphenylphosphine (without cooling).

The conversion (b) *(e) is carried out by reaction with a secondary lower aliphatic or cycloaliphatic amine, for example with morpholine, pyrrolidine, piperidine, 4--methylpiperidine, diethylamine, especially with morpholine. This reaction is preferably effected in an inert organic solvent such as methylene chloride or chloroform and at a temperature between about 0°C and the boiling point of the reaction mixture, preferably at room temperature.

III. R11: group (a) »• R1: group (b) ■■ » R10: group (c) -CH2-CH(OR4) 2 r-CH7-CH0 "-C0-CH (OH) 2 .

The transformation (a) »(b) is preferably carried out using a tri-lower alkyliodosilane, especially trimethyl-iodosilane, or p-toluenesulphonic acid. The reaction is preferably carried out in an inert organic solvent such as acetonitrile and at a temperature between about 0°C and 50°C.

The oxidation (b) »-(c) is preferably carried out using selenium dioxide under acidic conditions (e.g. in the presence of acetic acid). The reaction is preferably 205246 17 carried out in an inert organic solvent such, as dioxan and at a temperature between room temperature and the boiling point of the reaction mixture.

The first step, the oxidation of the phenylthio-ethyl group to phenylsulphinylethyl, is carried out by treatment with an organic or inorganic oxidizing agent. As oxidizing agents there can be used various compounds which readily yield oxygen such as, for example, organic peroxides, for example mcnosubstituted organic peroxides such as alkyl or alkanovl hydroperoxides such as t- -butyl hydroperoxide, performic acid, peracetic acid; as well as phenyl-substituted derivatives of these hydroperoxides such as cumene hydroperoxide, perbenzoic acid. If desired, the phenyl substituent can carry a further lower group (e.g. C^-C4 alkyl or alkoxy) or a halogen atom or a carboxy group (e.g. 4-methylperbenzoic acid, 4--methoxyperbenzoic acid, 3-chloroperbenzoic acid, mono-perphthalic acid). As the oxidation agent there can also be used various inorganic oxidizing agents, for example, hydrogen peroxide; ozone; permanganates such as potassium or sodium permanganate; hypochlorites such as sodium, potassium or ammonium hypochlorite; peroxymonosulphuric IV. R11: group (d) «• R10: vinyl R10: group (f) -ch2ch2-s } 205246 18 acid and peroxydisulphuric acid. The use of 3-chloroperbenzoic acid is preferred. The oxidation is advantageously carried out in an inert solvent, for example, in 5 an aprotic inert solvent such as tetrahydrofuran, dioxan, methylene chloride, chloroform, ethyl acetate or acetone; or in a pro tic solvent such as water, an alkanol containing up to 8 carbon atoms (e.g. methanol, ethanol) or an alkanecarcoxylic acid containing up to 8 carton atcms which is optionally halogenated (e.g. 10 formic acid, acetic acid, trifluoroacetic acid. The reaction temperature ranges particularly at about -20 °C to +75°C.

The degradation of the phenylsulphinylethyl group to the vinyl group is carried out by heating to about 100-200°C, 15 preferably in an aprotic organic solvent such as hexa-methylenephosphoric acid triamide, dimethyl sulphoxide, dimethylformamide, benzene or toluene. The reaction can be accelerated by the addition of an acceptor for the phenylsulphonic acid formed in the reaction, especially 20 suitable acceptors being triiuethyl phosphite or propiolic acid esters such as,e.g. methyl propiolate.

The degradation of the vinyl group to the formyl group (which is optional, since the vinyl group is cleavable 25 per se) is carried out in the same manner as described above in Section II for the conversion (e) *-(f).

The compounds of formula Ig can be obtained in 19 - 2 C 52 4 6 accordance with the invention by transforming the group R^° in a compound of formula If obtained into the amino group. This reaction is carried out according to methods which are known per se and which are familiar to any person skilled in the art, the method to be used depending on the nature of the group R . The phthalimido group can be removed, for example, by reaction with hydrazine, methyl-hydrazine or the like, conveniently in an inert organic solvent. Suitable solvents are, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like, ethers such as tetrahydrofuran, dioxan, t-butyl methyl ether and the like, etc. The azido group can be reduced to the amino group, for example, using elemental hydrogen in the presence of a catalyst such as palladium--carbon, Raney-nickel, platinum oxide and the like, or by the action of hydrogen sulphide and a tertiary amine such as triethylamine. The group ROCQ-CH=C(CH^)-NH- can be converted into the amino group, for example, by mild acid hydrolysis.

By treating a compound of formula Ig with an agent yielding the group 2 there is obtained in accordance with the invention a compound of formula Ih. Suitable agents yielding the group Z are, for example, di-t-butyl dicar-bonate or chloroformic acid esters such as benzyl chloro-formate, t-butyl chloroformate, 2,2,2-trichloroethvl chloro-formate and the like. The reaction is conveniently carried m 205246 out in an inert organic solvent, for example in a halogenated hydrocarbon such as methylene chloride, chloroform and the like, and conveniently in the presence of an acid-5 -binding agent such as butylene oxide, triethylamine, quinuclidine etc. The reaction is conveniently carried out at room temperature.

Some of the compounds of formula Ih obtained contain 10 non-cleavable groups R1 (groups R11; formula Ih1). These 11 1 ^ '' groups R can be converted into cleavable groups R (groups R1^) in the manner described above (see sections I-IV).

The group R30 in compounds of formulae lb, le, If and Ih obtained can be converted into other lower organic groups R3 as described above and as exemplified in Schemes I-III g hereinafter. For example, the hydrocarbon group R in an o obtained compound of the general formula r8 O 0-^H X0 R21 y-j Ik 0 N-,1 in which R^1 represents a group con— g vertible into amino, R represents a hydrocarbon group (e.g. methylene, 205246 ethylene, oxomethylene, cyclo- hexylidene or, preferably iso-propylidene) and R1 has the above significance, or the optical antipode thereof can be cleaved, for example by treatment with a mild acidic agent such as, for example, with a sulphonated ion exchanger, pvridinium p-toluene-sulphonate or p-toluenesulphonic acid, in an alkanol containing up to 8 carbon atans such as methanol or ethanol or in aqueous tetra-hydrofuran, preferably at roam temperature to about 80 °C. There is obtained an optically active diol of the general formula nificance, or the optical antipode thereof.

