FI56535C - VID FRAMSTAELLNING AV 3-CEFALOSPORINANTIBIOTIKA SAOSOM MELLANPRODUKTER ANVAENDBARA 7-SKYDDAD-AMINO- 2-CEFALOSPORANSYRAESTRAR - Google Patents

Description

N ^ r ·! [B] (11) ANNOUNCEMENT rrr ^ r 1 J '' UTLÄGGN I NGSSKRIFT 3D3J3 5¾¾ C (45) P11 c r 11 i ~ y "n.- :: y 11 '2 1933

Patent pending (51) Kv.lk. '/ Int.CI. * C 07 D 501/60 SUOMI - FINLAND (21) p «enKihike", UI - Pttentansökning 326/69 (22) Hakemlspilvi— Ansöknlngsdag 0 * 4.02.69 (23) Initial Cloud— Giltlghetsdag 0it.02.69 (41) Become Public - Bllvit offentlig 08.08.69

Patent and Registration Office .... ... . . ., .., 1 (44) Date of Nihtivikslpanon and heard | -

Patent and Registration Office Ansökan utlagd och utl.skrlften publicerad 31.10.79 (32) (33) (31) Claim claimed privilege —Begird prloritet 07.02.68 13.01.69, I3.OI.69 USA (US) 703523, 7908) 42, 790886 (71) Eli Lilly and Company, 7 ^ 0 South Aiabama Street, Indianapolis,

Indiana, USA (US) (72) John Alan Webber, Indianapolis, Indiana, Earle Marvin Van Heyningen, Indianapolis, Indiana, USA (US) (7 * 4) Oy Kolster Ab 3 (5 * 0 Intermediates used in the manufacture of Zy-cephalosporin antibiotics 7 The present invention relates to intermediates for the preparation of Z-'-cephalosporin antibiotics in the preparation of 7-cephalosporin antibiotics for use in the preparation of Z-' cephalosporin antibiotics - protected amino-β-cephalosporanic acid esters. Zl-cephaloeporin ester of formula

^ S

0CHoCO-NH ”CH ~ 9H,? H

Ö2 1 I II

0 = c CH 2 -Y I

C00R11 wherein R is a hydrogen atom or a methyl, (C1-C6) -tertalkyl, nitrobenzyl or methoxybenzyl group and Y is a cyano group or a group of the formula -OR, 2,56535 in the group R2 is ( C 1 -C 4 alkyl, acetyl or propenyl group.

The semisynthetic preparation of 7-acylamidodesacetoxycephalosporin antibiotics using penicillin as a starting material has recently become important due to the process invented by Morin and Jackson (TJS Patent 3,275,636), which discloses a process for converting penicillin sulfoxide esters The general formula of cephalosporin compounds derived from penicillins by this method is: o 7 R-C-KN-CH-CH / γ 2 CHO 1 6 3} CO-N 2 4 JJ-CH, 8 ^ 5 L,

COOR

wherein R is a residue of an acylamido group in the 7-position and R 1 is hydrogen, a salt-forming cation, an ester group or an anion charge when C 10 - forms a salt with a cation either inside or outside the molecule.

In an attempt to improve and expand the properties and uses of these penicillin-derived semisynthetic cephalosporin agents, e.g. attempted to convert the 3-methyl group of the above zX-deacetoxy-cephalosporins to a group which confers enhanced antibiotic activity on one or more gram-positive or gram-negative microorganisms of the resulting cephalosporin compound. But at least to date, it has not been possible to convert Ziv-deacetoxy-cephalosporin directly to a reactive 3-methyl group-containing cephalosporin in any significant yields. Therefore, there is a need for a new alternative method in antibiotic chemistry for the preparation of substantially more potent Zv-cephalosporin antibiotics containing a reactive 3-methyl group, which have hitherto only been obtained by fermentation of cephalosporin C and the resulting 7-amino-cephalosporinic acid (7-ACA ).

The novel compounds of this invention are useful as intermediates in a chemical process that overcomes the difficulty of converting deacetoxycephalosporins to reactive 3-methyl group-containing β-alosporinic acid antibiotics.

