Method of preparation of ethers of cephalosporine.

The present invention relates to a novel process for the preparation of ethers of cephalosporin, mistletoe comprises reacting an acid ester 7 a-acylamido and - or 7-amino 3" hydroxy ~céphem 3 and 4 with a~carboxy1ic diazoaicane. Removing the ester group provides an acid 3 alkoxy-3 a-cephem. The acids 3 a-alcoxy~3-to-cephem antibiotic compounds are of interest.

The invention relates to the cephalosporin antibiotics category. In particular, it relates to the ethers of cephalosporin represented by the following general formula

wherein R is a hydrogen atom or an acyl group derived from a carboxylic acid, the R -, is methyl, ethyl, 3 methyl-2 a-butênyle or diphenylmethyl, and is a hydrogen atom or a group forming an ester.

Many antibiotics of the cephalosporin class have already been described, these antibiotics although all having the same core cyclic structure comprising the ring P-lactam to 4 membered ring fused to a 6 membered dihydrothiazine to, differ from each other structurally and biologically in a number of ways. Structurally, known cephalosporin antibiotics differ by the nature of the substituent 7 a-acylamido and also by the nature of the substituent at position 3 of the dihydrothiazine ring. Cephalosporinic acids, e.g. cephalothin, acetoxymethyl group are characterized by a 3 position. Desacetoxycephalosporanic acids, such as cephalexin, have a methyl substituent at position 3. Many cephalosporins having in position 3 a methyl group substituted have also been described. The hydroxymethyl substituent désacétylcéphalosporines have a at position 3 and the 3 a-alkylthiométhylcéphalosporines centeredly ™ equal have been described. Recently, we have described some 3 a-mêthoxvméthyIcéphalosporine sec.

Some acids 7 to-acylamido and and 3 a-cêphem-to-4-carboxylic acids whose position 3 of the core dihydrothiazine door only hydrogen have also been described.

The present invention provides a process for preparing cephalosporin antibiotic compounds having the above formula wherein an ether group is directly attached to the position 3 of the dihydrothiazine ring.

As described in Patent no. 55,066 deposited at the oo.a.m.p.i. I^I laddie during daylight a request, are reacted acid esters 7 a-acylamido and - or 7-amino 3-methylene-cépham-to-4-carboxylic acids with ozone to form an ozonide intermediate on the part 3 a-exomethylene. The decomposition of 1 * ozonide provides esters of acids 7 to-acylamido and - or 7-amino 3-hydroxy 3 a-cephem-to-4-carboxylic acids.

According to the method of the invention, is then reacted ester 3-hydroxy 3 a-cephem with a suitable compound, for example the diazomethane or diazoéthane to obtain acid ester 3-methoxy - or 3 ethoxy 3 a-cephem-to-4-carboxylic, or more generally an ester of the core alcoxyléalcoxylé, it is to say acid ester 7-amino 3 alkoxy-3 a-cephem-to-4-carboxylic acid. Acylating the compound by procedures known by the desired carboxylic acid derivative to obtain in this case acid ester 7 a-acylamido and above 3 alkoxy-3 a-cephem-to-4-carboxylic acid. The willed the Appointments of the R ester group₂ protective of the carboxylic acid group provides the antibiotic compound wherein R is an acyl group and R₂ is hydrogen.

The ethers of cephalosporin provided by this invention arepolysiloxane antibiotic substances useful that can be used to combat infections caused by microorganisms including gram positive and gram-negative.

The cephalosporin derivatives of this invention are represented by the following formula I

wherein R is a hydrogen atom or an acyl group of formula

G

THE II

THE R ' A-C -

wherein R ' is A)

b.)

c.)

d.)

an alkyl group in c - ^ - Calcényle in cyanomethyl, halomethyl, 4-amino 4 a-carboxybutyl, 4 - alkylamino - 4 a-carboxybutyl; or

the group R "wherein R" is a group 1.4-to-cyclohexyldiényle, phenyl, or phenyl substituted with a halogen atom or a hydroxyl group, a nitro, amino, cyano group, lower alkyl in c ^ ^ - C., AI coxy lower in c - ^ - ^ C.,, hydroxymathyle, aminomethyl, protected aminomethyl, carboxyl or carboxymethyl; or

an aralkyl group of formula

where R " is as defined above,

Y is 0 or s,

m is O or to 1? or

an aralkyl group substituted of formula

H

THE R "' - - C.

I

Z

where R "' is R" as defined above or a group 2-thienyl or 3-thienyl, Z is a hydroxyl group or hydroxyl protected? or

e) a group of the formula R "" heteroarylmethyl - HC₂ -

wherein R "" is a group 2-thienyl, 3-thienyl, 2 a-furyl, 3 a-furyl, 2 a-thiazyl, 2 a-oxazyle, 5 a-tétrazyle or 1 a-tétrazyle?

^ and wherein R is methyl, ethyl, 3 methyl-2-butenyl or diphenylmethyl? and

The R ^ is a hydrogen atom or a group forming a protective ester of the carboxylic acid group.

The terms used in the previous resolution of the compounds of the invention have the following meanings when used herein. The term " alkyl group in c ^ - ^ C.'¹ denotes the aliphatic hydrocarbon chains such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-hexyl or n-heptyl. The term " alkenyl group in c ^ - Cy of unsaturated hydrocarbon chains refers to the moieties as propenyl (allyl), butenyl, pentenyl, hexenyl or heptenyl.

The expression "halomethyl" denotes chloromethyl or bromomethyl groups.

When in the definition above the R "represents a group substituted phênyle, the R" may be a grouping of mono - or dihalo as a group 4-chlorophenyl, 2.6 to-dichlorophenyl, 2.4 to-dichlorophenyl, 3.4 to-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3.4 to-dibromophenyl, 4-fluorophenyl or 2 a-fluorophény1e; single - dihydroxyphenyl or an array as an array 4-hydroxyphenyl, 3 a-hydroxyphéryle or 2.4 a-dihydroxyphenyl, * an array as an array mononitrophenyl 3 - or 4-nitrophenyl; an array as an array monoaminophényle 4-aminophenyl, 3-aminophenyl or 2-aminophenyl; cyanophenyl group, ordering 4-cyanophenyl; an array of mono or di - (lower alkyl) - phenyl group as 4 a-methylphényle, 2.4-dimethylphenyl, 2-methylphenyl, 4 a-isopropylphenyl, 4 a-éthylphênyle or 3 n-propylphenol ^ ^ EY as a MC; a mono - or di - oupement (lower alkoxy) phenyl, by/2.6 dimethoxyphenyl group, 4-methoxyphenyl, 3-Ethoxyphenyl, 4 a-isopropoxyphényle, 4 T-butoxyphenyl, 3 ethoxy 4-methoxyphenyl; an aminomethylphenyl group as the group or 3 - 4 a-aminomethylphenyl; a carboxyphenyl group as a group 3 - or 4 a-carboxyphênyle; or R " represents a group - 3 carboxyméthylphényle as an array or 4 a-carboxymêthylphényle. The R " also represents disubstituted phenyl moieties where the substituents may be different, for example the groups 3 to-méthy1-a 4 a-hydroxyphény1e, 3-chloro 4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4 ethyl 2-hydroxyphenyl, 3-hydroxy 4-nitrophenyl or 2 hydroxy-4-carboxyphenyl.

The term "protected amino group" as used in

the definition above refers to an amino group substituted by one of the amine-blocking is widely used as the t-butyloxycarbonyl (T-BOC-), the benzyloxycarbonyl group, the p-méthoxybenzyloxycarbone, the group P-nitrobenxyloxycarbonyl, the 2, 2, 2 a-trichloroéthvloxycarbonyle moiety, the moiety L carboméfchoxy-to-2-propenyl formed with 1' methyl acetoacetate, or trimethylsilyl group. When in formula I wherein R ' is the group 4-amino 4 a-carboxybutyl, then pine previous amine protective groups, chloroacetyl groups can be used, propionyl and 2.4 a-halogenation to better protect the amine moiety.

The term "protected hydroxy group" refers to the groups that can be removed easily and which are formed with a hydroxyl group, as the grouping a formyloxy, chloroacétoxy grouping, the grouping benzhydryloxy, trityloxy group, the p-nitrobenzyloxy or trimethylsilyl group.

0

the n

Examples acyl groups R ' a-c - as defined above, examples include the groups acetyl, propionyl, butyryl, hexanoyl, heptanoyl, 2 a-pentênoyle, acryloyl, 5 a-aminoadipoyle, chloroacetyl or bromoacetyl.

0

THE II

As exemplesdes acyl moieties of R " - - C., examples include benzoyl group the elements in turn, 2.6 to-dimethylbenzoyl, 4 a-chlorobenzoy1e, 4-methyl benzoyl, 3.4 and dichlorobensoyle, 4-cyanobenzoyl, 3 a-Bromobenzoyl, 3 a-aminobenzqyle or 4-nitrobenzoyl.