The diol grouping in the thus-obtained compound of formula Im or in the optical antipode thereof is cleaved, there being obtained an aldehyde of the general formula Im 1 21 in which R and R have the above sig- 205246 R21 HO -N N*1 In O 1 21 in which R and R have the above significance, or the optical antipode thereof. This cleavage is carried out according to methods known per se and can be accom-10 plished, for example, with an alkali metal periodate such as sodium metaperiodate in water, optionally in admixture with, for example, tetrahydrofuran or an alkanol containing up to 8 carbon atoms such as methanol. The aldehyde groups of the aldehyde or formula In or of the optical antipode thereof can be reduced 15 according to known methods, for example by treatment with a complex metal hydride such as sodium borohydride in an alkanol containing up to 8 carbon a terns such as ethanol, isopropanol or the like. There is obtained an alcohol of the general formula R 21 £H20H J Nv 6 V Io jT 1 21 in which R and R have the above significance, or the optical antipode thereof.

Benzyloxy groups present such as, for exap^li^^.^ r i V lf 150CT19867 compounds of the general formula 20524 6 «^-V, IP IS 1 21 wherein R and R have the above significance, or in the optical antipode thereof can be cleaved hydrogeno-lytically and the resulting corresponding carbinol of the general formula c^~ in which R1 and R^1 have the above significance, or the optical antipode thereof can be reacted further, for example in analogy to compound Io1 in Scheme I hereinafter .

The substituent in the 4-position can be functionally transformed further; for example, the aforementioned 4--formyl group or 4-hydroxymethyl group can be transformed in 205246 a manner known per se to a person skilled in the art (see the following Schemes I-III) .

In order to synthesize the desired antimicrobially- -active fl-lactams (e.g. the 3-lactams of formula II above) , the N-protecting group R10 present in an obtained compound of the general formula R21 R3 Ir f in which R , R^ and R^ have the above significance/ is cleaved off. Lower 1-alkenyl groups (e.g. 1-propenyl or vinyl) are cleaved off oxidatively, especially by treatment with an alkali metal permanganate such as potassium 20 permanganate, preferably an aqueous solution of potassium permanganate. If desired, the oxidation can be carried out using an alkali metal periodate (e.g. potassium periodate) in the presence of a catalytic amount of the aforementioned alkali metal permanganate. The reaction is preferably 25 carried out in an aqueous buffered medium, especially buffered to pH 7-8, but it can also be carried out in a water-miscible orgaric solvent (e.g. acetone, dimethoxy-ethane, dioxan or tetrahydrofuran) with the addition of a weak organic base such as pyridine or in a mixture of one 5246 of these solvents with the aforementioned aqueous buffer. If desired, the reaction can also be carried out under phase-transfer catalysis, i.e. in the presence of an 5 aqueous or non-aqueous phase, for example the above aqueous buffer as well as a water-Immiscible inert organic solvent such as, for example, methylene chloride or benzene. As phase-transfer catalysts there can be used the agents which are usually used for this purpose, especially organic 10 quaternary ammonium halides such as benzyltriethylammonium chloride, tetra-n-butylammonium bromide and cetyltrimethyl-ammonium bromide. The oxidative cleavage of l-alkenvl groups is preferably carried out at a temperature in the range of about 0°C and 25°C.

The hydroxyacety 1 group [R^ as group (c) ] and 10 the formyl group [Rx as group (f)] are preferably cleaved off with an aqueous strong base (e.g. with aqueous ammonia or aqueous caustic alkali) in an inert organic solvent (e.g. a halogenated hydrocarbon such as chloroform, carbon tetrachloride or methylene chloride) at a temperature between about 0°C and +50°C. The formyl group can, however, also be cleaved off by the action of a palladium- or rhodium-organic complex compound, for example tris-(triphenylphosphine)-chlororhodium. i o After removal of the above protecting group , the group -SO3H can be introduced in the 1-position by reaction with a reactive derivative of sulphur trioxide, for example, .1 2 ... : 2 4. by reaction with complexes of sulphur trioxide and a base such as pyridine, triraethylamine, picoline, dimethy1-forxoajnide etc at about 0-80°C in an inert organic solvent 5 (e.g. an ether such as dioxan, pyridine, dimethylformamide 2 etc). The amino group 3 in the 3-position can be liberated before or after the latter reaction by transformation of the group R20 (in the above manner) or by cleavage of the protecting group 2; for example, aralkoxycarbony1 groups (especially benzyloxycarbony1) or the benzhydryl group can be cleaved off hydrogenolvtically (e.g. by the action of hydrogen and palladium-carbon), the t-butoxycarbonyl group can be cleaved off by treatment with trifluoroacetic acid or formic acid, and the trichloroethoxycarbonyl group can be cleaved off by treatment with zinc and a protonic acid such as acetic acid or hydrochloric acid. The liberated 2 amino group R can subsequently be acylated with a correspondingly substituted carboxylic acid or a reactive functional derivative thereof, for example an acid anhydride, acid 20 amide, active ester (e.g. a thioester such as the benthia-zolvl thioester, by which means the widest variety of acyl groups such as those which are known, for example, from penicillin or cephalosphorin chemistry can be introduced. For example, in this manner there can be manufactured 25 according to methods known per se optically uniform anti-microbially-active 3-lactams of the general formula 2(•24o c h2n- \\ /, N ' L—C CONH II N iR3 \)R5 nn xso3h Ila wherein R represents hydrogen, lower 10 alkyl or carboxy-lower alkyl and R3 represents a lower organic group (e.g. carbamoyl or carbamoyloxy methyl), or the corresponding optical antipodes thereof.

Examples of corresponding conversions into end products are illustrated in Schemes I-III hereinafter, o o Scheme I .21 V & r-ll on 1 (.'iso nco -N IoJ \ .21 hi^OCONII i ■ I'y.SO 2.R2i-> Nil..

M.N-.