The novel intermediates of the invention are prepared by reacting N-bromosuccinimide with a compound of the formula: 56535 3

OCHoCO-NH-CH-CH CH

I II I IX

'v 0 - = C-N_ C-CH, 11

\ ^ 5 Π CH

L JJ I,

COOR

wherein R is as defined above, in a substantially anhydrous organic solvent at a temperature of 40 to 100 ° C, and that the resulting reaction product is reacted with a nucleophilic substance which provides a negatively charged group or is a neutral molecule having a free electron pair and which participates to a nucleophilic substitution reaction with a 3-bromomethyl group of a reaction product, wherein the nucleophilic substance is (1) MCN, wherein M is an alkali metal, earth metal, copper or silver ion, (2) a compound of formula 0

II

Lipase was C-O-M

wherein M is as defined above, or (3) a compound of the formula R 12 -OH, wherein R 12 represents a (C 1 -C 4) alkyl or propenyl group.

The patent literature describing cephalosporin antibiotics has already provided a myriad of examples of nucleophilic substances that can be used to prepare cephalosporin antibiotics having a nucleophile in the methyl group in the 3-position. These substances can also be used in this method.

The -7-acylamido-3- (nucleophile-methyl) -cephalosporin ester products of this invention are useful as intermediates 3 in the preparation of new and known β-cephalosporin antibiotics that can be used to treat diseases caused by gram-positive and gram-negative microorganisms. These Z ^. The -7-acylamido-3- (nucleophile-methyl) -cephalosporin ester products can be partially 3 converted to the corresponding -7-acylamido-3-nucleophilemethyl sulfide esters by heating in a weakly basic medium, resulting in a 2 3 transfer of the -doubil bond to the zZ position to give an equilibrium mixture. and the Zs-7-allyl®ido-3- (nucleophile-methyl) -cephalosporin ester, which is readily converted to the active antibiotic by removing the ester group by known methods. However, it is preferred that the ester product of 7-acylamido-3- (nucleophile-methyl) -2-cephem-4-carboxylate-4,56535 be chemically converted to the corresponding A-ester by process. 2 which is not part of this invention. The method comprises (1) A - 3.

oxidation of the sulfide ester product to the corresponding A sulfoxide ester 3,. .

peracid, (2) A-sulfoxide ester with a reducing agent such as sodium bisulfite or sodium dithionite, activator. such as acetyl chloride, in the presence of an organic solvent such as acetic acid. .

in acid or dimethylformamide to form A sulfides, 3 ...

and (3) then, if desired, de-esterifying the A sulfide ester to the antibiotically active A sulfide acid. If desired, mixtures of the pharmaceutically acceptable salts of the antibiotic active cephalosporinic acid 3a in such a mixture may be used for some antibiotic purposes, e.g. as a topical antibiotic for open wounds in veterinary medicine, in which case the mixture may be dusted or

The A, -7- (protected amino) -3- (nucleophile methyl D-sulfide ester products of this invention are useful intermediates 3 ...

in the formation of A-cephalosome antibiotics having a desired 7-acylamido group known to confer antibiotic activity to cephalosporins. These products are treated (1) in such a way that:. . The 2 7-protecting group is removed to give the N-7-amino-3- (nucleophile methyl) sulfide ester, which can be (2) acylated if desired, e.g.

thiophene-2-acetic acid, acid chloride or mixed anhydride to give 2 the corresponding A -7- (thienylacetamido) -3- (nucleophile-methyl) - • · · «* · ·« .3 cephalosporic ester (3), which can be isomerized to the corresponding A To -7- (thienylacetamido) -3- (nucleophile-methyl) -cephalosporin ester by an oxidation-reduction method and (4) de-esterify, e.g., by treatment with trifluoroacetic acid alone or with zinc in formic acid or acetic acid to form the active cephalosporin antibiotic.

. · 7

Alternatively, the A-cephalosporin ester can first be converted 3. 3A ester and this ester to A -7-amino-3- (nucleophile-methyl) -cephalosporin ester, which in turn can be N-acylated and de-esterified to A-cephalosporins. An example of such a compound that can be prepared by such a method is cephalothin, a widely accepted, commercially available cephalosporin antibiotic currently available only by fermentation prepared from cephalosporin C and 7-ACA derived therefrom.

