R7 is hydrogen, lower alkyl, lower cycloalkyl, formyl, acetyl or pivaloyl; R8 is hydrogen or halogen; and readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.

The compounds of the present formula I are useful in the treatment and prophylaxis of infectious diseases caused by gram-positive bacteria, èspecially infectious diseases caused by sensitive and resistant staphylococci, pneumococci, enterococci and the like.

The invention is also concerned with the manufacture of compounds of formula I, with their use as pharmaceutically active substances, particularly for the treatment and prophylaxis of infectious diseases, and with pharmaceutical preparations containing a compound of formula I for the treatment and prophylaxis of infectious diseases.

In the above compounds of formula I the 3-substituent can be present in the E-form: in the Z-form: Compounds of formula la, i. e. compounds wherein the pyrrolidinone is in the E- form, are generally preferred.

Further preferred compounds of formula I are those wherein R'is methyl; R2 is hydrogen; R3 is hydrogen or carbamoylmethyl; Z is phenylene;

R4 is phenyl, 2,4,5-trichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-hydroxymethylphenyl, 3,4- dimethoxyphenyl, 4-carboxyphenyl, 2-benzimidazolyl, 2-benzthiazolyl, 4-pyridinyl, 2-naphthyl, 6-carboxy-2-naphthyl or benzyl; particularly phenyl, 2-naphthyl, 4-carboxyphenyl, 6-carboxy-2-naphthyl or 2-benzthiazolyl; Q isS; Y isS; X is CH or N; m, s are both 1; R5, R6 are both hydrogen; R7 is hydrogen; and readily hydrolyzable esters thereof, pharmaceutically acceptable salts of said compounds and hydrates of the compounds of formula I and of their esters and salts.

Also preferred compounds of formula I are in the E-form and have the additional pyrrolidine moiety connected via its 3', 5'-positions, i. e. the compounds have the partial formula The term"halogen"or"halo"used herein refers to all four forms, that is chlorine or chloro; bromine or bromo; iodine or iodo; and fluorine or fluoro, unless specified otherwise.

As used herein, the term"lower alkyl"used alone or in combination such as"lower alkylamino or di-lower alkylamino", refers to both straight or branched saturated hydrocarbon groups having 1 to 8, and preferably 1 to 4, carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, t-butyl and the like.

As used herein, the term"lower alkoxy"used alone or in combination such as"lower alkoxycarbonyl"refers to a straight or branched hydrocarbonoxy group wherein the"alkyl" portion is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n- propoxy and the like.

By the term"lower cycloalkyl"is meant a 3-7 membered saturated carbocyclic moiety, e. g., cyclopropyl, cyclobutyl, cyclohexyl, etc.

As used herein,"heterocyclyl"refers to an unsaturated or saturated, unsubstituted or substituted 4-, 5-, 6-or 7-membered heterocyclic ring containing at least one hetero atom selected from the group consisting of oxygen, nitrogen or sulfur. Exemplary of heterocyclic rings include, but are not limited to, for example, the following groups; azetidinyl, pyridyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxido-pyridazinyl, pyrazolyl, triazinyl, imidazolyl, thiazolyl, 1,2,3- thiadiazolyl, 1, 2, 4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl; furyl, 1H- azepinyl, thienyl, tetrahydrothienyl, isoxazolyl, isothiazolyl, oxazolidinyl, etc. Substituents for the heterocyclic ring include, for example, lower alkyls such as methyl, ethyl, propyl, etc., lower alkoxys such as methoxy, ethoxy, etc., halogens such as fluorine, chlorine, bromine, etc., halogen substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxy, carbamoyl, or carboxy groups. A further substituent is oxo, such as in 2-oxo-oxazolidin-3-yl, 1,1-dioxo-tetrahydrothiophen-3-yl.

"Heterocyclylene"refers to a"heterocyclyl"residue as defined above but containing at least 2 carbon atoms and connected via two carbon bonds, such as 2,5-furylene, 2,5- thienylene, 2,4-pyridylene, 3,5-piperazylene, etc.

As used herein pharmaceutically acceptable salts useful in this invention include salts derived from metals, the ammonium salt, quaternary ammonium salts derived from organic bases and amino acid salts. Examples of preferred metal salts are those derived from the alkali metals, for example, lithium (Li+), sodium (Na+) and potassium (Kt).

Examples of quaternary ammonium salts derived from organic bases include tetramethyl- ammonium (N+ (CH3) 4), tetraethylammonium (Nt (CH2CH3) 4), benzyltrimethyl- ammonium (N+ (C6H5CH2) (CH3) 3), phenyltriethylammonium (N+ (C6H5) (CH2CH3) 3), and the like, etc. Those salts derived from amines include salts with N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, alkylamines or dialkylamines as well as salts with amino acids such as, for example, salts with arginine or lysine. Especially preferred are hydrochlorides, sulfates, phosphates, lactates, mesylates or the inner salt.

As readily hydrolyzable esters of the compounds of formula I there are to be understood compounds of formula I, the carboxy group (s) of which (for example, the 2- carboxy group) is/are present in the form of readily hydrolyzable ester groups. Examples of such esters, which can be of the conventional type, are the lower alkanoyloxy-alkyl esters (e. g., the acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), the lower alkoxycarbonyloxyalkyl esters (e. g., the methoxycarbonyloxymethyl, 1-ethoxy- carbonyloxyethyl and 1-isopropoxycarbonyloxyethyl ester), the lactonyl esters (e. g., the phthalidyl and thiophthalidyl ester), the lower alkoxymethyl esters (e. g., the methoxy- methyl ester) and the lower alkanoylaminomethyl esters (e. g., the acetamidomethyl ester).

Other esters (e. g., the benzyl and cyanomethyl esters) can also be used. Other examples of such esters are the following: (2,2-dimethyl-1-isopropoxy) methyl ester; 2- (2-methyl- propoxy) carbonyl-2-pentenyl ester; 1- [[(1-methylethoxy) carbonyl] oxy] ethyl ester; 1- (acetyloxy) ethyl ester; (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester; 1-(cyclo- hexyloxy) carbonyl oxy ethyl ester; and 3,3-dimethyl-2-oxo-butyl ester. It will be appreciated by those of ordinary skill in the art that the readily hydrolyzable esters of the compounds of the present invention can be formed at a free carboxy group of the compound.

The compounds of formula I as well as their salts and readily hydrolyzable esters can be hydrated. The hydration can be effected in the course of the manufacturing process or can occur gradually as a result of hygroscopic properties of an initially anhydrous product.

Particularly preferred compounds of formula I are (E)- (6R, 7R)-3- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrroli- dinyl-3-ylidenemethyl-7- 2- (naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-l- azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (E)- (6R, 7R)-7- [2- (6-carboxy-naphthalen-2-ylsulfanyl)-acetylamino-3- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-8-oxo-5- thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carboxylic acid

(6R, 7R)-7- (Z)-2- (5-amino- 1,2,4 thiadiazol-3-yl)-2-hydroxyimino-acetylamino-3- (E)-(3'S, 5'R)-5'-(4-methylaminomethyl-phenyl)-2-oxò- 1,3' bipyrrolidinyl-3-ylidene- methyl-8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-ene-2-carboxylic acid (6R, 7R)-7- (Z)-2- (2-amino-thiazol-4-yl)-2-hydroxyimino-acetylamino-3- (E)- (3'S,5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1, 3' bipyrrolidinyl-3-ylidenemethyl- 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid (E)- (6R, 7R)-3- [ (3'S, 5'R)-5'-(4-Methylaminomethyl-phenyl)-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl]-8-oxo-7- (2-phenylsulfanyl-acetylamino)-5-thia-1- aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid and their pharmaceutically acceptable salts.

The compounds of the present formula I are useful in the treatment and prophylaxis of infectious diseases caused by gram-positive bacteria, especially infectious diseases caused by sensitive and resistant staphylococci, pneumococci, enterococci and the like.

The products in accordance with the invention can be used as medicaments, for example, in the form of pharmaceutical preparations for parenteral administration, and for this purpose are preferably made into preparations as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt or carbohydrate (e. g. glucose) solution.

Depending on the nature of the pharmacologically active compound the pharmaceutical preparations can contain the compound for the prevention and treatment of infectious diseases in mammals, i. e. human and non-human. A daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated. The daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be contemplated.

Representative compounds of the present invention were tested. In vitro activity was determined by minimum inhibitory concentration in a microorganism spectrum by the agar dilution method in Mueller Hinton agar, inocolumn = 104 CFU/spot.

The following shows the minimum inhibitory concentrations (MIC; pg/ml) against a series of pathogenic microorganisms of two representative compounds of formula I. MIC , ug/ml Compounds of Example No. Organism 5 8 S. aureus 887 (MSSA) 0.25 2 S. aureus 270A (MRSA) 2 1 The compounds of the formula I in accordance with the invention as well as their pharmaceutical acceptable salts, hydrates, or readily hydrolyzable esters can be manufactured in accordance with the invention for example by (a) cleaving off any protecting group (s) in a compound of the general formula

in which Q, Z and R'are as above, R° is as R above except that R7 may additionally represent a hydroxy protecting group and the aminothia (dia) zol group may be protected, R9 is hydrogen or a carboxy protecting group, Rl° is hydrogen or an allyloxycarbonyl protecting group, R20 is hydrogen, lower alkyl or an allyloxycarbonyl protecting group and R30 is hydrogen, protected hydroxy-lower alkyl or carbamoylmethyl, except that at least one of R7, R9, Rl°, R20 and R30 is a corresponding protecting or protected group, or a salt thereof, or (b) for the manufacture of readily hydrolyzable esters of a compound of formula I subjecting a carboxylic acid or formula I to a corresponding esterification or (c) for the manufacture of salts or hydrates of a compound of formula I converting a compound of formula I into a salt or hydrate or into a hydrate of said salt.