0

THE II

As exemplesdes acyl moieties of R 'a-c -, when R' is a group of the formula R " - (it)_{the m} HM~₂ - and m is equal to O, examples include groups substituted cyclohexa-to-1.4-diene L-acetyl, phenylacetyl, 4 a-chlorophênylacétyle, 3 a-hydroxypîiênylacétyle, 4 a-carboxyphénylacétyle, 3 a-cyanophénylacétyle, 4 a-aminophénylacétyle, e-hydroxy Sméthylphénylacétyle, 4 a-bromophérrylacétyle, 4 a-éthoxyphénylacétyle, 4-nitrophenylacetyl, or 3.4 to-diméthoxyphénylacétyle; and when helix xu equals 1 and Y is 0, acyl groups representative are the groups phenoxyacetyl, 3 a-hydroxyphénoxyacétyle, 4 a-chlorophénoxyacétyle, 3.4 and dichlorophénoxyacétyle, 2 a-chlorophénoxyacétyle, 4 a-méthoxyphénoxyacétyle, 3 a-aminophénoxyacétyle, 4 a-carboxyméthylphénoxyaeetyle, 4~aminoéthylphénoxyacétyle, 2 a-éthoxyphénoxyacêty1e, 3, 4 a-diméthylphénoxyacétyle, 4 a-isopropylphénoxyacéty1e, 3 a-cyanophénoxyacéty1e, or 3 a-nitrophénoxyacétyle and when m is 1 and Y is O, the groups are the groups thiophénoxyacétylethiophénoxyacétyle representative, 2.6 and dichlorothiophénoxyacétyle, 4 a-chlorophyll gold othiophénoxy CEA Vty I 1, 4 a-cyancbhiophénoxyacétyle, 3 a-bromothiophénoxyacétyle or 3 a-aminothiophénoxyacétyle.

Coniine examples acyl groups when R ' is a group of the formula substituted arylalfcyle

H

R¹ *' - - C.

Z

examples include the arylalkyl groups as mandeloyl bydroxylés the moiety of the formula

V VBE1^NR CH C.' O.

THE OH - /

and the moieties substituted mandeloyl, for example the groups 4 to-méthoxymandé1oy1e, 4 a-hydroxymandé1oy1e, 3.4 and dichloromandëloyle, 3 a-cyanomandéloyle, 3 Br omomandé1oy1e, 3 a-hydroxymandé1 diu I 1, 4 a-aminomandéloyle, 3 a-nitromandéloyle, 4 a-fluoromandéloyle, 4 a-carboxymandéloyle, 4 a-carboxyméthylmandéloyle or 4 a-aminoraéthylmandéloyle? or groups as

or

0

the II

- cHR-C.

0

■

As examples of the acyl group of R 'a-c - when R' is a group of the formula R heteroarylmethyl^,,, - HC₂ "/ 2 a-thiénylacétyle coresheath groups, 3 a-thiénylacétyle, 2 a-furylacétyle, a group of formula 2 a-oxazylacétyle

a group of formula 2 a-thiazylacétyle

Ch-O₂ - - c.

or a group of formula 1 a-tétrazylacétyle

The ethers may be prepared previously defined cephalosporin by various synthetic routes. The starting material in each case is an acid ester 3-hydroxy 3 a-cephem-to-4-carboxylic acid. Starting materials are prepared as described in Patent no. 55,066 oo.a.m.p.i filed.

the same day as the present application, by reacting an acid with a 7 a-acylamidocephalosporanic nuclêophile containing sulfur according to procedures known to effect displacement of the acetoxy group nuclêophile cephalosporanic acid into acid and 7 a-acylamido and and 3 a-thiomethyl-a 3 a-céphem~4-carboxylic acid. The cephem product substituted in position 3 by thio group is then reduced with hydrogen in the presence of Raney nickel or by the system formate in the presence of zinc/dimethylformamide to give 3 a-exométhylènecépham.

The core can be prepared by reacting 3 a-exométhylènecépham acid ester 7 a-acylamido and and 3 a-exométhylènecépham-to-4-carboxylic acid with phosphorus pentachloride (NCV, -) in the presence of pyridine to obtain 1' iminochlorure intermediate.

Is reacted 1 'iminochlorure cold with methanol to obtain 1 'imino-ether. The imino-ether easily undergoes hydrolysis by giving the acid ester 7-amino 3 a-exométhylènecépham-to-4-carboxylic acid. The ester group is then removed to obtain the core 3 a-exométhylènecépham.

Then reacted acid ester 7 a-acylamido and and 3 a-exométhylènecépham-to-4-carboxylic or ester of the core 3 a-exométhylènecépham with ozone to form an intermediate which osonide by decomposition provides the acid ester 3-hydroxy 3 a-cephem-to-4-carboxylic corresponding_/ as shown by the following general reaction scheme.

H

Acyl.

COOH,

0

A COCR,

(1)

According to the method of the present invention, the ester is reacted 7 a-acylamido and above 3-hydroxy 3 a-cephem (1) or the ester of the core (2) 3-hydroxy compound with diazomethane, the diazoéthane, the diphényldiazométhane, or L-diazo 3-methyl 2-butene to obtain the corresponding ether as shown with diazomethane in the following reaction scheme.

(1) HC=NR ' C-HR

- -■)

THE OH_Q.

■' REDUNDANTABLE

0 CH₃ THE N +₂

COOH,

(3)

(2) HC₂ =D₂H₂ NR

"" }

X^SX

NR

osh₃ the n +₂ (4)^C00R 2

Or, it can be acylated ester of the core (2) 3-hydroxylated to obtain the acid ester 7 a-acylamido and above 3-hydroxy 3 a-cephem-to-4-carboxylic (1) which by reaction with the compounddiazoîque desired provides the compound (3).

Any other route for the synthesis of the present invention, can be acylating the ester of the core (4) 3-alkoxylated to obtain an ether

(3) cephalosporin.

Are prepared antibiotic compounds of this invention, the acids 3-methoxy, ethoxy, diphénylmëthyloxy and 3-methyl 2-butenyl L-oxy 3 a-willwill céphera-to-4-carboxylic acids, (formula I,

O

The R=' R-a-c -, the R ^=hr) by reacting an intermediate which is an ester of 3-hydroxy 3 a-cephem diazoîque corresponding with the compound. Then removed the R group₂ forming ester to provide antibiotic compound represented by formula I in O

THE II

which R is an acyl group, wherein R ' a-c -, and R₂ is hydrogen.

The compounds diazoîques used in the present reaction are diazomethane, the diazoéthane, the diphényldiazométhane and L-diazo 3-methyl 2-butene. diazoîques compounds are prepared by known procedures and are easily available.

The etherification reaction is carried out by adding an ethereal solution of diazoîque compound to a solution of the ester 3 a-hydroxycéphalosporine in an inert solvent. It is expedient to use a diazoîque excess of the compound. The etherification with satisfactory speed takes place at a temperature between about 20 and 25 °c. The inert solvents which can be used are those which do not react with the compound diazoîque, and are preferably the chlorinated hydrocarbon solvents, such as methylene chloride and chloroform.

The throughput can be improved etherification reaction by adding the reaction mixture a catalytic amount

the complex-boron trifluoride ethyl ether, ordinarily the etherification reaction with diazomethane is completed in about 2 hours.

Recovered easily ethers cephalosporin of the etherification reaction mixture and purified by evaporation to dryness of the mixture and crystallization of the residue.

It is also possible to react the esters 3-hydroxy 3 a-cephem etherification with reagents other than the compounds diazoîques, to obtain various ether substituents. For example, may be reacted esters 3-hydroxy 3 a-cephem in the presence of a base with methyl iodide, a lower alkyl ester of sulfuric acid as dimethyl sulfate or fluoroborate trimethyloxonium methylic ether to obtain superior homologous. It may also be activated halogen compounds react in the presence of base with esters of 3-hydroxy 3 a-cephem to obtain other ether derivatives. For example, may be reacted, to obtain 3 a-cephem-to-3-ether, halogenated compounds activated as the a-haloethers, the chloromethyl methyl and ethyl and bromomethyl oxide; esters of has-a hydrohalic acid such as ethyl bromoacetate, methyl chloroacetate, 1 'a tert-ethyl and the allyl halides such as allyl bromide and allyl chloride. The preparation of the 3 a-cephem-to-3-ethers by the reagents mentioned is accompanied by the alkylation in position 4 of the dihydrothiazine ring. for example, methyl iodide reacts with the 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl in the presence of a base by imparting a mixture of reaction products comprising the ester 3 a-methoxylated desired, the 4-methyl 3-hydroxy 2 a-cephem-to-4 carboxylate and 4-methyl 3 a-mêthoxy~2-to-cephem-to-4 carboxylate. These mixtures may be separated by chromatography to obtain the desired 3-ether.

The etherification preferred reagents, which are the compounds previously mentioned diazoîques as diazomethane, react with the esters 3-hydroxy 3 a-cephem giving the ethers of 3 a-cephem without alkylating simultaneously in position 4.

In a particular embodiment of the invention, dissolving the 1 - / 2 -(2-thienyl) acetamido / - 3 hydroxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl in methylene chloride and the solution is added an excess of diazomethane in methylene chloride. By leaving the reaction mixture at room temperature for 2 hours, the solvent evaporated, and the residue is dissolved in ethyl acetate. The solution is cooled ethyl acetate to precipitate the 1 - / 2 - (2 -thienyl) acetamido / - 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl as a crystalline solid.

Similarly, prepared with diazomethane derivative 3 ethoxylated.

