NO770104L - - Google Patents

Description

Intermediate product that is useful

for the production of cephalosporins.

The invention relates to intermediates for cephalosporins which generally have a broad spectrum of antibacterial1 activity, as they are active against many species of Gram-positive and Gram-negative bacteria. They are therefore useful as therapeutic (and to a lesser extent as prophylactic) agents for animals, also for humans and poultry.

The intermediates according to the invention have the general formula (II) which is indicated on pages 5 and 6 and where R^ can be one of four of the groups indicated on page 4.

In a particularly preferred connection, n = 1 and

the dashed line represents a bond in the 3-position.

Further, particularly preferred compounds are those in which R 4 has the formula:

Although a number of semi-synthetic cephalosporins are now available that have what is known as broad-spectrum activity, no single cephalosporin is available that has a clinically useful level of antibacterial activity against all the pathogenic organisms encountered in clinical practice . Research therefore continues for broad-spectrum cephalosporins that have advantages, either in terms of improved antibacterial effectiveness or a wider spectrum of activity compared to the available cephalosporins.

According to the invention, a cephalosporin of formula (I) or a pharmaceutically acceptable salt or such ester thereof is provided:

where Y is oxygen or sulfur, R is an organic radical containing up to 20 carbon atoms; R 2 is alkyl with from 1 to 3 carbon-1 2 atoms or benzyl; or R and R together with the carbon and nitrogen atoms to which they are attached form a 5-, 6- or 7-membered ring; R 3 is phenyl, phenyl substituted with one or more functional groups selected from hydroxyl, halogen, nitro, alkoxy with from 1 to 3 carbon atoms and amino groups, 2- or 3-thienyl, cycloalkyl with from 3 to 7 carbon atoms or alkyl with from 1 to 4 carbon atoms; R 4 is acetoxy or is a carbon, nitrogen or a sulfur nucleophile. Y is preferably oxygen. The group Ri can e.g. be C 1 -C 0 -alkyl 1; C 1 -C 4 -alkenyl; aralkyl or aralkenyl where the alkyl and alkenyl radicals are C^-^q and the aryl radicals are phenyl, thienyl, furyl, pyridyl or substituted phenyl where the substituents are selected from C-^_^2-alkyl, alkoxy, halogen, nitro and amino ; C 1-10 -Alkoxy, C 5-7 -Cyclo-Alkoxy; C 1-4 alkylamino; phenyl, furyl, thienyl, pyridyl, substituted phenyl where the substituents are selected from C 1-3 alkyl, C 1-4 alkoxy, halogen, nitro and amino; functionally substituted C 1 -C 0 -alkyl where the functional substituent e.g. is C 1-3 -alkylthio, C 1-3 -alkylthio, or phenoxy.

Specifically, the group R"*" can e.g. be methyl, ethyl, n- or isopropyl, n-, sec.- or tert.-butyl, n-pentyl, n-hexyl, n-heptyl, w-methylheptyl, n-octyl, t,co-dimethyloctyl, prop- 2-enyl, 3-methylprop-2-enyl, 1-methyl-prop-2-enyl, but-2-enyl, oct-2-enyl, 2-phenylethyl, 2-phenylethenyl, 2-(2<1-> methoxyphenyl)ethenyl, 2-(4<1->nitro "phenyl)ethen-yl,2-(31,41,51-trimethoxyphenyl)ethenyl, 2-(fur-2<1->yl)enyl. 3- phenylpropyl , 1-methyl-2-phenylethenyl, 4-phenylbut-2-enyl, 5-phenyl-pent-2-enyl, 1-methyl-5-phenylpent-2-enyl, methoxy, ethoxy, n- or sec.-propoxy , n-, sec.- or tert.-butoxy, n-pentoxy, n-hexyloxy, cyclohexyloxy, methylamino, dimethylamino, phenyl, 2-methoxyphenyl, 2-chlorophenyl, 2-methoxyphenyl, 3,4,5-trimethoxyphenyl, 4 - nitrophenyl, 2-methylphenyl, 4-methylphenyl, methoxymethyl, ethoxymethyl, methylthiomethyl, phenoxymethyl.

The group R 2 can e.g. be methyl, ethyl or benzyl.

2

R is preferably methyl.

When R 2 and R 1 are seen together with the carbon and nitrogen atoms to which they are attached, the ring that is formed can e.g. be one of the following:

where n is an integer from 3 to 5, and m is an integer from 2 to 4 and R a is hydrogen, C 1-3 alkyl, C 1-3 acyl or C 1-3 alkyl sulfonyl. The ring formed is preferably imidazolidin-2-on-1-yl, 3-acetylimidazolidin-2-on-1-yl, 3-methylsulfonyl-imidazolidin-2-on-1-yl or hexahydroazepin-2-on-1 - howl.

The group R 3 can e.g. be phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 4-nitrophenyl, 4-aminophenyl, 2-thienyl, 3-thienyl, cyclopropyl, cyclohexyl, cyclohexa-1,4-dienyl, isopropyl or methyl. R 3 is preferably phenyl, 4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl or 3-thienyl.

The group R<4> can, among other things, be a strong carbon-,

nitrogen or sulfur nucleophile. Such nucleophiles displace the acetoxy group from the core of 7-aminocephalosporanic acid, and such

displacement has been observed with various pyridines (Hale et al. Biochem J. 79, 403 (1961) and Spencer et al. J. Org. Chem (U.S.A.) 32 500 (1967); other aromatic heterocycles (Hale et al. , loe. eit;) Kariyone et al. J. Antibiotics, 23, 131 (1970); and Spencer et al. loe. eit); Xanthates and dithiocarbamates (Van Heyningen et al.,

J. Chem. Soc. (London) 5015 (1965)) and anilines (Bradshaw et al.,

J. Chem. Soc. (London) 801 (1968)).

Examples of special R 4 groups include the following:

R 4 is preferably 2-methyl-1,3,4-thiadiazolyl-5-thio, 1-methyl-(1H)-1,2,3-tetrazolyl-5-thio, 2-methyl-1,3,4-oxadiazolyl -5-thio or (1H)-1,2,4-triazolyl-5-thio.

The configuration of the carbon atom to which the group R 3 is attached is preferably D.

Suitable pharmaceutically acceptable salts include the sodium, potassium, calcium, magnesium or aluminum salts and the ammonium or substituted ammonium salts, e.g. those with trialkyl amines, e.g. triethylamine, procaine, dibenzylamine and triethanolamine.

In the case of compounds (I) containing a basic nitrogen site in the side chain, acid addition salts can also be formed.

Such salts include e.g. inorganic salts, e.g. sulphate, nitrate, phosphate, borate and hydrohalides, e.g. hydrochloride, hydrobromide and hydroiodide, and organic salts, e.g. acetate, oxalate, tartrate, malate, citrate, succinate, benzoate, ascorbate and methanesulfonate.

Suitable pharmaceutically acceptable esters include in particular

those that break down easily in the human body and leave behind the malic acid, e.g. acyloxyalkyl esters, e.g. acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, o-acetoxybenzyl and α-pivaloyloxymethyl, and alkoxycarbonylalkyl esters, e.g. methoxycarbonyloxymethyl or α-methoxycarbonyloxyethyl esters. Other suitable esters of the readily hydrolyzable type include lactone, thiolactone and dithiolactone esters (ie compounds of formula (I) in which the 4-carboxyl group is esterified as

where X"*" and Y"*" are oxygen or sulphur, and 7?~ is a divalent radical) especially phthalide and substituted phthalide esters, e.g. 5,6-dimethoxyphthalide esters.

The compounds of formula (I) will be seen to fall within two structural classes, namely those where the group R"*" is linked to the carbonyl group via a C - C bond and those where it is bound via an N - C bond.

The aforementioned compounds can be prepared by reacting a compound of formula (II) or a salt, an ester or a silyl derivative thereof: where the dashed line represents a bond in the 2- or 3-position, n is 0 or 1. and R4 is as defined for formula (I), with a reactive N-acylation derivative of an acid of formula (III):

where Y, R 1, R 2 and R 3 are as defined for formula (I), and where any react ion groups, e.g. amino and hydroxyl groups,

may be blocked, after which, if necessary, one or more of the following steps are performed:

(i) transferring an A 2 -isomer to the desired A 3 -isomer;

(ii) removal of any silyl groups by alcoholysis or hydrolysis, (iii) reduction of a sulfoxide compound to form the desired sulfide compound, (iv) removal of any blocking groups in the acyl side chain R, (v) conversion of an ester compound into a free acid compound or a salt thereof.

With the designation . "silyl derivative" of compound (II) means the reaction product between compound (II) and a silylating agent, e.g. a halogenodialkylsilane, a halogenotrialkylsilane, a halogeno-dimethoxysilane or a halogenotrioxysilane, or the

corresponding aryl or aralkylsilane and such compounds as hexamethyldisilazane. The silyl derivatives of compound (II) are unusually sensitive to moisture and hydroxyl debonding, and after reaction with the N-acylation derivatives of the acid (II), the silyl groups of the intermediate acylated compound can be removed by alcoholysis or hydrolysis.

A reactive N-acylation derivative of the acid (II) is used in the above process. The choice of reactive derivative will naturally be influenced by the chemical nature of the substituents in the acid. Thus,

when the acid contains only acid-stable groups, an acid halide is a suitable N-acylation derivative, preferably the acid chloride.

However, such reagents would be avoided when an acid-

labile group was present in the acid (III). In such cases, a suitable N-acylation derivative is a mixed anhydride. For this purpose, the alkoxy-formic anhydrides are particularly suitable mixed anhydrides.

Alternative N-acylation derivatives of acid (III) are activated esters. Such activated esters, e.g. the ester formed with

1-hydroxybenzotriazole or N-hydroxysuccinimide, can be prepared

in situ by reacting the acid with the appropriate hydroxyl compound

in the presence of a carbodiimide, preferably dicyclohexylcarbodiimide. Other reactive N-acylation derivatives of the acid (II) include the reactive intermediate formed by in situ reaction with a carbodiimide or carbonyldiimidazole, but the literature regarding the preparation of semi-synthetic penicillins contains examples of other reactive N-acylation derivatives of acids suitable for coupling to 6 -APA.

It will of course be realized that if a free acid of type (1) or a salt thereof is desired, it may be convenient to carry out the acylation reaction using an ester of (II), after which the ester group is removed. Conversely, if an ester is desired, it may be convenient to carry out the acylation reaction using 7-ACA

or a salt thereof and then esterify the free acid.

In the above process, if it is necessary to block any reactive substituents in the acid (III), conventional

chemical blocking groups known. Thus, if desired, any free amino groups can be blocked by transfer to t-butyloxycarbonyl or benzyloxycarbonylamino groups, or the amino group can be blocked like the nitro group which is later transferred to the amino group.

When the compound resulting after N-acylation contains a sulfoxide group at the 1-position of the cephem ring, this can be reduced by conventional methods, e.g. such as are described in GB-PS 1,280,693. One such method involves treatment with triphenylphosphine and acetyl chloride. When the resulting compound is an A 2 -cephem, the desired A 3 -cephem can be obtained by treating the former with a base, e.g. an alkali metal hydroxide or tertiary amine bases, e.g. pyridine and triethylamine, or by oxidation to the A 2-cephem sulfoxide followed by reduction to the A 3-cephem. The procedure for transferring an ester compound to a free acid or base will depend on the particular ester in question, e.g. acid or base hydrolysis as well as enzymatically catalyzed hydrolysis can be used. However, in order to reduce the isomerization and side reactions to a minimum, it is better to avoid aqueous solvents, and Lewis acids are preferred as auxiliaries for de-esterification in relevant cases.

Another method for preparing compound (I)

is to react a compound of formula (IV) or a salt, an ester or a silyl derivative thereof:

where the dashed line represents a bond in the 2- or 3-position, R 3 and R 4 are as defined for formula (I), with a compound of formula (V)

12 3

where Y, R , R and R are as defined for formula (I), and then

if necessary, performing one or more of the following steps:

(i) transfer of an A 2 isomer to the desired A 3 isomer, (ii) removal of any silyl groups by alcoholysis or hydrolysis, (iii) reduction of a sulfoxide compound to form the desired sulfide compound, (iv) removal of any blocking groups in the acyl side chain R, (v) transfer of an ester compound to a free acid compound or a salt thereof.

