Method of preparation of made up B-lactam.

Significant research efforts in the field of cephalosporin antibiotics have given a number of cephalosporin derivatives clinically relevant. One of the most recent developments in this field has been the discovery of cephem derivatives substituted by a halogen atom directly c-3. A number of 3-halo 3 a-cephem compounds have been described in patents of E.U.A. № 3.925.372, 4.064.343 and 3.962.227.

The antibiotic compounds are prepared by halogenation of potent 3-hydroxy 3 a-cephem compounds corresponding. The L * halogenation of 3-hydroxy 3 a-cephem compounds to obtain the 3-chloro-and 3 a-bromo 3 a-cephem compounds typically has been carried out by reaction of derivatives 3-hydroxy 3 a-cephem compounds with chlorinating or brominating agents comprising phosgene, oxalyl chloride, thionyl chloride, thionyl bromide and phosphorus halides such as phosphorus trichloride and phosphorus tribromide, generally in the presence of dimethylformamide.

Further, in the preparation of semisynthetic penicillin-type antibiotics and cephalosporin, most chemical modifications are previously performed on substrates of P-lactam arrays are acylamino C-6 or c-7 that are stable under the. process conditions but which are not preferred for maximum antibiotic activity. Thus, a step of the method common to the production of most if not all of the penicillins and cephalosporins known clinically important, is the switching off of the acylamino C-6 or c-7 to give the amino compounds substances or 6 or c-7 thereof which can be réacyler if desired. It is not doubtful that the most widely used for cutting the side chains acylamino groups and cephalosporin is the direction in which the derivative containing substances or 6 acylamino or c-7 is first transformed into imino corresponding halide and then imino ether which, by acid hydrolysis or alcoholysis, gives derivatives called "nuclear" (it is to say having a group year s the n -^{, r.} c-6 or c-7). This general process ο

and improvements have been described in a number of patents including the numbers of E.U.A. 3.549.628, 3.575.970, 3.697.515, 3.845.043 and 3.868.368.

A number of acid halides, especially acid chlorides, phosphorus derivatives, carbon and sulfur or their oxygen acids, have been described as useful for preparing the intermediates of the imino halides cut-off method in three steps of the amido group. Phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, thionyl chloride, phosgene, oxalyl chloride and trichloride catéchylphosphore have, in particular, been described as suitable reagents forming of imino-halides. Laboratory experiments showed that phosphorus pentachloride is the preferred reagent for the preparation of intermediate imino halides.

The sulfoxides of cephalosporin intermediates are widely utilized in the synthesis of cephalosporin antibiotics. Once completed reactions or the synthesis procedures using form of a cephalosporin sulfoxide, the sulphoxide function is reduced to obtain the cephalosporin molecule in reduced form or sulfide.

Before this invention, a preferred method of reduction of sulfoxides cephalosporin was that of the Patent of E.U.A. № 3.641.014. In this method, cephalosporin sulfoxides are reduced with 1) hydrogen and a hydrogenation catalyst, 2) stannous cations, ferrous, cuprous or manganous, 3) a dithionite, iodide or ferrocyanide, 4) compounds of trivalent phosphorus, 5) halosilanes or 6) chlorides chlorométhylëneiminium, where some of these reducing agents require the use of an activation agent such as acetyl chloride or phosphorus trichloride. For example, the sodium dithionate is activated by acetyl chloride in the reduction. Another method of reducing the sulfoxides of cephalosporin is described in U.S. Patent no. 4.044.002 E.U.A. of which describes the reduction of sulfoxides cephalosporin using acyl bromides binding agents in the presence of bromine. Most recently, Kukolja and Spry have disclosed the rëduction/chlorination of sulfoxides 3 a-hydroxycëphem using phosphorus trichloride, phosphorus pentachloride or phosgene in the presence of dimethylformamide.

It has recently been discovered a new class of compounds which have not drifted oxygen acids phosphorus but their aryl esters. More particularly, it has been found that triaryl phosphites selected react with equivalent amounts of chlorine or bromine by imparting kinetic products initially which, although unstable thermodynamic, may also be advantageously used in the preparation of 3-lactam. The novel triaryl phosphite/halogen compounds are described and claimed in Patent n° ^ TheS CFOs deposited on the same day qœ the present request.