The process of the present invention involves deprotection of a protected amino group in the 2-position of the thiazol or the thiadiazol ring and/or the protected pyrrolidin ring (R10 as the protecting group), and/or protected hydroxy or carboxylic groups present in a compound of formula II and can be carried and as follows: Removal of amino protecting groups The amino protecting groups may be cleaved off by acid hydrolysis (e. g. the tert- butoxycarbonyl or trityl group), e. g. aqueous formic acid, trifluoroacetic acid or by basic hydrolysis (e. g. the trifluoroacetyl group). Further protecting groups may be cleaved off by hydrazinolysis (e. g. the phthalimido group). The allyloxycarbonyl group may be cleaved off by Pd catalysed transfer to nucleophiles. The chloroacetyl group can be cleaved off by treatment with thiourea.

Amino-protecting groups which are cleavable by acid hydrolysis are preferably removed with the aid of a lower alkanecarboxylic acid which may be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in the acid

or in the presence of a co-solvent such as a halogenated lower alkane, e. g. methylene chloride. The acid hydrolysis is generally carried out at room temperature, although it can be carried out at a slightly higher or slightly lower temperature (e. g. a temperature in the range of about-30°C to +40°C). Protecting groups which are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali at 0°C to 30°C. The chloroacetyl protecting group can be cleaved off using thiourea in acidic, neutral or alkaline medium at about 0°C-30°C.

Removal of hydroxy protecting groups The term"hydroxy protecting group"refers to protecting groups as conventionally used in the art such as trityl (triphenylmethyl), trimethylsilanyl, tert.-butyl-dimethylsilanyl, dimethylphenylsilanyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-nitrobenzyl and the like.

Preferred hydroxy protecting groups are such as are commonly known in the art, e. g. for protection of hydroxyimino groups (R7 = hydrogen in compounds of formula I), usually trityl, lower alkanoyl (especially acetyl) or tetrahydropyranyl.

These protecting groups are e. g. removed as follows: trityl in acidic solvents like 90% formic acid at about 0 to 50°C or triethylsilane in trifluoroacetic acid at about-20 to 25°C; in organic solutions of hydrochloric acid at about-50 to 25°C; acetyl with weak inorganic bases like sodium bicarbonate in methanol or ethanol/water at about 0 to 50°C; tetrahydropyranyl with weak organic acids like p-toluenesulfonic acid in an alcohol, e. g. ethanol, at about 0°C to the boiling point of the mixture.

Removal of protecting groups at the carboxy function The term"carboxylic acid protecting group"refers to protecting groups conventionally used to replace the acidic proton of a carboxylic acid. As carboxyl protecting groups one may utilize an ester form which can be easily converted into a free carboxyl group under mild conditions, for example, methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2- (trimethylsilanyl) ethyl, tert-butyl, allyl, benzyl, triphenylmethyl (trityl), diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, trimethyl-

silanyl, triethylsilanyl, tert-butyldimethylsilanyl, i-propyl-dimethylsilanyl. Preferred are benzhydryl, tert-butyl, p-nitrobenzyl, p-methoxybenzyl and allyl.

These protecting groups may be removed as follows: benzhydryl trifluoroacetic acid with anisol, phenol, cresol or triethylsilane at about-40°C to room temperature; BF3-etherate in acetic acid at about 0 to 50°C; tert-butyl formic acid or trifluoroacetic acid with or without anisol, phenol, cresol or triethylsilane and a solvent such as dichloromethane at about-10°C to room temperature; p-nitrobenzyl sodium sulfide in acetone/water at about 0°C to room temperature; p-methoxybenzyl formic acid at about 0 to 50°C; or trifluoroacetic acid and anisol, phenol or triethylsilane at about-40°C to room temperature; allyl palladium (0) catalyzed transalkylation reaction in the presence of tri- n-butyltinhydride and acetic acid, see for example J. Org. Chem.

(1987) 52,4984-4993.

The compounds of the invention can be manufactured according to the following reaction schemes 1-7. Other compounds falling under the claims are obtainable in analogy thereto, in analogy to methods described in USP 5,523,400, EP 841,339 and EP 849,269 or in analogy to the examples given below.

SCHEME 1 (cf. Example 1) oBr-.. Br meo Br (J. Org. Chem. (1998), 63 (3), 582-591) A MeO B > nBuLi HO TBDMSO HO, TBDMSO 0 un 1. TBDMSCI 1. Meo HO 2.boc2o MeO c C O O N 2. NaBH4 boc 3. MsCl H 4. H+ 2 3 1.allocCl 2.TBDMSCI ) 3. NaBH4 HO TBDMSO 1. MsCI TBDMSO ^Bu, F 2. R'NHz N 1 NR'alloc 3. allocCl /N I/NR'alloc'N 1/OH allyl alloc alloc 65 4 1.MsCI 2.NaN3 3.PPh3 H2N 'N'-NRNRalloc alloc 7 Scheme 2 (cf. Example 2) -- Br Meo Br (J. Org. Chem. (1998) 63 (3), 582-591) A Meo B "bulb t HOTBDMSO Meo TBDMSO 1. TBDMSCI 1. u 2.boc20 Meo C O O N N-1, O N 2. NABH, 3. MsCI OU 23 °~ 1.1. Hf 2. NaBH4 HA HO TBDMSO 1. MsCi TBDMSO 1.H 2. R'Nhl2 2.AilocCl 3. boc20 N, NR'alloc E--- at! oc"'L her.'-" N NR boc alloc 6 5 4 1.MsCI 2.NaN3 3.PPh3 H2N e ZNR'alloc alloc 7 SCHEME 3 SCHEME 4 AB Me0 A B ^BuLi HOTBDMSO HO HO TBDMSCI, imidazole N p Moo C 0 N N 0 2. NaBr 3. MCI 1a (JP° 1254658A2 ; C) 2a 4 Hs CJ 3a JPO 1045360A2) 1.TBDMSCI 2. (EtO) 2P (O) CH2COOEt TBDMSO3. ph il N Ph \ 1MOU Ph Ph 1. NaBH, TBDMSO Li OTHP / . N CooEt Ph 14 I/1 Ph Ph/ Ph 13 1. H,, Pd (OH) Ph Ph 13 2.allocCi 1. nBu4NF TBDMSO 2. MsCI H2N 3. NaN. 15 al ; < OTHP 4. PPh3>, Nm eOTHPOTHP 4. PPh OTHP OTHP 15 alioc 1/alloc NHa)) oc NHaXoc 16 SCHEME 5 , = NHCbz NHCbzNHCbz NHCbz (J. Am. Chem. Soc. (1998), 120 (6), 1207-1217; W09744312A1) AH OTHP A B "BuLi Y TBDMSO NHCbz TBDMSO i. u \/ -OTHP N NHCbz N /NHCbz 2. nabi, 2annsa I /2a/17 1. H2, Pd/C 2.a)) oca ) 3. nBu4NF H2N HO 2 \ s NNHalloc N 11 NHalloc alloc 2 NaN3 alloc OTHP 3. PPh, OTHP 18 19 SCHEME 6 SCHEME 7

The symbols in the above schemes 1-7 have the following significance: TBDMS = tert-butyl-dimethyl-silanyl boc = tert-butoxycarbonyl Me = methyl MsCI = methanesulfonyl chloride alloc = allyloxycarbonyl Ph = phenyl TFA = trifluoroacetic acid THP = tetrahydropyranyl Cbz = carbobenzoxy (benzyloxycarbonyl) R'= hydrogen or lower alkyl R20 hydrogen, lower alkyl or an allyloxycarbonyl protecting group R30 = hydrogen, protected hydroxy-lower alkyl or carbamoylmethyl R4, R5, R6, R', X, Y and s = the same significance as in formula I.

The following examples illustrate the invention without limiting the scope thereof.

Example 1 (E)- (6R, 7R)-3- [ (3'S, 5'R)-5'- (4-Methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl]-7- [2- (naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1-aza- bicyclo [4.2.0] oct-2-ene-2-carboxylic acid

250.0 mg (0.29 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-aUyloxycarbonyl-5'- 4- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl]-7- 2- (naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-l-aza- bicyclo [4.2.0] oct-2-ene-2-carboxylic acid are suspended in 8 ml dichloromethane and 194 ptl (0.73 mmol) N, O-bis (trimethylsilanyl) trifluoroacetamide are added dropwise. After a clear solution has formed 6.32 mg (0.009 mmol) bis (triphenylphosphine) palladium (II) chloride, 0.34 ml (5.87 mmol) acetic acid and 0.76 ml (2.82 mmol) tri-n-butyltin hydride are added successively. After complete deprotection (HPLC) the suspension is poured on 200 ml diethyl ether containing 13.2 ul (0.73 mmol) water. The precipitated solid is collected by filtration and purified by column chromatography on MCI gel (75-150, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (1: 0,4: 1,3: 1,2: 1, 1: 1). The organic solvent is stripped off in a rotary evaporator and the aqueous phase is freeze-dried.