The compounds produced according to the invention, where R 4 is a carbon, sulfur or nitrogen nucleophile, can also be produced from the corresponding compound where R 4 is acetoxy, by nucleophilic displacement of the acetoxy group. In such a process, a compound of formula (VI) or a salt, an ester or a silyl derivative thereof is reacted:

5

where the dashed lines represent a bond in 2- or 3-

position, n is 0 or 1, Y, R 1 , R 2 and R 3 are as defined for

formula (I), and where any reactive groups can be blocked,

with the relevant carbon, nitrogen or sulfur nucleophile, after which, if necessary, one or more of the following steps are performed:

(i) transfer of an A 2 isomer to the desired A 3 isomer, (ii) removal of any silyl groups by alcoholysis or hydrolysis, (iii) reduction of a sulfoxide compound to form the desired sulfide compound, (iv) removal of any blocking groups in the acyl side chain R, (v) transfer of an ester compound to a free acid compound or a salt thereof.

The compounds produced according to the invention,

are broad-spectrum cephalosporins, i.e. cephalosporins that not only have activity against Gram-positive bacteria, but also against a number of clinically important Gram-negative organisms. The preferred compounds prepared according to the invention are active against such important organisms as Pseudomonas spp. against which the commercially available cephalosporins are normally

inactive. In addition, the preferred compounds are active against

a variety of Gram-negative cephalosporinase-producing organisms,

e.g. Enterobacter spp., Serratia spp., indole^positive Proteus. The following examples illustrate the preparation of some of the indicated compounds.

Example 1

Preparation of sodium D-α-(N-imidazolidin-2-onyl-carbonylamino)-benzylcephalosporin

2.2 g of D-cx-aminobenzylcephalosporin dihydrate was dissolved in

30 ml of water, 5 ml of acetone and 0.7 ml of triethylamine. A solution of

0.75 g of imidazolidin-2-onylcarbonyl chloride in 20 ml of dry acetone was added slowly along with a further equivalent of triethylamine (0.7 ml) at such a rate that the pH of the reaction mixture was maintained between 7.5 and 8.0 . After the addition was finished, which took approx. 5 minutes, the mixture was stirred for 1 hour with little further change in pH. The acetone was then removed under reduced pressure, the aqueous concentrate was covered with 35 ml of ethyl acetate and the two phases cooled to 0°C. The pH value was carefully monitored

adjusted to 1.5 with dilute hydrochloric acid under vigorous stirring. The phases were separated and the water phase quickly re-extracted with 15 ml

fresh ethyl acetate. The combined organic phases were washed with

20 ml of water and then with saturated salt solution (2 x 50 ml). The organic phase was then filtered through a siliconized filter paper.

to remove the final traces of salt solution and then treated with 5 ml of 1,10 sodium 2-ethylhexoate/isopropanol with stirring.

The pale yellow precipitate was filtered, washed thoroughly with dry diethyl ether and finally dried in vacuo to give the desired cephalosporin, [(1.2 g), i.r. v ITlcLK , s(nujol) 1768 cm<-1>(3-lactam CO)]. This material gave an iodometric analysis of 54%, and when subjected to paper chromatography in butanol/ethanol/water it had an R^=0.23, while the starting material, cephaloglycin, had

Rf=0.19.

Example 2

Preparation of sodium D-g-(N-3-cinnamoyl-3-methylureido)-benzyl cephalosporin

A solution of 2.2 g of D-α-aminobenzylcephalosporin in 30 ml of water, 5 ml of acetone and 0.7 ml of triethylamine was treated with 1.12 g of N-chloroformyl-N-methylcinnamide in 25 ml of dry acetone, simultaneously with a further equivalent of 0.7 ml of triethylamine, so that the pH value of the reaction mixture was maintained at 7.5-8.0. After completion of

the addition, which took approx. 5-8 min, the reaction mixture was stirred for 1 h more while the acetone was removed by two thorough diethyl extractions (2 x 100 mL). The pale yellow aqueous phase was covered with 40 ml of ethyl acetate, cooled to 0°C and carefully acidified to 1.5 with dilute hydrochloric acid with continuous vigorous stirring.

The phases were separated and the aqueous phase re-extracted with 20 ml of fresh ethyl acetate. The combined organic phases were washed with 20 mL of water, followed by saturated saline (2 x 50 mL). The last traces of salt solution were removed by filtration through a silicone filter paper and then treated with 1.0N sodium 2-ethylhexoate/isopropanol (5 mL) with stirring. The thick white precipitate was filtered, washed well with dry diethyl ether and finally dried in vacuo to give the desired material [(2.8 g), i.r.^max (nujol)1770 cm ^

(3-lactam CO)].. When subjected to paper chromatography (butanol/-

ethanol/water) the product showed an R^= 0.51 and gave an iodometric analysis of 58%.

Example 3

Sodium- D-g-(3- ethoxycarbonyl- 3- methylureido) benzyl cephalosporin

2.2 g of D-g<->aminobenzylcephalosporin dihydrate and 1.5 ml of triethylamine in 30 ml of anhydrous dichloromethane were stirred with a molecular sieve,

type 4A (2.0 g) for 2 hours. The mixture was filtered, cooled in an ice bath and treated with 0.84 g of ethyl N-chloroformyl-N-methylcarbonate in

15 ml of dichloromethane. The solution was stirred at room temperature for 2 hours and evaporated to dryness in vacuo. The evaporation residue was dissolved

in 100 ml of water, washed with ethyl acetate (2 x 50 ml), covered with 50 ml of ethyl acetate and acidified to pH 1.5 with 1N hydrochloric acid and then filtered to remove insoluble material. The ethyl acetate was separated and the aqueous layer re-extracted with water (2 x 50 ml) and 50 ml saturated brine, dried over anhydrous magnesium sulfate,

diluted with 100 ml of anhydrous ether and treated with 2N sodium 2-ethylhexoate in methyl isobutyl ketone until there was no further precipitation. The cephalosporin sodium salt was collected, washed with anhydrous ether and dried in vacuo over phosphorus pentoxide. Yield 1.25 g, 43.1%, n.m. r-spectrum [ (CD^) 2S0 + D2O-'' ^ = 7'55 (5H, s, aromatic protons). 5.9-5.6 (2H, m, - and C7~ protons), 5.3-4.7 (3H, m, Op proton and -CH2OCOCH3), 4.38 [2H, q (J = 7HZ ), NC0 2 CH 2 CH 3 ], 2.13

(3H, S, -COCH3), 1.41 [3H, t (J = 7Hz) -CO2CH2CH3) . Paper chromatograph in butanol/ethanol/water showed a single zone, R f = 0.49.

Example 4

Sodium D-α-(3-cyclohexyloxycarbonyl-3-methylureido)benzyl cephalosporin 2.2 g of D-g<->aminobenzyl cephalosporin dihydrate and 1.1 g of cyclohexyl-N-chloroformyl-N-methylcarbonate were reacted with each other using the method which is described in example 3, so that the cephalosporin sodium salt was obtained, 1.01 g 32%. N.m.r. spectrum [(CD3)2SO + D2O], 6= 7.40 (5H, s, aromatic protons), 5.8-5.4

(2H, m, C7~ and g protons) , 5.3-4.5 (4H, m, Cg proton, -CH_2OCOCH3 and cyclohexylmethine proton), 3.5-3.0 (2H, m, C2 ~protons), 3.10

(3H, s, ^N-CH3)7 2.01 (3H, s, -0COCH3) , 3.1-1.2 (10H, m, cyclohexylmethylene protons). Paper chromatography in butanol/ethanol/water showed one spot, R = 0.60.

Example 5

Sodium- D- g-( 2, 4- dimethylallofanamido) benzyl cephalosporin

Anhydrous triethylammonium D-g<->aminobenzyl cephalosporinate (0.005 m) in dichloromethane (30 ml) [prepared from the dihydrate of 2.2 g of D-g<->aminobenzyl cephalosporin as in Example 3] was cooled in an ice bath, and then 0.75 g 2,4-Dimethylallophanoyl chloride in 15 ml of dichloromethane added. The solution was stirred at room temperature for 2 hours

and then evaporated to dryness in vacuo. The evaporation residue was dissolved in 100 ml of water, washed with ethyl acetate (2 x 50 ml), covered with 50 ml of fresh ethyl acetate and acidified to pH 1.5 with 1N hydrochloric acid. The mixture was filtered to remove the insoluble material,

the ethyl acetate was separated and the aqueous layer extracted with 50 ml of ethyl acetate. The combined ethyl acetate solutions were washed with water

(2 x 50 ml) and 50 ml saturated saline, after which they were dried over anhydrous magnesium sulfate. After the magnesium sulfate had been filtered out, the ethyl acetate solution was reduced to approx. 25 ml in vacuo and 2N sodium 2-ethylhexoate in 1.5 ml methyl isobutyl ketone. added.

The precipitated sodium salt was collected and washed with anhydrous ether and then dried in vacuo over phosphorus pentoxide. Yield 1.29 g, 49.2%, n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.38 (5H, s, aromatic protons), 5.9-5.3 (2H, m, C ^- and α-protons), 5.2-4.6 (4H, m, Cg-proton and -CH_2OCOCH3) , 3.5-2.9 (2H, m, C2-methylene protons) , 3.13 (3H , s, ^N-CH 3 ), 2.73 (3H, s, -NHCH 3 ), 2.01 (3H, s, -OCOHCH 3 ); u.v.-spectrum (95% ethanol<l>), X max, s<2>61.5 nm (e = 7.276). Paper chromatography in n-butanol/ethanol/water showed a single zone, R f = 0.41.

The following examples 6-17 were carried out using the method described in example 5.

Example 6

Sodium D-a-(hexahydroazepin-2-on-l-carbonylamino)benzyl-cephalosporin From l-chlorocarbonylhexahydroazepin-2-one and D-g<->aminobenzyl-cephalosporin dihydrate in 40.3% yield; n.m.r. spectrum [(CD3)2SO +

D26], 6 = 7.44 (5H, s, aromatic protons), 5.7-5.5 (2H, m, g-proton and ^-proton), 5.2-4.6 (4H, m, Cg proton and -CH2OCOCH3), 4.1-3.8 (2H, m, hexahydroazepinone C3~ methylene), 3.5-2.1 (2H, m, C2~ methylene), 3.0-2.6 (2H, m, hexahydroazepinone C^-methylene) 2.01 (3H, s, -OC0CH<3>), 1.9-1.4 (6H, m, hexahydroazepinone C^, CV and C^-methylene protons); u.v. spectrum (95% ethano<l>), X maK , s<2>63.5 nm (e = 6.509). Paper chromatography showed one zone with R^= 0.58.

Example 7

Sodium D-g-(3-cinnamoyl-3- methylureido) benzyl cephalosporinate

From N-chlorocarbonyl-N-methylcinnamamide and D-g<->aminobenzyl-cephalosporin dihydrate in 37.5% yield; n.m.r. spectrum [(CD3)2SO + D2O[, 6 = 8.0-7.1 (12H, m, aromatic and olefinic protons), 5.8-5.5 (2H, m, C?- and g< ->protons), 5.3-4.6 (3H, m, Cg and -CH20C0 protons), 3.35 (5H, singlet covering a multiplet, C2 methylene

and ((N-CH3) , 2.04 (3H, s, -OC0CH3) ); u. v. spectrum (95% ethanol),

X , 279 nm (e = 18,326). Paper chromatography showed a zone of

R f = 0.52.

Example 8

Sodium- D-g-(3-crotonoyl-3-methylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-methylcrotonamide and D-α-aminobenzylcephalosporin dihydrate in 24% yield; n.m. r.-spectrum [(CD^^SC- +

D2O], 6 = 1.89 (3H, m, =CHCH_3) , 2.02 (3H, s, -OC0-CH_3) , 3.23 (3H, singlet covering a multiplet, ^N-CH3 and C^ -methylene protons), 4.85-4.95 (3H, m, Cg and -CH2-OCOCH3), 5.5-5.7 (2H, m, C?- and g<->protons), 6.7 -7.5 (2H, m, olefinic protons), 7.40 (5H, s, aromatic protons); u.v. spectrum (95% ethanol), A maKs 265 nm (e = 8,684). Paper chromatography showed a zone at R f = 0.48.