As described in the methods and procedures of the present invention, the carboxylic acid group of the cephalosporin derivative is protected with an ester-forming group which can readily be removed as one of those disclosed previously. Similarly, in the case of compounds of formula I wherein the moiety acylamido and carries a hydroxyl or amine substituent, such as mandeloyl aminoadipoyle and groups, carboxylic acid group, these reactive functional groups are protected by a caging group which can be removed® the protecting groups of carboxylic acid groups, amine and hydroxyl groups that are described herein are only examples of the many known protective groups which are recognized as applicable for this invention. The only requirement is that these groups are groups of blockages stable under the conditions described ozonolysis, acylation and etherification and they can be removed easily by acidic or basic hydrolysis or catalytic hydrogenolysis under conditions that do not destroy the cephalosporin molecule.

The preferred protecting groups are carboxylic acid groups of the present invention are the groups P~nitrobenzyl, p-methoxybenzyl and benzhydryl. The P-nitrobenzyl the ester group is removed by catalytic hydrogenolysis under acidic conditions. The groups P-methoxybenzyl and benzhydryl are cut by trifluoroacetic acid 0 and 10 °C in anisole, as described in J. The 92. Chem., ^ 6, 1259 (ΐ 971) · however, other groupings may be used ester-forming carboxylic acid protecting groups such as benzyl groups, 2, 2, 2 a-trichloroethyl and T-butyl.

Preferred protective groups of the hydroxyl group are the formyl group and the group ch-methoxyethyl ^ O ch CNY formed by reaction of the hydroxyl group with the methyl vinyl.

The amine moiety of the preferred protecting groups are the group tert-buty1oxycarbamido and the group 1 and the carbo-methoxy-2-propenyl formed by condensation of the amine group with an acetoacetic ester.

After preparation of a cephalosporin ether (formula I), by removing the ester group protecting the carboxylic acid and, if they are present in the side chain, the protecting groups of hydroxyl groups and amine, to yield an antibiotic. Thus, the esters of cephalosporin, the protected amine group to compounds and compounds with protected hydroxy group are useful as intermediates in the preparation of antibiotics that are ethers of cephalosporin.

Examples of cephalosporin antibiotics of provided

by the method of the invention, examples include the following:

1' acid 7-acetamido-3-methoxy-3 a-cephem-to-4-carboxylic acid,

1¹ acid 7-propionamido-linked-to-3-methoxy-3 a-cephem-to-4-carboxylic, acid 7 a-cyanoacétamido-to-3-methoxy-3 a-cephem-to-4-carboxylic, 1¹ acid 7-chloroacetamido and 3-methoxy-3 a-cephem-to-4-carboxylic, acid 7 a-phenylacetamido-3-methoxy-3 a-cephem-to-4-carboxylic, acid 7 - (4 a-chlorophénylacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic,

acid 7 - (4 a-méthoxyphénylacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

acid 7 - (3.4 to-dichlorophénoxyacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

1' acid 7 a--phenoxyacetamido-to-3 ethoxy 3 a-cephem-to-4-carboxylic, acid 7 a-thiophénoxyacétamido-to-3-methoxy-3-to-a-cephem-to-4 carboxy " lic,

1' acid 7 - (4 a-chlorothiophénoxyacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

1' acid 7 a--phenoxyacetamido-a 3 a-Methoxy-phenylazo 3 a-cephem-to-4-carboxylic, acid 7-acetamido-3 ethoxy 3 a-cephem-to-4-carboxylic, acid 7 - (4 a-hydroxyphénoxyacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic,

1' acid 7 a-benzamido-to-3-methoxy-3 a-cephem-to-4-carboxylic, acid 7 - (2.6 to-diméthoxybenzamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

acid 7 - (3.4 to-dichlorobenzamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

1' acid 7 - (3 a-bromobenzamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

acid 7 - (2 a-chlorophénoxyacétamido) - 3 a-méthoxy~3-to-cephem-to-4~carboxylic,

1' acid 7 - (4 a-cyanophénylacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

1' acid 7 - (4 a-nitrophénylacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

1' acid/2 - 7 - (2-thienyl) acetamido / - 3 a-raéthoxy and 3 a-cephem-to-4-carboxylic acid,

1' acid 1 - / 2 -(2-thienyl) acêtamido7-to-3 ethoxy 3 a-cephem-to-4-carboxylic acid,

1' acid/2 - 7 - (3-thienyl) acétamidp / - 3-methoxy-3 a-cephem-to-4-carboxylic acid,

1' acid 7 - / 2 * - (2-furyl-) acétamido7-to-3-methoxy-3 a-cephem-to-4-carboxylic acid,

The I ' acid 7 - / - 2 * (L tétrazyl) acetamido / - 3-methoxy-3 a-cephem-to-4-carboxylic acid,

acid 1 - / 2 -(2 a-oxazyl) acétamida7-to-~méfcho 3: ^-Y 3 a-cêphein-a 4 a-caxboxylic_/

7 - / acid 2 - (2 a-thiazyl) - 3/acétamidp "methoxy" 3 a-cephem-to-4-carboxylic acid,

7 - / acid 2 - (5 a-tétrazyl) acetamido / - 3-methoxy-3 a-cephem-to-4-carboxylic acid,

acid 7 - (d mandélamido) - 3 a-raêthoxy and 3 a-cêpIieiri-to-4-carboxylic_C.I^I acid 7 - (2 a-chlorothiophénoxyacétamido) - 3 methoxy 3 a-cephem-a 4 a-carboxy1ic,

acid 7 - (d 4 a-hydroxymandélamido) - 3 methoxy 3 a-cephem-a 4 a-carboxyligue,

1' acid 7 - (d 3 a-hydroxymandêlamido) - 3 a-Methoxy-phenylazo 3 a-cephem-to-4-carboxylic acid,

1' acid 7 - (d 3 a-méthoxymandélamido) - 3 a-Methoxy-phenylazo 3 a-cephem-to-4-carboxylic acid,

1¹ acid 7 - (d mandélamido) - 3 ethoxy 3 a-cephem-to-4-carboxylic, 1' acid 7 a-phenylacetamido-3 a-benzhydryloxy-a 3 a-cephem-to-4 carboxy " lic *,

acid/F. - 7 - (2-thienyl) acetamido - 3 / - (3 methyl-2-butenyl-L-oxy) - 3 a-cephem-to-4-carboxylic acid,

1' acid 7 a--phenoxyacetamido-a 3 a-benzhydryloxy-a 3 a-cephem-to-4-carboxylic acid,

acid 7-acetamido-3 - (3 methyl-2-butenyl-L-oxy) - 3 a-cephem-to-4-carboxylic acid,

1' acid 7 - / 2 * - (2 a-oxazyl) acetamido / - 3 ethoxy 3 a-cephem-to-4-carboxylic acid,

acid 7 - (5-amino 5 a-carboxyvaléramido) -3 "=- methoxy" 3 a-cephem-to-4 'carboxy lic,

1' acid 7 - (4 a-aminométhylphénylacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid,

1¹ acid 7 - (4 a-carboxyméthylphénylacétamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid, and

a 7 - (3 chloro-4 a-hydroxyphénoxyacétamido) - 3 a-méthoxy~3-to-cephem-to-4 carboxylate.

The cores of cephalosporin ether (formula I, r=h) are of particular interest because they can be acylated with the desired acyl group to obtain a compound antibiotic (formula I, the R=acyl).

Pages may be acylation of these cores by the known methods used for acylation of 7 a-aminocephalosporanic acid or acid 7 a-aminodesacetoxycephalosporanic. It can be acylated esters or acids nuclei ether cephalosporin by acylation methods under anhydrous conditions and in the presence of water. Or, it can be acylated free acid form of a cephalosporin core ether or an ester thereof by a carboxylic acid halide in an aqueous solvent system, for example aqueous acetone, in the presence of a hydrohalic acid acceptor such as triethylamine, pyridine or sodium bicarbonate. The acylation can be carried out also by reacting an ester of the core ether with a carboxylic acid in the presence of a condensing agent such as N-ethoxycarbonyl-2-ethoxy-L-, 2 a-dihydroquinoline (EEDQ) or dicyclohexylcarbodiimide. Acylating the ester can also be ether of the core with the anhydride of a carboxylic acid or with a mixed anhydride, by yet another known method of acylation, can be acylating the core ether by an active ester of the carboxylic acid, e.g. pentachlorophenylic ester of a carboxylic acid.

By exenç " the, reacting the 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl chloride with thiophene-2-acetyl in aqueous acetone containing sodium bicarbonate to obtain the^7 - 2 - (2-thienyl) acétamido7-to-3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl.

Reacting the 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl with phenoxyacetic acid in a solvent mixture of tetrahydrofuran and acetone in the presence of EEDQ to obtain the 1 - β - / (t-butyloxycarbonyl) - D-α phénylglycylamid_o / - 3-methoxy-3 a-céphem~4 carboxylate of P-nitrobenzyl.

Reacting the 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl with 1' 0 carboxy anhydride mandelic acid in ethyl acetate to obtain the 7 - (D-α mandélamido)~>3-methoxy - " 3 a-cephem-to-4 carboxylate of P-nitrobenzyl.