The starting (E)- (6R, 7R)-3- [ (3'S, 5'R)-l'-allyloxycarbonyl-5'- [4- (allyloxycarbonyl- methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- 2- (naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1-aza-bic yclo [4.2.0] oct-2-ene-2- carboxylic acid can be prepared as follows: (R)-4-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidin-2-one To a solution of 146.3 g (1.44 mol) (R)-4-hydroxy-pyrrolidin-2-one in 900 ml N, N- dimethylformamide, 148.0 g (2.18 mol) imidazole and 239.7 g (1.59 mol) tert- butyldimethylsilanyl chloride are added successively. After 3 hours the reaction is complete (TLC) and the solvent is evaporated. The residue is suspended in ethyl acetate and the precipitate formed is removed by filtration. The clear filtrate is washed with 2% aqueous citric acid solution, followed by water and brine. The organic phase is concentrated in a rotary evaporator to give the desired compound as a crystalline material.

MS (EI): 158 (M-(CH3) 3C) IR (NJL): 1670,1254 cm-1 (R)-4- (tert-Butyl-dimethyl-silanyloxy)-2-oxo-pyrrolidine-1-carboxy lic acid tert-butyl ester

258.4 g (1.20 mol) (R)-4- (tert-butyl-dimethyl-silanyloxy)-pyrrolidin-2-one are dissolved in 2200 ml tetrahydrofuran and the solution is cooled to O'C. After the addition of 7.33 g (0.06 mol) 4-dimethylaminopyridine, 288.1 g (1.32 mol) di-tert-butyl dicarbonate dissolved in 900 ml tetrahydrofuran are added dropwise. The reaction is allowed to warm to room temperature and is stirred for 16 hours. The reaction mixture is concentrated on a rotary evaporator. To the resulting slurry n-hexane is added. After 1 hour the solid material is filtered off, dissolved in ethyl acetate and n-hexane and is chromatographed on silica gel (MERCK, 0.040-0.063 mm) with ethyl acetate: n-hexane (1: 3) as eluent.

MS (EI): 316 (M+H+) IR (NJL): 1769,1693 cm-1 (2R)- [2- (tert-Butyl-dimethyl-silanyloxy)-4- (4-dimethoxymethyl-phenyl)-4-oxo-butyl- carbamic acid tert-butyl ester A solution of 383.6 g (1.66 mol) 1-bromo-4-dimethoxymethyl-benzene in 3500 ml tetrahydrofuran under argon atmosphere is cooled to-78°C and treated dropwise with 1038 ml (1.66 mol) 1.6M butyllithium-n-hexane solution. After 30 min a solution of 350.2 g (1.11 mol) (R)-4-(tert-butyl-dimethyl-silanyloxy)-2-oxo-pyrrolidine-l-c arboxylic acid tert-butyl ester in 1200 ml tetrahydrofuran is added thereto and stirring is continued for another 30 min. After the addition of aqueous ammonium chloride solution the cooling bath is removed. The reaction mixture is extracted twice with ethyl acetate, the combined organic phases washed with water and brine and dried over magnesium sulfate, filtrated and then concentrated. The resulting residue is purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with a gradient of ethyl acetate : n-hexane (1: 9-1 : 4) as eluent.

MS (ISP): 468.3 (M+H+) IR (Film): 1718,1691,1508 cm-i (2R)- (tert-Butyl-dimethyl-silanyloxy)-4- (4-dimethoxymethyl-phenyl)-4-hydroxy-butyl- carbamic acid tert-butyl ester To a solution of 430.3 g (0.92 mol) 2-(R)-(tert-butyl-dimethyl-silanyloxy)-4-(4- dimethoxymethyl-phenyl)-4-oxo-butyl]-carbamic acid tert-butyl ester in 4000 ml ethanol at 0°C 52.2 g (1.38 mol) sodium borohydride are added portionwise. Stirring is continued for another hour at the same temperature and then the cooling bath is removed. After 3 hours 2% aqueous citric acid is added and the mixture extracted with ethyl acetate. After reextraction of the aqueous phase the organic phases are washed with water and brine, dried over magnesium sulfate, filtrated and evaporated. The resulting residue is purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with ethyl acetate: n- hexane (1: 3 and 1: 2) as eluent.

MS (EI): 438 (M-CH30') IR (Film): 1717,1699,1510 mol (2R, 4R)-4- (4-Hydroxy-pyrrolidin-2-yl)-benzaldehyde A solution of 385.1 g (0.82 mol) 2- (R)- (tert-butyl-dimethyl-silanyloxy)-4- (4- dimethoxymethyl-phenyl)-4-hydroxy-butyl-carbamic acid tert-butyl ester in 4000 ml dichloromethane under argon is cooled to 0°C and 455.9 ml (3.28 mol) triethylamine are added. To this solution, 139.3 ml (1.80 mol) methanesulfonyl chloride are added dropwise.

After 1 hour at 0°C the cooling bath is removed and the reaction mixture stirred at ambient temperature until completion of the reaction (TLC). The pH of the reaction mixture is adjusted to 1 with 80% aqueous trifluoroacetic acid solution and stirred for 30 min. The

reaction mixture is concentrated under reduced pressure to give the desired compound as the trifluoroacetate salt which is used for the next step without further purification.

(2R, 4R)-2- (4-Formyl-phenyl)-4-hydroxy-pyrrolidine-l-carboxylic acid allyl ester A solution of 53.5 g (0.28 mol) (2R, 4R)-4- (4-hydroxy-pyrrolidin-2-yl)-benzaldehyde in 400 ml dioxane and 200 ml water is cooled to 0°C, and the pH is adjusted to 10 with 1M aqueous sodium hydroxide solution. To this, 32.9 ml (0.31 mol) allyl chloroformate in 100 ml dioxane are added dropwise while maintaining the pH of the reaction solution at pH 9- 10 by using 1M aqueous sodium hydroxide solution. After completion of the reaction the reaction mixture is poured on ethyl acetate and water (1: 1 v/v) and the organic phase is separated, dried over magnesium sulfate, filtrated and concentrated under reduced pressure. The crude product so obtained is used for the next step without further purification.

(2R,4R)-4-(tert-Butyl-dimethyl-silanyloxy)-2- (4-formyl-phenyl)-pyrrolidine-1-carboxylic acid allyl ester To a solution of 55.1 g (0.20 mol) (2R, 4R)-2- (4-formyl-phenyl)-4-hydroxy-pyrrolidine-l- carboxylic acid allyl ester in 760 ml N, N-dimethylformamide, 20.4 g (0.30 mol) imidazole and 33.2 g (0.22 mol) tert-butyldimethylsilanyl chloride are added successively. After the reaction is complete (TLC), the solvent is evaporated. The residue is suspended in ethyl acetate and the precipitate formed is removed by filtration. The clear filtrate is washed with 2% aqueous citric acid solution, followed by water and brine. The organic phase is concentrated in a rotary evaporator and the resulting residue dried under high vacuum.

(2R, 4R)-4- (tert-Butyl-dimethyl-silanyloxy)-2- (4-hydroxymethyl-phenyl)-pyrrolidine-1- carboxylic acid allyl ester

To a solution of 62.3 g (0.16 mol) (2R, 4R)-4- (tert-butyl-dimethyl-silanyloxy)-2- (4-formyl- phenyl)-pyrrolidine-l-carboxylic acid allyl ester in 780 ml methanol, 9.10 g (0.24 mol) sodium borohydride are added portionwise under argon atmosphere at 0°C. After 1 hour the cooling bath is removed and the reaction mixture stirred at room temperature until completion of the reaction (TLC). The solution is neutralized with 10% aqueous citric acid solution and evaporated. The residue is taken up in ethyl acetate and water and extracted.

The aqueous phase is extracted twice with ethyl acetate and the combined organic phases dried over magnesium sulfate, filtrated and evaporated. The oily residue so obtained is pure enough for the next step.

(2R,4R)-4- (tert-Butyl-dimethyl-silanyloxy)-2- (4-methanesulfonyloxymethyl-phenyl)- pyrrolidine-1-carboxylic acid allyl ester A solution of 47.0 g (0.12 mol) (2R, 4R)-4- (tert-butyl-dimethyl-silanyloxy)-2- (4- hydroxymethyl-phenyl)-pyrrolidine-1-carboxylic acid allyl ester in 650 ml dichloromethane is cooled to 0°C, and, under argon atmosphere, 66.7 ml (0.48 mol) triethylamine are added. To this solution 27.5 ml (0. 24 mol) methanesulfonyl chloride are added dropwise. The cooling bath is removed, and the reaction mixture is stirred at ambient temperature until completion of the reaction. Water is added, and the reaction mixture is extracted. The aqueous phase is reextracted with dichloromethane and the combined organic phases washed with water and brine, dried over magnesium sulfate, filtrated and evaporated. The crude product can be used in the next step without further purification.