Example 9

Sodium- D-g-(3- methyl- 3- phenylpropionoylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-methylphenylpropionamide and D-α-aminobenzylcephalosporin dihydrate in 55.5% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 1.03 (3H, s, -0C0CH_3) , 2.8-3.5 (9H, m,^N-CH3, -OCH2CH2 and C2 methylene protons ), 4.8-5.0 (3H, m, Cg proton and -CH20C0-), 5.5-5.7 (2H, m, C^- and g<-> protons), 7.30 ( 5H, pp.

aromatic protons), 7.40 (5H, s, aromatic protons); u.v.-spectrum (95% ethanol), A ITlcl-, K S • 264 nm (e =7,300). Paper chromatography showed a zone at R^= 0.63.

Example 10 Sodium D-α-[3-methyl-3-(o-methoxycinnamoyl)ureido]benzylcephalosporin

From N-chlorocarbonyl-N-methyl-o-methoxycinnamamide and D-g-aminobenzyl cephalosporin dihydrate in 34.3% yield; n.m.r. spectrum [(CD3)2SO + D2O], δ = 2.03 (3H, s, -0C0CH_3) , 3.36 (3H, s, -OCHg), 3.75 (5H, singlet covering a multiplet, I> N-CH3~and C2~methylene), 4.85-5.05 (3H, m, Cg-proton and -CH20C0-), 5.60-5.80 (2H, m, C7~and g< ->protons), 7.0-8.2 (11H, m, olefinic and aromatic protons;

UV spectrum (95% ethanol), *max<2>29 (e = 17,856), 277 (e 17,767)

and 331 nm (e = 11,249). Paper chromatography showed a zone at Rf = 0.38.

Example 11

Sodium- D- g-[ 3- methyl- 3-( 2'- thienyl) acryloylureido] benzyl cephalosporin

From N-chlorocarbonyl-N-methyl-(2-thienyl)acrylamide and D-g-aminobenzyl cephalosporin dihydrate in 26.3% yield; n.m.r. spectrum

[(CD3)2SO + D20], 6 = 2.03 (3H, s, -0C0CH3) , 3.32 (5H, m, ^N-CH_3 and C2~methylene protons) , 4.7-5.1 (2H , m, Cg proton and -CH_20C0-) , 5.5-5.8 (2H, m, C7~and g<->protons), 6.8-8.1 (10H, m, olefinic and aromatic protons ); u.v. spectrum (95% ethanol), ^max 267 (e = 12,843) and

322.5 nm (e= 15,205). Paper chromatography showed one zone at R f = 0.63.

Example 12

Sodium- D- a-[ 3- methyl- 3-( p- nitrocinnamoyl) ureido] benzyl cephalosporin

N From N-chlorocarbonyl-N-methyl-p-nitrocinnamamide and D-g<->amino-benzylcephalosporin dihydrate in 13% yield; n.m.r. spectrum [(CD 3 ) 2 SO + D 2 O], δ = 1.97 (3H, s, -OCCH_3) , 2.74 (5H, m,^N-CH_3 and C2 methylene protons) , 4.7-5 .2 (3H, m, -CH_20C0- and Cg proton), 5.5-6.0 (2H, m, C^- and g<-> protons), 7.0-8.3 (11H, m , aromatic and olefinic protons); u.v.-spectrum (95%ethano<l>), A maK, s<2>66 nm

(e = 13,797). Paper chromatography showed a zone at R^ = 0.57.

Example 13

Sodium- D- a-[ 3- methyl- 3-( a- methylcinnamoyl) ureidobenzyl cephalosporin

From N-chlorocarbonyl-N-methyl-g<->methylcinnamamide and D-g<->amino-benzyl cephalosporin dihydrate in 33.5% yield; n.m.r. spectrum [(CD 3 ) 2 SO + D 2 O], δ = 2.03 (3H,. s, -0C0CH_ 3 ) , 2.10 (3H, d, CH 3~CH= ) , 3.23 (3H, s,^ N-CH3), 3.2-3.5 (2H, m, C2-methylene) , 4.8-5.0 (3H, m,

-CH-OCO- and C,-proton), 5.5-5.7 (2H, m, C_- and g<->protons), 6.80 (1H, m, ^C=CH-) , 7 .3-8.1 (10H, m, aromatic protons); u.v. spectrum

A maK, s 266 nm (e =13,797). Paper chromatography showed a zone of

R. = 0.67.

r

Example 14

Sodium- D-g-(3- benzyl- 3- cinnamoylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-benzylcyannamamide and D-α-aminobenzylcephalosporin dihydrate in 49.5% yield; n.m.r. [(CD3)2S0 + D20],

6 = 2.Q3 (3H, s, CH30C0-), 3.33 (2H, m, C2-methylene protons),

4.95 (3H, m, -CH20C0- and Cg proton), 5.28 (2H, m, PhCH2~), 5.67

(1H, d, C^ proton), 5.72 (1H, s, g<->proton), 7.40 (17H, m,.aromatic and olefinic protons); u.v. spectrum (95% ethanol), ^max 289 nm (e = 14,100). Paper chromatography showed a zone at R^ = 0.64.

Example 15

Sodium- D- g-[ 3-( 3', 4', 5'- trimethoxybenzoyl)- 3- methylureido 3 benzyl-.

cephalosporin

From N-chlorocarbonyl-N-methyl-3,4,5-trimethoxybenzamide and D-g<->aminobenzylcephalosporin dihydrate in 27% yield; n.m.r

[(CD3)2SO + D2O], 6 = 2.03 (3H, s, CBLjOCO-)", 3.17 (5H, m, ^TN-CH3 and C2-methylene), 3.83 (9H, m, 3 x CHjO-), 4.96 (3H, m, -CH2OCO- and

C,-proton) , 5.63 (1H, d, C-,-proton) , 5.68 (1H, s, g<->proton), 6.88 (2H, s, trisubstituted phenyl protons), 7, 40 (5H, s, Ph-);

u.v. spectrum (95% ethanol), \IU3.K S265 nm (e = 11,832). Paper chromatography showed a zone at Rf = 0.42.

Example 16

Sodium- D- a-[ 3-( 33- dimethylacryloyl)- 3- methylureido] benzyl- cephalosporin From N-chlorocarbonyl-N-methyl-33-dimethylacrylamide and D-a-aminobenzylcephalosporin dihydrate in 24.7% yield; n.m.r. spectrum [(CD3)2SO'+ D2O], 6 = 1.9-2.1 (9H, m, yCH^ and -OCOCHj), 3.20

NCH3

(2H, s, ^N-CH3) , 3.2-3.4 (2H, m, C2-methylene) , 4.8-5.0 (3H, m, -CH_20C0-and Cg-proton), 5 .6-5.8 (2H, m, C? and a protons), 6.20 (1H, m, -CH=CC^), 7.42 (5H, s, aromatic protons); u.v. spectrum (95% ethanol), ^max 227 nm (e = 18,460). Paper chromatography showed a zone at R f = 0.62.

Example 17

Sodium- D- a-[ 3- methyl- 3-( 3', 4', 5'- trimethoxycinnamoyl)- ureido] benzyl-cephalosporin

From N-chlorocarbonyl-N-methyl-3,4,5-trimethoxycinnamamide and D-α-aminobenzylcephalosporin dihydrate in 33.5% yield; n.m.r. spectrum

[(CD3)2SO + D2O], 6 = 2.03 (3H, s, -0C0CH_3) , 3.2-3.5 (2H, m, C2~methylene) , 3.36 (3H, s, ^N -CHg) , 3.77 (3H, s, -OHCH_3) , 3.87 (3H, s,

-0CH3) , 3.96 (3H, s, -OCHg) , 4.8-5.0 (3H, m, Cg- and -CH_20C0-) , 5.5-5.7 (2H, m, a- and C7~ protons), 7.1-7.7 (9H, m, aromatic and olefinic protons); u.v.-spectrum (95% ethano<l>), ^max<2>35.5

(e = 21,396) and 320 nm (e = 17,935). Paper chromatography showed a zone at R^ = 0.63.

Example 18

Sodium- D- a-( 2- imidazolidonecarbonylamino) benzyl cephalosporin

D-α-(2-imidazolidonecarbonylamino)phenylacetic acid (1.32 g, 0.005 m) in 20 mL of anhydrous tetrahydrofuran was cooled below -10° and treated with 1 drop of N-methylmorpholine, 0.71 mL of triethylamine, and 0.48 mL of ethyl chloroformate. The resulting suspension was stirred at < -10° for 15 min, after which an ice-cooled solution of 7-aminocephalosporanic acid (1.36 g, 0.005 m) and 0.71 mL of triethylamine in 30 mL of 50% aqueous tetrahydrofuran was added. The solution was stirred at

room temperature for 3 hours, tetrahydrofuran was removed in vacuo and the residue dissolved in 100 ml of water. This aqueous solution was washed with

ethyl acetate (2 x 50 ml) and acidified to pH 1.5 with 1N hydrochloric acid. The precipitate was collected and dried in vacuo, yield 0.87 g,

after which it was suspended in 10 ml of water and 0.95 equivalent of

ln sodium bicarbonate solution added. The solution was filtered and

the filtrate was evaporated to dryness in vacuo. Yield 0.70 g, 26%; n.m.r. [(CD3)2SO + D2O], 6 = 9.17 [1H, d(J = 8 Hz), -NH-], 7.41

(5H, s, aromatic protons), 5.9-5.4 (2H, m, C^- and a-protons), 5.3-4.6 (3H, m, Cg- and -CH_20C0-protons) , 4.1-3.1 (6H, m, C2-methylene and imidazolidone methylenes), 2.01 (3H, s, -OC0CH3); u.v.-spectrum (95% ethanol) ^max<2>64 nm U = 6.527). Paper chromatography

in n-butanol/ethanol/water showed one zone, Rf = 0.32.

Example 19

Sodium D-α-(3-cinnamoyl-3-methylureido)benzylcephalosporin D-α-(3-cinnamoyl-3-methylureido)phenylacetic acid (1.69 g, 0.005 m) in 15 mL of anhydrous acetone was cooled to < -10° after which 1 drop of N-methylmorpholine, 0.71 ml of triethylamine and 0.48 ml of ethyl chloroformate were added. The resulting suspension was stirred at < -5° for 15 minutes after which 7-aminocephalosporanic acid (1.36 g,

0.005 m) and 0.71 ml of triethylamine in 30 ml of 50% aqueous acetone pre-cooled to 0° were added. The solution was stirred at room temperature for 3 hours, after which the acetone was removed in vacuo and

the rest diluted with approx. 50 ml of water. The aqueous solution was washed with ethyl acetate (2 x 50 mL), covered with 50 mL of ethyl acetate,

acidified to pH 1.5 with ln hydrochloric acid, the layers separated and that

aqueous layers extracted with 50 ml ethyl acetate. The combined organic solutions were washed with water (2 x 50 mL) and 50 mL brine, dried over anhydrous magnesium sulfate, concentrated in vacuo and treated with 2N sodium 2-ethylhexoate in 1.5 mL methyl isobutyl ketone. The precipitated solid was collected, washed with anhydrous ether and dried in vacuo. Yield 0.70 g, 22.8%; n.m.r. [(.CD3)2SO + D20], 6 = 8.0-7.1 (12H, m, aromatic and olefinic protons), 5.8-5.4 (2H, m, C^- and a-protons) , 5.2-4.7 (3H, m, Cg and -CH20C0 protons) , 3.34 (5H, singlet covering a multiplet, r^-N-CH3 and C2 methylene), 2.05 (3H , s, -0C0CH3); etc. spectrum (95% ethanol), ^max 2 75 nm (e = 17.119). Paper chromatography showed a single zone, Rf = 0.52.

Example 20

Sodium- D- a-( 3- furylacryloyl- 3- methylureido) benzyl cephalosporin

Of D-α-(3-furylacryloyl-3-methylureido)phenylacetic acid and

7-aminocephalosporanic acid as in example 21 in 14% yield; n.m.r. spectrum [(CD^SO + D 2 O], 6 = 2.03 (3H, s, -OCH 3 ) , 3.32

(5H, singlet covering a multiplet ,^N-CH3~ and C2~ methylene protons), 4.8-5.1 (3H, m, -CH2OCO- and Cg-proton), 5.5-5.8 (2H , m,

C^- and α-protons), 6.6-7.9 (10H, m, furyl, olefinic and aromatic protons). Paper chromatography showed a zone at R f = 0.58.