W // N—J~ii—CO* \ OH 50 soif° Q<? Cleavage of any protecting groups _ 50 present on R O o » 1 ro oo -N. c»l20c0nii2 so3h -f^L (:ii2oconii2 s03 h K> o (J1 ro 4^ 14 O O v) 21 K (Y in r -N \ Clio io Scheme II . 21 « S. >COOCII. i. ^ 2. ai3nK2(X)3 21 coocii i IJ..N 11-iN lf-,; 1)1 \ bo tj It Cleavage of any protecting groups .50 present on R" <5^ -N \ 1 . l'y .iiO-j 2. R2i-»N1I., Vw^> /> DM O NOH5 ,<7 (Y II ,N i « (Y Q) . ^COOCIL '■ N ~ O r -N^ COUCH.

"SOjH jH-'Oociij N\ so3m Ki W> KJ o {fl to O O 0 o Scheme III «2,v r COOCII. nh,on 4 N \ 8 II r2V rCONII. ' —N \ 9 II II..N- ii COX \ 50 OR Cleavage of II. ,N (Y II->N any protecting groups ,50 present on R" .CON II., sojii CON1I, so3n U) O *0 O cn io a 0^ fj5?» r* 205 46 Abbreviations used in Schemes I, II and III DMT =» dime thy lformamide Py » pyridine Py.SO^ - sulphur trioxide-pyridinium complex COX =» reactive derivative of a carboxylic acid (e.g. acid anhydride, acid amide, active ester such as benzthiazolyl ester) 10 R^° ■ hydrogen, lower alkyl (e.g. methyl), protected carboxy-lower alkyl (e.g. protected carboxy-methyl, protected 1-methyl--1-carboxy-ethyl). Protecting group: e.g. t-butyl (cleavable with, for example, tri-15 fluoroacetic acid), benzyl and p-nitro- benzyl (cleavable with,, for example, hydrogen and palladium-carbon), 2-(trimethylsilyl)--ethyl (cleavable with, for example, tetra-butylammonium fluoride). 20 R^ » hydrogen, lower alkyl (e.g. methyl), car boxy-lower alkyl (e.g. carboxymethv1,1--methyl-l-carboxv-ethyl) .

R^, R^ = above significance.

O Reactions which are not explained more precisely in Schemes I, II and III are carried out in the manner described in detail above. 2C The following Examples illustrate the present invention. All temperatures are given in degrees Centigrade. Ar » aromatic.

Example 1 A solution of 3.75 ml (0.05 mol) of allylamine, and 5.04 ml (0.05 mol) of benzaldehyde in 100 ml of benzene is 10 heated to boiling; the water formed being separated on a water separator. The reaction has finished after 30 minutes and the reaction mixture is then evaporated. The residue is dissolved in lOO ml of tetrahydrofuran. The solution obtained is treated dropwise at -25° while stir-15 ring with 7 ml (0.05 mol) of triethylamine and with a solution of 11.15 g (0.05 raol) of JJ-phthaloylglycyl chloride in 100 ral of tetrahydrofuran. The mixture is left to stand at room temperature. After 4 hours, the mixture is evaporated. The residue is taken up in ethyl 20 acetate and water. The organic phase is washed once with 3% aqueous sodium bicarbonate solution and three times with water. The organic phase is dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with cyclohexane/ethyl acetate (7:3). There are 25 obtained N-(rac-trans-l-allyl-2-oxo-4-phenyl-3-azetidinyl)--phthalimide as white crystals of melting point 151-153° and N-(rac-cis-l-allyl-2-oxo-4-phenyl-3-azetidinyl)-phthalimide of melting point 171-174°. 205246 Example 2 A solution of 7.5 ml (0.1 mol) of allylamine and 13.1 g (0.1 mol) of p-cyanobenzaldehyde in 150 ml of benzene is heated to boiling, the water formed being separated on a water separator. After 40 minutes, the mixture is evaporated. The residue is dissolved in 200 ml of di-chloromethane. The solution obtained is cooled to -30° in an argon atmosphere and treated while stirring with 13.9 ml (0.1 mol) of triethylamine. A solution of 22.4 g (0.1 mol) of phthaloylglycyl chloride in 350 ml of dry methylene chloride is then added dropwise within 2 hours and the mixture is subsequently stirred_at 0.5° for a further 2 hours. The mixture is washed three times with in each case 300 ml of water and 300 ml of aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with eyelonexane/ethyl acetate (1:1). There is obtained p-(rac-cis-l-allyl-2-oxo~3-phthalimido-4-azetidinyl)--benzonitrile as white crystals of melting point 211-213°.

Example 3 (a) A suspension of 9.2 g (25.6 iranol) of p-(rac-cis-1--allyl-2-oxo-3-pnthaliinido-4-azetidinyl) -benzonitrile and 1 g of tris(triphenylphosphine)-rhodium (I) chloride in 4QO ml of ethanol and 50 ml of water is heated under reflux for 3 hours in an argon atmosphere. After cooling and filtration, the filtrate is evaporated. The crystalline residue is taken up in ethyl acetate and filtered off under suction. There are obtained 8.5 g of p-[rac-cis-2-oxo-3--phthalimido-1-(1-propenyl)-4-azetidinyl]-benzonitrile as white crystals of melting point 234-238°. (b) A suspension of 0.5 g (1.4 mmol) of p-(rac-cis-1--allyl-2-oxo-3-phthalimido-4-azetidinyl)-benzonitrile and 10 mg of palladium chloride in 20 ml of methylene chloride and 2 ml of water is heated under reflux for 2 hours while stirring. After cooling and filtration, the organic phase is separated, washed with water, dried over magnesium sulphate, filtered and evaporated. The crystalline residue is treated as described under (a). There is obtained 0.4 7 g of p-[rac-cis-2-oxo-3-phthalimido-l-(1-propenyl)-4--azetidinyl]-benzonitrile of melting point 234-236°.

Example 4 A solution of 7.4 g (20.6 mmol) of p-[rac-cis-2-oxo--3-phthalimido-l-(1-propenyl)-2-azetidinyl]-benzonitrile in 150 ml of methylene chloride is treated with 3.25 ml (61.8 mmol) of methylhydrazine. The mixture is heated at 30° for 12 hours while stirring. The precipitated material is filtered off and the filtrate is evaporated. The residue is taken up in 200 ml of ethyl acetate, washed with water, the organic phase is dried over magnesium sul- \ 205246 phate, filtered and evaporated. There are obtained 14.0 g of crude p-[rac-cis-3-amino-l-(1-propenyl)-4-azetidinyl]--benzonitrile which is used in the next step without 5 further purification.