(2R,4R)-4- (tert-Butyl-dimethyl-silanyloxy)-2- (4-methylaminomethyl-phenyl)-pyrrolidine- 1-carboxylic acid allyl ester

To a solution of 47.0 g (0.10 mol) (2R, 4R)-4- (tert-butyl-dimethyl-silanyloxy)-2- (4- methanesulfonyloxymethyl-phenyl)-pyrrolidine-1-carboxylic acid allyl ester in 590 ml diethyl ether, 84 ml (0.50 mol) of a 6M methylamine solution in diethyl ether are added at- 70°C. After complete addition the reaction mixture is stirred for an additional hour at the same temperature, the cooling bath is removed and the mixture is stirred at room temperature for an additional 4 hours. After filtration the volatile components are removed in a rotary evaporator, the resulting solid dried under high vacuum and used for the next step without further purification.

(2R, 4R)-2- {4- [ (Allyloxycarbonyl-methyl-amino)-methyl-phenyll-4-(tert-butyl -dimethyl- silanyloxy)-pyrrolidine-l-carboxylic acid allyl ester The crude amine from the step above (14.5 g, 0.05 mol) is dissolved in 450 ml dichloromethane and cooled to 0°C. The pH of the solution is brought to 7 with triethylamine, then 5.84 ml (0.055 mol) allyl chloroformate are added dropwise. The cooling bath is removed and the reaction mixture stirred at room temperature for an additional 1 hour. The reaction mixture is poured on water and extracted. The aqueous phase is reextracted twice with dichloromethane and the combined organic phases washed with water and brine and finally dried over magnesium sulfate. After evaporation of the solvent the resulting residue is purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with ethyl acetate: n-hexane (1: 2) as eluent.

(2R, 4R)-2- {4- [ (Allyloxycarbonyl-methyl-amino)-methyl-phenyl}-4-hydroxy-pyr rolidine- 1-carboxylic acid allyl ester

A solution of 19.2 g (0.04 mol) (2R, 4R)-2-{4-(allyloxycarbonyl-methyl-amino)-methyl- phenyl}-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-car boxylic(tert-butyl-dimethyl-silanyloxy)-pyrrolidine-1-carbox ylic acid allyl ester in 230 ml tetrahydrofuran is cooled to 0°C and 48.0 ml (0.048 mol) of a 1M tetrabutylammonium fluoride solution in tetrahydrofuran are added. The cooling bath is removed, and, after complete deprotection, the solvent is evaporated under reduced pressure, and the remaining oily residue is poured on a mixture of ethyl acetate and water and extracted. The aqueous phase is reextracted with ethyl acetate and the combined organic phases dried over magnesium sulfate, filtrated and evaporated.

MS (ISP): 375.4 (M+H+) IR (NJL): 3442,1702,1648 cm-1 (2R, 4S)-2- [4- (Allyloxycarbonyl-methyl-amino)-methyl-phenyl-4-amino-pyrrol idine-1- carboxylic acid allyl ester To a solution of 13.5 g (36.0 mmol) (2R, 4R)-2- 4- (allyloxycarbonyl-methyl-amino)- methyl-phenyl-4-hydroxy-pyrrolidine-1-carboxylic acid allyl ester in 240 ml tetrahydrofuran 18.1 ml (0.13 mol) triethylamine are added and the solution is cooled to 0°C. After dropwise addition of 3.3 ml (43.2 mmol) methanesulfonyl chloride the cooling bath is removed, and stirring is continued until completion of the reaction (TLC). After filtration the solvent is removed in a rotary evaporator, and the residue is purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with ethyl acetate: n- hexane (1: 1) as eluent.

The resulting oil (14.5 g, 32.0 mmol) is dissolved in 115 ml N, N-dimethylformamide and 2.50 g (38.4 mmol) sodium azide are added. The solution is stirred overnight at 80°C and is then allowed to cool to room temperature. The solvent is evaporated in a rotary evaporator and the residue dissolved in 120 ml ethyl acetate and extracted twice with 100 ml water.

The organic phase is dried over magnesium sulfate, filtrated and concentrated to a volume

of about 60 ml, then 10.0 g (32.0 mmol) triphenylphosphine are added portionwise. After foaming has ceased, the solution is concentrated at 40°C in a rotary evaporator and the residue dissolved in 120 ml diethyl ether. The solution is extracted with 68 ml aqueous 0.5M sodium hydroxide solution, and the aqueous phase is reextracted twice with each 40 ml diethyl ether. The ethereal phases are dried over magnesium sulfate, filtrated and the solvent evaporated under reduced pressure. The resulting residue is dissolved in 130 ml tetrahydrofuran, 50 ml 25% aqueous ammonium hydroxide solution added and the mixture stirred 24 hours at room temperature. The organic solvent is stripped off and the aqueous phase is extracted with 80 ml ethyl acetate. The aqueous phase is reextracted twice with each 30 ml ethyl acetate and the combined organic phases are extracted three times under each 40 ml 10% aqueous citric acid. The pH of the aqueous phase is adjusted to 14 with 4M aqueous sodium hydroxide solution. The aqueous phase is extracted four times with each 50 ml dichloromethane and the combined organic phases dried over magnesium sulfate, filtrated and evaporated. The resulting product can be used for the next step without further purification.

MS (ISP): 374.5 (M+H+) IR (Film): 3371,1708,1648 cm-1 Mixture of (3R, 3'S, 5'R)- and (3S, 3'S, 5'R)-5'- 4- (allyloxycarbonyl-methyl-amino)- methyl]-phenyl]-3-bromo-2-oxo- 1,3') bipyrrolidinyl-1'-carboxylic acid allyl ester A solution of 10.5 g (28.0 mmol) (2R, 4S)-2- 4- (allylo3cycarbonyl-methyl-amino)-methylJ- phenyl-4-amino-pyrrolidine-1-carboxylic acid allyl ester in 60 ml dichloromethane is treated with 23 ml (0.28 mol) 50% aqueous sodium hydroxide solution. The vigorously stirred mixture is cooled to 0°C and 6.80 g (31.0 mmol) 2-bromo-4-chloro-butanoyl chloride in 30 ml dichloromethane are added dropwise keeping the temperature below 5°C.

The reaction mixture is stirred at 0°C for 1 hour. The phases are separated, the aqueous phase extracted twice with 40 ml dichloromethane and the combined organic phases washed twice with 20 ml water and dried over magnesium sulfate. After filtration the solvent is removed in a rotary evaporator. The residue is redissolved in 120 ml dichloromethane, them 180 ml 50% aqueous sodium hydroxide solution and 1.10 g Dowex 2x10 are added under vigorous stirring. After completion of the reaction (TLC) the phases are separated and the aqueous phase extracted twice with 60 ml dichloromethane. The

combined organic phases are washed with 40 ml water, followed by brine, dried over magnesium sulfate and concentrated.

MS (ISP): 522.1 (M+H+) IR (MIR): 1686,1647 cm'' Mixture of (3R, 3'S, 5'R)- and (3S, 3'S, 5'R)- 1'- allyloxycarbonyl-5'- 4- (allyloxycarbonyl- methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-yl-triphenyl-phosphonium bromide 17.3 g (0.07 mol) triphenylphosphine and 11.6 g (22.0 mmol) mixture of (3R, 3'S, 5'R)- and (3S, 3'S, 5'R)-5'- 4- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl-3-bromo-2-oxo- 1,3' bipyrrolidinyl-1'-carboxylic acid allyl ester are dissolved in 50 ml dichloromethane.

The solvent is removed in a rotary evaporator and the residual oil heated for 2.5 hours at 100°C. The resulting solid is dissolved in 40 ml dichloromethane and added under vigorous stirring to 450 ml n-hexane. After 1 hour the solvent is decanted off and the residue triturated with 450 ml diethyl ether. The resulting solid is collected by filtration, washed with n-hexane and diethyl ether and dried under high vacuum.

MS (ISP): 702.3 (M+) IR (NJL): 1687,1647 cm-l (E)- (2R, 6R, 7R)-3- (3'S, 5'R)-1'-Allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7-tert-butoxycarbonyl- amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-3-ene-2-carboxylic acid benzhydryl ester A suspension of 7.72 g (16.0 mmmol) (2R, 6R, 7R)-7-tert-butoxycarbonylamino-3-formyl- 8-oxo-5-thia-l-azabicyclo [4.2.0] oct-3-ene-2-carboxylic acid diphenylmethyl ester and 14.1

g (18.0 mmol) mixture of (3R, 3'S, 5'R)- and (3S, 3'S, 5'R)- 1'-allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-yl- triphenyl-phosphonium bromide in 280 ml 1,2-epoxybutane is refluxed for 2 hours. The solvent is evaporated under reduced pressure and the resulting residue purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with ethyl acetate: n-hexane (1 : 1 and 2: 1) as eluent.