As exemplesdes acylating that can be used in prior methods, examples include chloride thiophene-2 a-acêtyle, the chlorure.de phenoxyacetyl, phenylacetyl chloride, the thiophene-3-carboxylate pentachlorophenyl, bromide of oxazole and 2-acetyl, chloride thiazole-2-acetyl, the tetrazole 1-acetic acid, 1 '0 carboxyanhydride mandelic acid, 1' 0 carboxyanhydride 4-hydroxymandelic acid, cyanogen bromide .6 *=4 a-chlorophénoxyacétyle, benzoyl chloride, 4-cyanobenzoyl chloride, chloride 4 a-cyanophénylacêtyle chloride and 3.4 to-dichlorothiophénoxyacétyle.

Examples of acids of nuclei of cephalosporin ether and ester thereof which are provided by the method of the invention, examples include acid 7-amino 3-methoxy-~céphem 3 and 4-carboxylic, acid 7-amino 3 ethoxy 3 a-cephem-to-4-carboxylic, the 7-amino 3~methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl, the 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-methoxybenzyl, the 7-amino 3-methoxy-3 a-cephem-a 4 - carboxylate 2, 2, 2 a-trichloroethyl, the 7-amino 3 ethoxy 3 a-cephem-to-4-carboxylate 2, 2, 2 a-trichloroethyl, the 7-amino 3-methoxy-3 a-cephem-to-4-carboxylate diphenylmethyl, the 7-amino 3 a-benzhydryloxy-a 3 a-cephem-to-4 carboxylate of P-nitrobenzyl, acid 7-amino 3 a-benzhydryloxy-a 3 a-cephem-to-4-carboxylic acid, and the 7-amino 3 - (3 methyl-2-butenyl-L-oxy) - 3 ~cêphem-to-4 carboxylate of P-nitrobenzyl.

Esters can also be prepared cores ether

cleavage of the cephalosporin side chain (protected amino) adipoyl derivative bearing a cephalosporin C *" centeredly ether in position 3. For example, reacting the ester dibenzhydrylic acid 7 - (5 conjugate thereof 5 a-carboxyvaléramiâo) - 3 methoxy 3 a-cephem-to-4-carboxylic acid with phosphorus pentachloride in the presence of pyridine to obtain 1 'imino-halide which by reaction with methanol added provides the énol ether methylic. Hydrolyzed easily the énol-ether to obtain the 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of the benzhydryl. The reaction is carried out off the side chain using and operative modes known cleavage PClg used in the clipping of the side chain aminoadipoyle cephalosporin c to obtain a 7 a-aminocephalosporanic acid ester.

Accordingly, reacting the 7 - acid diesters (5 amino-protected-5 a-carboxyvaléramido) - 3 hydroxy-3 a-cephem-to-4 carboxy lic wherein the amine moiety is the group protected chloroacetamido, conjugate or 2.4 a-dichlorobenzamido, in derivatives carrying an ether group in position 3 (formula I, r=5 (protected amino) - 5 a-carboxyvaléryle) by the etherification process of this invention as described previously. Accordingly, the acid 7 - (5 conjugate thereof 5 a-carboxyvaléramido / - 3-methoxy-3 a-cephem-a 4 a-carboxyli - that, acid 7 - (5-chloroacetamido-a 5 a-carboxyvaléramido) - 3 methoxy 3 a-cephem-to-4 carboxy league and acid 1 - / - I(2.4 a-dichlorobenzamido) - 5 a-carboxyvaléramidp / - 3-methoxy-3 a-cephem-to-4-carboxylic acid and their diesters and especially esters readily removable benzhydrylic, form a group particularly useful compounds. Of Laddie, esters 3-hydroxy 3 a-cephem correspondingly substituted starting materials useful for preparing these compounds.

By following steps described previously, can be converted to ester 7 a-néthoxy-to-3-hydroxy 3 a-cephem derivative 7 a-methoxylated cephalosporin C obtained as a fermentation product of a Streptomycete as described in J.

The AM. Mal. Share. 93, 2308 (1971). By following the etherification reaction described herein, can be prepared ester 3.7-dimethoxy-a 3 a-cephem, and cleavage of the side chain (protected amino) adipoyl pc1 by₅ in the presence of pyridine, obtained acid ester 7-amino 3.7-dimethoxy-a 3 a-cephem-to-4-carboxylic acid, for example the ester benzhydrylic or P-nitrobenzyl. Can be acylating the ester of the core 7-amino 3.7-dimethoxy by known methods to obtain the 7 a-acylamido and-a 3.7-dimethoxy-a 3 a-cephem-to-4 carboxylates. Removing the ester group provides an acid 7 a-acylamido and-a 3.7-dimethoxy-a 3 a-cêphem-to-4-carboxylic antibiotic. For example, may be prepared acid 7 a-mandélamido-to-3.7-dimethoxy-a 3 a-cephem-to-4-carboxylic, 7 - ^ T-acid - (2-thienyl) acétamido7-to-3.7-dimethoxy-a 3 a-cephem-to-4-carboxylic acid and 7 - (3 - or 4 a-hydroxymandélamido) - 3.7 to-dimethoxy-3 a-cephem-to-4-carboxylic acid.

Acids 7 to-acylamido and and 3 a-cephem-to-4-carboxylic acids etherified

0

the TT

in position 3 (formula I, the R ≈ ' R-a-c -, the R - ^ ≈ methyl, ethyl, diphenylmethyl, or 3-methyl 2-butenyl, R.₂ =hydrogen) are compounds useful antibiotics that inhibit the growth of microorganisms including gram positive and gram-negative.

In table I which follows, the minimum inhibitory concentration (MIC) of the compounds prepared by the method of the invention is illustrated by the data indicated for the compounds of the list. The data is obtained by the traditional disks on agar.

table I

Spectrum antibiotic ethers of cephalosporins of disks on plate

^ Antibiotic (Milligram/milliliter) concentration of microorganism zone of inhibition (diameter in mm)²

1/Compound has=acid 2 - 7 / - (2-thienyl) acetamido / - 3-methoxy-3 a-cephem-to-4-carboxylic

Compound b=acid 7 - (d mandélamido) - 3 methoxy 3 a-cephem-to-4-carboxylic

2/"T-" indicates that there exists a trace of zone of inhibition.

A dash indicates that zone of inhibition was observed at the concentration tested.

Table II gives the minimum inhibitory concentrations (MIC) for the compounds of the invention against clinical isolates of The Staphylococcus penicillin resistant and in the presence of serum and 1' absence of serum. MIC values were determined by the technique of the gradient on plate carried out essentially as described by ByrsonSzybalski and, Forensic science, 116, 45 (1952).

TABLE II

Antibiotic activity against Staphylococcus penicillin resistant

Clinical isolates of Staphylococcus

-, MIC (GP/ml.)

Compound^{the X}

V 41 V 32 X 400² V 84 xlxl.l nsec³ E e e e nsec nsec nsec nsec ^ ^ s■ > 20 20 20>20) 20 > 20, 4.8) 20, 0.8 3.0 b. 18.4^20>20>20>20>20, 9.4 11.1 0.6 0.5 1/the compounds a and b are the compounds mentioned in returning 1 Table I

2/ The Staphylococcus methicillin-resistant

3 Nsec=/ serum

E=serum

The table II below gives MIC values for compounds tested against representative gram-negative organisms. The indications were obtained by the technique of the gradient on plate.

TABLE III

Antibiotic activity against

Organism

The Shigella SPs.

In Escherichia coli

K. pneumoniae

Aerobacter aerogenes was

Salmonella

The Pseudomonas aeruginosa

Serratia

gram-negative organisms CIM in the compound tested ^ (GP/ml.) AB

>200,164

1/The compounds a and b are the compounds named in returning Table I 1.

The antibiotics that are ethers of cephalosporin prepared by the method of this invention are relatively non-toxic substances which are useful for combatting infections in warm blooded mammals when administered parenterally in a dosage form nontoxic pharmaceutically effective. Oxides are effective antibiotics for combating infections when administered at a dose of about 25 to 50 mg/kg body weight. In combating infections in particular hosts, repeated administration of lower doses can suffice while in other cases larger non-toxic doses can be administered to obtain desired destruction.

A preferred group of antibiotic compounds prepared by

the method of the invention is consisting of 3 a-méthoxycéphalosporines represented by formula I wherein R is 0

I

an acyl group of R ' a-c -, wherein R is a methyl group ^ ^ and R is hydrogen. A particularly preferred group of antibiotics is represented by formula I wherein R ' is the group

H

THE R "' - - C.

2

wherein Z is a hydroxyl group, the R ^ is a methyl group and is hydrogen. Examples of these preferred compounds, examples include acid 7 - (d mandélamido) - 3 methoxy 3 a-cephem-to-4-carboxylic, acid 7 - (d 4 a-hydroxymandélamido) - 3 a-méthony and 3 a-cephem-to-4-carboxylic, acid 7 - (d 3 a-hydroxymandélamido) - 3 methoxy 3 a-cephem-to-4-carboxylic, acid/2 - 7 - (2-thienyl) - 2 a-hydroxyacétamido / - 3-methoxy-3 a-cephem-to-4-carboxylic acid and 2 - 7 / - (3-thienyl) - 2 a-hydroxyacétamidq / - 3-methoxy-3 a-cephem-to-4-carboxylic acid.

The antibiotic can be administered conposés prepared by the method of the invention in free acid form or in the form of a nontoxic pharmaceutically acceptable salt such as the sodium or potassium salt. Salts are prepared by reacting the acid with a suitable base antibiotic such as sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate and similar bases.

The following examples are given to better illustrate 1' disclosure.