Example 5 A stirred solution of 3.73 g (16.4 mmol) of p-£rac-cis-10 -3-amino-l-(1-propenyl)-4-azetidinyl]-benzonitrile and 1.7 ml (20 mmol) of butylene oxide in 10 ml of methylene chloride is treated dropwise with 0.2S ml of carbobenzoxy chloride, the mixture is stirred for 2 hours and then evaporated. The crystalline residue is taken up in ether and 15 filtered off under suction. There are obtained 5 g of benzyl rac-cis-4-(p-cyanophenyl)-2-oxo-l-(1-propenyl)-3--azetidinecarbamate as a crystalline material of melting point 120-122°.

Example 6 A solution of 3.24 g (8.9 mmol) of benzyl rac-cis-4--(p-cyanophenyl)-2-oxo-l-(1-propenyl)-3-azetidinecarbamate in 200 ml of dimethoxyethane is treated with 4.2 ml (53 25 mmol) of pyridine. While stirring at 50 the mixture is treated dropwise with a solution of 4 g of potassium permanganate in 300 ml of water. The mixture is stirred at room temperature for 2 hours, filtered over siliceous earth 2052 46 and the filtrate is evaporated. The crystalline residue is taken up in ether and filtered. There are obtained 2.5 g of crystalline benzyl rac-cis-4-(p-cyanophenyl)-2-oxo--3-azetldinecarbaraate.

NMR (dg-DMSO) a (ppm): 4.7-5.22 (4H, m, Ar-CH2, &3, H4), 7.0-8.0 (10H, m, 2 Ar), 8.7 (IH, s, NH azetidinone).

Example 7 To a solution, stirred at room temperature, of 18.6 ml CO.25 mol) of allylamine in 500 ml of methylene chloride are added 50 g of molecular sieve 4S and, after 20 minutes, 32.5 g (0.25 mol) of isopropylidene-L-glyceraldehvde and 100 g of magnesium sulphate. The mixture is subsequently stirred at room temperature for a further 1 hour. The organic solution of isopropylidene-L-glvceraldehyde allyl-imine is cooled to -30° under argon and treated while stirring with 31.3 ml (0.25 mol) of triethylamine. A solution of 45.25 g (0.25 mol) of phthalovlglycvl chloride in 200 ml of dry methylene chloride is then added dropwise within 2 hours and the mixture is subsequently stirred at room temperature for a further 12 hours. The mixture is washed three times with in each case 700 ml of water and 700 ml of sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The residue is chromato-graphed on silica gel with cyclohexane/ethyl acetate (6:4). There are obtained 50 g of N—[cis-(3S,4S)—1-allyl—4-[(R)- -S c C'' O 2 0 5246 -2, 2-dlmethyl-l,3-dioxolan-4-yl)-2-oxo-3-azetidinyl]--phthalimide as an oil; = +115° (0.13 in chloroform).

NMR (CDC13) 6 (pom): 1.28 (3H, s) , 1.41 (3H, s), 3.36- -4.5 (6H), 5.87 (IH, d, 5Hz), 5.13-5.5 (2H, m, CH2») , 5.68-6.16 (1H, m, CH») , 7.87 (4H, m, Ax).

Example 8 A suspension of 25 g (70.2 mmol) of M-[cis-(3S,4S)--l-allyl-4-{(R)-2,2-dimethy1-1,3-dioxolan-4-yl)-2-oxo-3--azetidinyl]-phthalimide and 0.5 g of palladium dichloride in 300 ml of methylene chloride and 30 ml of water is heated 15 under reflux conditions for 3 hours while stirring. After cooling and filtration, the organic phase is separated, washed with water, dried over magnesium sulphate, filtered and evaporated. There are obtained 24 g of N-[cis-(3S,4S)--4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl)-2-oxo-l-(1-propenyl) 20 -3-azetidinyl]-phthalimide as a foam; = +77.7° (c = 0.153 in chloroform).

NMR (CDC13) 5 (ppm) : 1.26 (3H, s, CH-j), 1.42 (3H, s, CH3), 1.71 (3H, dd, 1.5 and 6.5 Hz CH3), 3.34-3.76 (2H, m, CH2), 3.97 25 -4.52 (2H, m, H4 and CH), 5.38 (IH, d, 5.5 Hz, H3), 5.67-6.05 (IH, m, =CH-CH3), 6.4 (IH, dd, 1.5 and 14 Hz, =CH-N-), 7.82 (4H, m, Ar) . m 2052 46 Example 9 A solution of 0.356 g (1 mmol) of N-[cis-(3S,4S)-4-5 -[(R)-2,2-dimethy1-1,3-dioxolan-4-yl]-2-oxo-l-(1-propenyl)--3-azetidinyl]-phthalimide and 0.26 ml of pyridine in 50 ml of acetone and SO ml of water is treated dropwise while stirring at 50 with a solution of 0.22 g (1.4 mmol) of potassium permanganate in 50 ml of acetone and 50 ml of 10 water. After 3 hours, the mixture is filtered and the filtrate is evaporated. The residue is chromatographed on silica gel with cyclohexane/ethvl acetate (6:4). There is obtained 0.29 g of N-[cis-(3S,4S)-4-[(R)-2,2-dimethy1-1,3--dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide as a foam. 15 NMR (CDC13) 5 (ppra): 1.3 (3H, s, CH3), 1.45 (3H, s, CH3), 3.3-4.5 (4H, m), 5.4 (IH, d, 5.5Hz, H3), 7.0 (IH, s, -NH), 7.9 (4H, Ar).

Example 10 A solution of 36 ml (0.25 mol) of aminoacetaldehyde diethyl acetal and 25.2 ml (0.25 mol) of benzaldehyde in 200 ml of benzene is heated to boiling and the water formed 25 is separated. After 35 minutes, the mixture is evaporated. The residue is dissolved in 400 ml of tetrahydrofuran. The solution obtained is treated dropwise at -30° while stirring with 34.7 ml (0.25 mol) of triethvlamine. A solution of 55.3 g (0.25 mol) of phthaloylglycvl chloride in 600 ml S3 21524 6 of methylene chloride is then added dropwise within 3 hours and the mixture is subsequently stirred at 0-5° for a further 3 hours. The mixture is washed three times with 5 in each case 700 ml of water and 700 ml of aqueous sodium chloride solution, dried over magnesium sulphate, filtered and evaporated. The crystalline residue is taken up in ether and filtered off under suction. There is obtained N-[rac-cis-1-(2,2-diethaxyethyl)-2-oxo-4-phenyl-3-azeti-10 dinyl]-phthalimide as white crystals of melting point 125- C" 127°.