Example 21

Sodium- D- a-( 3- cinnamoyl- 3'- methylureido)- 4- hydroxybenzyl- cephalosporin

From D-α-(3'-cinnamoyl-3'-methylureido)-4-hydroxyphenylacetic acid and 7-aminocephalosporanic acid by the method according to example 21 in 35.9% yield; n.m.r. [(CD^SO + D2O], 6 = 8.0-6.6 (11H, m, aromatic and olefinic protons), 5.8-5.4 (2H, m, C^- and a-protons), 5.1-4.7 (3H, m, Cg and -CH20C0-), 3.35 (5H, s, ^N-CH-^-and C2-methylene), 2.05 (3H, s, -0C0CH3 ); u.v.-spectrum (95% ethanol), Amax225 ^£= 24-468) 0<3 282 nm (e = 19,152). Paper chromatograph in showed one zone, Rf = 0.65.

Example 22

Sodium- 7-[ D- a-( 3'- cinnamoyl- 3'- methylureido) phenylacetamido]- 3-( 2"- methyl- 1", 3", 4"- thiadiazol- 5"- ethylthio) methylceft- 3 - em- 4-carboxylate D-α-(3-cinnamoyl-3-methylureido)phenylacetic acid (0.85 g, 0.0025 m) in 10 mL of anhydrous acetone was cooled to < -10 , and then 1 drop of N-methylmorpholine, 0.35 ml triethylamine and 0.24 ml ethyl chloroformate added The resulting suspension was stirred at < -10° for 15 min after which 7-amino-3-(2'-methyl-1',3',4'-thiadiazole -5'-ylthio)-methyl-cef-3-em-4-carboxylic acid (0.86 g, 0.0025 m) and 0.35 mL of triethylamine in 15 mL of 50% aqueous acetone precooled to 0° were was added. The solution was stirred at room temperature for 2 hours, and the acetone was removed in vacuo, the residue diluted with 50 ml of water and washed with ethyl acetate (2 x 50 ml). The aqueous phase was covered with 50 ml of ethyl acetate and acidified to pH 1, 5 with 1N hydrochloric acid, after which the ethyl acetate layer was separated from and the aqueous layer extracted with 50 ml of ethyl acetate.The combined ethyl acetate solutions were washed with water (2 x 50 ml) and 50 ml brine, dried over anhydrous magnesium sulfate and treated with 2N sodium 2-ethylhexoate in 0.7 ml methyl isobutyl ketone. The precipitated sodium salt was collected, washed with anhydrous ether and dried in vacuo. Yield 0.53 g, 30.9%; n.m.r.

[(CD )2S0 + D20], 6 = 8.0-7.0 (12H, m, aromatic and olefinic

protons), 5.8-5.4 (2H, m, C7 and a-protons), 5.1-4.8 (1H, m, Cg-prpton), 4.8-4.0 (2H, m, -CH2~S-), 3.34 (5H, singlet covering a

multiplet, 2^N-CH3- and C2-methylene) , 2.67 (3H, s, thiadiazolemethyl protons); u. v. spectrum (95% ethanol) ^max<2>19 (e, = 24.010) and

and 282 nm (e = 27,901). Paper chromatography showed one zone, R f = 0.63.

Example 2 3

Sodium- 7-[ D- a-( 3'- cinnamoyl- 3'- methylureido) phenylacetamido]- 3-( 1"- methyl- 1"- H- tetrazol- 5"- ylthio) methyl eph- 3- em- 4 - carboxylate 1 drop of N-methylmorpholine, 0.35 ml of triethylamine and 0.24 ml of chloroformate were added to D-α-(3-cinnamoyl-3-methylureido)phenyl-acetic acid (0.85 g, 0.0025 m) in 20 ml of anhydrous acetone at < -10° and stirred at this temperature for 15 minutes.7-Amino-3-(1'-methyl-1'H-tetrazol-5'-ylthio)methylcef-3-em-4-carboxylic acid ( 0.82g,

0.0025 m) and 0.35 ml of triethylamine in 30 ml of 50% aqueous acetone which had been cooled to 0° were added and the solution stirred at room temperature for 2 hours. Acetone was removed in vacuo and the residue diluted with 100 ml of water, washed with ethyl acetate (2 x 50 ml), covered with 50 ml of ethyl acetate and acidified to pH 1.5 with 1N hydrochloric acid. The layers were separated and the aqueous solution extracted with 50 ml of ethyl acetate.

The combined extracts were washed with water (2 x 50 ml), dried

over anhydrous magnesium sulfate and treated with 2N sodium 2-ethylhexoate in 0.8 ml of methyl isobutyl ketone. The precipitated salt was collected, washed with anhydrous ether and dried in vacuo. Yield 0.64 g,

38.2%; n.m.r. [(CD^SO + D2O. 6 = 8.0-7.1 (12H, m, aromatic and olefinic protons), 5.8-5.5 (2H, m, C^- and a-protons), 5 ,1-4,8

(1H, m, Cg proton), 4.6-4.1 (2H, m, -CH2-S-), 3.95 (3H, s, tetrazole methyl protons), 3.33 (5H, singlet as covering a multiplet of ^N-CH^ and C0 methylene protons); u.v.-spectrum (95% ethanol), X ,OQ<O>

z maKs.£oznm

(e = 25,277). Paper chromatography showed one zone, R^ = 0.66.

Example 2 4

Sodium- D- g-(3- benzoyl- 3- methylureido) benzyl cephalosporin

Anhydrous triethylammonium-D-g<->aminobenzylcephalosporin

(0.005 m) in 30 ml of dichloromethane (prepared from 2.2 g of D-g<->amino-benzylcephalosporin dihydrate as in Example 3) was cooled in an ice bath, and then N-chlorocarbonyl-N-methylbenzamide (0.98 g, 0.005 m) in 15 ml of dichloromethane added. The solution was stirred at room temperature for 2 hours and then evaporated to dryness in vacuo. The evaporation residue was dissolved in 100 ml of water, washed with ethyl acetate (2 x 50 ml)

and acidified to pH 1.5 with ln hydrochloric acid in the presence of 50 ml of ethyl

acetate. The organic layer was separated from the aqueous layer

extracted with 50 mL ethyl acetate, and the combined ethyl acetate extracts were washed with water (2 x 100 mL) and 50 mL saturated brine and then dried over anhydrous magnesium sulfate. It dried

solution was treated with 2N sodium 2-ethylhexoate in 1.5 ml of methyl isobutyl ketone, diluted with 200 ml of anhydrous ether and the precipitated

sodium salt collected and dried in vacuo. Yield 1.68 g, 57.2%; n.m.r. spectrum [(CD3)2SO + D20], 6 = 7.7 - 7.2 (10H, m, aromatic protons), 5.8 - 5.4 (2H, m, C - and a-protons), 5.2 - 4.6 (3H, m, Cg proton and -CH20CO-), 3.6 - 2.8 (2H, m, C2 methylene protons),

3.08 (3H, s, ^NCH3), 2.00 (3H, s, -OCOH3), u.v. spectrum (95% EtOH), ^max 2^ nm ^E = 8.710). Paper chromatography in n-butanol/ethanol/water showed one zone, R,. = 0.52.

The following examples 25-37 were prepared by the method described in example 24.

Example 2 5

Sodium- D- a-( 3- methyl- 3- acetylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-methylacetamide and D-α-aminobenzyl-cephalosporin dihydrate in 27.0% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.43 (5H, s, aromatic protons), 6.8 - 6.5 (2H, m, C^- and

a-protons), 5.2 - 4.6 (3H, m, Cg proton and -CH20C0-), 3.7 - 2.7

(2H, m, C2-methylene protoether) , 3.20 (3H, s,^NCH3), 2.33 (3H, s,

-COCH 3 ), 2.03 (3H, s, -COCH 3 ); UV spectrum (95% ethanol),

^max 2^ nm ^e = 7.920). Paper chromatograph i showed one zone, R^ = 0.42.

Example 26

Sodium- D- a-[ 3-( 2- methylcrotonoyl)- 3- methylureido] benzyl cephalosporin

From N-chlorocarbonyl-N-methyl-2-methylcrotonamide and D-α-amino-benzyl cephalosporin dihydrate in 37.4% yield; n.m.r. spectrum [(CD 3 ) 2 SO + D 2 O], 6 = 1.5 - 2.2 (6H, m, = CHCH_ 3 and -OCCH 3 ), 3.12 (3H, s,Z^N-CH 3 ), 3.2 - 3.4 (2H, m, C2-methylene protons), 4.9 (3H, m, Cg-proton and -CH20C0-), 5.6 (2H, m, C?- and a-protons), 7, 4 (5H, m, aromatic protons); u.v. spectrum (95% ethanol), \ , 257 nm (e =7,930). Paper chromatography showed one zone, R^ = 0.62.

Example 2 7

Sodium- D- a-( 3- phenylacetyl- 3- methylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-methylphenylacetamide and D-α-aminobenzyl-cephalosporin dihydrate in 10.5% yield; n.m.r. spectrum [(CD3)2SO + D2O], δ = 2.03 (3H, s, -OCOCHj), 3.29 (5H, singlet covering a

multiplet^:NCH3 and C2~ methylene protons), 4.04 (2H, s, -C0CH2Ph), 4.92 (3H, m, -0C0CH2~ and Cg proton), 5.7 (2H, m, C?- and a-protons),

7.32, 7.40 (10H, d, aromatic protons); u.v. spectrum (95% ethanol), X' 264 nm (e = 5,720). Paper chromatography showed one zone of wood

• max

R f = 0.51

Example 2 8

Sodium- D- a-[ 3-( 4- phenylbutanoyl)- 3- methylureido] benzyl cephalosporin

Of N-chlorocarbonyl-N-methyl-4-phenylbutyramide and D-α-amino-benzylcephalosporin dihydrate in 49.2% yield; n.m.r. spectrum [(CD3)2SO + D2O], δ = 2.02 (7H, singlet covering a multiplet, -OC0CH3and -CH2CH2Ph), 2.7 (2H, m, -COCHj-), 3.18 (5H , singlet covering multiplet, ^NCH3 and C2 methylene protons) , 4.92 (3H, m,

-CH20C0 and Cg proton), 5.65 (2H, m, C_ and a protons), 7.26

(5H, s, aromatic protons), 7.40 (5H, s, aromatic protons);

u.v. spectrum (95% ethanol), A , 261 nm (e = 7,785). Paper-

ITlcl-K S

chromatograph showed a zone at R = 0.62.

Example 2 9

Sodium- D- a-( 3- oct- 2'- enoyl- 3- methylureido) benzyl cephalosporin

Of N-chlorocarbonyl-N-methyloct-2-enamide and D-α-aminobenzyl-cephalosporin dihydrate in 25% yield; n. m. r. spectrum [ (CD3) 2S0 + D,>0] , 6 = 0.8 - 1.5 (9H, m, -(CH2)3CH3), 2.02 (5H, singlet covering

one. multiplet, -0C0CH3and -CH_2CH=) , 3.25 (5H, singlet covering a

multiplet, ^rNCH3 and C-j-methylene protons) , 4.8 - 5.0 (3H, m, Cg-proton and -CH20C0-), 5.5 - 5.7 (2H, m, C^- and a-protons ), 6.5 - 7.5

(2H, m, olefinic protons), 7.42 (5H, s, aromatic protons). Paper chromatography showed a zone at R^ = 0.58.

Example 30

Sodium- D- a-( 3- furoyl- 3- methylureido) benzyl cephalosporin

Of N-chlorocarbonyl-N-methyl-2-furamide and D-a-aminobenzyl- . cephalosporin dihydrate in 55.0% yield; n.m.r. spectrum [(CD3)2SO + , D2O], 6 = 2.04 (3H, s, -0C0CH3), 3.37 (5H, singlet covering a multiplet, J>NCH3 and C2 methylene protons), 4, 8-5.0 (3H, m, -0C0CH2" and Cg proton), 5.5 - 5.8 (2H, m, C^- and a-protons), 6.6 - 8.0 (8H, .m, aromatic and furyl protons); u.v. spectrum (95% ethanol), ^max 268 nm ^e = 19'"°)* Paper chromatograph i showed a zone at Rf = 0.39.