MS (ISN): 916.2 (M-H') IR (MIR): 1779,1741,1692 cm-1 1: 1 Mixture of (E)- (5R, 6R, 7R)- and- (5S, 6R, 7R)-3- [ (3'S, 5'R)-1'-allyloxycarbonyl-5'- [4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1, 3' bipyrrolidinyl-3- ylidenemethyl-7-tert-butoxycarbonylamino-5,8-dioxo-5-thia-l- aza-bicyclo 4.2.0 oct-2- ene-2-carboxylic acid benzhydryl ester A solution of 11.0 g (12.0 mmol) (E)- (2R, 6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza- bicyclo [4.2.0] oct-3-ene- 2-carboxylic acid benzhydryl ester in 70 ml dichloromethane is cooled to-10°C. To this a solution of 3.0 g (70%, 2.1 g, 12.0 mmol) m-chloroperbenzoic acid in 50 ml dichloromethane is added dropwise. The reaction mixture is stirred for 2.5 hours at-5°C to 0°C, then 25.0 ml of a 5% aqueous sodium thiosulfate solution are added and the mixture stirred for 15 min. The phases are separated and the aqueous phase extracted twice with 30 ml dichloromethane. The combined organic phases are washed with each 30 ml 5% aqueous solutions of sodium thiosulfate, sodium bicarbonate and finally with brine. The solution is dried over magnesium sulfate, filtered and the solvent stripped off at a rotary evaporator. The residue is purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with a gradient of ethyl acetate: n-hexane (2: 1,3: 1,4: 1,5: 1 and ethyl acetate).

MS (ISN): 932.7 (M-H-) IR (MIR): 1790,1681 cm-1

(E)- (6R, 7R)-3- [ (3'S, 5'R)-l'-Allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7-tert-butoxycarbonyl- amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester To a solution of 6.40 g (6.80 mmol) of a 1: 1 mixture of (E)- (5R, 6R, 7R)- and- (5S, 6R, 7R)-3- [ (3'S, 5'R)-1'-allyloxycarbonyl-5'- 4- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2- oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7-tert-butoxycarbonylamino-5, 8-dioxo-5-thia- l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester in 70 ml dichloromethane, 6.0 ml N, N-dimethylformamide and 8.0 ml N-acetamide is added within 20 min at-30°C a solution of 2.60 ml (30.0 mmol) phosphorus tribromide in 10 ml dichloromethane. After stirring for 1.5 hours at-30°C the mixture is allowed to warm to -5°C and quenched with 150 ml ice-cold water. The phases are separated and the aqueous phase extracted twice with 60 ml dichloromethane. The combined organic phases are washed with 90 ml water and brine and dried over magnesium sulfate. After filtration the solvent is stripped off in a rotary evaporator and the residue treated with a 1: 1 mixture of ethyl acetate and n-hexane (130 ml). The precipitated product is collected by filtration and dried under high vacuum.

MS (ISP): 918.7 (M+H+) IR (MIR): 1779,1694 cm-l (E)- (6R, 7R)-3- [ (3'S, 5'R)-l'-Allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl]-7-amino-8-oxo-5-thia-1- aza-bicyclo 4.2.0 oct-2-ene-2-carboxylic acid To a solution of 3.0 g (5.40 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7-tert-butoxycarbonylamino-8-oxo-5-thia-1-aza- bicyclo 4.2.0 oct-2-ene-

2-carboxylic acid benzhydryl ester in 50 ml dichloromethane are added at 0°C 3.85 ml (35.0 mmol) anisole and 20.8 ml (0.27 mol) trifluoroacetic acid. The reaction mixture is stirred for 2.5 hours at room temperature, concentrated to a volume of 10 ml and poured on 150 ml ice-cold diethyl ether. The precipitated solid is collected by filtration, washed with diethyl ether and dried under high vacuum.

MS (ISP): 652.1 (M+H+) IR (NJL): 1785,1698 cm~' Elemental analysis: C32H37N508S (C2HF302) 0.4 (697. 344) calc.: C 56.49 H 5.41 N 10.04 S 4.60 F 3.27 foundg): C 56.48 H 5. 28 N 9.91 S4.58 F3.05 #) Calculated with 1.3% water (E)- (6R, 7R)-3- [ (3'S, 5'R)-1'-Allyloxycarbonyl-5'- [4- (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl]-7- 2- (naphthalen-2- ylsulfanyl)-acetylamino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid 183.3 mg (0.84 mmol) (2-naphthylthio) acetic acid are dissolved in 5 ml N, N- dimethylacetamide and treated with 136.2 mg (0.84 mmol) 1, l'-carbonyldiimidazole. After 30 min 500.0 mg (0.77 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-1'-allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- [1,3'] bipyrrolidinyl-3- ylidenemethyl-7-amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid are added in one portion and stirring is continued until completion of the reaction (HPLC).

The brown solution is added dropwise with stirring on 250 ml diethyl ether. The precipitate is collected by filtration and dried under high vacuum. The crude product is suspended in 10 ml water, and the pH is adjusted to 7 with 1M aqueous sodium hydroxide solution. The brown solution is purified by reversed phase chromatography (RP-18 LiChroPrep gel) with a gradient of water: acetonitrile (1: 0,4: 1,3: 1,2: 1,1: 1). The organic solvent is stripped off on a rotary evaporator and the pH of the aqueous phase is adjusted to 2 with 1W

hydrochloric acid. The resulting solid is collected by filtration, washed with water and dried under high vacuum.

Example 2 Alternative synthesis of intermediate B: (2R, 4R)-2- {4- [ (Allyloxycarbonyl-methyl-amino)-methyl-phenyl}-4-hydroxy-pyr rolidine- 1-carboxylic acid allyl ester from intermediate A: (R)- [2- (tert-Butyl-dimethyl-silanyloxy)-4- (4-dimethoxymethyl-phenyl)-4-oxo-butyl- carbamic acid tert-butyl ester A solution of 383.6 g (1.66 mol) 1-bromo-4-dimethoxymethyl-benzene in 4000 ml tetrahydrofuran under argon atmosphere was cooled down to-75°C and treated dropwise with 1038 ml (1.66 mol) 1.6M butyllithium-hexane solution. After 30 min a solution of 350.2 g (1.11 mol) (R)-4- (tert-butyl-dimethyl-silanyloxy)-2-oxo-pyrrolidine-l-carboxy lic acid tert-butyl ester in 1300 ml tetrahydrofuran was added thereto and stirring was continued for another 30 min. After addition of 1000 ml aqueous ammonium chloride solution the reaction mixture was poured on a mixture of 6000 ml ethyl acetate and 2500 ml ice-cold aqueous ammonium chloride solution and stirred for 10 min. The phases were separated and the organic layer was washed with 2500 ml water and 2500 ml brine, dried over magnesium sulfate, filtered and then concentrated at a rotary evaporator. The resulting oily residue was purified by column chromatography on silica gel (MERCK, 0.040 -0.063 mm) with a gradient of ethyl acetate: n-hexane (1: 9 to 1: 3) as eluent.

MS (ISP): 468.3 (M+H+) IR (Film): 1718,1691,1508 cm~'

[2- (R)- (tert-Butyl-dimethyl-silanyloxy)-4- (4-dimethoxymethyl-phenyl)-4-hydroxy- butyl]-carbamic acid tert-butyl ester To a solution of 430.3 g (0.92 mol) (R)- 2- (tert-Butyl-dimethyl-silanyloxy)-4- (4- dimethoxymethyl-phenyl)-4-oxo-butyl-carbamic acid tert-butyl ester in 5250 ml tetrahydrofuran and methanol (9: 1 v/v) was added portionwise under argon atmosphere 17.6 g (0.46 mol) sodium borohydride. After 4 h the reaction mixture was cooled down to 0°C and 2400 ml 10% aqueous citric acid was added slowly and the mixture was poured on 8000 ml ethyl acetate and extracted. The organic layer was washed successively with 4000 ml water, 5% aqueous sodium bicarbonate solution and brine and was dried over magnesium sulfate, filtered and evaporated. The resulting oily residue was purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with dichloromethane: ethyl acetate (4: 1) as eluent.

MS (EI): 438 (M-CH30) IR (Film): 1717,1699,1510 cm'' 4-(R)- (tert-Butyl-dimethyl-silanyloxy)-2- (4-dimethoxymethyl-phenyl)-pyrrolidine-1- carboxylic acid tert-butyl ester To a solution of 367.0 g (0.78 mol) 2- (R)- (tert-butyl-dimethyl-sHanyloxy)-4- (4- dimethoxymethyl-phenyl)-4-hydroxy-butyl-carbamic acid tert-butyl ester in 4100 ml dichloromethane 436.0 ml (3.12 mol) triethylamine were added. The solution was cooled down to 0°C and treated dropwise with 147.5 ml (1.92 mol) methanesulfonyl chloride in 700 ml dichloromethane. After 1 h the cooling bath was removed and the reaction mixture was stirred for 5 h at ambient temperature. The reaction mixture was extracted three times with 5000 ml water, dried over magnesium sulfate, filtered and concentrated at a rotary

evaporator. The crude product was purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with n-hexane: ethyl acetate (4: 1) as eluent.