2,56535 The -deacetoxycephalosporin esters used as starting materials can be obtained from a variety of penicillin or cephalosporin substances by known methods. They are obtained by treating the corresponding 3-methyl-cephem-4-carboxylate ester with a base, as described, for example, in Example 4, U.S. Patent No. 3,275,626 to Morin and Jackson. They can also be obtained by hydrogenating a cephalosporin ester derived from cephalosporin C to form the corresponding Z 1 -deacetoxycephalosporin ester and then treating the 3 / x-deacetoxycephalosporin ester with a base such as pyridine in the cold at 3 ° C (0-10 ° C) to give two The allylic 3-methyl-2 group of the bromata-desacetoxycephalosporanate esters failed and our successful method for bromination of the -deacetoxy-cephalosporanate esters was amazing and unpredictable.

Substituent R is a residue of an ester-forming alcohol. The alcohol used to form these esters should be one which can be decomposed by known methods such as treatment with dilute aqueous base or using trifluoroacetic acid or hydrogenation in the presence of a palladium or rhodium catalyst on a suitable support such as carbon, barium sulphate or alumina without decomposition. The most preferred ester groups are those listed above.

Example 1 Preparation of 2H-acid 3 * 65 g (0.01 mol) of methyl 7- (phenoxyacetamido) -3-methyl-N-cephem-4-carboxylate (prepared from deacetoxycef V and diazomethane) 100 in 1: 1 pyridine: HgO was cooled in an ice-water bath. One equivalent of 1 NaOH solution was added and the mixture was stirred in the cold for 5 hours. After diluting with 100 mL of water and 100 mL of Sila ethyl acetate, the mixture was cooled and acidified to pH 2.5 with 20% HCl. The ethyl acetate was removed and the aqueous layer was extracted once with ethyl acetate. The combined organic layers were cooled, water was added and the pH was adjusted to 8.2 with solid NaHCO 3. The aqueous layer was removed, washed once with ethyl acetate, then cooled, covered with an ethyl acetate layer and acidified to pH 2.5. The ethyl acetate was removed and the aqueous layer was washed with ethyl acetate and the combined organic layers were washed twice with brine, dried over magnesium sulfate, filtered and evaporated to give a foam.

6 56535

The foam was dissolved and crystallized from ethyl acetate to give 1.6 g (45%) of 7- (phenoxyacetamido) -3-methyl-s-cephem-4-carboxylic acid, m.p. 180-183 ° (decomposes).

Esterification of 2-desacetoxycephalosporinic acid.

2β-Methoxybenzyl 3-methyl-7-phenoxyacetamido-p-cephem-4-carboxylate.

2

To a stirred suspension of 1.75 g (0.005 mol) of -deacetoxycefin V-phenoxyacetamido-3-methyl-Δ-cephem-4-carboxylic acid and 700 mg (0.005 mol) of p-methoxybenzyl alcohol in 20 ml. methylene chloride, a solution of condensing agent, 1.23 g (5% excess) of IME * dineopentyl acetal in methylene chloride was added. Dissolution was complete within minutes. The reaction mixture was stirred overnight at room temperature. The solvent was removed and benzene was added. After heating to effect dissolution, the mixture was allowed to stand at room temperature.

After the crystalline by-product of the reaction was removed, the benzene broths were diluted, washed three times with bicarbonate solution, twice with brine, dried over magnesium sulfate, filtered and evaporated. The residue was crystallized from CCl 4 to give p-methoxybenzyl 2- [7-phenoxyacetamido-3-methyl-N-cephem-4-carboxylate. First yield 1.15 g »m.p. 108-112 °, second yield 0.16 g, m.p. 107-111 °, 55% yield.

Coupling of a reactive group to p-methoxybenzyl 3-methyl-7- 2 phenoxyacetamido-Δ-cephem-4-carboxylate.

A mixture of 235 mg of p-methoxybenzyl 3-methyl-7-phenoxy-2,3-acetamido-Δ and Δ-cephem-4-carboxylate, 90 mg of N-bromosuccinimide (NBS), 14 mg of azo-bis-isobutyronitrile and 30 mg of ml of CCl 4, refluxed under a condenser atmosphere protected from light for 14 hours. The reaction mixture was cooled, filtered and the golden yellow filtrate evaporated to dryness. To the residue were added 25 mg of potassium acetate and 15 ml of acetone, and this mixture was refluxed for six hours under Ngs, protected from light, and then stirred at room temperature overnight. The dark red-brown solution was evaporated to dryness, the residue taken up in chloroform, filtered and evaporated to give 250 mg of a red-brown oil.

The oil was purified twice by preparative thin layer chromatography to give 103 mg of a mixture of Δ-β-methoxybenzyl esters of kef V.