EXAMPLE 1

Hydrochloride 7-amino 3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl

Cooled in an acetone bath at mediates dry ice a solution of 3.85 g of the hydrochloride of the 7-amino 3-methylene-cépham-to-4 carboxylate of P-nitrobenzyl in 600 ml of méthanef. Ozone is bubbled into the reaction mixture for about 20 min, after which time the reaction mixture has a pale blue staining, nitrogen is passed into the reaction mixture to expel the excess ozone. Then, the ozonide is decomposed intermediate by passing sulfur dioxide gas into the reaction mixture until the mixture gives a negative response to the testing in starch and potassium iodide.

The reaction mixture is evaporated under reduced pressure and dissolved

the residue in 200 ml of hydrochloric acid 0, the Li! in methylene chloride. The solution is evaporated to dryness and dissolving the reaction product residue in acetone, by cooling, 3.15 g of hydrochloride 7-amino 3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl precipitate as crystalline solid.

I.R. (suspended in the a Nujol);

absorption of the carbonyl group at

5.55 (carbonyl of the β - 1 ^ ηηΐ℮ η) and

5.02 (carbonyl group of the ester linkage forming

hydrogen with the grouping 3-hydroxyl) micron.

Electrometrically titration (DMF to 66%) pKa of 4.0 and 6.3.

EXAMPLE 2

Hydrochloride 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl

Agitated slurry has a 445 mg of hydrochloride 7 a-amxno-to-3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl (prepared as described in example 1) in 30 ml of methylene chloride, is added 131 mg of mono-triméthylsilylacetamide and the mixture is stirred at room temperature for 30 mins.

An ethereal solution is added an excess of diazomethane and after 20 min is evaporated mixture to drive off the solvent and the excess diazomethane. The residue is treated with 1 ml of methanol and then dissolved in a mixture of ethyl acetate and water. Separating the layer of ethyl acetate, then washed with water and dried. HCl gas is passed in the dried layer of ethyl acetate to precipitate the reaction product which is hydrochloride 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl.

NMR (DMSO to Dc): signals to 6.97 (e wide, 3:00, the NH₃⁺ ), 6.31

(e, 2 Η, h2 carbon C^), 6.23 (e, 3:00, methoxy carbon

C₀ ), 5.39 (d., 1:00, H of the carbon C_C. ), 5.05 (d-, 1:00, H of the carbon O-O

C₇ ), and 2, 5 - 1, 92 (Q-, 4:00, aromatic hr).

EXAMPLE 3 7-amino 3-methoxy-~céphem 3 and 4 carboxylate of P-nitrobenzyl

Agitated slurry has a 445 mg of hydrochloride of 7-amino 3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl (prepared as described in example 1) in 35 ml of dry tetrahydrofuran is added one equivalent of triethylamine followed by 10 ml of a solution of diazomethane in excess êthérée. After 30 min, the solvent evaporated and excess diazomethane and the residue is dissolved in a mixture of water and ethyl acetate. The organic layer is separated and washed with water and dried.

Evaporated to dry the solution made to ethyl acetate dried to obtain 310 mg of 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl. The composition is obtained in crystalline form by trituration with diethyl ether.

Elemental analysis for c ^ ^ ^ j-H-n-MCOs:

Theory: c=49.31; h=4.14; n=11.50

Found: c=49.51; h=4.40; n=11.25

I.R. (suspension in the a Nujol): absorption peaks at 2.99 (amid), 5.75 (wide, carbonyl containing P-lactam ester), and 5.98 (carbonyl of 1' amid) micron.

UV (ethanol), absorption maximum 268 xqp,

=T- 14.600.

NMR (DMSO to Dc): signals to 7.10 (e wide, 2:00, containing carbon C NHj_? ), 6.22 (e, 2 Η, h2 carbon C^), 6.20 (e, 3:00, containing carbon C methoxy₃ ), 5.27 (d-, 1:00, H of the carbon GC), 4.93 (D., 1:00, H of the carbon C₇ ), 4.60 (e, 2:00, ester) and 2, 35 - 1, 6 (Q-, 4:00, aromatic hr) 'T' A.

EXAMPLE 4

Acid 7-amino 3-methoxy-3 a-cephem-to-4-carboxylic acid.

Is acidified to pH 1 with momentarily concentrated hydrochloric acid solution of 730 mg of 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl in 20 ml water and 20 ml of d¹ acetonitrile derivative. Immediately after, is returned to the solution at a pH of 2.5 with 1' sodium hydroxide in vivo. Then the solution is evaporated to dryness and the residue is dissolved in a mixture of 40 ml of THF, 80 ml of methanol and 6 ml of water. Then the solution is hydrogenated in the presence of 730 mg of palladium-on-charcoal to 5% (prereduced in ethanol) during 2 hours under a hydrogen pressure of 3.5 kg./ cm. at room temperature.

The catalyst is filtered off and washed with THF and water. Evaporation of the washing liquid and the filtrate combined and bringing the aqueous residue suspended in ethyl acetate.

The pH is adjusted to 3.5 of the slurry is separated and the aqueous layer is then washed with ethyl acetate. The aqueous layer is concentrated to a volume of 4 ml and then cooled to precipitate 160 mg acid 7-amino 3-methoxy-3 a-cephem-to-4-carboxylic acid as a crystalline solid.

Elemental analysis for^C. O^H lo^NR 2 °4^Sii

Theory: c=41.73; hr ≈ 4.38? N=12.17

Found *. C=43.45; H=4.50; N=12.52

I.R. (suspended in the a Nujol): absorption peaks at 5.61 micron (P-lactam carbonyl).

NMR (DMSO to Dc): signals to 6.35 (e, 2:00, hr₂ the carbon C₂ ), 6.20 (e, 3:00, methoxy carbon GC), 5, 3 θ (D., 1:00, H of the carbon GC) and 4.94 (d-, 1:00, H of the carbon C₇ )~7.

UV (pH 7 buffer) : iF max. mji 268, of £=6.500

EXAMPLE 5 7 - / 2 - {2-thienyl) acétamido7-to-3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl

To a solution of 2.4 grams of 7-amino 3-methoxy-3 a-cephem-to-4~p-nitrobenzyl carboxylate (example 3) in 50 ml of acetone is added 1.7 g of sodium bicarbonate. The suspension is stirred while adding dropwise over a period of 45 min, 1.15 g of chloride thiophene-2-acetyl in dry acetone.

After stirring for 30 min, the reaction mixture is evaporated and the residue is dissolved in a mixture of water and ethyl acetate. The organic layer is separated, washed with water, is dried and then evaporated to obtain a concentrate, by cooling the material crystallizes 1, 9 g of 7 - / 2' - (2-thienyl) acêtanddo7-to-3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl of the concentrate.

NMR (CDCl ^ / DMSO to Dc) e signals to 6.41 (e, 2:00, hr₂ carbon THE C ^)" 6.15 (e, 2:00, EYC the side chain), 6.10 (e, 3:00, methoxy containing carbon C ^), 4.91 (D., 1:00, H of the carbon C_grams ), 4, 7 - 4, 35 (w, 3:00, HC₂ of the ester, H of the carbon C_? ), 3, 1 - 1, 7 (m-, 7:00, aromatic hr) and 1.0 (D., 1:00, NH-containing carbon C_? ) ^.

UV (ethanol) ftmax 260 MPs, the X= 15,000

^ max. 235 MPs, 00=16,200.

EXAMPLE 6

2 - 7 / - (2-thienyl) acétamidp7-to-3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl.

A. At a solution of 1.55 g of the hydrochloride of the 7-amino 3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl (prepared as described in example 1) in 30 ml of acetone and containing 364 mg (0.5 ml, 3.6 mmol) of triethylamine, 962 mg added urea.

Stirring at room temperature, is added dropwise to the mixture a solution of 730 mg (4.4 mmol) of chloride 2-thiophene-acetyl in 20 ml of acetone. After 2.5 hours, filtered and evaporation of the reaction mixture. The residue is dissolved in ethyl acetate and the solution washed successively with water, a 5% solution of sodium bicarbonate, 5% hydrochloric acid and a saturated solution of sodium chloride, dried solution is dried and is then concentrated by evaporation under vacuum, giving 1.2 g of the reaction product as a crystalline residue, the product is recrystallized in ethyl acetate to yield the 7 - 2 / - (2-thienyl) acétamid (the d / - 3 hydroxy-3 a-cêphem-to-4 carboxylate of P-nitrobenzyl pure having the following spectral properties.

I.R. (suspended in the a Nujol): absorption peaks at 3.0 (the NH

of 1' amid), 5.68 (carbonyl group of β - 1 ^ ℮ ℮ΐη℮) and 6.1 (amido, and ester forming a bonded with the grouping 3 OH) micron.