Example 31

Sodium- D- a-( 3- cinnamoyl- 3- ethylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-ethylcinnamamide and D-α-aminobenzyl-cephalosporin dihydrate in 27.4% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 1.2 - 1.4 (3H, m, CH_3CH2-) , 2.04 (3H, s, -OC0CH3) , 3.2-3.5

(2H, m, C2-methylene protons), 3.7 - 4.2 (2H, m, ^N-CH2~), 4.9-5.05 (3H, m, -OC0CH2~ and Cg-proton), 5.6-5.8 (2H, m, C?- and a-protons),

7.3 - 8.0 (12H, m, aromatic and olefinic protons), u.v. spectrum (95% ethanol, ^max 285 nm (e = 19,370). Paper chromatograph in shown

a zone at R = 0.57.

Example 32

Sodium- D- a-(3- acetylimidazolidin- 2- on- l- ylcarbonylamino) benzyl-cephalosporin

Of D-α-aminobenzylcephalosporin dihydrate and 3-acetyl-1-chloro-carbonylimidazolidin-2-one in 61.9% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.42 (5H, s, aromatic protons), 5.8 - 5.3

(2H, m, C7~ and a-protons), 5.2 - 4.6 (3H, m, Cg-proton and -CH20C0-), 3.73 (4H, s, imidazolidinone-methylene protons), 3.6 - 2.9 (2H, m, C2~ methylene protons) , 2.42 (3H, s, Z^NC0CH3)., 1.99 (3H, s, -0C0CH3) ;

UV spectrum (95% ethanol), A max. s 260 nm (e = 8,180). Paper chromatography showed one zone R^= 0.30.

Example 33

Sodium- D- a-( 3- methylsulfonylimidazolidin- 2- on- 1- ylcarbonylamino)- benzyl cephalosporin

Of D-α-aminobenzylcephalosporin dihydrate and 1-chlorocarbonyl-3-methylsulfonylimidazolidin-2-one in 38.1% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.48 (5H, s, aromatic protons), 5.7 - 5.4

(2H, m, C7~ and a-protons), 5.2 - 4.5 (3H, m, Cg-proton and -CH20C0-), 3.89 (4H, s, imidazolidinone-methylene protons), 3.7 - 2.8 (2H, m, C2 methylene protons), 3.38 (3H, s, -SO2CH3), 2.03 (3H, s, -OC0CH3);

u. v. spectrum (95% ethanol), ^max 262 nm (e = 7,825). Paper chromatograph i showed one zone, R^ = 0.27.

Example 34

Sodium- D- a-(2, 4, 4- trimethylallafanamido) benzyl cephalosporin

From 1-chlorocarbonyl-1,3,3-trimethylurea and D-α-aminobenzyl-cephalosporin dihydrate in 33.2% yield; n.m.r. spectrum [(CD3)2SO + D2O], δ = 2.02 (3H, s, -OC0CH3), 2.88 [6H, s, -N(CH3)2], 3.0 (3H, s, ^TNCH3), 3.33 (2H, m, C2-methylene protons), 4.93 (3H, m, Cg-proton and -CH20C0-), 5.58 (2H, m, C7- and a-protons), 7.40 (5H, m, aromatic protons); u.v.-spectrum (95% ethanol), A maK, s<2>66 nm (e = 6,890). Paper chromatography showed a zone at R^ = 0.30.

Example 35

Sodium- D- a-( 3- Phenoxyacetyl- 3- methylureido) benzyl cephalosporin

From N-chlorocarbonyl-N-methylphenoxyacetamide and D-α-aminobenzyl-cephalosporin dihydrate in 62.1% yield; n.m.r. spectrum [(CD3)2SO + D20],

6 = 2.01 (3H, s, -0C0CH3) , 3.23 (5H, m, ^NCH3 and C2-methylene protons) , 4.92 (3H, m, -CH20C0- and Cg-proton) 5.10 (2H , p, PhOCH2~), 5.61

(2H, m, Cj and α protons), 6.9 - 7.5 (10H, m, aromatic protons); u.v. spectrum (95% ethanol, A IT13.K, S<2>66 nm (e = 9,000). Paper chromatography showed a zone at Rf = 0.50.

Example 36

Sodium- D- a-[ 3-( 2- chlorobenzoyl)- 3- methylureido] benzyl cephalosporin

From N-chlorocarbonyl-N-methyl-2-chlorobenzamide and D-α-amino-benzyl cephalosporin dihydrate in 28.5% yield; n.m.r. spectrum [ (CD 3 ) 2 SO=D 2 O] , 6 = 2.03 (3H, s,. -OCOCH-j), 3.01 (3H, s, ^N-CH 3 ), 3.2-3.5 (2H, m, C2-methylene protons), 4.8-5.1 (3H, m, -CH20C0- and Cg-protons), 5.6-5.8 (2H, m, C^- and a-protons ), 7.3-7.7 (9H, m, aromatic protons); u.v.-spectrum (95% ethanol), A maK, s<2>66 nm (e = 7,920). Paper chromatography showed a zone at = 0.58.

Example 37

Sodium- D- a-[ 3-( 2- methylbenzoyl)- 3- methylureido] benzyl cephalosporin

Of N-chlorocarbonyl-N-methyl-2-methylbenzamide and D-α-aminobenzyl-cephalosporin dihydrate in 51.5% yield; n.m.r. spectrum [(CD 3 ) 2 SO + D 2 O], δ = 2.01 (3H, s, -OCOCH 3 ), 2.28 (3H, s, benzoyl -CH 3 ), 2.96 (3H, s, ^N- CH3) , 3.2-3.4 (2H, m, C2 methylene protons) , 4.9-5.1 (3H, m,

-CH20C0- and Cg-proton), 5.6 - 5.8 (2H, m, C^- and a-protons),

7.3 - 7.5 (9H, m, aromatic protons); UV spectrum (95% ethanol),

^max 260 nm ^e = 8,310). Paper chromatography showed a zone of

Rf = 0.50.

Example 38

Sodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 2- methyl-1, 3, 4- thiadiazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

7-(D-α-Aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-methylcef-3-em-4-carboxylic acid trifluoroacetic acid (t.f.a.) salt

(1.77 g, 0.003 m) and 1.35 mL of triethylamine in 30 mL of dichloromethane were cooled in an ice bath and treated with N-chlorocarbonyl-N-methylcinnamamide (0.78 g, 0.0035 m) in 10 mL of dichloromethane. The solution was stirred at room temperature for 3 hours and then evaporated to dryness in vacuo, the evaporation residue dissolved in 50 ml of water and washed with ethyl acetate

(2 x 50 ml). The aqueous solution was covered with 50 ml of ethyl acetate, acidified to pH 1.5 with 1N hydrochloric acid, filtered, the ethyl acetate

collected and the aqueous layer extracted with a further portion of

50 ml ethyl acetate. The combined extracts were washed with water

(2 x 50 ml) and 25 ml saturated saline, dried over anhydrous magnesium

sulfate and treated with 2N sodium 2-ethylhexoate in 1.0 mL of methyl isobutyl ketone. 200 ml of anhydrous ether was added and it precipitated

sodium salt collected and dried in vacuo. Yield 0.96 g, 46.6%; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 8.0 - 7.0 (12H, m, aromatic and olefinic protons), 5.8 - 5.5 (2H, m, C^- and a- protons), 4.93 [1H, d, (J = 5 Hz), Cg proton], 4.7 - 4.1 (2H, m, -CH2S-), 3.8 - 2.9 (2H, m, C2 methylene protons) , 3.25 (3H, s,^NCH3), 2.67 (3H, s,

thiadiazole~CH3); u.v. spectrum (95% ethanol), ^max<2>82 nm (e = 30,630). Paper chromatography showed one zone, R f = 0.65.

The following examples were prepared as described in Example 40.

Example 39

Sodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 1- methyl-1H- tetrazo1- 5- ylthio) methyl eph- 3- em- 4- carboxylate

Of 7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)-methylcef-3-em-4-carboxylic acid t.f.a. salt and N-chlorocarbonyl-N-methylcinnamamide in 50.7 % dividend; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.9 - 7.1 (12H, m, aromatic and olefinic protons), 5.8 - 5.5

(2H, m, C7~ and a-protons), 5.1 - 4.8 (1H, m, Cg proton), 4.7 - 4.0 (2H, m, -CH2S-), 3.93 (3H, s, tetrazole -CH3), 3.8 - 3.1 (2H, m,

C2 methylene protons), 3.33 (3H, s, 2lNCH3); u.v. spectrum (95% ethanol), ^max 282 nm ^e = 24,490). Paper chromatography showed one zone,

R f = 0.51.

Example 40

Sodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 1H- 1, 2, 4-triazol- 3- ylthio) methyl eph- 3- em- 4- carboxylate

From 7-(D-α-aminophenylacetamido)-3-(1H-1,2,4-triazol-3-ylthio)-methylcef-3-em-4-carboxylic acid-t.f.a.-salt and N-chlorocarbonyl-N-methylcinnamamide in 55 .7% dividend; n.m.r. [(CD3)2SO + D20], 6 = 8.0-7.0 (13H, aromatic, olefinic and triazole protons), 5.7 - 5.4 (2H, m, C7~and a-protons), 5, 0 - 4.3 (3H, m, Cg proton and -CH2S-), 3.8 - 3.0 (2H, m, C2 methylene protons), 3.33 (3H, s, ^:N-CH3) ; u.v. spectrum

(95% ethanol), ^max 287 nm (c = 21,980).'Paper chromatograph i showed a zone at R^ = 0.58.

Example 41

Sodium- 7-[ D- a-( 2, 4- dimethylallofanamido) phenylacetamido]- 3-( 2- methyl-1, 3, 4- thiadiazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

From 7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-methylcef-3-em-4-carboxylic acid t.f.a. salt and 2,4-dimethylallophanoyl chloride in 58 .7% dividend; n.m. r.-spectrum [(CP^SO + D2O],

6 ' = 7.7 - 7.1 (5H, m, aromatic protons), 5.7 - 5.5 (2H, m,

C_/ - and a-protons), 5.0 - 4.8 (1H, m, Cb, -<p>roton), 4.7 - 4.1

(2H, m, -CH2S-), 3.10 (3H, s,^NCH3), 2.70 (6H, s, -NHCH^ and thiadiazole -CH^); u.v. spectrum (95% ethanol), ^max 274 nm

(e = 13,010). Paper chromatography showed one zone R^= 0.41.

Example 42

Sodium- 7-[ D- a-( 2, 4- dimethylallofanamido) phenylacetamido]- 3-( 1- methyl-1H- tetrazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

From 7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)-methylcef-3-em-4-carboxylic acid t.f.a. salt and 2,4-dimethyl-allophanoyl chloride in 53, 0% dividend; n.m.r. spectrum [ (CD 3 ) 2 SO + D 2 O], δ = 7.42 (5H, s, aromatic protons), 5.7 - 5.5 (2H, m, C 2 and a protons), 4.88 [1H, d, (J = 5Hz), Cb,-<p>roton],4.6 - 4.0 (2H, m, -CH2S-), 3.93 (3H, s, tetrazole~CH3), 3.8 - 3.1 (2H, m, C2-methylene protons), 3.10 (3H, s, N-CH3), 2.70 (3H, s, -NHCH3); u.v. spectrum (95% ethanol) , ^max 268 nm (e = 8.020). Paper chromatography showed one zone Rf = 0.47.

Example 4 3

Sodium- 7-[ D- a-( 3- acetyl- 3- methylureido) phenylacetamido]- 3-( 2- methyl-1, 3, 4- thiadiazol- 5- ylthio) methyl ceft- 3- em- 4- carboxylate

From 7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)-methylcef-3-em-4-carboxylic acid t.f.a. salt and N-chlorocarbonyl-N-methylacetamide in 76.9% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.47 (5H, s, aromatic protons), 5.8 - 5.4 (2H, m, C^- and

a protons), 4.93 1H, d, (J = 5Hz), Cg proton, 4.7 - 4.0 (2H, m, .

-CH2S-), 3.8 - 3.0 (2H, m, C2-methylene protons), 3.21 (3H, s,J^IN-CH3), 2.72 (3H, s, thiadiazole~CH3), 2.33 (3H, s, -COCH3); u.v. spectrum

(95% ethano<l>),^max 275 nm (e = 12,410). Paper chromatography showed one zone, R^= 0.31.