MS (EI): 420 (M-CH30') IR (Film): 1695 cm l 4- (R)- (tert-Butyl-dimethyl-silanyloxy)-2- (4-formyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of 286.0 g (0.63 mol) 4- (R)- (tert-butyl-dimethyl-silanyloxy)-2- (4- dimethoxymethyl-phenyl)-pyrrolidine-l-carboxylic acid tert-butyl ester in 3000 ml ethyl acetate, 3000 ml 1M hydrochloric acid were added and the soultion was stirred for 3 h at room temperature. The phases were separated, the organic layer was washed four times with 2500 ml water, dried over magnesium sulfate, filtered and evaporated at a rotary evaporator. The crude product was purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with a gradient of dichloromethane: ethyl acetate (50: 1 to 20: 1) as eluent.

MS (EI): 406 (M+H+) IR (Film): 1702,1608 cm~l (2R, 4R)-4- (tert-Butyl-dimethyl-silanyloxy)-2- (4-hydroxymethyl-phenyl)-pyrrolidine-1- carboxylic acid tert-butyl ester and (2S, 4R)-4-(tert-butyl-dimethyl-silanyloxy)-2-(4- hydroxymethyl-phenyl)-pyrrolidine-l-carboxylic acid tert-butyl ester To a solution of 231.2 g (0.57 mol) 4- (R)- (tert-butyl-dimethyl-silanyloxy)-2- (4-formyl- phenyl)-pyrrolidine-l-carboxylic acid tert-butyl ester in 3100 ml tetrahydrofuran/methanol (9: 1 v/v), 6.74 g (0.18 mol) sodium borohydride were added portionwise. After 30 min the reaction mixture was cooled down to 0°C and 840 ml 5% citric acid solution was added slowly. After foaming had ceased, the reaction mixture was

poured on 8000 ml ethyl acetate and extracted. The organic layer was washed successively with 1500 ml water, 5% sodium bicarbonate solution and brine. After drying over magnesium sulfate and filtration, the organic solvents were evaporated under reduced pressure. The crude product was purified and the diastereomers were separated by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with n-hexane: ethyl acetate (2: 1) as eluent.

MS (EI): 408 (M+H+) IR (Film): 3435,1698,1677 cm'' (2R, 4R)-2- [4- (tert-Butoxycarbonyl-methyl-amino)-methyl-phenyl-4- (tert-butyl- dimethyl-silanyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester To a solution of 106.0 g (0.26 mol) (2R, 4R)-4- (tert-butyl-dimethyl-silanyloxy)-2- (4- hydroxymethyl-phenyl)-pyrrolidine-l-carboxylic acid tert-butyl ester in 1400 ml dichloromethane several drops of N, N-dimethylformamide were added, followed by 43.6 ml (0.31 mol) triethylamine. After cooling down to 0°C, 22.3 ml (0.29 mol) methanesulfonyl chloride in 100 ml dichloromethane were added dropwise. After 1 h the reaction mixture was washed with 1200 ml water followed by 1200 ml brine, dried over magnesium sulfate and filtered. After evaporation of the solvent, the crude mesylate was dissolved in 1100 ml tetrahydrofuran and the solution was cooled down to-70°C. To this, 480 ml (0.96 mol) of a 2M methyl amine solution in tetrahydrofuran was added dropwise.

After 30 min the cooling bath was removed and the reaction mixture was stirred for another 3h at ambient temperature. Argon was bubbled through the solution for 2 h to remove the remaining methyl amine. Then 75.0 g (0.34 mol) di-tert-butyl dicarbonate dissolved in 340 ml tetrahydrofuran were added and the reaction was stirred for 90 min at ambient temperature. The suspension was poured on 6000 ml ethyl acetate, washed successively with 2500 ml water and 2500 ml brine. After drying over magnesium sulfate and filtration the solvent was evaporated at a rotary evaporator. The crude product was purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with n- hexane: ethyl acetate (9: 1 and 4: 1) as eluent.

MS (ISP): 538.4 (M+NH4+) IR (Film): 1699,1514 cm-1

(2R, 4R)-2- 4- (Methyl-amino)-methyl-phenyl-4-hydroxy-pyrrolidine dihydrochloride A solution of 77.9 g (0.15 mol) (2R, 4R)-2- 4- (tert-butoxycarbonyl-methyl-amino)- methyl-phenyl-4-(tert-butyl-dimethyl-silanyloxy)-pyrrolidine -1-carboxylic acid tert- butyl ester in 780 ml dichloromethane was cooled to 0°C and treated with 310 ml trifluoroacetic acid. After 2 h the cooling bath was removed and and the solution was stirred for another 3h at ambient temperature. The volatile components were evaporated at a rotary evaporator, the residue was taken up with 800 ml ethyl acetate and again evaporated. The crude oily residue was dissolved in 1100 ml ethanol and 312 ml (0.81 mol) 2.6M hydrochloric acid in dioxane were added. The resulting suspension was stirred for 1 h at room temperature and kept in a refrigerator overnight. The solid material was collected by filtration, washed with ethanol and diethyl ether and dried in high vacuum.

MS (EI): 205 (M-H') IR (NJL): 3344,2721,1561 cm-1 (2R, 4R)-2- {4- [ (Allyloxycarbonyl-methyl-amino)-methyl-phenyl}-4-hydroxy-pyr rolidine- 1-carboxylic acid allyl ester To a suspension of 36.7 g (0.13 mol) (2R, 4R)-2- [4- [ (methyl-amino)-methyl-phenyl-4- hydroxy-pyrrolidine dihydrochloride in 780 ml N, N-dimethylformamide were added 87.6 ml (0.63 mol) triethylamine. After 5 min the suspension was cooled down to 0°C and 33.8 ml (0.32 mol) allyl chloroformate were added dropwise. After 1 h the reaction mixture was poured on 3500 ml ethyl acetate and 1700 ml water and the pH was adjusted to 7 with 1M hydrochloric acid. The organic layer was separated, washed with 1500 ml water and brine, dried over magnesium sulfate, filtered and evaporated. The resulting oily residue purified by column chromatography on silica gel (MERCK, 0.040-0.063 mm) with ethyl acetate: n-hexane (2: 1, then ethyl acetate) as eluent.

MS (ISP): 375.4 (M+H+) IR (Film): 3442,1702,1648 cm-1 Example 3 (E)- (6R, 7R)-7- 2- (6-Carboxy-naphthalen-2-ylsulfanyl)-acetylamino-3- (3'S, 5'R)-5'- (4- methylaminomethyl-phenyl)-2-oxo- 1, 3' bipyrrolidinyl-3-ylidenemethyl-8-oxo-5-thia-1- aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid To a suspension of 310 mg (0.35 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyI-5'- [4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1, 3' bipyrrolidinyl-3- ylidenemethyl-7- 2- (6-carboxy-naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia -l- aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 7 ml dichloromethane was added 0.27 ml (1.04 mmol) N, O-bis (trimethylsilyl) trifluoroacetamide. After 30min a yellow solution forms to which 7.3 mg (0.01 mmol) bis (triphenylphosphine) palladium (II) chloride, 0.40 ml (6.92 mmol) acetic acid and 0.92 ml (3.46 mmol) tri-n-butyltin hydride were added successively. The resulting suspension was diluted with 2 ml of dichloromethane and stirred for lh. The reaction mixture was poured on 150 ml diethyl ether, the solid material was collected by filtration, washed with diethyl ether and was dried under high vacuum to give 0.22 g (85.7%).

MS (ISP): 728.2 (M+H+) IR (NJL): 1770,1667,1626 cm'' The starting (E)- (6R, 7R)-3- [ (3'S, 5'R)-1'-allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl- methyl-amino)-methyl]-phenyl]-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl-7- [2- (6- carboxy-naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1- aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid can be prepared as follows:

(E)- (6R, 7R)-3- [ (3'S, 5'R)-1'-Allyloxycarbonyl-5'- 4- [ (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- (2-bromo-acetylamino)- 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid To a solution of 1.0 g (1.43 mmol) (E)-(6R, 7R)-3-(3'S, 5'R)-(1'-allyloxyvarbonyl-5'-84- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl}-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7-amino-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid trifluoro-acetate (1: 0.4) in 12 ml dichloromethane was added dropwise under Argon at room temperature 0.12 ml (1.43 mmol) bromoacetyl bromide. The clear solution was cooled to 0°C and a solution of 0.2 ml (1.43 mmol) triethylamine in 1 ml dichloromethane was added dropwise. After 5h the reaction mixture was poured on 150 ml diethyl ether, the resulting suspension was kept in an ultrasonic bath for 30 min and then filtered. The solid was dried under high vacuum and then suspended in water. To this suspension 1M aqueous sodium hydroxide solution was added dropwise until pH 7 was reached. The brown solution was chromatographed on MCI gel (75-150, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (1: 0 to 7: 3) as eluent. The fractions containing the product were pooled and concentrated at a rotary evaporator. The pH was adjusted to 2 with lm hydrochloric acid and the resulting solid material was collected by filtration, washed and dried under high vacuum to give 0.35 g (31.3%) of the product as a beige powder.