The present invention relates to methods of using triaryl phosphite derivatives/halogen recently discovered, to perform:

a) 1' halogenation of a penicillin or cephalosporin having acylamino C-6 or c-7,

b) 1' halogenating a 3 hydroxy-3 a-cephem,

c) 1' halogenation in one step of a 7 acylamino-3 hydroxy-cephem,

d) reducing a cephalosporin sulfoxide,

e) the reduction/halogenation in a step d'a sulfoxide of 3 hydroxy-cephalosporin,

f) the reduction/halogenation step sulfoxide 7 acylamino-cephalosporin,

g) the reduction/halogenation step sulfoxide 7 acylamino-3 hydroxy-cephalosporin.

The present invention provides in particular the embodiments spivants:

1) A process for the preparation of imino-halides of penicillin or cephalosporin, which comprises reacting a 6 a-acylaminopénicilline or 7 acylamino-cephalosporin with about 1.0 to about 2.0 equivalents of a triaryl phosphite complex/halogen in the presence of about 1.0 to about 1.2 equivalents of a tertiary amine per equivalent of halogenating compound used, in an essentially anhydrous inert organic solvent at a temperature of about 30 °c or less, provided that, when the 6 a-acylaminopénicilline or 7 a-acylaminocéphalosporine is substituted by a hydroxy group, amino or carboxy, these moieties are first protected by appropriate conventional protective groups.

The 6 a-acylaminopénicilline or 7 a-acylaminocéphalosporine is a compound of formula

wherein R is a protecting group of the array carbonic acid;

R¹ is a hydrogen atom or a methoxy group RyCO - is an acyl group derived from a carboxylic acid? and

Y is a divalent radical selected from the group comprising

The HS VBE1/V.

^{/ N.} hM₃ ' HAS.

VBE1

T

WITH

' CHzB

VBE1

WITH

' CHsB

V-VBE1

j. yCHa

, / OR HAS_{The CHA}

where a is hydrogen, chlorine or bromine atom or a protected hydroxy group, alkoxy in c ^ ^ - C., methyl, alcanesulfonvloxy ^ ^ c-c - or (alkyl-c ^ ^ - C.) phenylsulfonyloxy; and

B is

1) an alkanoyl group in c₂ " ^ C., or carbamoyloxy group (alkyl-C.₁ ~C.₄ ) carbamoyloxy group, *

2) an alkoxy group in c - ^ - ^ C.;

3) a chlorine atom or bromine atom;

4) a group of formula - ^ the SR wherein R_grams is

a) an alkanoyl group in c ^ ^ - C.;

b) an alkyl group in the Cj c ^, phenyl or phenyl substituted with 1 or 2 substituents selected from the group consisting of alkyl radicals

the Cj c ^ alkoxy, protected hydroxy, chlorine, bromine, fluorine, a nitro, a cyano, trifluoromethyl and methanesulfonamido; or

c) a heterocyclic 5 or 6 membered ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, said ring being unsubstituted or substituted with alkyl radicals in c - ^ - ^ C., alkoxy in c ^ ^ - C., chlorine, bromine, substituted oxo, halo alkyl in the Cj-C.^>artino protected, amino C alkyl ^ - ^ c-protected, protected hydroxy, protected hydroxy alkyl, protected carboxy, or carboxy-C ^ - ^ c-protected.