In an analogous manner, there is obtained N-[rac-cis--1-(2,2-dimethoxyethyl)-2-oxo-4-phenyl-3-azetidinyl]-15 -phthalimide as white crystals of melting point 139-141°.

Example 11 A solution of 4.08 g (10 mmol) of N-[rac-cis-1-(2,2-20 -diethoxyethyl)-2-oxo-4-phenvl-3-azetidinyl]-phthalimide and 4.5 g (30 mmol) of sodium iodide in 50 ml of acetonitrile is treated dropwise while stirring with 1.4 ml (11 mmol) of trimethylchlorosilane. The yellow suspension is stirred at 20° for 20 minutes and evaporated. The residue is taken 25 up in 200 ml of water and 200 ml of ethyl acetate. The mixture is treated with sodium bicarbonate to pH 7. The organic phase is back-washed three times with 200 ml of water each time, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica O 52 4 gel with cyclohexane/ethvl acetate (2:8). There are obtained 2.5 g of rac-cis-2-oxo-4-phenyl-3-phthalimido-l--azetidineacetaldehyde as yellowish crystals of melting 5 point 185-187°.

'•Ju-' Example 12 A suspension of 5.7 g (17 mmol) of rac-cis-2-oxo-4-10 -phenyl-3-phthalimido-l-azetidineacetaldeh.yde, 2.1 g (19 mmol) of selenium dioxide and 1.5 ml (26 mmol) of acetic acid in 25 ml of dioxan is heated under reflux conditions for 4 hours while stirring. After cooling and filtration, the filtrate is treated with 2.15 g of sodium bicarbonate 15 and evaporated. The residue is taken up in 100 ml of ethyl acetate and back-washed with water. The organic phase is separated, dried ever magnesium sulphate, filtered and evaporated. The crystalline residue is taken up in ether and filtered off under suction. There are obtained 5 g of 20 rac-cis-1-(dihydroxyacetyl)-4-phenyl-3-phthalimido-2- -azetidinone as yellowish crystals of melting point 145° V } (decomposition).

Sxample 13 A solution of 1 g (3 mmol) of rac-cis-1-(dihydroxyacetyl) -4-phenyl-3-phthalimido-2-azetidinone in 20 ml of methylene chloride is treated at 20° while stirring with 20 m 205246 drops of concentrated ammonium hydroxide and 20 ml of water. After 4 hours, the phases are separated and the aqueous phase is extracted with methylene chloride. The combined 5 methylene chloride solutions are dried over magnesium sulphate, filtered and evaporated. The white crystalline residue is taken up in ether and filtered off under suction.

' There is obtained 0.8 g of rac-cis-4-phenyl-3-ph.thali-mido--2-azetidinone of melting point 253-255°. u Exairrole 14 A suspension of 7.65 g (50 mmol) of 3-aminoeth.vlphenyl sulphide and 9.25 g (50 mmol) of p-sulphamoylbenzaldehyde in 15 150 ml of benzene is heated to boiling. After completion of the reaction, the mixture is evaporated. The crystalline residue is dissolved in 100 ml of tetrahydrofuran, the solution obtained is cooled to -20° in an argon atmosphere and treated with 6.9 ml (50 mmol) of triethvlamine 20 while stirring. A solution of 11.1 g (50 mmol) of phthalovl-glycyl chloride in 100 ml of tetrahydrofuran is added drop-wise within 2 hours. The mixture is subsequently stirred at 20° for a further 12 hours. The mixture is evaporated and extracted with 300 ml of ethyl acetate and 300 ml of 25 water. The organic phase is washed with water, dried over (^y magnesium sulphate, filtered and evaporated. The crystal line residue obtained is treated with ethyl acetate and filtered off under suction. There are obtained 19 g of 52 46 p—[rac-cis-2-oxo—1-[2-(phenylthio)-ethyl]-3-phchalimido-4--azetidinyl]-benzenesulphonamide as white crystals of melting point 201-203°.

Example 15 A solution of 8.4 g (16.5 iranol) of p-[rac-cis-2-oxo--1-[2-(phenylthio)-ethyl]-3-phthalimido-4-azetidinyl]--benzenesulphonamide in 500 ml of tetrahydrofuran is treated portionwise at 60° while stirring with 3.16 g (16.5 mmol) of 90% 3-chloroperbenzoic acid. After 15 minutes, the mixture is cooled and evaporated. The residue is taken up in 300 ml of ethyl acetate, extracted with 3% aqueous sodium bicarbonate solution and washed neutral with water. The organic phase is dried over magnesium sulphate, filtered and evaporated. The yellowish crystalline residue is taken up in ethyl acetate and filtered off under suction. There are obtained 8.5 g of p-irac-cis-2-oxo-l-[2-(phenylsulphinyl-ethyl)-3-phthalimido-4-azetidinyl]-benzenesulphonamide of melting point 158° (decomposition).

Sxample 16 A suspension of 5.8 g (11.08 mmol) of p-[rac-cis-2--oxo-1-[2-(phenylsulphinylethyl)-3-phthalimido-4-azetidinyl]--benzenesulphonamide and 1.24 ml of trimethyl phosphite in 25 ml of hexamethylphosohortriamide is heated at 150" for 1 hour while stirring. After cooling, the mixture is - 43 205246 poured into 200 ml of ice—vater and extracted with. 200 ml of ethyl acetate. The organic phase is washed neutral with water, dried over magnesium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with cyclohexane/ethvl acetate (6:4) . There are obtained 0.9 g of p-(rac-trans-2-oxo-3-phthalimido-l-vinyl-4--azetidinyl)-benzenesulphonamide as white crystals of melting point 144-146° and 3 g of p-(rac-cis-2—oxo-3--phthalimido-l-viny1-4-azetidinyl)-benzenesulphonamide as light beige crystals of melting point 120-123°.