MS (ISP): 772.1 and 774.2 (M+Ht) IR (NJL): 1785,1698,1543 cm'' (E)- (6R, 7R)-3- (3'S, 5'R)-1'-Allyloxycarbonyl-5'- 4- [ (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- [2- (6-carboxy- naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1-aza-bicy clo [4.2.0] oct-2-ene-2- carboxylic acid

To a solution of 0.35 g (0.45 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyl-5'- 4- (allyloxyvarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7-(2-bromo-acetylamino)-8-oxo-5-thia-1-aza-bic yclo [4.(2-bromo-acetylamino)-8-oxo-5-thia-1-aza-bicyclo [4. 2.0] oct-2-ene-2- carboxylic acid in 4 ml N, N-dimethylformamide, 0.13 g (0.54 mmol) 6-mercapto- naphthalene-2-carboxylic acid disodium salt was added in one portion. After lh the reaction mixture was poured on 150 ml diethyl ether. The solid material was collected by filtration, washed with diethyl ether and dried under high vacuum. The crude product was suspended in 22 ml O. 1M hydrochloric acid and kept in an ultrasonic bath for lh. The suspension was filtered, the solid material washed with 20 ml water and dried under high vacuum to give 0.31 g (76.3%) as a pale yellow solid.

MS (ISN): 894.2 (M-H)- IR (NJL): 1783,1693,1540 cm-' Elemental analysis: C45H45NsOuS2 (NaCI) 0.05 (NaBr) 0.01 (899.95) calc.: C 60.06 H 5.04 N 7. 78 S7.12 Cl 020 Br 0. 09 found): C 59.83 H 4.95 N 7.60 S 7.09 Cl 0.15 Br 0.36 Calculated with 1.61% water Example 4 (E)- (6R, 7R)-7- [2- (6-Carboxy-naphthalen-2-ylsulfanyl)-acetylamino-3- [ (3'S, 5'R)-5'- (4- methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-8-oxo-5-thia-1- aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid

250.0 mg (0.28 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1, 3'Jbipyrrolidinyl-3- ylidenemethyl-7- 2- (6-carboxy-naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia -l- aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid are suspended in 8 ml dichloromethane, and 186 gel (0.70 mmol) N, O-bis (trimethylsilanyl) trifluoroacetamide are added dropwise. After a clear solution has formed, 5.90 mg (0.0084 mmol) bis (triphenylphosphine) palladium (II) chloride, 0. 34 ml (5.87 mmol) acetic acid and 0.76 ml (2.82 mmol) tri-n-butyltin hydride are added successively. After complete deprotection (HPLC) the reaction mixture is poured on 200 ml diethyl ether containing 13.2 ptl (0.73 mmol) water. The precipitated solid is collected by filtration and purified by column chromatography on MCI gel (75-150, Mitsubishi Kasei Corporation) with, a gradient of water: acetonitrile (1: 0,4: 1,3: 1,2: 1, 1: 1). The organic solvent is stripped off in a rotary evaporator, and the aqueous phase is freeze-dried.

MS (ISP): 728.2 (M+H+) IR (NJL): 1770,1667,1626 cm~' The starting (E)- (6R, 7R)-3- (3'S, 5'R)-1'-allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl- methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- [2- (6- carboxy-naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1- aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid can be prepared as follows: (E)- (6R, 7R)-3- [ (3'S, 5'R)-1'-Allyloxycarbonyl-5'- 4- [ (allyloxycarbonyl-methyl-amino)- methyl]-phenyl]-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- (2-bromo-acetylamino)- 8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-ene-2-carboxylic acid To a suspension of 0.50 g (0.77 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyl-5'- 4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 10 ml dichloromethane are added 0.51 ml (1.92 mmol) N, O-bis (trimethylsilanyl)- trifluoroacetamide. After a clear solution has formed, 0.067 ml (0.77 mmol) bromoacetyl bromide are added, and the reaction mixture is stirred for 3 hours. The solution is poured on 250 ml diethyl ether containing 35 u. l (1.92 mmol) water. The precipitate is filtered off

and washed with diethyl ether. The crude product can be used for the next step without further purification.

MS (ISP): 722.1 and 774.2 (M+H+) IR (NJL): 1785,1698,1543 cm-1 (E)- (6R, 7R)-3- (3'S, 5'R)-1'-Allyloxycarbonyl-5'- [4- (allyloxycarbonyl-methyl-amino)- methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- 2-(6-carboxy- naphthalen-2-ylsulfanyl)-acetylamino-8-oxo-5-thia-1-aza-bicy clo [4.2.0] oct-2-ene-2- carboxylic acid 0. 30 g (0.39 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)-l'-allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl- methyl-amino)-methyl-phenyl-2-oxo- 1, 3' bipyrrolidinyl-3-ylidenemethyl-7- (2- bromo-acetylamino)-8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-ene-2-carboxylic acid are dissolved in 5 ml N, N-dimethylformamide, and 0.13 g (0.43 mmol) 6-mercapto- naphthalene-2-carboxylic acid disodium salt are added in one portion. After completion of the reaction (HPLC) the solution is added dropwise on 200 ml diethyl ether. The resulting suspension is filtered and washed with diethyl ether. The crude product is suspended in 10 ml water and the pH adjusted to 7 with 1M aqueous sodium hydroxide solution. The brown solution is purified by reversed phase chromatography (RP-18 LiChroPrep gel) with a gradient of water: acetonitrile 1,3: 1,2: 1,1: 1). The organic solvent is stripped off in a rotary evaporator and the pH of the aqueous phase adjusted to 2 with 1M hydrochloric acid. The resulting solid is collected by filtration and dried under high vacuum.

MS (ISN): 894.2 (M-H-) IR (NJL): 1783,1693,1540 cm-' Elemental analysis: C45H45N501IS2 (NaCI) 0.05 (NaBr) 0.01 (899.95) calc.: C 60.06 H 5.04 N 7. 78 S7.12 C10.20 Br 0. 09 found": C 59.83 H 4.95 N 7.60 S7.09 C10.15 BrO. 36

#) Calculated with 1.61% water Example 5 (6R, 7R)-7- [ (Z)-2- (5-Amino- 1,2,4 thiadiazol-3-yl)-2-hydroxyimino-acetylamino-3- [ (E)- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl- 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid hydrochloride (1: 1.15) A solution of 0.90 g (1.0 mmol) (6R, 7R)-7- (Z)-2- (5-amino- l, 2,4] thiadiazol-3-yl)-2- trityloxyimino-acetylamino]-3- [ (E)- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2- carboxylic acid in 8 ml 90% formic acid is stirred at ambient temperature for 45 min. The solution is poured on 200 ml diethyl ether and stirred for 30 min. The resulting suspension is filtered and the solid material is dried under high vacuum. The crude product is dissolved in 8 ml water and the pH is adjusted to 1 with 1M hydrochloric acid. The solution is then chromatographed on MCI gel (75-150 g, Mitsubishi Kasei Corporation) with a gradient of water: acetonitrile (95: 5,9: 1,3: 1,2: 1). The fractions containing the product are pooled and freeze-dried to give 0.31 g (44.2%) of a colourless lyophilisate.

MS (ISP): 654.2 (M+H+) IR (NJL): 1769,1662,1621 crri 1 Elemental analysis: C28H3lN906S2 (HCI) 1.15 (695.663) calc.: C 48.34 H 4.66 N 18.12 S 9.22 Cl 5.86 fond7): C 48.44 H 4.60 N 18.11 S9.28 Cl 6.14 Calculated with 10.38% water The starting (6R, 7R)-7- (Z)-2- (5-amino- 1,2,4 thiadiazol-3-yl)-2-trityloxyimino- acetylamino-3- [ (E)- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1, 3'- bipyrrolidinyl-3-ylidenemethyl-8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid can be prepared as follows: (6R, 7R)-3- (E)-(3'S, 5'R)-3-(l'-Allyloxycarbonyl-5'-{4- [ (allyloxycarbonyl-methyl-amino)- methyl-phenyl}-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- (Z)-2- (5-amino-

1,2,4 thiadiazol-3-yl)-2-trityloxyimino-acetylamino-8-oxo-5-thia-1 -aza-bicyclo- 4.2.0 oct-2-ene-2-carboxylic acid To a solution of 0.91 g (1.30 mmol) (E)-(6R, 7R)-3-(3'S, 5'R)-(1'-allyloxycarbonyl-5'-44- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl}-2-oxo- [1,3'] bipyrrolidinyl-3- ylidenemethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid trifluoroacetate (1: 0.4) in 50 ml N, N-dimethylformamide 0.90 g (1.56 mmol) (Z)- (5- amino- 1,2,4 thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester was added in a single portion and the reaction mixture was stirred for 20 h. The solvent was evaporated at a rotary evaporator, the residue was distributed in 50 ml ethyl acetate and water (1/1 w/w) and extracted. The aqueous phase was extracted once with ethyl acetate and the combined organic phases were washed with water. After drying over magnesium sulfate and filtration, the filtrate was concentrated and at the same time the product starts to precipitate. The solid material was collected by filtration, washed with diethyl ether and dried under high vacuum to give 1.20 g (77.1 %) of a beige solid.