N-DICHROISIN.. (CDC1₃/ Ii) ms0 D._grams ); signals to 6.54 (2d, 2:00, hr₂ the carbon C₂ ), 6.16 (e, 2:00, HC₂ the side chain), 4.90 (d-, LHRH, H of the carbon grams_grams ), 4.60 (d-, 2:00, HC₂ of the ester), 4.43 (Q-, LHRH, H of the carbon C₇ ), 3, 1 - 1, 6 (the m, 7:00, aromatic hr) and 1.30 (D., LHRH, Nh 1' amid) 7 **

b.. To a solution of 2 g of the 2 - 7 / - (2-thienyl) acetamido / - 3 hydroxy-3 a-cephem-to-4-carboxylate in 50 ml of p-nitrobenzyl methylene chloride, is added an excess of diazomethane in methylene chloride and the reaction mixture is allowed to stand for 2 hours at ambient temperature. The reaction mixture is evaporated and the residue is dissolved in ethylacetate found: c=51.49; h=3.76? N=8.49; s=12.90; 0=23.03 determination of the methoxy group:

Theory: 6.33%

Found: 6.09%,

I.R. (suspended in the a Nujol); absorption peaks at 3.02 (Nh 1' amid, 5.65, 5.75 and 6.01 (carbonyl groups of the P-lactam, and of the ester and amide respectively) micron. NMR (CDClg): signals to 6.62 (e, 2:00, hr₂ the carbon C_? ), 6.18 (e, 3:00, containing carbon C methoxy₃ ), 6.16 (e, 2:00, HC₂ the side chain), 4.98 (d-, 1:00, H of the carbon GC), 4.71 (d-, 2:00, HC₂ of the ester), 4.42 (Q-, 1:00, H of the carbon C^), 3.19 (d., LHRH, NH-amide) and 3, 1 - 1, 65 (m-, 7:00, aromatic hr) of X "

UV (ethanol): absorption maxima;

% max.: 237 χψ, ' the X, =15,400

max.: 268 rtju, GBP, =16,000.

EXAMPLE 7

Acid 1 - / 2 -(2-thienyl) acétamido7 " 3-methoxy-3 a-willwill céphera-to-4-carboxylic

Hydrogen is a solution containing 490 mg of P-nitrobenzyl ester of 1' example 5 or 6, 20 ml of THF, 60 ml of methanol and 5 drops of hydrochloric acid in vitro in the presence of 490 mg

pd-on-c 5% (pre-reduced in 1' ethanol) during 2 hours and

2

half under a hydrogen pressure of 3.5 kg/cm at room temperature.

Filtering the catalyst is rinsed tank with THF and water. A wash liquid is evaporated and the filtrate combined and adjusted the pH of the aqueous residue to 2.5. The residue is extracted with ethyl acetate and water is added to the extract. The pH of the mixture is adjusted to 7 and is separated from the aqueous phase and then is made suspended in ethyl acetate. The slurry is acidified to pH 2.5 and the organic layer is separated, washed with water, is dried and evaporated, then washed with water, dried and evaporated to dryness is. The triturate the residue with diethyl ether to obtain 156 mg of acid/2 - 7 - (2-thienyl) acetamido / - 3-methoxy-3 a-cephem-to-4-carboxylic acid in the form of a crystalline solid that melts at about 168 and 171 °C with decomposition.

Elemental analysis for^C. i4^H i4^NR 2 °5^S 2' *

Theory: c=47.45? H=3.98; N=7.90

Found: c=47.52; hr ≈ 4.20; n=7.42

NMR (DMSO to D._grams ): signals to 6.35 (e, 2:00, hr₂ the carbon C₂ ), 6.24

(e, 5:00, méthanoxy carbon and CH₂ the side chain), 4.94 (d-, 1:00, H of the carbon C_grams ), 4.55 (q-, LHRH, H of the carbon C_? ), 3, 10 - 2, 55 (m-, 3:00, aromatic hr) and 1.10 (D., 1:00, Nh 1' amid) χ·.

EXAMPLE 8 7 - (D-phenyl-formyloxyacétamido) - 3 methoxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl)

To a solution of 4 g of 7-amino 3-methoxy-3 a-cephem-to-4 carboxy~P-nitrobenzyl ETL (prepared as described in example 3) in 50 ml of acetone is added 2.8 g of sodium bicarbonate. Has the suspension is added dropwise, with stirring, a solution of 2.3 g of chloride of d-to-formyloxyphénylacétyle in dry acetone. The acylation is complete in one hour as shown by thin layer chromatography.

The reaction mixture is evaporated under reduced pressure and

the residue is dissolved in a mixture of water and ethyl acetate.

The organic layer is separated, washed with hydrochloric acid to 5% cold, dried and then evaporated. The residual oil is suspended in diethyl ether to obtain 4.8 g of crystalline product.

Elemental analysis for^C 24^H 21^NR 3 °9 ^^:

Theory: c=54.65? H=4.01? N=7.97

Found: c=54.47; h=4.06; n=7.75.

NMR (CDC1₃ ): signals to 6.68 (e, 2:00, containing carbon C₂ ),

6.20 (e, 3:00, methoxy containing carbon C ^), 4.99 (d-, LHRH, H of the carbon C_grams ), 4.71 (d-, 2:00, HC₂ of the ester), 4.48 (Q-, LHRH,

H of the carbon C_? ), 3.74 (e, LHRH, CT-Ch), and 2, 75 - 1, 75 (w, 11:00, Nh 1' amid, - the O-formyl GFF aromatic hr) T-VBE1

I.R. (CHCl₃ ): absorption peaks at 2.9 (amid), 5.58, 5.74 and 5.82 (wide, carbonyls of the P-lactam, ester and 1' amid) micron.

EXAMPLE 9

7 - (D-phenyl-foriryloxyacétamido) 3 - methoxy - 3 - cephem - 4 - carboxylate p-nitrobenzyl.

A. At a solution of 1.54 g of hydrochloride 7-amino 3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl (prepared as described in example 1) in 120 ml of acetone and 40 ml of water, are added 936 mg sodium bisulfite, is added dropwise with stirring at room temperature a solution of 960 mg

acid chloride O forrayl d-mandelic acid in 20 ml of anhydrous acetone. The reaction mixture was stirred at room temperature for 16 hours then evaporated to remove acetone. The aqueous residue is suspended in ethyl acetate and the organic layer is separated. The extract is washed with water, dried and evaporated. Triturate the residue is crystalline with diethyl ether and dried, yielding 1 g of 7 - (d-phenyl-formyloxyacétamido) - 3 hydroxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl.

Elemental analysis for^C 23^H 19^NR 3 °9^O:

Theory: c=53.80; h=3.73; n=8.18

Found: c=53.51; h=3.81; n=8.46

I.R. (CHClg): absorption peaks of the carbonyl group at 5.55, 5.73, 5.85 and 5.93 micron.

NMR (CDCl a-j): signals to 6.61 (e, 2:00, carbon C^), 4.95

(d., 1:00, H of the carbon GC), 4.61 (d-, 2:00, HC₂ of the ester), 4.39 (Q-, 1:00, H of the carbon C_? ), 3.70 (e, 1:00, -CH) and 2, 80 - 1, 70 (m-, 11:00, Nh 1' H-amide and aromatic)

To a solution of 500 mg B.V. of 7 - (D-α phênyl-to-fcrmyloxyacé-to-tamido) - 3 hydroxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl in 20 ml of methylene chloride, is added a solution of an excess of diazomethane in diethyl ether. After 20 min, the mixture is evaporated and the residue of the triturate with ether to obtain the crystallized product which is the 7 - (D-α phênyl-to-aformyloxyacétamido) - 3 methoxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl with a yield of 48%.

Elemental analysis for^C 24^H 21^NR 3 °9 ^ DEGREES

Theory: c=54.65; hr ≈ 4.01; n=7.97

Found: c=54.43; hr ≈ 4.23; n=7.99.

EXAMPLE 10

Acid 7 - (d mandélamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid.

Hydrogen is a solution of 7 - 528 mg of (d-phenyl 2 a-formyloxyacétamido) - 3 methoxy 3-to-a-caphem-to-4 carboxylate of P-nitrobenzyl (prepared as described in the example 8 or 9) in 20 ml of acetonitrile and 60 ml of methanol containing 3 drops of hydrochloric acid in vivo, in the presence of 530 mg of palladium

on coal to 5% (prereduced in ethanol) under a hydrogen pressure of 3.5 kg/cm during 2 and one-half hours at room temperature.

The catalyst is filtered off and washed with THF and water. One joins the filtrate and wash liquids and evaporated to remove the solvent, the aqueous concentrate is suspended in ethyl acetate and adjusted momentarily the pH of the suspension to 10 with 1' sodium hydroxide in vivo. Immediately the pH is readjusted to 7 with hydrochloric acid in vivo. The aqueous phase is separated off, washed with ethyl acetate and cooled in an ice bath. Adding ethyl acetate to the solution cold and the pH is adjusted to 2.5 with hydrochloric acid in vivo. Separating the layer with ethyl acetate and washed with water and then dried.

Evaporated to dry the solution dried and triturate the residue with diethyl ether to obtain 115 mg of acid 7 - (d mandélamido) - 3 a-Methoxy-phenylazo 3 a-cephem-a 4 a-carboxy1ic as a crystalline solid.

Elemental analysis for c ^ ^ ^ H-n-MCOs:

Theory: c=52.74; h=4.43; n=7.69

Found; c=52.76; h=4.30; n=7.46

I.R. (suspended in the a Nujol): absorption peaks at 3.0 (wide, Nh 1 'amide and-OH), 5.55, 5.84, 6.1 (carbonyls of the P-lactam, carboxylic acid and 1' amid, respectively) and 6.55 (band II of 1' amid) micron.