2) A method which comprises reacting the complex triaryl phosphite/halogen with a derivative 7 acylamino-cephalosporin of formula

wherein R is a protective group of the carboxylic acid group;

is a hydrogen atom or a methoxy group;

R7co - is an acyl group derived from a carboxylic acid; and

M is hydrogen, chlorine or bromine

or a protected hydroxy group, alkoxy methyl, (alkyl-C.₁ - C.₄ ) phenylsulfonyloxy or a group of formula - CH2₂ B or b is

1) an alkanoyl group in c₂ The c ^ -, or carbamoyloxy group (alkyl-C.₁ ~C.₄ ) carbamoyloxy group;

2) an alkoxy group in the Cj c ^;

3) a chlorine atom or bromine atom;

4)' a group of formula - GIS where RG is

a) an alkanoyl group in c ^ ^ - C. >

b) an alkyl group at c ^ ^ - C., phenyl or phenyl substituted with 1 or 2 substituents selected from the group consisting of alkyl radicals in c ^ ^ - C., alkoxy C - ^ - ^ C., protected hydroxy, chlorine, bromine, fluorine, a nitro, a cyano, trifluoromethyl and methanesulfonamido; or

c) a heterocyclic 5 or 6 membered ring containing 1 to 4 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, said ring being unsubstituted or substituted with alkyl radicals in c₁ ~C.₄ , the Cj c ^ alkoxy, chlorine, bromine, substituted oxo, halo C alkyl ^ - ^. C., protected amino, amino C alkyl ^ - ^ c-protected, protected hydroxy, hydroxy-alkyl in the Cj c ^ protected, protected carboxy or carboxy-c ^ - ^ c-protected.

3) A method for preparing a compound of formula

which comprises reacting a compound of formula

with about 1.0 to about 1.3 equivalent of a triaryl phosphite complex/halogen in an inert organic solvent at a temperature essentially anhydrous lower at approximately 30 °c, where in the above formulae

X is chlorine or bromine;

Z is hydrogen or halogen or a group C alkyl or alkoxy ^ - ^ c-c ^ ^ - C.;

R is a protecting group of the carboxylic acid group?

is a hydrogen atom or a methoxy group;

and

^{the R} 3

N - is an amino group protected by a

conventional protecting group; or

R₂ is a hydrogen atom or an acyl group derived from a carboxylic acid; and

R₃ is an acyl group derived from a carboxylic acid; or

R₂ ^ and R taken together with the nitrogen atom to which they are attached form a group of formula

wherein R ^ is the residue of an acyl group derived from a dicarboxylic acid; provided that, when R₂ and R ^ are substituted with amino groups, hydroxy or carboxy, these moieties are first protected by a suitable conventional protective groups.

4) A method of preparing a derivative of imino-halide of formula

R

THE R? '

/

; c=n -

THE AA

the L

COOH

IX.

the GUI comprises reacting a compound of formula

X

about 2.0 to about 3.0 with equivalents of a triaryl phosphite complex/halogen in the presence of about 1.0 to about 1.2 equivalents of a tertiary amine per equivalent has

a tertiary amine per equivalent of halogenating compound used, in an essentially anhydrous inert organic solvent, at a temperature below about 30 °c, where in the above formulae

X is chlorine or bromine;

Z is hydrogen or halogen or a group C alkyl or alkoxy ^ - ^ c-c ^ ^ - C.;

R is a protecting group of the carboxylic acid group;

The R ^ is a hydrogen atom or a methoxy group;

and R ^ is the residue of an acyl group derived from a carboxylic acid; provided that, when R ^ is substituted by amino groups, hydroxy or carboxy, these moieties are first protected by a suitable conventional protective groups.

5) A method of reducing a cephalosporin sulfoxide corresponding cephalosporin, which comprises reacting said sulfoxide|cephalosporin with about 1.0 to about 1.3 equivalent of a triaryl phosphite complex/halogen, in the presence of at least 1 equivalent of a fixing agent of halogen in an inert organic solvent substantially free of water at a temperature of about 30 °c or less; provided that, when the sulfoxide of cephalosporin has on the substituent in C-7 amino group, free hydroxy or carboxy, these moieties are first protected by appropriate conventional protective groups.

The sulfoxide of cephalosporin of formula

in which

Wherein R ' is hydrogen or a protective group of the carboxylic acid group?

The R ^ is a hydrogen atom or a methoxy group;

THE R.^! VBE1

The n - / is an amino group protected by a

THE R.

conventional suitable protecting group; or r2 is a hydrogen atom or an acyl group derived from a carboxylic acid, and

R₃ is an acyl group derived from a carboxylic acid; or r2 and taken with 1' nitrogen atom to which they are bonded form a group of formula

0

it

<V.