56535 7 2 3

When Δ. The β-ester mixture was quenched with trifluoroacetic acid in benzene to give a substance containing kef V acid, a known antibiotic; the substance was identified by thin layer chromatography and paper chromatogram b i o aut ogramma1a.

Example 2 2 3

Preparation of methyl 3-acetoxymethyl-7-phenoxyacetamido-N-ε-cephem-4-carboxylate mixture.

To a 50 mL round bottom flask was placed mg (0.25 moles) of crystalline 2-methyl-3-methyl-7-phenoxyacetamido-cephem-4-carboxylate, 45 mg (0.25 moles) of N-bromosuccinimide, 7 mg of azo-bis isobutyronitrile and 15 mL of CCl 4 to form methyl 3-bromomethyl-7-phenoxyacetamido-2-cephem-4-carboxylate. The mixture, protected from light, was refluxed under nitrogen for 14 hours, cooled, filtered and evaporated to dryness. To the residue were added 25 mg (0.25 mol) of potassium acetate and 15 ml of acetone. The light-protected mixture was refluxed under nitrogen for six hours and stirred at room temperature overnight. After the solution was evaporated to dryness, the residue was taken up in chloroform and filtered. Evaporation of the solvent gave 130 mg of a golden oil.

When the oil was separated into its components by preparative thin layer chromatography, 11 mg of starting material and 70 mg (65% yield) of methyl 3-acetoxymethyl-7-phenoxyacetamido-N-cephem-4-carboxylate and methyl 3-acetoxymethyl-7-phenoxy were recovered. -acetamido-A-cephem-2 3 4-carboxylate (structure confirmed by NMR; 3: 1 ratio).

Example 3

To one arrow equivalent of 4-acetocelbenzyl 7- (phenoxyacetamido) -2-bromomethyl A.-cephem-4-carboxylate dissolved in absolute methanol was added 2 molar equivalents of anhydrous scavenged potassium carbonate. The mixture was stirred at room temperature for 24 hours to ensure a complete reaction, filtered and the filtrate evaporated to dryness. The residue containing the 4-methoxybenzyl 7- (phenoxyethamido) -3-2-methoxymethyl- <4 ± k.-cephem-4-carboxylate product was dissolved in benzene. Example 4

Eateröiminen.

O

To a stirred suspension of 6.98 g (0.002 moles) of β-deacetoxy-ceph-T-acid (3-methyl-7- (phenoxyacetamido) -2H-cephem-4-carboxylic acid) and 2.6 g (0.002 moles) of ) 4-methoxybenzyl alcohol in 100 ml of β 55535 methylene chloride, a solution of 4.62 g of dimethylformamidine dinopentyl acetal in 25 ml of methylene chloride was added. Dissolution was complete within minutes. The reaction mixture was stirred for 48 hours at room temperature to ensure complete reaction. The solvent was removed and benzene was added. The resulting solution was washed three times with aqueous sodium bicarbonate solution, twice with aqueous sodium chloride solution, dried over magnesium sulfate, filtered and evaporated. The residue was crystallized from carbon tetrachloride to give 6.74 g (92% yield based on the γ-acid not recovered) of 4-methoxy-2-benzyl-3-methyl-7-phenoxyacetamido) -4'-cephem-4-carboxylate ester. mp. 108-112 ° C.

The aqueous sodium bicarbonate solutions used were covered with an ethyl acetate layer, cooled and the pH was adjusted to 2.5. The organic layer gave 1.56 g of colorless, crystalline 3-methyl-7-phenoxy-2-acetamidocephem-4-carboxylic acid, which could be reused in the esterification process.

Reactivation of the 3-methyl group.

A 1.17 g portion of 4-methoxybenzyl 3-methyl-7-phenoxyacetamido-2-cephem-4-carboxylate ester was treated with N-bromosuccinimide in carbon tetrachloride in the presence of azo-bis-isobutyronitrile to give 2 to form 4-methoxybenzyl-3-bromomethyl. -phenoxyacetamido-4-k-2-fem-4-carboxylate ester. This β-allyl bromide ester was dissolved in 100 mL of absolute methanol containing 2 molar equivalents of Η, Ν-diethylaniline to absorb the hydrogen bromine by-product. This mixture was stirred at room temperature for 24 hours to ensure complete reaction and then evaporated to dryness, taken up in benzene, extracted twice with cold 5% hydrochloric acid solution, sodium bicarbonate solution, sodium chloride solution, dried over magnesium sulphate, filtered and evaporated to give 970 mg of oil. This brown oil was chromatographed on a silica gel column containing 15% water using a mixture of benzene and ethyl acetate as extractant. A benzene solution containing about 4% ethyl acetate extracted about 15% unreacted deacetoxy starting material. A benzene solution containing about 8% ethyl acetate extracted 4-methoxybenzyl 3-methoxymethyl-7-phenoxyacetamido-4-cephem-4-carboxylate ester; mp. 116-118 ° methanol; 40% yield. The structure was confirmed by nuclear-magnetic resonance spectrum and elemental analysis.