NMR (DMSO to Dc): signals to 6.36 (e, 2:00, hr₂ the carbon C₂ ), 6.23 (e, 3:00, containing carbon C methoxy₃ ), 4, 98 - 4, 45 (w, 3:00,

H of the carbon C -, CH the side chain containing carbon C and H "), 6, 7 3.80 (s-wide, 1:00, OH of the side chain, moved with d² Degrees), 2, 78 - 2, 38 (m-, 5:00, aromatic hr) and 1.45 (D., 1:00, H 1' amid) Υ.

EXAMPLE 11

Acid 7 - (- d-(mandélamido) - 3 methoxy 3 a-cephem-to-4-carboxylic acid.

Is cooled in an ice bath solution of 528 mg

of 7 - (d-phenyl-formyloxyacétamido) - 3 methoxy 3 a-cêphem-to-4 carboxylate of P-nitrobenzyl (examples 8 or 9) in 7 ml of acetonitrile and added 1 ml of concentrated hydrochloric acid.

Then, added, by go there and stirring, 260 mg of zinc powder and stirred the reaction mixture at 30 minutes and during cold ambient temperature for 2 hours.

The reaction mixture is poured into a mixture of water and ethyl acetate and separating the layer with ethyl acetate, washed with water and dried. Evaporated to dry the solution dried to obtain the acid 7 - (d-phenyl-formyloxyacéfcamido)" 3-methoxy-3 a-cephem-to-4-carboxylic crude.

The crude acid is dissolved in 15 ml of a solution to 5%

sodium bicarbonate and extracting the solution with ethyl acetate. The aqueous solution is allowed to stand for 2 hours and is in fact a suspension with ethyl acetate. The slurry is cooled to 5 °c and is acidified to pH 2 with hydrochloric acid in vivo. Separating the layer with ethyl acetate, washed with water, is dried and evaporated to dry. The triturate the residue with diethyl ether to obtain the reaction product, either the acid 7 - (d mandélamido) - 3 a-méthoxy~3-to-cêphem-a 4 a-carboxylic having spectral properties consistent with that of the product obtained by the method for unlatching the example 10.

EXAMPLE 12

7 - (D Mandélamido) - -3>mêthoxy and 3 a-cephem-to-4 carboxylate of P-nitrobenzyl

With a suspension of 365 mg of 7-amino 3 a-mêthoxy and 3 a-cephem-a 4" carboxylate in 20 ml p-nitrobenzyl of ethyl acetate is added 200 mg of O-carboxy anhydride in mandelic. Then added a solution of 200 mg of sodium bisulfite in 20 ml of water and vigorously stirred the two-phase mixture during 30 min.

Separating the layer with ethyl acetate, washed with water, is dried and evaporated to dry. The triturate the residue with diethyl ether to obtain 350 mg of crystalline product.

NMR (CDC1₃/ D.₂ 0): signals to 6.70 (e, 2:00, the EL, carbon THE C ^), 6.22 (e, 3:00, containing carbon C methoxy₃ ), 5.06 (d-, 1:00, H of the carbon GC), 4.90 (e, LHRH, CH the side chain), 4.75 (e, 2:00, HC₂ of the ester), 4.58 (Q-, LHRH, H of the carbon THE C ^), and 2, 66 - 1, 75 (w, 9:00, aromatic hr)~7.

Elemental analysis for^C 23^H 21^NR 3 °8^S

Theory; C. ≈ 55.31? H=4.24? N=8.41

Found: c=55.07? H - 4.17? H=8.13.

EXAMPLE 13 7-a-phenoxyacetamido-to-3-methoxy-3 a-cephem-to-4-carboxylate methyl.

A. cooled in an acetone bath and dry ice a solution of 1.6 g of 7 a--phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate methyl in 300 ml of methylene chloride. Ozone is bubbled in the cool solution for three minutes, after which time the reaction mixture has a slight blue coloration. Excess ozone is knocked in a flow of oxygen and added 10 g of sodium bisulfite.

the reaction mixture was stirred and allowed to warm up to 0 °c. The liquid phase is separated by settling and then washed successively with a solution to 5% hydrochloric acid, water and a saturated solution of sodium chloride. The mixture is dried washed and is evaporated, yielding 1.5 g of 7-phenoxy-benzylamide 3-hydroxy 3 a-cephem-to-4 carboxylate crude methyl in the form of an amorphous solid.

The raw product is dissolved in ethyl acetate and

it is extracted with a solution to 5% sodium bicarbonate, is added to the ethyl acetate extract that is then acidified to pH 2 with hydrochloric acid in vivo. The organic phase is separated, washed with a saturated solution of sodium chloride and dried. Evaporated to dryness the dried extract, resulting in 709 mg of the reaction product contaminated with a small amount of sulfoxide 3-hydroxy 3 a-cephem corresponding which is a product of over-oxidation. Separating the product of the sulfoxide and obtained in pure form by preparative chromatography on silica gel thin layer with the mixture of chloroform: methanol (9:1).

Elemental analysis for *.^C. lg^H lg^NR 2 °6^S *^H 2°

Theory; c=50.26? H=4.75? N=7.33? S=8, 38

Found: c=51.03? H=4.62? N=7.06? S=8, 37

(Chloroform) I.R.: absorption peaks at 2.8 (NH-amide), 5.6 (carbonyl group of the P-lactam), 5.85 (wide, carbonyl groups of the amide and ester) and 6.6 (band II of the amide) micron.

NMR (CDCl₃ ).* signals to 6.65 (e, 2:00, hr₂ carbon-O,),

6.13 (e, 3:00, methyl ester), 5.40 (e, 2:00, HC₂ the side chain), 4.93 (D., 1:00, H of the carbon GC), 4.32 (Q-, 1:00, H of the carbon Cj), 3, 15 - 2, 38 (m-, 6:00, aromatic hr

and the amide), and 1.60 (e wide, 1:00, OH of the carbon C ^) titration electrometrically (66% aqueous PMD) 5 pKa of 5.6.

To a solution of 107 mg B.V. of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate in 10 ml of methyl methylene chloride, is added an excess of diazomêthane in methylene chloride. After 30 min, the reaction mixture is evaporated and the residue is dissolved in ethyl acetate. The solution is washed with water and dried. Evaporation of the dried solution gives the product which is the 7-a-phenoxyacetamido-to-3-methoxy-3 a-cephem-to-4-carboxylate methyl having the following spectral properties,

I.R. (CHClj): absorption bands at 2.3 (Nh 1 'amid), 5.60 (carbonyl group of the P-lactam), 5.70 (group oarbonyle ester) and 5.91 (carbonyl group of 1' amid) micron.

NMR (CDCl ^): signals to 6.60 (e, 2:00, hr₂ the carbon C₂ ), 6.20

(e, 3:00, Ch methyl ester), 5.13 (e, 3:00, containing carbon C methoxy₃ ), 5.43 (e, 2:00, HC₂ the side chain), 4.93 (D., 1:00, H of the carbon GC), 4.40 (Q-, 1:00, H of the carbon C ^), 3, 27 - 2, 47 (m-, 5:00, aromatic hr) and 2.22 (D., 1:00, Nh 1' amid) Υ

UV (ethanol): max. 2.68 MPs, ≈ 7.800.

EXAMPLE 14 7 ~Phénoxyacétamido-to-3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl

To the etherification process described. in the example 13, reacting the 7-a-phenoxyacetamido-a 3 a-hydxcxy and 3 a-willwill céphera-a 4" carboxylate p-nitrobenzyl with the diazomêthane to give, after crystallization in hot benzene and ether, the 7 a-phénoxyacêtamido-to-3-methoxy-3 a-cephem-to-4 carboxylate P-nitrobenzylenitrobenzyle.cristallin.

NMR (CDClj): signals to 6.62 (e, 2:00, H of the carbon C₂ ), 6.20

(e, 3:00, containing carbon C methoxy₃ ), 5.46 (e, 2:00, human gh₂ the side chain), 4.98 (d-, 1:00, H of the carbon GC), 4.72 (d-, 2:00, HC₂ of the ester), 4.44 (Q-, LHRH, H of the carbon C_? ), and 3.2 - 1, 7 (the m, 10 hr, hr aromatic and NH of 1' amid)" the P *.

EXAMPLE 15 7-phenoxyacetamido-to-3-methoxy-3 a-cephem-to-4 carboxylate of P-methoxybenzyl

A. cooled in an acetone bath and dry ice a solution of 2.5 g of 7 a--phenoxyacetamido-a 3 a-méthylèneeêphais-a 4 a-carboxyiate P-methoxybenzyl in 350 ml of ethyl acetate.

Ozone is bubbled into the solution cold for 8 minutes and then passed oxygen in the reaction mixture ozonized to expel the excess ozone. The ozonide is decomposed intermediate reaction mixture by adding 25 g of sodium bisulfite with stirring at a temperature of about 0 °c. The concentrated reaction solution and then washed successively with water, hydrochloric acid to 5% and a saturated solution of sodium chloride. The mixture is dried washed and is evaporated to obtain the reaction product which is the 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4 carboxylate of P-methoxybenzyl as an amorphous solid.

NMR (CDClj): signals to 6.73 (e, 2:00, the II₂ the carbon C₂ ), 6.23 (e, 3:00, p mêthoxy), 5.53 (e, 2:00, HC₂ the side chain), 5.03 (d-, 1:00, H of the carbon C, . ', 4.87 (e, 2:00, HC₂ of the ester), 4.47 (Q-, 1:00, H of the carbon 0), 3, 40 - 2, 50 (w, 9:00, aromatic hr), 2.33 (d-, 1:00, Nh 1' amid), and 1.53 (e wide, 1:00, OH in position 3) t'a.