THE II

0

wherein R ^ is the residue of an acyl group derived from a dicarboxylic acid; and Y is a divalent radical selected from the group comprising -

uu a is hydrogen, chlorine or bromine atom or a hydroxy group, protected hydroxy, alkoxy in c ^ ^ - C., methyl, C alkanesulphonyloxy ^ - ^ C., (alkyl phenylsulfonyloxy or a group of formula - CH2B where

is

1) an alkanoyl group in THE C ^ - C.^, or carbamoyloxy group (alkyl-C.₁ The c~^) carbamoyloxy group;

2) an alkoxy group in c ^ ^ - C.;

3) a chlorine atom or bromine atom;

4) group (alkoxy in c ^ ^ ^ - C.) carbonyl or (C haloalkoxy₂^_ GC) carbonyl; or

5) a group of formula - SR is_grams where R_grams is

a) an alkanoyl group in c₁ ~C.₄ ;

b) an alkyl group at c ^ ^ - C., or phenyl substituted with 1 or 2 phênyle substituents selected from the group consisting of alkyl radicals

or it is a sulfoxide derivative of cephalosporin wherein is an acyl group of formula R ^ coextruded - where

R is

7

1) a hydrogen atom or an alkyl group in c ^ - GC, halo alkyl 0. ^ ^ - C., cyanomëthyle, trifluorométhylthiométhyle, ' or 4 - (protected amino) - 4 - (protected carboxy) butyl;

2) the group R_has where R_has is phenyl or phenyl substituted with 1 or 2 substituents selected from the group consisting of alkyl radicals

alkoxy in c ^ ^ - C., protected hydroxy, chlorine, bromine, fluorine, iodine, nitro group, cyano group, carbamoyl, methanesulphonamido and trifluoromethyl;

3) an aralkyl group having the formula

^R (QS)- DEGREES_{the m} - CQiQ₂ -

wherein r° is R_& as defined above

or a group 1.4-to-cyclohexadiënyle or a heterocyclic 5 membered ring containing 1 to 4 of hëtéroatomes selected from the group consisting of oxygen, nitrogen and sulfur, said ring being unsubstituted or substituted with alkyl radicals in c ^ ^ - C., alkoxy in c ^ ^ - C., chlorine, bromine, substituted oxo, protected amino, protected amino alkyl, protected hydroxy or protected carboxy;

m is 0 or 1;

Q is oxygen or sulfur, and

Q₁ and Q₂ are independently

alkoxy in c ^ ^ - C., protected hydroxy, chlorine, bromine, ... fluorine, a nitro, a cyano, ' methanesulphonamido and trifluoromethyl; or

c) a heterocyclic 5 or 6 membered ring containing 1 to 4 hëtéroatomes selected from the group consisting of oxygen, sulfur and nitrogen, said ring being unsubstituted or substituted with alkyl radicals in c ^ ^ - C., alkoxy C - ^ - ^ C., chlorine, bromine, substituted oxo, halo C alkyl - ^ - ^ C., protected amino, amino C alkyl - ^ ^ c-protected, protected hydroxy, hydroxyalkyl ^ - ^ c-c-protected, protected carboxy or protected carboxy alkyl,

hydrogen or methyl groups;

provided that, in the above formula when m is 1, r° is limited to R;

4) substituted arylalkyl group of formula

R°CH -

4'¹

W.

wherein r° is as defined above and W is a ureido group, protected amino, protected carboxy or protected hydroxy; or

5) a group of the formula substituted oximino-

- R°-C.

An NR, b.

where r° is as defined in paragraph (3) immediately preceding and R ^ is an alkoxy group in.

6) A method for preparing a compound of formula R-Rl p_:

The Ra - \ α β /<•VI.

I

COOH

by reacting a compound of formula

0

The R: the Ra ' yRi has * XIII.