MS (ISP): 1063.2 (M+H+) IR (NJL): 1788,1682,1621 cm-' (6R, 7R)-7- (Z)-2- (5-Amino- 1,2,4 thiadiazol-3-yl)-2-trityloxyimino-acetylamino-3- (E)- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1, 3' bipyrrolidinyl-3-ylidenemethyl- 8-oxo-5-thia-l-aza-bicyclo 4. 2.0 oct-2-ene-2-carboxylic acid

A solution of 1.10 g (1.03 mmol) (6R, 7R)-3-(E)-(3'S, 5'R)-3-(1'-allyloxycarbonyl-5'-f4- [(allyloxycarbonyl-methyl-amino)-methyl-phenyl}-2-oxo- 1, 3' bipyrrolidinyl-3- ylidenemethyl-7- [ (Z)-2- (5-amino- 1,2,4 thiadiazol-3-yl)-2-trityloxyimino-acetylamino- 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 12 ml dichloromethane was treated successively with 35 mg (0.05 mmol) bis (triphenylphosphine) palladium (II) chloride, 1.2 ml (20.6 mmol) acetic acid and 2.8 ml (10.3 mmol) tri-n-butyltin hydride.

The resulting suspension was stirred for 30 min and then filtered. The solid material was digerated in diethyl ether, filtered and dried under high vacuum to give 0.94 g (95.7%) of a beige solid.

MS (ISP): 896.6 (M+H+) IR (MIR): 1779,1677,1622 cm'' Example 6 (6R, 7R)-7- (Z)-2- (5-Amino- 1,2,4 thiadiazol-3-yl)-2-hydroxyimino-acetylamino-3- (E)- (3'S, 5'R)-5'- (4-methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl- 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid To a solution of 850.0 mg (0.80 mmol) of (6R, 7R)-3-(E)-(3'S, 5'R)-l'-allyloxycarbonyl- 5'- [4- [ (allyloxycarbonyl-methyl-amino)-methyl]-phenyl]-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7- [ (Z)-2- (5-amino- 1,2,4 thiadiazol-3-yl)-2-trityloxyimino-acetylamino- 8-oxo-5-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 40 ml dichloromethane and 0.40 ml (1.62 mmol) N, O-bis (trimethylsilanyl) acetamide are added successively 14.0 mg (0.02 mmol) bis (triphenylphosphine) palladium (II)-chloride, 0.90 ml (16.0 mmol) acetic acid and 2.0 ml (7.50 mmol) tri-n-butyltin hydride with stirring at room temperature. A vigorous gas evolution takes place and a precipitate forms immediately. The suspension is stirred for 10 min and the solid is collected by filtration and dried under reduced pressure. The solid is dissolved in 90% formic acid and the solution stirred at room temperature for 1 hour. The solvent is evaporated off and the residue dried under high vacuum. The residue is distributed between ethyl acetate and 1N hydrochloric acid.

The phases are separated and the aqueous phase purified by chromatography on MCI-gel (75-150, Mitsubishi Kasei Corporation) using a gradient of water to 50% acetonitrile.

The product-containing fractions are collected, concentrated to ca 20 ml and lyophilized.

MS (ISP): 654.2 (M+Ht) IR (NJL): 1769,1662,1621 crri 1 Elemental analysis: C2sH3lN9O6S2 (HCl) 1.15 (695.663) calc.: C 48.34 H 4.66 N 18.12 S9.22 Cl 5.86 found): C 48.44 H 4.60 N 18.11 S9.28 Cl 6.14 Calculated with 10.38% water The starting (6R, 7R)-3- (E)-(3'S, 5'R)-1'-allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl- methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- (Z)-2- (5- amino- [1,2,4] thiadiazol-3-yl)-2-trityloxyimino-acetylamino]-8-oxo-5-thia- 1-aza- bicyclo 4.2.0 oct-2-ene-2-carboxylic acid: can be prepared as follows: To a solution of 652.0 mg (1.00 mmol) (E)- (6R, 7R)-3- (3'S, 5R)-l'-allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo 4.2.0 oct-2-ene-2-carboxylic acid in 7 ml dry N, N-dimethylformamide are added 695.2 mg (1.20 mmol) of (Z)- (5-amino- 1,2,4 thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester at once, and the mixture is stirred at room temperature for 18 hours. The N, N-dimethylformamide is evaporated off under high vacuum and the residue taken up in 20 ml ethyl acetate, a beige precipitate being formed. The solid is collected by filtration and dried to constant weight under high vacuum.

MS (ISP): 1063.2 (M+H+) IR (NJL): 1788,1682,1621 cm-1 Example 7 In analogy to Example 5 the following compound is prepared:

(6R, 7R)-7- (Z)-2-(2-Amino-thiazol-4-yl)-2-hydroxyimino-acetylamino-3- (E)- (3'S, 5'R)- 5'- (4-methylaminomethyl-phenyl)-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-8-oxo-5- thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid From (6R, 7R)-3- (E)-(3'S, 5'R). l'-Allyloxycarbonyl-5'- [4- [ (allyloxycarbonyl-methyl- amino)-methyl-phenyl-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7- [ (Z)-2- (2-amino- thiazol-4-yl)-2-trityloxyimino-acetylamino-8-oxo-5-thia-1-az a-bicyclo [4.2.0] oct-2-ene-2- carboxylic acid Said starting material is obtained by reacting (E)- (6R, 7R)-3- (3'S, 5'R)-1'-allyloxycarbonyl- 5'- 4- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl-2-oxo- 1, 3' bipyrrolidinyl-3- ylidenemethyl-7-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid with S- (2-benzothiazolyl) 2- [ (triphenylmethyl)-amino-4-thiazoleglyoxylate (Z)-O- (triphenylmethyl) oxime.

Example 8 (E)- (6R, 7R)-3- [ (3'S, 5'R)-5'- (4-Methylaminomethyl-phenyl)-2-oxo- 1, 3' bipyrrolidinyl-3- ylidenemethyl-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia- 1-aza-bicyclo(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bic yclo [4.2.0] oct-2- ene-2-carboxylic acid

To a solution of 0.26 g (0.32 mmol) (E)- (6R, 7R)-3- ( (3'S, S'R)- (1'-allyloxycarbonyl-5'- {4- (allyloxycarbonyl-methyl-amino)-methyl-phenyl}-2-oxo- 1,3' bipyrrolidinyl-3- ylidenemethyl)]-8-oxo-7- (2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo [4.2.0] oct-2- ene-2-carboxylic acid in 5 ml dichloromethane, 7 mg (0.01 mmol) bis (triphenyl- phosphine) palladium (II) chloride, 0.4 ml (7.0 mmol) acetic acid and 0.8 ml (3.0 mmol) tri-n-butyltin hydride were added successively. The reaction mixture was stirred for 1.5 h and then poured on 150 ml diethyl ether. The solid material was collected by filtration and dried under high vacuum. The crude product was suspended in 3 ml of water and the pH was adjusted to 1 with 1M hydrochloric acid. The solution was chromatographed on MCI gel (75-150, u, Mitsubishi Kasei Corporation) with water: acetonitrile (1: 1) as eluent. The fractions containing the product were pooled, concentrated at a rotary evaporator and the pH was adjusted to 7.1 with a 5% aqueous sodium bicarbonate solution. The unsoluble material was filtered off and the filtrate was freeze-dried. The lyophilisate was digested in a small amount of water, filtered and dried under high vacuum to yield 33 mg (16.1 %) of the desired product as a beige powder.

MS (ISP): 634.3 (M+Ht) IR (MIR): 1768,1654,1576 cm-1 The starting (E)- (6R, 7R)-3- [ (3'S, 5'R)- (1'-allyloxycarbonyl-5'- {4- [ (allyloxycarbonyl- methyl-amino)-methyl-phenyl}-2-oxo- [1,3'] bipyrrolidinyl-3-ylidenemethyl)]-8-oxo-7- (2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid can be prepared as follows: To a solution of 79.2 mg (0.47 mmol) (phenylthio) acetic acid in 3 ml N, N-dimethyl- acetamide were added under Argon at room temperature 76.4 mg (0.47 mmol) 1,1'- carbonyldiimidazole. After 30 min 0.3 g (0.43 mmol) (E)- (6R, 7R)-3- (3'S, 5'R)- (1'- allyloxycarbonyl-5'- {4- [ (allyloxycarbonyl-methyl-amino)-methyl-phenyl}-2-oxo- 1,3' bipyrrolidinyl-3-ylidenemethyl-7-amino-8-oxo-5-thia-1-aza-bi cyclo [4.2.0] oct-2- ene-2-carboxylic acid trifluoroacetate (1: 0.4) were added in one portion. After 5 h the suspension was poured on 150 ml diethyl ether, and the solid material was collected by

filtration and dried under high vacuum. The crude product was distributed between 50 ml ethyl acetate and 20 ml 0.5M hydrochloric acid. The organic phase was washed twice with 10 ml water and evaporated at a rotary evaporator. n-Hexane was added to the oily residue until a suspension forms. Filtration and drying under high vacuum yields 0.27 g (78.6%) of a yellow solid.

MS (ISP): 802.3 (M+H+) IR (NJL): 1782,1696,1581 cm'1 The following example illustrates pharmaceutical preparations containing the cephalosporin derivatives provided by the present invention: Example A Production of dry ampoules for intramuscular administration: A lyophilisate of 1 g of active ingredient is prepared in the usual manner and filled into an ampoule. The sterile water ampoule contains 10% propylene glycol. Prior to the administration, the lyophilisate is treated with 2.5 ml of a 2% aqueous lidocaine hydrochloride solution.

As active ingredient can be used one of the end products prepared according to the above Examples 1-8.