B has a 1.5 g of solution 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cêphem-to-4 carboxylate of P-methoxybenzyl in methylene chloride, is added an excess of diazomethane in methylene chloride followed by two drops of the complex-boron trifluoride ethyl ether to catalyze the etherification. The reaction mixture was stirred at room temperature for 1.5 hour and then evaporated under vacuum. The residue is dissolved in ethyl acetate and the solution is washed successively with water, 5% hydrochloric acid, a 5% solution of sodium bicarbonate and a saturated solution of sodium chloride.

Drying the washed solution and is evaporated to obtain 1.5 g of crude product which is the 7-a-phenoxyacetamido-to-3-methoxy-3 a-cêphem-to-4 carboxylate of P-methoxybenzyl.

Product is purified by preparative thin layer chromatography on silica gel using a solvent system of benzene and 7:3 ethyl acetate.

Elemental analysis for^C 24^H 24^NR 2 °7^O:

Theory: c=59.49; h=4.99; n=5.78; s=6, 62

Found: c=59.35; h=5.16; n=5.56; s=6, 68

I.R. (CHClg): absorption bands at 2.95 (Nh 1' amid), 5.6

and 5.9 (wide, carbonyl group of the P-lactam, and carbonyl groups of the ester and the 1' amid).

NMR (CDC1₃ ): signals to 6.73 (e, 2:00, E₀ the carbon C₂ ), E, 23 (e, 6:00, p Osh₃ and 3 a-ochoch.j), 5.45 (e, 2:00, HC₂ the side chain), 5.00 (d-, 1:00, H of the carbon C ^), 4.85 (e, 2:00, human gh ^ ester), 4.47 (Q-, 1:00, H of the carbon C_? ), 3.33 - 2, 50 (w, 9:00, aromatic hr) and 2.25 (D., 1:00, HH of the amide)

UV (ethanol))>) max. 268 MPs, 00 - 5.000

The mu-max. 220, 00=14,000.

EXAMPLE 16

Acid 7 a--phenoxyacetamido-to-3-a-methoxy-3 a-céph€m-to-4-carboxylic acid.

To a solution of 176 mg of 7 a--phenoxyacetamido-a 3" - methoxy-3 a-cephem-to-4 carboxylate P-mêthoxybenzyle in Lo ml of benzene containing 50 mg is added anisole triflaoroacetic 770 mg of acid. The mixture is stirred at room temperature for 45 minutes and then evaporated under vacuum, the residual oil is dissolved in ethyl acetate and washing the solution with water. Water is added and added 1' 0 . 1n sodium hydroxide until the pH to 6.5. Is separated from the aqueous phase and the extracted by ethyl acetate. Returning the mixture at pH 2.8 with hydrochloric acid to cold. The organic layer is separated, washed with water, is dried and evaporated to dry to obtain 54 mg of acid 7 a-phénoxyacétamidc-to-3-methoxy-3 a-cephem-to-4-carboxylic acid in the form of an amorphous solid.

1. R (CHCLj): absorption peaks at 2.95 (NH-amide), 5.60 (P-lactam carbonyl), 5.89 (wide, carbonyl of the amide and carboxylic acid), and 6.5 (band II of the amide) micron.

NMR (CDC1₃ ) ii signals to 6.77 (e, 2:00, hr₂ the carbon C,), 6.13 (e, 3:00, containing carbon C methoxy₃ ), 5.47 (e, 2:00, HM ^ of the side chain), 4.97 (D., 1:00, H of the carbon C_grams ), 4.50 (q-, 1:00, H of the carbon C_? ), 3, 30 - 2, 53 (m-, 5:00, aromatic hr), 2.33 (d-, LHRH, KH amide) and 1.5 (e wide, 1:00, COOH carbon C₄ ) THE T -

EXAMPLE 17 7-acetamido-3-methoxy-3 a-cephem-to-4 carboxylate of P-nitrobenzyl.

A. cooled in an ice bath and water a solution of 10 mmol of hydrochloride 7-amino 3-hydroxy 3 a-cêphem-to-4 carboxylate of P-nitrobenzyl (prepared as described in example 1) in a mixture of 325 ml of acetone and 125 ml of water. While stirring, is obtained by bubbling a stream of ketene gas in the solution for 30 min. The reaction mixture is evaporated to drive off the acetone and the aqueous residue is suspended in ethyl acetate. Separating the layer of ethyl acetate and washed with hydrochloric acid enjoying 5% and a saturated solution of sodium chloride. Drying the washed extract and is evaporated under vacuum to give the reaction product as a crystalline residue, triturate is

the residue with diethyl ether and dried in vacuum, giving 3.55 g of 7-acetamido-3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl melts at about 146 and 152 °C with decomposition.

Elemental analysis for^C. i5^H x5^W 3 °7^S

Theory: c=48.85; h=3.84; n=10.68.

Found: c=48.97; h=3, 96; n=10.42.

(CHCl a-j) I.R.: absorption bands at 2.3 and 3.0 (does of 1' amid and OH;, 5.63 (carbonyl group of the P-lactam) and 5.95 (wide, amide derivatives, and the carbonyl group of the ester forming a hydrogen bond with the OH group in position 3) micron.

R.H.N. (CDCly: signals to 7.90 (e, 3k, HC₃ the group 7-acetamido), 6.55 (e, 2:00, hr₂ uSA carbon C ^), 4.92 (d-, 1:00, H of the carbon GC), 4.63 (m-, 2:00, HC₂ of the ester), 4.30 (Q-, 1:00, H of the carbon C_? ), 2.81 (d., 1:00, the NH of the amide), 2, 5 - 1, 8 (m-, 4:00, aromatic hr), and 2.8 (e, 1:00, OH of the carbon C,) titration electrometrically (di4f aqueous 66 c/o)

pKa of 5.9.

B following the procedure of methylation in example 15, reacting the 7-acetamido-3-hydroxy 3 a-cephem-to-4 carboxylate of P-nitrobenzyl with the diazomathane to obtain the 7-acetamido-3-methoxy-3 a-cephem-to-a-carboxylate P-nitrobenuyle crystalline.

Elemental analysis for c ^ ^ ^ ^ n-O-H-O -

Theory: c=50.12; h=4.21; n=10.31

Found * c=50.09; h=4.20; n=10.59

I.R. (suspended in the a Nujol); absorption of carbonyl group at 5.64 and 5.9 microns thick.

NMR (di OSI Dc); signals to 8.05 (e, 3:00, HC₃ the group 7 a-ac4tamiâo,^; , 6.30 (e, 2:00, hr₂ the carbon C₂ ), 6.10 (e, 3:00, methoxy group), 4.91 (D., 1:00, H of the carbon GC), 4.60 (e, 2:00, this₂ of the ester), 4.53 (Q-, 1k, H of the carbon C₇ ) eCs 2, 4 - 1, 8 (m-, 4:00, aromatic hr) 'T' A .

UV (ethanol production) ^ max. MPs 265, 1.=16,400

EXAMPLE 18

The ester dibenzhydrylic acid/5 - 7 - (2.4 a-dichlorobenzamido) - 5 a-carboxyvaléramidq / - 3 a-mét'mét'hoxy-a 3 a-cephem-to-4-carboxylic acid.

To -78 °c is cooled in an ice bath and acetone a carbonic ester solution dibenzhydrylic acid/5 - 7" (2.4 a-dichlorobenzamido) - 5 a-carboxyvaléramidq / - 3 a-exoinethylene-to-cépham-to-4-carboxylic acid in methylene chloride and ozone is bubbled in the mixture to form 1' triphenyl phosphite.

Then the reaction mixture is purged of excess ozone by passing nitrogen in the cold mixture "then treated the reaction mixture with sulfur dioxide gas to the excess to decompose 1' triphenyl phosphite and obtain the ester dibenzhydrylic acid 7 - / 5 - (2.4 a-dichlorobenzamido)" 5 a-carboxyvaléramido / - 3 hydroxy-3 a-cephem-to-4-carboxylic acid.

To a solution of the diester 3-hydroxy-methylene chloride is added diazomethane in methylene chloride containing excess diazomethane, the mixture is allowed to stand for 2 hours etherification and half to 25 °c to obtain the etherification product it is to say the ester dibenzhydrylic acid/5 - 7 - (2.4 a-dichlorobenzamido) - 5 a-carboxyvaléramido / - 3-methoxy-3 a-cephem-to-4-carboxylic acid.

EXAMPLE 19

Hydrochloride 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of the benzhydryl

To a solution of ester dibenzhydrylic acid/5 - 7 - (2.4 a-dichlorobenzamido) - 5 a-carboxyvalér/amide - 3 a-methoxv-to-3 CE phem-to-4-carboxylic acid in methylene chloride maintained at 0 and 5 degrees centigrade is added dry pyridine and phosphorus pentachloride in methylene chloride and stirred the reaction mixture for 3 hours. At cold reaction mixture is added, with stirring, an excess of sec-butanol. Filtering the precipitated hydrochloride 7-amino 3-methoxy-3 a-cephem-to-4 carboxylate of the benzhydryl and it may be purified by recrystallization.