Example 17 A solution of 1.34 g (3.35 mmol) of p-(rac-cis-2-oxo--3-phthalimido-l-vinyl-4-azetidinyl)-benzenesulphonamide in 100 ml of acetone and 100 ml of water is treated with 0.8 ml of pyridine. While stirring at about 5° the mixture is treated dropwise with a solution of 0.78 g of potassium permanganate in 100 ml of acetone and 100 ml of water. The mixture is stirred at about 5° for 2 hours, filtered over siliceous earth and the filtrate is evaporated. The residue is chromatographed on silica gel with acetone/cyclohexane (1:1). There is obtained 1 g of p-[rac-cis-2-oxo-3-phthali-mido-2-azetidinyl]-benzenesulphonamide as white crystals. NMR (DMSO dg) S (ppm): 5.18 (IH, d, 5.5 Hz), 5.68 (IH, d, 5.5 Hz), 7.16-7.45 (4H, m, Ar + NH2) , 7.6-7.87 (6H, m, Ar) , 9.09 (IH, s, CO-NH).

Examole 18 2 z 4 6 In analogy to Example 14, there is obtained N-[rac-5 -cis-2-oxo-4-phenyl-l-[2-(phenylthio)-ethyl]-3-azetidinyl]--phthalimide.

£\ NMR (CDC13) 6 (ppm) : 5.08 (IH, d, 5.5 Hz),.5.43 (IH, d, .5 Hz), 7.06-8 (14H, m, Ar).

Example 19 v......

In analogy to Example 15, there is obtained N-[rac--cis-2-oxo-4-phenyl-l-[2-(phenylsulphinyl)-ethyl]-3-azetidinyl] -phthalimide as a diastereoisomeric mixture. 1st diastereoisomer: NMR (CDC13) 5 (ppm): 4.93 (0.5H, d, 5 Hz), 5.31 (0.5H, d, 5 Hz) . 2nd diastereoisomer: NMR (CDC13) 6 (ppm): 5.18 (0.5H, d, 5 Hz), 5.53 (0.5H, d, 5 Hz). o Example 20 In analogy to Example 16, there is obtained N-(rac-cis- QJ) -2-oxo-4-phenyl-l-vinyl-3-azetidinvl)-phthalimide of melting point 178-179°. 0 Example 21 In analogy to Example 17, there is obtained N-(rac-5 -cis-2-oxo-4-phenyl-3-azetidinyl)-phthalimide of melting point 248-250°. fC * Example 22 A solution of 20 g (56 mmol) of N-[cis- (3S,4S)-4- •O.

-[ (R) -2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-l-(1-propenyl)--3-azetidinyl]-phthalimide in 200 ml of methylene chloride is treated with 5.9 ml (119 mmol) of methyl hydrazine. The mixture is heated to 60° while stirring for 2 hours. 15 After cooling and filtration, the filtrate is evaporated. The residue is dissolved in 200 ml of methylene chloride and treated with 14.6 ml of butylene oxide. While stirring at 20° the mixture is treated dropwise with 12 ml of carbo-benzoxy chloride and stirred overnight. The mixture is 20 washed three times with 200 ml of water each time, dried over magnesium sulphate, filtered and evaporated. The residue is treated with 200 ml of ether and the crystalline precipitate is filtered off under suction. There are obtained 14.5 g of benzyl cis-(3S,4S)-4-[(R)-2,2-dimethyl-25 -1,3-dioxolan-4-yl]-2-oxo-l-(1-propenyl)-3-azetidine-^ carbamate; [a]^° = +8° (c = 1 in chloroform) .

NMR (CDC13) S (ppm): 1.35 (3H, s, CH-j), 1.43 (3H, s, CHj), 1.6 (3H, d, 6 Hz, CH3), 2 0 5246 3.68-4.32, (4H, m) , 5.03-5.2 (3H, m) , 5.5-6.3 (3H, in), 7.3 (5H, Ar) .

Example 23 A solution of 32.7 g (90.8 ramol) of benzyl cis-(3S,4S) -4-[(R)-2,2-dimethyl-l,3-dioxolan-4-y1]-2-oxo-l-(1-propenyl) -3-azetidinecarbamate and 25 ml of pyridine in 150 ml of acetone, 75 ml of water and 150 ml of dimethoxyethane is treated while stirring at 20° within 90 minutes with 27.5 g (173.7 mmol) of potassium permanganate. The internal temperature of the reaction vessel is held below 50°. The mixture is filtered over siliceous earth and the filtrate is evaporated. The residue is dissolved in methylene chloride, dried over magnesium sulphate, filtered and the filtrate is evaporated. The crystalline residue is taken up in ether and filtered off under suction. 20 g of benzyl cis-(3S,4S)-4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo--3-azetidinecarbamate are obtained.

Example 2 4 A solution of 1 g (2.77 mmol) of benzyl cis-(3S,4S)--4-[(R)-2, 2-dimethyl-l,3-dioxolan-4-vl]-2-oxo-l-(1-propenyl) -3-azetidinecarbamate in 110 ml of methanol is cooled to -30° ana treated with 6 mmol of ozone during 15 minutes. The cooling means is subsequently removed and the mixture is treated with 5 ml of dimethylsulphide. After 4 hours, the 2 0 52 4-€ mixture is evaporated. The residue is dissolved in methylene chloride and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated.

There is obtained 0.98 g of benzyl cis-(3S,4S)-4-((R)-2,2-- dimethy1-1,3-dioxolan-4-yl]-2-oxo-l-formy1-3-azetidine-carbama te.

NMR (CDC13) 6 (ppm): 1.36 (3H, s), 1.38 (3H, s), 4-4.56 (4H, m), 5.17 (2H, s), 5.41-5.67 (1H, q), 6 (NH, d), 7.4 (5H, Ar), 8.87 (IH, s) .

Example 25 0.1 g (2.8 mmol) of benzyl cis-(3S,4S)-4-[(R)-2,2--dimethy1-1,3-dioxolan-4-yl]-2-oxo-l-formyl-3-azetidinecarbamate is dissolved in 10 ml of methylene chloride.