9 56535

Example 5 2 p-Methoxybenzyl 3-cyanomethyl-7-anoxazestamido-p-cephem-4-carboxylate.

A portion of crude p-methoxybenzyl 3-bromoethyl 7-phenoxyacetamido-2H-cephem-4-carboxylate was obtained from 585 mg of the corresponding p-methoxy-2-benzyl-3-methyl-7-phenoxyacetamido. cephalosporanate ester, was dissolved in 10 ml of dry dimethyl sulfoxide and added to a suspension of 55 mg of cuprocyanide (0.5 molar equivalents based on the starting material) in 5 ml of dimethyl sulfoxide. The mixture was stirred for 6 hours at room temperature. Benzene was then added and the resulting mixture was extracted as follows: 3 times with aqueous sodium chloride solution, 2 times with cold 5% hydrochloric acid solution, 2 times with aqueous sodium bicarbonate solution, 2 times with aqueous sodium chloride solution. The residue was dried over anhydrous magnesium sulfate, filtered and evaporated to give 392 mg of crude product.

This crude product was applied to a silica gel (+ 15% fi ^ O ^ a) column. The starting p-methoxybenzyl-3-methyl-7-phenoxy-2-acetamido-γ-cephem-4-carboxylate ester was extracted with benzene containing 2% ethyl acetate and benzene containing 4% ethyl acetate. Mixtures containing benzene and 4% ethyl acetate and benzene and 8% ethyl acetate extracted the desired p-methoxybenzyl 3-cyanomethyl-7-phenoxyacetamido-2H-cephem-A-carboxylate, which was crystallized from ethyl ether, m.p. 119-120 ° C. The structure of this desired product was confirmed by NMR spectrum, mass spectrometry and elemental analysis.

Example 6 Preparation of 2-t-butyl 7-phenoxyacetamido-3-bromomethyl-cephem-4-carboxylate.

A solution of 8.08 g (20 moles) of 4-t-butyl 7- (phenoxy-2-acetamido) -3-methyl-4-cephem carboxylate, 5 * g of N-bromosuccinimide and 50 mg of azo-bis -isobutyronitrile in 800 ml of carbon tetrachloride, was refluxed under a nitrogen atmosphere until the starch-iodide test was negative (5 hours). The reaction mixture was cooled, the succinimide was removed by filtration, and the solvent was removed under reduced pressure to give 11.8 g of a crude product. The HMR spectrum showed only 2 tert-butyl 7-phenoxyacetamido-3-bromomethyl-4-cephem-4-carboxylate with a slight succinimide as an impurity (90% yield).

56535 10

Example 7 2

Tert-butyl 7-phenoxyacetamido-3-isopropoxymethyl cephem-4-carboxylate.

A solution of 3 to 51 g of 4-tert-butyl 7- (phenoxyacetamido) -2,3-bromoethyl cephem-4-carboxylate prepared as in Example 6 in 100 ml of isopropanol was heated on a steam bath to about 70 ° To C for 20 minutes. Excess isopropanol was removed under reduced pressure. The residue was dissolved in benzene, washed with 3% aqueous sodium bicarbonate, then water, dried over sodium sulfate and evaporated to dryness to give 2.32 g of crude tert-2-butyl-7-phenoxyacetamido-5-isopropoxymethyl-x'-cephem-4-carboxylate. . Spectral analysis confirmed the structure.

Example 8 2

Tert-Butyl 7-phenoxyacetamido-3-tert.butoksimetyyli- ^ Ak-cephem-4-carboxylate.