COOH

with about 2 to about 3 equivalents of a triaryl phosphite complex/halogen in the presence of at least 1 molar equivalent of a fixing agent of halogen in an inert organic solvent to an essentially anhydrous.

temperature of about 30 °c or less; wherein in the above formulae

R₁ is a hydrogen atom or a methoxy group of n - is an amino group protected by a

classque protecting group; or

R₂ is a hydrogen atom or an acyl group derived from a carboxylic acid, and

R3. is an acyl group derived from a carboxylic acid, or R₂ and R₃ taken together with the nitrogen atom to which they are bonded form a group of formula

wherein R ^ is the residue of an acyl group derived from a dicarboxylic acid;

provided that,

when the substituent

N - C-7 on the

cephalosporin sulfoxide is hydroxy substituted, amino or carboxy, such moieties are first protected by appropriate conventional protective groups.

7) A method of preparing an imino halide cephalosporin of formula

-XIV

which comprises reacting a sulfoxide faiye 7 acylamino * cephalosporin of formula

xv frames

with about 2 to about 3 equivalents of a triaryl phosphite complex/halogen in the presence of at least 1 equivalent of a fixing agent of halogen and about 1 to about 2 equivalents of a tertiary amine in an essentially anhydrous inert organic solvent at a temperature of about 30 °c at least, where in the above formulae

R is a protecting group of a carboxylic acid group;

The R ^ is a hydrogen atom or a methoxy group? The R ^ is the residue of an acyl group derived from a carboxylic acid in^C. the I " C.₂ the O f°^eMR the L^I R7cooh; and Y is a divalent radical selected from the group comprising

where A ' is hydrogen, chlorine or bromine atom, a protected hydroxy group, alkoxy in c ^ ^ - C., methyl, C alkanesulphonyloxy ^ - ^ C., (the alkyl * c ^ ^ - C.) phenylsulfonyloxy, or a group of formula - ^ ch-b wherein

B is

1) an alkanoyl group in c₂ - C.₄ , or carbamoyloxy group (alkyl-c ^ ^ - C.) carbamoyloxy group;

2) an alkoxy group in c₁ THE C~^;

3) a bromine or chlorine atom;

4) group (alkoxy in c ^ ^ - C.) carbonyl or (C haloalkoxy₂ - Dc) carbonyl; or

5) a group of formula - GIS where R ^ is

a) an alkanoyl group in c ^ ^ - C.;

b) a C alkyl group₁ ~C.₄ , phenyl or phenyl 14

O

!

the I

'•^! 1 Or 2 substituted pot|substituents selected from the group Continental icians|nse the alkyl radicals in c ^ ^ - C.,

c - alkoxy, protected hydroxy, chlorine, bromine,

4 i-J.

fluorine, - nor|ER, one cyano, methanesulphonamido and. trifluorométhfle; or

c) a heterocyclic 5 .ou 6 membered ring having 1 to 4 hétéroa; volumes selected from the group consisting 1' oxygen, sulfur and nitrogen, said ring being unsubstituted or substituted with alkyl radicals in c ^ ^ - C., alkoxy C ^ - Cchloro, the bromo, oxo acid, a halo (C alkyl ^ - ^ C.), protected amino, amino alkyl c - c ^ protected, protected hydroxy, hydroxy C alkyl - ^ - ^ c-protected, protected carboxy or carboxy-c ^ - ^ c-protected; provided that, when is hydroxy substituted, amino or carboxy, these moieties are first protected by appropriate conventional protective groups.

8) A method of preparing an imino haïogénure of 3 a-halocéphalosporine of formula

IX.

which comprises reacting a sulfoxide 7 acylamino-3 a-hydroxycéphalosporine of formula

with about 3 to about 5 equivalents of a triaryl phosphite complex/halogen, in the presence of at least 1 equivalent of a fixing agent of halogen and about 2.0 to about 5.0 equivalents of a tertiary amine in an inert organic solvent essentially anhydrous, at a temperature of about 30 °c or less; wherein in the above formulae

R is a protecting group of the carboxylic acid group;

is a hydrogen atom or a methoxy group ;. X is chlorine or bromine; and

The R ^ is the residue of an acyl group derived from a carboxylic acid in ^ " ^ £20 formula R-COOH;

provided that, when is hydroxy substituted, amino or carboxy, these moieties are first protected by appropriate conventional protective groups.