After the addition of a mixture of 0.1 ml of a 25% aqueous ammonium hydroxide solution and 5 ml of water, the mixture is stirred vigorously for 5 hours. The organic phase is separated and the aqueous phase is extracted twice with 10 ml of methylene chloride each time. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated. There is obtained 0.08 g of benzyl cis-(3S,4S)--4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl]-2-oxo-3-azetidine-carbamate.

NMR (CDC13) <5 (ppm): 1.32 (3H, s), 1,43 (3H, s), 3.6-4.4 (4H, m), 5.12-5.2 (3H, m) , 5.93 (IH, d, NH) , 6.22 (IH, s, 2.0 b> 2 4- 6 mixture is evaporated. The residue is dissolved in methylene chloride and washed with water. The organic phase is dried over magnesium sulphate, filtered and evaporated.

There is obtained 0.98 g of benzyl cis-(3S,4S)-4-[(R)-2,2--dimethyl-1,3-dioxolan-4-vl]-2-oxo-l-formyl-3-azetidinecarbamate .

NMR (CDC13) 4 (ppm): 1.36 (3H, s), 1.38 (3H, s), 4-4.56 (4H, m), 5.17 (2H, s), 5.41-5.67 (IH, q), 6 (NH, d), 7.4 (5H, Ar), 8.87 (IH, s).

Example 25 0.1 g (2.8 mmol) of benzyl cis-(3S,4S)-4-[(R)-2,2--dijnethy 1-1, 3-dioxolan-4-yl] -2-oxo-l-formyl-3-azetidine-carbamate is dissolved in 10 ml of methylene chloride.

After the addition of a mixture of 0.1 ml of a 25% aqueous ammonium hydroxide solution and 5 ml of water, the mixture is stirred vigorously for 5 hours. The organic phase is separated and the aqueous phase is extracted twice with 10 ml of methylene chloride each time. The organic extracts are combined, dried over magnesium sulphate, filtered and evaporated. There is obtained 0.08 g of benzyl cis-(3S,4S)--4-[(R)-2,2-dimethyl-l,3-dioxolan-4-yl] -2-oxo-3-azetidinecarbamate .

NMR (CDC13) 5 (ppm): 1.32 (3H, s), 1,43 (3H, s), 3.6-4.4 (4H, m), 5.12-5.2 (3H, m) , 5.93 (IH, d, NH) , 6.22 (IH, s, 205246 NH azetidine).

Example 26 0.2 g (6.2 mmol) of N-(rac-cis-l-allyl-2-oxo-4--phenyl-3-azetidinyl)-phthalimide is dissolved in methanol and treated with ozone in analogy to Example 24. There is obtained 0.18 g of rac-cis-2-oxo-4-phenyl-3-phthalimido-l-10 -azetidineacetaldehyde of melting point 183-185°.

Example 27 A solution of 0.18 g (5.3 mmol) of rac-cis-2-oxo-4-15 -phenyl-3-phthalimido-l-azetidineacetaldehyde in 10 ml of methylene chloride is treated with 0.048 ml of morpholine while stirring. After 10 minutes at 20°, the methylene chloride is evaporated. There is obtained crude rac-cis--1-(2-morpholino-vinyl)-4-phenyl-3-phthalimido-2-azetidi-20 none as an oil.

NMR (CDC13) 6 (ppm): -~2.78 (4H, m) , 3.71 (4H, m) , .16 (1H, d, J = 5 Hz) , 5.73 (IH, d, J = 5 Hz), 5.96 (IH, d, J = 13 Hz), 6.08 (IH, d, J = 13 Hz). '\_J The oil obtained is dissolved in 20 ml of methanol and treated with ozone in analogy to Example 24. There is obtained 0.1 g of rac-cis-4-phenyl-3-phthalimido-l-formyl-

Claims (1)