A solution of 1.00 g of tert-butyl 7-phenoxyacetamido-3-bromomethyl cephem-4-carboxylate in 30 ml of tert-butyl alcohol was stirred at reflux (about 83 ° C) for 90 minutes. The alcohol solvent was then removed under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was heated, treated with decolorizing carbon, filtered and evaporated to dryness to give 1.36 g of crude tert-butyl 7-phenocelacetamido-3-tert-butoxymethyl-2H-cephem-4-carboxylate product. The crude product was chromatographed on 73 g of silica gel (+ 13% water) to give 0.363 g of 2 tert. butyl 7-phenoxyacetamido-3-tert-butoxymethyl-cephem-4-carboxylate product in an extract extracted with benzene containing 10% ethyl acetate. The structure of the product was confirmed by spectra.

Example 9

Following the procedures described above, the following 3-oxymethyl-β-cephem-4-carboxylate esters were prepared by dissolving tert-butyl 2,7-phenoxyacetamido-3-bromomethyl-β-cephem-4-carboxylate in an excess of the indicated alcohol and heating the mixture; tert-butyl 7-phenoxyacet-2-amido-3-n-butoxymethyl-4-cephem-4-carboxylate from n-butanol; tert-butyl 7-phenoxyacetamido-3- (2'-allyloxy) methyl-N-cephem-4-carboxylate allyl alcohol.

The following table shows the HMB values for the 3 'group of some of the novel compounds of this invention. Values are reported in parts per 11,56535 million units (delta ppm.) Relative to tetramethylsilane in deuterium chloroform solvent. The values are given as follows: (a) = chemical change in ppm. () (b) - description of peaks in the spectrum s - Singlet ti d - doublet t »triplet m« multiplet q - quartet (c) = number of protons

The first group of compounds were 2-tert-butyl-7-phenoxyacetamido-3-ocemethyl ether-A.-cephem-4-carboxylate esters of the following formula: g OCHoCONH-CH-

0 * »f M

0-C-N C-CH «OR

\ / N ch / COg-t-butyl where R varies as follows:

Compound (R) 3-methylene attached to 3-methylene -CH 3 4.0 (d) 3.29 (s) (3) -CH 2 CH 3 3.92 (s) 3.30 (q) (2), 1.2 ( t) (3) -CH <CH 3 4.05 (s) 3.60 (m) (1), 1.18 (d) (6) CH, CH 7 -C-ch 3 3.95 (s) 1 , 20 (s) (9) ch3 -CH2CH-CH2 4.0 (m) 4.0 (m) (2) * 5.0-5.5 (m) (3)

Compounds of the following formula were also prepared:

0CIiyC $ TH

ό Υχ '\ ® CO2-t-butyl 12 56635 where X is as defined below · The compounds were analyzed by NMH spectral methods.

Thdiste 5-methylene -Br 4.20 (q) -CN 2.01 (s)

Example 10 2 4-Nitrobenzyl 7- (phenoxyacetamido) -3- (cyanomethyl) -4-cephem-4-carboxylate.

2

The crude nitrobenzyl 3-bromomethyl-7-phenoxyacetamido-cephem carboxylate obtained from 4835 mg of the corresponding nitrobenzyl 3-2-methyl-7-phenoxyacetamido-cephalosporanate ester was dissolved in 30 ml of dry dimethylformamide and 130 ml of dry dimethyl sulfoxide and cooled in an ice bath. 896 mg of cuprocyanide was added thereto, and the mixture was stirred for 2 hours under cooling and for 2 hours at room temperature. The reaction mixture was re-cooled in an ice bath and a solution of 4 S FeCl 3 · 6H 2 O in 30 mL of 5 - HCl was added and the resulting mixture was stirred for 45 minutes. The reaction mixture was poured into 400 ml of ethyl acetate and extracted with aqueous sodium chloride solution and hydrochloric acid solution, and dried over magnesium sulfate and filtered to give 4600 mg of a crude product. The structure of the desired title compound (mp 164.5-167 ° C) was confirmed by NMR.

Claims (1)

56535 Claim: A 7-protected-amino-cephalosporanic acid ether of the formula (S) -DCH 2 CO-SH-CE-OH OH X-o-oh 2 -t (I) - OOOE 1 which is used as an intermediate in the preparation of Z 1 -cephalosporin antibiotics is a hydrogen atom or a methyl, (C 1 -C 6) tert-alkyl, nitrobenzyl or methoxybenzyl group and I is a cyano group or a group of the formula -OR 1g, wherein R 12 is a (C 1 -C 4 alkyl, acetyl or propenyl group and its salts.