Of acylamino groups exemmles position 06 07 and the groups formamido, aeëtamido, conjugate, butyramido, chloroacetamido, 2 a-bromopropionamido, cyanoacétamido, trifluorométhylthioacétamido, 4 T-butoxycarbonylamino 4 T-butoxycarbonylbutyramido, 2 a-iodobenzamido, 4 a-benzyloxybenzamido, 3 a-cyanobenzamido, 2.6 and dichlorobenzamido, 4 a-trifluorométhylbenzamido, 3.4 and diëthoxybenzamido and 3 a-méthanesulfonamidobenzamido.

When R is a group - ^ r° (Qs)_{the m} " QC₁Q₂ -, an acylamino groups types are the groups phenylacetamido, 4 a-bromophénylacétamido, 3.5 and dinitrophénylacétamido, 4 a-benzyloxyphénylacétamido, -phenoxyacetamido, 4 a-chlorophénoxyacétamido, 2 a-propoxyphênoxyacêtamido, 4 a-carbamvlphénoxyacétamido, cyclohexadiénylacétamido, phénylthioacétamido, 2.5 to-dichlorophénylthioacétamido, 3 a-nitrophênylthioacétamido, 2 a-trifluorométhylphénylthioacétamido, 2 a-phénylpropionamido, 2 a-phénoxypropionamido, 2 phenyl 2 a-méthylpropionamido, 2 - (4-chlorophenyl) conjugate, 2 a-furylacêtamido, 2 a-thiénylacétamido, 5 a-isoxazolylacétamido, 2 a-thiazolylacétamido, 2 a-thiénylpropionamido, 5 a-thiazolylacétamido, 2 a-chloroacetamidothiazol-a 5 a-ylacétamido, 5 a-bromo thien-a 2 a-ylacétamido, 1 a-tétrazolylacétamido, 5 a-tétrazolylacétamido, andc...

Examples of an acylamino groups when R ^ is a group of the formula substituted arylalkyl r° Ch - and

W

when W is a protected hydroxy group are the groups 2 and a formyloxy-a 2 a-plénylacétamido, 2 benzyloxy-2 - (4-methoxyphenyl) acëtamido, 2 - (4 a-nitrobenzyloxy-a 2 - (3 a-chlorophênyl) acetamido, 2 a-chloroacétoxy and 2 - (4-methoxyphenyl) acetamido, 2 benzyloxy-2 a-phenylacetamido, 2-trimethyl-silyloxy groups and 2 - (4-chlorophenyl) acetamido, 2 a-benzhydryloxy-a 2 a-phênylacëtamido, andc... examples of such groupings when W is a group protected amino groups are the 2 - (4 a-nitrobenzyloxycarbonylamino) - 2 a-phênylacêtamido, 2 - (2, 2, 2 a-trichloroéthoxycarbonylamino) - 2 a-phenylacetamido, 2-chloroacetamido-a 2 - (1.4 to-cyclohexadiên l-yl) acetamido, 2 - (4 a-méthoxybenzyloxycarbonylamino) - 2 - (4-methoxyphenyl) acëtamido, 2 a-benzhydryloxycarbonylamino and 2 a-phenylacetamido, 2 - (1 a-carbometalated methoxy-2 a-propenyl) amino 2 a-phenylacetamido, 2 - (4 a-nitrobenzyloxycarbonylamino) - 2 - (2-thienyl) acetamido, andc...

When W is a carboxyl group protected, the group R ^ CONE may be a grouping - 2 - (4 a-nitrobenzyloxycarbonyl) - 2 - (2 a-thiënyl) acetamido, 2 a-benzhydryloxycarbonyl-a 2 - phenylacetamido, 2 - (2, 2, 2 a-trichloroéthoxycarbonyl) - 2 - (4-chlorophenyl) acetamido, 2 T-butoxycarbonyl 2 - (4 a-benzyloxyphenyl) acetamido and group similar.