Example 4 4 Sodium 7-[D-a-(3-acetyl-3-methylureido)phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ethylthio)methyl-3-em-4-carboxylate

Of 7-(D-α-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)-methylcef-3-em-4-carboxylic acid-t.f.a.-salt and N-chlorocarbonyl- •

N-methylacetamide in 24.8% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.40 (5H, s, aromatic protons), 5.7 - 5.4 (2H, m, C^- and

a protons), 4.89 [1H, d, (J = 5Hz), Cg proton], 4.6 - 4.0 (2H, m,

-CH2S-), 3.94 (3H, s, tetrazole"CH3), 3.8 - 3.1 (2H, m, C2-methylene-

protons), 3.18 (3H, s,Z^:N-CH 3 ), 2.30 (3H, s, -COCH 3 ); u.v. spectrum (95% ethanol), ^max 265 nm (e = 8,040). Paper chromatography showed

one zone R_ = 0.33.

Example 45

Sodium- 7-[ D- a-[ 3-( 4- phenylbutanoyl)- 3- methylureido] phenylacetamido]- 3-( 2- methyl- 1, 3, 4- thiadiazol- 5- ylthio) methylceft- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-4-phenylbutyramide and 7-(D-α-amino-phenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylceph-3-em-4- carboxylic acid t.f.a. salt in 46.8% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 1.8 - 2.2 (2H, m, PhCH2CH2CH2-), 2.5 - 2.9

(7H, m, thiadiazole~CH3, -COCH2CH2CH2Ph) , 3.17 (3H, s,2^N-CH3),

3.3 - 3.5 (2H, m, C2 methylene protons), 4.2 - 4.7 (2H, m, -CH2S-),

4.8 - 5.0 (1H, m, CD ,-proton), 4.5 - 4.8 (2H, m, C-/,-and a-protons), 7.27 (5H, s, aromatic protons), 7.41 (5H, s, aromatic protons);

u.v. spectrum (95% ethanol), ^max 275 nm (c = 12,770). Paper chromatograph i showed a zone at R^ = 0.62.

Example 4 6

Sodium- 7-[ p- a-[ 3-( 4- phenylbutanoyl)- 3- methylureido] phenylacetamido]- 3-( 1- methyl- 1H- tetrazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

From N-chlorocarbonyl-N-methyl-4-phenylbutyramide and 7-(D-α-amino-phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylcef-3-em-4-carboxylic acid-t.f.a.- salt in 17.5% yield; n.m.r. spectrum [(CD3)2S0 + D2O], 6 = 1.7 - 2.2 (2H, m, PhCH2CH2CH2~), 2.5 - 2.7 (4H, m, PhCH2CH2CH2CO),

3.16 (3H, s,^:N-CH3), 3.4 - 3.6 (2H, m, C2 methylene protons), 3.94 (3H, s, tetrazole -CH3), 4.3 - 4 .5 (2H, m, -CH2~S-), 4.8 - 5.0

(1H, m, Cg-proton), 5.5 - 5.8 (2H, m, C^- and a-protons), 7.25 (5H,

s, aromatic protons) 7.37 (5H, s, aromatic protons);

u. v. spectrum (95% ethanol), *max<2>70nm (e = 8,410).'Paper chromatograph i showed a zone at R^ = 0.47.

Example 47

Sodium- 7-[ D- a-[ 3-( 2- methylcrotonoyl)- 3- methylureido] phenylacetamido]- 3-( 1- methyl- 1H- tetrazol- 5- ylthio) methylceph- 3- em- 4- carboxylate-

From N-chlorocarbonyl-N-methyl-2-methylcrotonamide and 7-(P-α-amino-phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylcef-3-em-4-carboxylic acid-t.f.a.- salt in 17.1% yield, n.m.r. spectrum

[(CP3)2SO + P20], 6 = 1.6 - 1.9 (6H, m, 2 x crotonoyl - CH3), 3.11

(3H, s,^N-CH3), 3.4 - 3.6 (2H, m, C2 methylene protons) , 4.96 (3H, s, tetrazole -CH3), 4.2 - 4.4 (2H , m, -CH2S-), 4.7 - 5.1 (1H, m, Cg proton), 5.5 - 6.0 (3H, m, -CH=CC^'c7-°9a protons) , 7.40 (5H, p,

aromatic protons); UV spectrum (95% ethanol), ^max 270 nm

(e = 9,260). Paper chromatography showed a zone at Rf = 0.43.

Example 48

Sodium- 7-[ D- a-[ 3-( 2- methylcrotonoyl)- 3- methylureido) phenylacetamido]- 3-( 2- methyl- 1, 3, 4- thiadiazol- 5- ylthio) methylceft- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-2-methylcrotonamide and 7-(D-g<->amino-phenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em- 4-carboxylic acid t.f.a. salt in 35.6% yield; n.m.r. spectrum [(CD 3 ) 2 SO + D 2 O], δ = 1.6 - 1.9 (6H, m, 2 x crotonoyl~CH 3 ), 2.69 (3H, s, thiadiazole -CH 3 ), 3.12. (3H, s,r^N-CH3), 3.4 - 3.6 (2H, m, C2 methylene protons) , 4.3 - 4.6 (2H, m, -CH_2S-) , 4.9 - 5.1 (1H, m, Cg proton), 5.5 - 6.0 (3H, m, -CH=Cd , C?- and a-protons), 7.41

(5H, s, aromatic protons); u.v. spectrum (95% ethanol), ^max 275 nm (e = 13,470). Paper chromatography showed a zone at R f = 0.52.

Example 49

Sodium- 7-[ D- a-[ 3-( 3- phenylpropionyl)- 3- methylureido] phenylacetamido]- 3-( 2- methyl- 1, 3, 4- thiadiazol- 5- ylthio) methyleph- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-3-phenylpropionamide and 7-(D-α-amino-phenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methyl-cef-3-em- 4-carboxylic acid t.f.a. salt in 34.9% yield; n.m.r. spectrum

[(CD3)2SO + D2O], 6 = 2.68 (3H, s, thiadiazole -CH3), 2.94 (4H, s,

-CH2CH2Ph) , 3.19 (3H, s,^N-CH3), 3.3 - 3.5 (2H, m, C2 methylene protons), 4.2 - 4.5 (2H, m, -CH- S-), 4.8 - 5.0 (1H, m, C,-proton), 5.4 - 5.7 (2H, m, C^- and a-protons), 7.28 (5H, s , aromatic protons), 7.37 (5H, s, aromatic protons); u.v. spectrum

(95% ethanol), ^max 275 nm (e = 13,500). Paper chromatography showed a zone at R^ = 0.61.

Example 50

Sodium- 7-[ D- g-[ 3-( 3- phenylpropionyl)- 3- methylureido] phenylacetamido]- 3-( 1- methyl- 1H- tetrazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-3-phenylpropionamide and (7-D-g<->aminophenyl-acetamido)-3-(1-methyl-1H-tetrazol-'5-ylthio)methyl-cef - 3-em- 4-carboxylic acid-t. f. a. salt in 26.8% yield; n.iri. r.-spectrum [(CD3)2SO+D20], 6 = 2.94 (4H, s, -Cj^CH^Ph) , 3.19 (3H, s, r^N-CH3) , 3, -3 .8 (2H, m, C2 methylene protons), 3.95 (3H, s, tetrazole -CH3), 4.2 - 4.5 (2H, -CH2S-), 4.8 - 5.0 (1H, m, Cg proton), 5.5 - 5.8 (2H,

m, Cy and g<->protons), 7.2 - 7.5 (10H, d, aromatic protons); u. Vi spectrum (95% ethanol), ^max 260 nm (e = 9,120). Paper chromatograph i showed a zone at R^ = 0.54.

Example 51

Sodium- 7-[ D- a-[ 3-( 3- methylcrotonoyl)- 3- methylureido] phenylacetamido]- 3-.

( 2- methyl- 1, 3, 4- thiadiazol- 5- ylthio) methyl cef- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-3-methylcrotonamide and 7-(D-α-amino-phenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em-4- carboxylic acid t.f.a. salt in 24.6% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 1.9-2.1 (6H, m, -CH=C (CH-j) 2 ), 2.70 (thiadiazole

-CH3) , 3.18 (3H, s,^N-CH3), 3.3 - 3.6 (2H, m, C2 methylene protons), 4.3 - 4.5 (2H, m, -CH2S- ), 4.8 - 5.0 (1H, m, Cg proton), 5.5 - 5.7 (2H, m, C7~ and a-protons), 6.1 - 6.3 (1H, m , -CH=C 1^7 ) , 7.41 (5H, s, aromatic protons); u.v.-spectrum (95% ethanol), ^ ks 270nm (e = 11,870). Paper chromatograph i showed a zone at Rf = 0.56-. Example 52 Sodium- 7-[ D- a-[ 3-( 3- methylcrotonoyl)- 3- methylureido) phenylacetamido]- 3-( 1- methyl- 1H- tetrazol- 5- ylthio) methylcef- 3- em- 4- carboxylate Of N-chlorocarbonyl-N-methyl-3-methylcrotonamide and 7-(D-α-amino-phenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylcef-3-em-4-carboxylic acid-t.f.a. -salt in 56.7% yield; n.m.r. spectrum'[(CD3)2SO + D2O], 6 = 1.9 - 2.1 (6H, m, -CH=C (CH_3) 2) , 3.18 (3H, s, ^N-CH3) , 3.4 - 3.6 (2H, m, C2 methylene protons) , 3.96 (3H, s, tetrazole -CH_), 4.3 - 4.5 (2H, m, -CH„S-), 4.9 - 5.0 (1H, m, C, -J z b proton), 5.5 - 5, 8 (2H, m, C^- and α-protons), 6.1 - 6.3 (1H, m, -CH=Cc^"), 7.40 (5H, s, aromatic protons); u. v. spectrum (95% ethanol<l>), ^max<2>74 nm (e = 10,130).Paper chromatography showed a zone at R f = 0.40.

Example 5 3

Sodium- 7-[ D- a-( 3- furoyl- 3- methylureido) phenylacetamido]- 3-( 2- methyl-1, 3, 4- thiadiazol- 5- ylthio) methyl ceft- 3- em- 4- carboxylate

From N-chlorocarbonyl-N-methylfuramide and 7-(D-a-aminophenyl-acetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em-4-carboxylic acid-t.f.a.- salt in 32.6% yield, n.m.r. spectrum [(CD3)2SO + D2O], 6 = 2.69 (3H, s, thiadiazole -CH3), 3.35 (5H, singlet covering multiplet, ^N-CH3 and C2 methylene protons), 4.2 - 4.5

(2H, m, -CH2S-), 4.9 - 5.1 (1H, m, Cg-proton), 5.5 - 5.8 (2H, m, C?-and a-protons), 6, 6 - 8.0 (8H, m, aromatic and furyl protons);

u.v. spectrum (95% ethanol), ^max 272 nm (e = 25,690). Paper chromatograph i showed a zone at R^= 0.50.

Example 54

Sodium- 7-[ D- a-( 3- crotonoyl- 3- methylureido) phenylacetamido]- 3-( 2- methyl-. 1, 3, 4- thiadia2ol- 5- ylthio) methylceph- 3- em- 4- carboxylate

From N-chlorocarbonyl-N-methylcrotonamide and 7-(P-α-aminophenyl-acetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em-4-carboxylic acid-t.f.a.- salt in 38.8% yield; n.m.r. spectrum [(CP3)2SO + D2O], 6 = 1.8 - 2.1 (3H, m, crotonyl~CH3), 2.70 (3H, s, thiadiazole~CH3), 3.25 (3H, s, N-CH3), 3.5 - 3.7 (2H, m, C2 methylene protons), 4.3 - 4.5 (2H, m, -CH2S-), 4.9 - 5.1 (1H , m, Cg proton), 5.5 - 5.8 (2H, m, C^ and a protons), 6.6 - 7.1 (2H, m, olefinic protons), 7.40 (5H , s, aromatic protons); u.v. spectrum

(95% ethanol), ^max 273 nm (e = 14,510). Paper chromatography showed a zone at R f = 0.65.