1. - 49 - 2 0 524 6 -2-a2etidinone. NMR (CDC13) 6 (ppm) 5.57 (IH, d, J~7 Hz) , 5.77 (1H, d, J^7 Ha), 7.25 (5H, Ar) , 7.75 (4H, Ar), 9.3 (IH). O" Example 28 C The rac-cis-4-phenyl-3-phthalimido-l-forjnyl-2-a2eti-10 dinone obtained according to Example 27 is dissolved in methylene chloride and treated with 25% aqueous airunonium hydroxide solution and water in analogy to Example 25. There is obtained rac-cis-4-phenyl-3-phthalimido-2-azeti-dinone which is identical with the product obtained 15 according to Example 13. 20 25 e <sj 2 0 52.46 what4#we claim is: - 50 - cd -nio/loo OIAIMO: 1. 3-Lactams of the general formula r2 r3 15 34] 2 1, in which R^" represents lower 2-alkenyl 10 or 1-alkenyl or a group of the formula -CE2-CH(OR4) 2 (a) -CH2-CHO (b) -CO-CH(OH)2 (c) (d) -cHacH^~0 [°]„ 20 -CH=CH-R9 (e) or -CHO (f) 4 9 wherein R signifies lower alkyl, R sig- 25 nifies a tertiary lower cycloalipnatic or aliphatic amino group and n signifies the 2 number 0 or 1, and wherein further R represents amino or a group convertible into amino and R^ represents a lower organic 2 group with the proviso that when R sig- r r> 25 2 0 5 2 4 6 - 51 - CO 4410/100 nifies amino R^" represents lower 2--alkenyl or 1-alkenyl or one of the groups (a), (c) and (d). 5 2. Compounds according to claim 1, wherein represents lower 2-alkenyl or 1-alkenyl or one of the groups (a) , (b) , (c) and (d) . 3. Compounds according to claim 2, wherein R^" rep- 10 resents vinyl, 2-propenyl (allyl), 1-propenyl, 2,2-dimethoxy-ethyl, 2,2-diethoxyethyl, fonnylmethyl, dihydroxy acetyl, 2-phenylthioethyl or 2-phenylsulphinylalkvl. 4. Compounds according to claim 2 or claim 3, wherein 15 R"^" represents 2-propenyl or 1-propenyl. 5. Compounds according to claim 1, wherein represents 2-morpholinoviny1 or formyl. 20 5. Compounds according to any one of claims 1-5, 2 wherein R signifies amino, azido, phthalimido, (lower alkyl)-0C0-CH=C (CH^)-NH- or readily cleavable acvl-amino, i.e. Z-NH- in which Z represents a readily cleavable acyl group. 2 7. Compounds according to claim 6, wherein R represents amino, phthalimido, benzyloxycarbonylamino, t-butoxv-carbonylamino or 2-methoxycarbonvl-l-methyl-vinylamino. 8. Compounds according to any one of claims 1-7, wherein R^ represents styryl or phenyl optionally substituted by 205246 " 32 - na 4410/100 lower alkyl, lower alkoxy, halogen, cyano, sulphamoyl or lower alkylsulphonyl; lower cycloalkyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanethioyl or a group of the general formula r7o h r79 h or wherein R® and R^ each signify a lower hydrocarbon group which optionally contains oxygen and which is attached via a carbon atom, whereby these groups can also be joined with one another to form a ring including the carbon atom to which R is attached and the oxygen atom 7 to which R is attached. 9. Compounds according to claim 8, wherein R^ represents phenyl, styryl, p-cyanophenvl, p-sulphamovlphenyl, C,_g alkoxycarbonyl or the crouD o^H 9 [ (R)-2,2-dimethyl-l,3-dioxolan-4-yl] . 10. N-[cis-(3S,4S)-l-allyl-4-[(R)-2,2-dimethyl-l,3--dioxolan-4-yl]-2-oxo-3-azetidinyl]-phthalimide. \ - v -c V 11. N- [cis - ( 3S , 4S) - 4- [ (R) - 2 ,2-dimethyl-l, 3-dioxol,^p- -4-yl] -2-oxo-l-( 1-propenyl) -3-azetidinyl] -phthalimide'!^^^"1986 o 2 0 524 E-a 5 Q 12. Benzyl cis-(3S,4S)-4-[(R)-2,2-dimethyl-l,3-dioxolan--4-yl]-2-oxo-l-(1-propenyl)-3-azetidinecarbamate. 13. Benzyl cis-(3S,4S)-4-[(R)-2,2-dimethyl-l,3-dioxolan--4-yl] -2-oxo-l-formyl-3-azetidinecarbaciate. 14. A process for the manufacture of the compounds set forth in any one of claims 1-13, which process comprises reacting a reactive derivative of a carboxylic acid of the general formula or the group R0C0-CH=C(CH^)-NH-and R represents lower alkyl, in the presence of a base with a compound of the general formula R20— CH2—COOH III 15 in which R20 represents azldo, phthalimido 20 h r30 n IV CJ 25 in which R^ represents lower 2-alkenyl or one of the groups (a) and (d) given in claim 1 and represents styryl or phenyl optionally substituted by lower alkyl, lower alkoxy, halogen, cyano; SS 4410/100 206246 sulphamoyl or lower alkylsulphonyl; lower cycloalkyl, lower alkoxycarbonyl, lower alkanoyl, lower alkanethioyl or a group of the general formula R70 h R' O or \ H ,1^-R wherein R6 and R7 each signify a lower hydrocarbon group which optionally contains oxygen and which is attached via a carbon atom, whereby these groups can also be joined with one another to form a ring^ including the carbon atom to which R6 is attached and the oxygen atom 7 to which R is attached t if desired in a thus-obtained compound of the general formula in which R"*"1, R20 and R^° have the above significance, converting a lower 2-alkenyl group present as into the corresponding 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as into the group (b) V ft50CT1986 2 0 52 46 - 55 - CD 4410/1&& or (c) or transforming a group (d) present as into the vinyl or formyl group, if desired transforming the group R^® in a resulting compound of the general formula c r20 r30 ^ f' If © 10 in which R^", R2° and R^® have the above significance, into the amino group, if desired reacting a thus-obtained compound of the general formula 15 G r30 ig "V 20 in which R^" and R^° have the above significance , with an agent yielding the group Z to give a compound of the general formula 25 z—nh, R3 0 Ih <r -n ISO? 2C5246 - 56 - GS 4410/100 in which R^" and R^ have the above significance and Z represents a readily cleavable acyl qroup, andT if desired, in a resulting compound of the general formula o30 Z—^ 10 N Ih1 N11 in which R^, R^° and Z have the above significance, converting a lower 2-alkenyl grpup present as RiJ- into the ,11 15 corresponding 1-alkenyl group or into the group (e) or (f) or converting a group (a) present as R^ into the group (b) or (c) or transforming a group (d) present as R^ into the vmyl or formyl group and, if desired, subsequently further transforming the group within the meaning of . 205246 "57— CT3 1 ^ 1 'J / 1 15. The use of the compounds defined in any one of claims 1-13 for the manufacture of antimicrobially active 3--lactams. 16. The use of the compounds defined in any one of claims 1-13 for the manufacture according to methods known per se of optically uniform antimicrobially active Q-lactams of the general formula C CONH- *R3 ^OR5 C7 -N Ila S03H wherein R5 represents hydrogen, lower alkyl 3 or carboxy-lower alkyl and R represents a lower organic group, or ox corresponding optical antipodes of these compounds. 17. The use of the compounds defined in any one of claims 1-13 for the manufacture according to methods known per se of optically uniform antimicrobially-active fj—lactams of formula Ila in claim 16 in which represents carbamoyl or carbamoyloxymethyl. ' v \z 15 OCT 1986 '.\\c e 1 ^ - 58 - 205246 18. The use of the compounds defined in any one of claims 1-13 for the manufacture according to methods known per se of optically uniform antimicrobially-active fl-lactams of formula Ila in claim 16 in which R^ represents 1-methyl-l--carboxyethyl and R^ represents carbamoyloxymethyl. 19. The use of the compounds defined in any one of claims 1-13 for the manufacture according to methods known per se of optically uniform antimicrobially-active S-lactams of formula Ila in claim 16 in which represents carboxy-methyl and represents carbamoyloxymethyl. 20- The compounds defined in any one of claims 1-13 suitable for use as intermediates for the manufacture of antimicrobially active (3-lactams. 21. A process for the manufacture of 6-lactaip.s of the formula I defined in claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 28. 22. B-Lactams of the formula I defined in claim 1 whenever manufactured according to the process as claimed in claim 14 or claim 21. DATHD THIS DA i' OF OcZtrtuW j5 £6 A. J. PARK & SON nK (p*"* ■ ^ \~rr '"'**• n "*"!]'• »"r>! f—r- _ ^ * ■ \ ' 150CT1986 6^'- r. ( \!