Example 55

Sodium- 7-[ β- a-( 3- crotonoyl- 3- methylureido) phenylacetamido]- 3-( 1- methyl-1H- tetrazol- 5- ylthio) methyl eph- 3- em- 4- carboxylate

From N-chlorocarbonyl-N-methylcrotonamide and 7-(β-α-aminophenyl-acetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)methylcef-3-em-4-carboxylic acid t.f.a. salt in 30, 6% dividend; n.m.r. spectrum [(CP3)2SO + P2O],

6 = 1.9 - 2.1 (3H, m, crotonyl~CH3), 3.23 (3H, s, ^TN-CH3), 3.4 - 3.7 (2H, m, C2 methylene protons), 3.94 (3H, s, tetrazole~CH3), 4.2 -

4.4 (2H, m, -CH2S-), 4.9 - 5.1 (1H, m, Cg proton), 5.5 - 5.8 (2H, m, C^- and a-protons) , 6.6 - 7.1 (2H, m, olefinic protons), 7.39

(5H, s, aromatic protons); u.v. spectrum (95% ethanol), ^max 270 nm (e = 10,010). Paper chromatography showed a zone at R^ = 0.45.

Example 56

Sodium- 7-[ P- g-[ 3-( 2- chlorobezoyl)- 3- methylureido] phenylacetamido]- 3-( 2- methyl- 1, 3, 4- thiadiazol- 5- ylthio) methylcef- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-2-chlorobenzamide and 7-(β-α-amino-phenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylephed-3-em-4- carboxylic acid t.f.a. salt in 31.8% yield; n.m.r. spectrum t(CP3)2S0 + P2O], 6 =2.68 (3H, s, thiadiazole -CH3), 2.98 (3H, s, ^N-CH3) , 3.3 - 3.6 (2H , m, C2-methylene protons) , 4.3 - 4.6 (2H, m,

-CH2S-), 4.8 - 5.0 (1H, m, Cg proton), 5.5 - 5.8 (2H, m, C?- and a-protons), 7.3 - 7.7 (9H, d, aromatic protons); u.v.-spectrum (95% ethanol), ^max 276 nm (e = 11,910). Paper chromatography showed

a zone at R^= 0.54.

Example 57

Sodium- 7-[ D- a-[ 3-( 2- methylbenzoyl)- 3- methylureido] phenylacetamido]- 3-( 2- methyl- 1, 3, 4- thiadiazol- 5- ylthio) methylceft- 3- em- 4- carboxylate

Of N-chlorocarbonyl-N-methyl-2-methylbenzamide and 7-(D-α-amino-phenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em-4- carboxylic acid t.f.a. salt in 32.7% yield; n.m.r. spectrum [(CD3)2SO. + D 2 O], 6 = 2.27 (3H, s, benzoyl -CH 3 ), 2.68 (3H, s, thiadiazole~CH 3 ), 2.97 (3H, s,J^rN-CH 3 ), 3.3 - 3.6 (2H, m, C2 methylene protons), 4.4 - 4.6 (2H, m, -CH2S-), 5.3 - 5.5 (1H, m, Cg proton), 5, 6 - 5.8 (2H, m, C^- and α-protons), 7.3 - 7.6 (9H, m, aromatic

protons); u.v.-spectrum (95% ethano<l>), ^max 274 nm (e = 12,190).

Paper chromatography showed a zone at Rf = 0.62.

Example 5 8

Sodium- 7-[ D- a-( 3- acetylimidazolidin- 2- on- l- ylcarbonylamino)- phenyl- acetamido ]- 3-( 2- methyl- l, 3, 4- thiadiazol- 5- ylthio) methylephet- 3 - em-4-carboxylate

Of 7-(D-α-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em-4-carboxylic acid-t.f.a.-salt and 3-acetyl-1-chloro- carbonylimidazolidin-2-one in 74.3% yield; n.m.r. spectrum

[(CD3)2SO + D20], 6 = 7.43 (5H, s, aromatic protons), 5.7 - 5.4 (2H, m, C7~and a-protons), 5.1 - 4.8 (1H, m, Cg proton), 4.7 - 4.1

(2H, m, -CH2S-), 3.70 (4H, s, imidazolidinone methylene protons), 3.8 - 3.0 (2H, m, C2 methylene protons), 2.70 (3H, s, thiadiazole~ CH 3 ), 2.45 (3H, s, ^NC0CH 3 ); u. v. spectrum (95% ethanol), ^max 274.5 nm (e = 10,270). Paper chromatography showed one zone, R_ = 0.43.

Example 5 9

Sodium- 7-[ D- a-( 3- acetylimidazolidin- 2- on- l- ylcarbonylamino) phenyl- acetamido) - 3-( l- methyl- lH- tetrazol- 5- ylthio) methylcef- 3- em- 4- carboxylate

From 7-(D-a-aminophenylacetamido)-3-(1-methyl-1H-tetrazol-5-ylthio)-methylcef-3-em-4-carboxylic acid-t.f.a.-salt and 3-acetyl-1-chloro-carbonylimidazolidine-2 -on in 43.5% dividend; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 7.47 (5H, s, aromatic protons), 5.8 - 5.4 (2H, m, C7~ and a-protons), 5.0 - 4.8 (1H, m, Cg proton), 4.7 - 4.0 (2H, m, -CH2S-), 3.96 (3H, s, tetrazole~CH3), 3.70 (4H, s , imidazolidinone methylene protons), 3.8 - 3.1 (2H, m, C2 methylene protons), 2.45 (3H, s,!^NC0CH3); u. v. spectrum (95% ethanol), *max<2>65 nm (e = 8,400). Paper chromatography showed one zone, Rf = 0.38.

Example 60 Sodium-D-α-(imidazolidin-2-on-1-ylcarbonylamino)benzylcephalosporin

Anhydrous triethylammonium-D-a-aminobenzylcephalosporin

in 30 ml of dichloromethane (prepared from the dihydrate (2.2 g, 0.005 m) as described in Example 3) was cooled in an ice bath, and 1-chlorocarbonyl-imidazolidin-2-one (0.75 g, 0.005 m) in 10 ml of dichloromethane was added. The solution was stirred at room temperature for 3 hours and then evaporated to dryness in vacuo, the evaporation residue dissolved in 100 ml of water and washed with ethyl acetate (2 x 50 ml). The aqueous solution was covered with 50 ml of ethyl acetate and acidified to pH 1.5 with 1N hydrochloric acid. The cephalosporin-free acid which precipitated was collected, washed with 100 ml of water and dried in vacuo. The free acid was suspended in 25 ml of water and adjusted to pH 6.5 with 5N sodium hydroxide solution and then filtered and freeze-dried to give the sodium salt. Yield 1.77 g, 68.4%; n.m.r. spectrum [(CD 3 ) 2 SO + D 2 O], δ = 7.43 (5H, s, aromatic protons), 5.8 - 5.4 (2H, m, C^ and α protons), 5.2 - 4.6 (3H, m, Cg proton and -CH20C0-), 4.0 - 3.0 (6H, m, C^- and imidazolidinone methylene protons), 2.00 (3H, s, -0C0CH3) ; u.v. spectrum (95% ethanol), ^max 264 nm ^e = 6,950). Paper chromatography showed one zone, R f = 0.27.

Example 61

Sodium- 7-[ D- a-( imidazolidin- 2- on- l- ylcarbonylamino) phenylacetamido]- 3-( 2- methyl- l, 3, 4- thiadiazol- 5- ylthio) methylceft- 3- em- 4- carboxylate-Prepared from 7-(D-a-aminophenylacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthio)methylcef-3-em-4-carboxylic acid and 1-chlorocarbonyl-imidazolidin-2-one i 6 3.5% yield by the method described in example 60. N.M.R. spectrum [(CD3)2SO + D20],

6 = 7.43 (5H, s, aromatic protons), 5.8 - 5.4 (2H, m, C^- and a-protons), 4.88 [1H, d, (J = 5 Hz), Cb,-proton], 4.8 - 4.1 (2H, m, -CH2S-), 4.0 - 3.0 (6H, m, C2~ and imidazolidinone methylene protons), 2.69 (3H, s , thiadiazole -CH3); u.v. spectrum (95% ethanol), ^max 275 nm (e = 12,210). Paper chromatography showed one zone, R^ =0.38.

Example 62

Sodium- 7-[ D- g-( imidazolidin- 2- onylcarbonylamino)- 3-( 1- methyl- tetrazol-5- ylthio)- methylceph- 3- em- 4- carboxylate

7-(D-α-Aminophenylacetamido)-3-(1-methyltetrazol-5-ylthio)-methylcef-3-em-4-carboxylic acid (1.72 , 0.003 m) was acylated with 1-chlorocarbonylimidazolidin-2-one, as indicated in example 60, so that

the free acid was obtained as a gummy solid. This was dissolved in 30 ml of acetone, dried over anhydrous magnesium sulphate and

treated with 2n. sodium 2-ethylhexoate in methyl isobutyl ketone. The precipitated sodium salt was collected, washed with anhydrous ether and

dried in vacuum. Yield 1.16 g, 65.0%; n.m.r. spectrum

[(CD3)2SO + D2O], 6 = 7.43 (5H, s, aromatic protons), 5.8 - 5.4

(2H, m, C7~and a-protons), 4.88 [1H, d, (J = 5 Hz), Cg-proton],

4.7 - 4.0 (2H, m, -CH2S-), 3.95 (3H, s, tetrazole~CH3), 4.0 - 3.0

(6H, m, C2~ and imidazolidinone methylene protons); u.v. spectrum (95% ethanol), ^max 271 nm (e = 8,600). Paper chromatography showed one zone, Rf = 0.24.

Example 6 3

Sodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 2- methyl-1, 3, 4- thiadiazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

D-α-(3-cinnamoyl-3-methylureido)benzylcephalosporin (1.18 g,

0.002 m) and 2-methyl-5-mercapto-1,3,4-thiadiazole (0.53 g, 0.004 m)

was dissolved in 25 ml d.m.f. and 25 ml of phosphate buffer solution of pH 6.5, adjusted to pH 6.5 with solid sodium bicarbonate and then heated at 60° for 10 hours. The cooled solution was washed with ethyl acetate (2 x 100 mL) and acidified to pH 1.5 with 1N hydrochloric acid in the presence of

50 ml ethyl acetate. The organic phase was separated from the aqueous phase

layer extracted with more ethyl acetate (50 mL), and then the combined ethyl acetate extracts were washed with water (2 x 100 mL) and

50 ml saturated salt water, dried over anhydrous magnesium sulfate,

treated with 2n sodium 2-ethylhexoate in 0.5 ml methyl isobutyl-

ketone and diluted with 200 ml of anhydrous ether. The precipitated sodium salt was washed with anhydrous ether and dried in vacuo. Yield 0.83 g,

60.5%. n.m.r. spectrum [(CD3)2SO + D2O], 6 = 8.0 - 7.0 (12H, m, aromatic and olefinic protons), 5.9 - 5.4 (2H, m, C^- and a- protons), 4.89 [1H, d, (J = 5Hz), Cg proton], 4.8 - 4.0 (2H, m, -CH2S-), 3.9 - 3.0 (2H, m , C2 methylene protons), 3.36 (3H, s, lTN-CH3), 2.70 (3H, s, thiadiazole -CH3), u.v. spectrum (95% ethanol), ^max 282 nm (e = 27,470) . Paper chromatography showed one zone, R^=0.66.

Example 64

Sodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 2- methyl-1, 3, 4- oxadiazol- 5- ylthio) methylceph- 3- em- 4- carboxylate

Prepared by the method described in Example 65

of D-α-(3-cinnamoyl-3-methylureido)-benzylcephalosporin and 2-methyl-5-mercapto-1,3,4-oxadiazole in 55.2% yield; n.m.r. spectrum

[(CD3)2SO + D20], 6= 8.0 - 7.0 (12H, m, aromatic and olefinic protons), 5.8 - 5.4 (2H, m, C?- and a-protons), 4.88 [1H, d, (J = 5 Hz),

Cg proton], 4.6 - 3.9 (2H, m, -CH2S-), 3.8 - 2.8 (2H, m, C2 methylene protons) 3.33 (3H, s, ^N-CH3 ) , 2.48 (3H, s, oxadiazole -CH 3 );

u.v.-spectrum (95% ethanol<l>), X ma, Ks<2>80 nm (e = 24,800). Paper-

w chromatography showed one zone, R f = 0.59.

Example 65

Sodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 1- methyl 1- 1H- tetrazol- 5- ylthio) methyl eph- 3- em- 4- carboxylate

Prepared by the method described in Example 63,

of D-α-(3-cinnamoyl-3-methylureido)benzylcephalosporin and 5-mercapto-1-methyl-1H-tetrazole in 56.7% yield; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 8.0 - 7.0 (12H, m, aromatic protons), 5.8 - 5.5 (2H, m, C^ and α protons) , 4.92 [1H, d, (J = 5Hz), Cb, proton], 4.7 - 4.0 (2H, m,

-CH2S-), 3.97 (3H, s, tetrazole -CHg), 3.8 - 3.0 (2H, m, C^methylene protons), 3.34 (3H, s,^N-CH3); u. v. spectrum (95% ethanol), ^max 284 nm ^e = 25.075). Paper chromatography showed one zone, R^ = 0.53. Example 66 Sodium 7-[D-g-(3-cinnamoyl-3-methylureido)phenylacetamido]-3-(benz-oxazol-2-ylthio)methylceph-3-em-4-carboxylate D-g<->(3- cinnamoyl-3-methylureido)benzylcephalosporin and (1.18 g, 0.002 m), 2-mercaptobenzoxazole (0.60 g, 0.002 m) in 20 ml formamide and 25 ml water was adjusted to pH 7.0 with solid sodium bicarbonate and then heated at 60° for 10 hours. The cooled solution was washed with ethyl acetate (2 x 100 ml), filtered, covered with 100 ml ethyl acetate and acidified to pH 1.5 with 1N hydrochloric acid. The ethyl acetate was separated from, the aqueous layer extracted with 100 ml of ethyl acetate and the organic extracts combined, washed with water (2 x 100 ml) and 50 ml of brine, after which it was dried over anhydrous magnesium sulfate,

treated with 2N sodium 2-ethylhexoate in 0.7 ml of methyl isobutyl ketone and diluted with 200 ml of ether. The precipitated sodium salt was collected, washed with ether, dried in vacuo, dissolved in 50 ml of water, acidified to pH 1.5 with 1N hydrochloric acid and the precipitated free acid collected. This was dissolved in 25 ml of ethyl acetate, filtered, diluted with 25 ml of ether, filtered and then evaporated to dryness in vacuo and the evaporation residue triturated with ether to give 0.21 g of an off-white solid which was dissolved in 3 ml of acetone , treated with 2N sodium 2-ethylhexoate in methyl isobutyl ketone (0.31 mL) and diluted with 25 mL of ether to precipitate the sodium salt. The sodium salt was collected and

dried in vacuo, 0.16 g, 12% yield; n.m.r. [(CD3)2S0 + D20],

6 = 8.0 - 6.9 (16H, m, aromatic and olefinic protons), 5.8 - 5.5 (2H, m, C7~and a-protons), 5.0 - 4.8 (1H, m, Cg proton), 4.8 - 4.0 (2H, m, -CH2S-), 3.8 - 3.0 (2H, m, C2 methylene protons), 3.34

(3H, m, I>N-CH3_), u.v.-spectrum (95% ethanol), \ma, ks 290 nm (e = 33.050). w Paper chromatography showed a zone at R^ = 0.80.

Example 67

Disodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3-( 4- sulfophenylthio) methyl cef- 3- em- 4- carboxylate

D-α-(3-cinnamoyl-3-methylureido)benzylcephalosporin (1.18 g, 0.002 m) and 4-mercaptobenzenesulfonic acid (0.42 g, 0.002 m) in 10 ml water and 15 ml d.m.f. was adjusted to pH 6.5 with solid sodium bicarbonate and heated at 60° for 8 hours. The solution was evaporated to dryness in vacuo at room temperature and the residue dissolved in 100 ml of water, acidified to pH 1.5 with "Amberlite" resin 1R-120(H), washed with

ethyl acetate (2 x 50 ml) and extracted with n-butanol (2 x 50 ml). The butanol was removed in vacuo leaving a solid which was triturated with ether and collected, 0.83 g; n.m.r. spectrum [(CD^^SO + D2O], 6 = 8.0 - 7.0 (16H, m, aromatic and olefinic protons),

5.9 - 5.5 (2H, m, C_, and a protons), 5.2 - 4.9 (1H, m, Cg protons), 4.8 - 4.0 (2H, m, -CH2S-), 3.9 - 3.0(2H, m, C2~methylene protons),

3.33 (3H, m, N-CH 3 ). The solid was dissolved in water, adjusted v to pH 6.5 with ln sodium hydroxide solution, washed with n-butanol and freeze-dried to give the disodium salt, 0.66 g, 41.8% yield;

u.v.-spectrum (H 2 O), ^max 275 nm (e = 8,040). Paper chromatography showed a zone at R^= 0.35.

Example 6 8

Disodium- 7-[ D- a-( 3- cinnamoyl- 3- methylureido) phenylacetamido]- 3- sulforenethyl- cef- 3- em- 4- carboxylate

Sodium D-α-(3-cinnamoyl-3-methylureido)benzylcephalosporin (0.5 g, 0.8 mmol) was dissolved in 8 mL of warm formamide. Sodium sulfite (0.15 g, 1.2 mmol) in 12 mL of water was added, and sufficient SO 2 gas was introduced to give a pH of 7.0. The mixture was heated at 60° for 5 hours. If necessary, the pH value was adjusted during this period by adding SO 2 or 5N sodium hydroxide solution. The mixture was diluted with water and ice (total 30 ml) and acidified to pH 1.5 with strong acid ion exchange resin "Amberlite" IR-120(H). The solution was filtered, extracted with ethyl acetate (2 x 50 mL) and then with n-butanol (2 x 30 mL). The butanol layers were combined,

washed with a little water, and then 30 ml of water was added and the pH adjusted to 7.0 by careful addition of ln sodium

hydroxide solution. The aqueous solution was evaporated as far as possible under reduced pressure, and the evaporation residue was distilled

under high vacuum at 40°. The remaining gum was triturated with

"5.0 ml of acetonitrile and the solid collected, dissolved in 10 ml of water and 20 ml of n-butanol. "IR-120 (H)" resin was added to pH 1.5, the butanol layer separated from, evaporated to near dryness, again evaporated with another 2 x 20 ml portions of n-butanol. The residue was distributed between 10 ml of water and 10 ml of n-butanol and 1.0 N sodium hydroxide solution added to pH 7.0. The aqueous layer was freeze-dried, to 0.20 g, n.m.r. spectrum (D2O) 6 = 7.2 - 7.6 (12H, m, aromatic and olefinic protons), 3.25 (3H, s,<I>^ N-CH^), u.v. spectrum (H_0), A 265 nm (e = 6,990). Paper chromatography showed one zone at R^ = 0.10.

Example 6 9

Sodium- D, L- g-( 3- cinnamoyl- 3- methylureido) thien- 2- ylmethylcephalosporin

D,L-α-(3-cinnamoyl-3-methylureido)thien-2-ylacetic acid (1.72 g, 0.005 m), N-methylmorpholine (1 drop) and triethylamine (0.71 mL, 0.005 m)

in anhydrous acetone (15 mL) was cooled to -10° and treated with ethyl chloroformate (0.48 mL, 0.005 m). The solution was stirred at between -5° and 10° for 20 minutes, and then a solution of 7-amino-v cephalosporanic acid (1.36 g, 0.005 m) and 0.71 ml of triethylamine in 30 ml of 50% aqueous acetone, cooled to 0°, added. The mixture was stirred at room temperature for 2 hours, the acetone removed in vacuo, 50 ml of water added and washed with ethyl acetate (2 x 50 ml). The aqueous solution was acidified to pH 1.5 with 1N hydrochloric acid in the presence of 50 ml of ethyl acetate and extracted with a further portion of ethyl acetate (50 ml). The extracts were washed with water (2 x 100 mL) and 50 mL brine then dried over anhydrous magnesium sulfate, treated with 2N sodium 2-ethylhexoate in methyl isobutyl ketone (1.8 mL) and diluted with 200 mL anhydrous ether. The precipitated sodium salt was collected, washed with ether and dried. Yield 1.12 g, 36.1%; n.m.r. spectrum [(CD3)2SO + D2O], 6 = 8.0 - 6.7 (10H, m, aromatic, olefinic and thienyl protons), 6.0 - 5.8 (1H, m, α-proton ), 5.7 - 5.3 (1H, m, C7~ proton), 5.2 - 4.5 (3H, m, Cg proton and -CH20C0-), 3.8 - 3.0 (2H, m, C2-methylene protons), 3.33 (3H, s,rN-CH3), 2.01 (3H, m, -OCOHCH3);

u. v. spectrum (95% ethanol), ^max. 286 nm (e = 21,650). Paper chromatography showed one zone, R^ = 0.53.

Example 70

Sodium- 7-[ D, L- a-( 3- cinnamoyl- 3- methylureido) thien- 2- ylacetamido]- 3-( 1- methyl- 1H- tetrazol- 5- ylthio) methyleph- 3- em- 4- carboxylate

Prepared from 7-amino-3-(1-methyl-1H-tetrazol-5-ylthio)-methylcef-3-em-4-carboxylic acid and D,L-a-(3-cinnamoyl-3-methylureido)-thien-2- ylacetic acid by the method described in example 69 in 34.0% yield, n.m. r.-spectrum [(CD3)2SO + D2O], 6 = 8.0 - 6.8 (10H, m, aromatic, olefinic and thienyl protons), 6.0 - 5.7 (1H, m, a- proton), 5.7 - 5.3 (1H, m, C_/ -proton), 5.1 - 4.8 (1H, m, Cb, -proton), 4.6 - 4.0 (2H, m , -CH2S-), 2.93 (3H, s, tetrazole -CH3), 3.8 - 3.1

(2H, m, C2 methylene protons), 3.34 (3H, s, Z^N-CH3); u.v. spectrum (95% ethanol), ^max 285 nm (e = 25,190). Paper chromatography showed one zone, = 0.52.

Example 71

Sodium D-α-(3-cinnamoyl-3-methylureido)benzylcephalosporin D-α-(3-cinnamoyl-3-methylureido)phenylacetic acid (1.69 g, 0.005 m) and 1-hydroxybenztriazole monohydrate (0.77 g, 0.005 m) in 10 ml t.h.f.

was cooled in an ice bath and then treated with dicyclohexyl

* carbodiimide (13 g, 0.005 m). The mixture was allowed to stand at 5° overnight, and then 4 drops of acetic acid were added, the mixture was

w stirred at room temperature for 15 minutes, after which the dicyclohexyl urea was filtered off and washed with 5 ml of tetrahydrofuran. The filtrate was added to 7-aminocephalosporanic acid (1.36 g, 0.005 m) in 30 ml of 50% aq. r.h. which had been adjusted to pH 6.5 with N-methylmorpholine. The solution was stirred at pH 6.5 - 7.0 for 3 hours, and then the t.h.f. removed in vacuo and the residue diluted with 50 ml of water. This aqueous solution was worked up so that the above-mentioned sodium salt was obtained. Yield 1.21 g, 39.4%; n.m.r. [(CD3)2SO + D20], 6 = 8.0 - 7.0 (12H, m, aromatic and olefinic protons), 5.8 - 5.5 (2H, m, C7~and a-protons), 5 .2 - 4.6 (3H, m, Cg proton and -CH20C0-), 3.8 - 2.9 (2H, m, C2 methylene protons), 3.33 (3H, s, ^TN-CH3) , 2.02 (3H, s, -OCOHCH3); u.v. spectrum (95% ethanol), ^max 286 nm

(e = 21,010). Paper chromatography showed one zone R^ = 0.54.

Claims (5)

1. Intermediate product which is applicable in the production of cephalosporins, characterized in that it is a compound of formula: or or a salt, an ester/silyl derivative thereof; where the dashed line represents a bond in the 2- or 3-position, n is zero or 1, and R 4 is a group of formula: 2. Intermediate as stated in claim 1, characterized in that n is 1 and that the dashed line represents a bond in the 3-position. 3. Intermediate as stated in claim 1 or 2, characterized in that R ^ is a group of formula: 4. Intermediate product for the use of cephalosporins, characterized by the formula: 5. Antibacterially active cephalosporin, prepared from an intermediate as set forth in any one of claims 1-4.