The imido group represented by the formula

0

THE II

^ ^ R4! - are the groups maleimido, 3 a-êthylmaléimido,

•

THE II

0

3 - 4 a-diméthylmaléimido, succinimide, phthalimido and 3, 4, 5, 6 a-tetrahydrophthalimido.

Examples RG in the formula XII as unsubstituted heterocyclic ring are pyridyl, pyrazinyl, pyridazinyl, pyrimidyl, 1, 2, 4-triazinyl, pyrazolyl, imidazolyl, thiazolyl, 1, 2, 4-triazolyl, 1, 2, 3-triazolyl, 1, 2, 3 and thiadiazolyl, 1, 2, 4 a-thiadiazolyl, 1, 3, 4 a-thiadiazolyl, 1, 2, 3 a-oxadiazolyl, 1, 2, 4 a-oxadiazolyl, 1, 3, 4 a-oxadiazolyl, lH têtrazolyle, 2h-tetrazolyl, c...

A preferred group of heterocyclic rings represented by the rg includes moieties of the formula:

where a is a hydrogen atom or a group

The compounds used in these methods, the triaryl phosphite complex/halogen, are compounds derived from reaction of newly discovered triaryl phosphites selected and chlorine or bromine.

Triaryl phosphites of the formula

in which Z is hydrogen or halogen or c ^ - ^ c-alkoxy or THE C ^ ^ C., react with equivalent amounts of chlorine or bromine, in an inert organic solvent to yield essentially anhydrous, initially, of the kinetic product having the empirical formula

wherein Z is as defined hereinbefore and X is chlorine or bromine.

The term "halogen" in the definition of Z comprises chlorine, bromine or iodine. The expression "c1 - c4 alkyl" includes methyl, ethyl, isopropyl, n-propyl, n-butyl, s-butyl, tert-butyl and isobutyl. Examples of groups "alkoxy in the Cj c ^" are the groups methoxy, ethoxy, isopropoxy group, tert-butoxy and n-butyloxy.

The point (.) in the general formula used to represent kinetic products used in the present methods is simply used to indicate that equivalent amounts of halogen and triaryl phosphite are chemically combined and in a manner which is distinguishable from that existing in the thermodynamically stable derivatives that are known in the technique and are typically represented without the point [e.g. (PhOj-to-jPC ^]. The exact molecular complexes kinetic triaryl phosphite/halogen described herein has not been finalized; however, the results indicate that the physico-chemical kinetic product is a product in which the phosphorus center acquires a certain cationic character. The terms "kinetic compound", "complex kinetics", " complex (compound) phosphite_; triaryl/"," halogen "and" kinetic products halogenating compounds (reduction) kinetic " are used herein as synonymous.

Triaryl phosphites suitable for preparing the compounds useful in the present methods kinetics include triphenyl phosphite, sorting the phosphite (P mëthoxyphényle), sorting the phosphite (ochlorophényle), sorting the phosphite (p-chlorophenyl), sorting the phosphite (p-tolyl), sorting the phosphite (o-tolyl), phosphite (the m-bromophenyl) sorting, sorting the phosphite (P bromophënyle), sorting the phosphite (p-iodophenyl), sorting the phosphite (P n-propylphenyl), sorting the phosphite (p-tert butylphenyl), sorting the phosphite (m-tolyl), sorting the phosphite (P isopropoxyphényle), andc... preferred phosphite triphênyle, essentially because of its commercial availability.

You can use any of a wide variety of inert organic solvents as a medium for the preparation of the compounds and kinetic for pulping and reduction-halogenation described below.

By "inert organic solvent", is designated an organic solvent which, under the reaction conditions of the preparation, which does not react appreciably with the reagents or products. As the halogenating compounds are capable of reacting with the protonated compounds, such compounds comprising water, alcohols, amines (other than tertiary), thiols, organic acids and such other compounds protonic, should be excluded from the reaction medium.

Preferred an aprotic organic solvent is substantially anhydrous. The expression "substantially anhydrous" as used in this specification means that, although it is normally preferred anhydrous organic solvents, trace amounts of water, such as that which is common in commercially available solvents, can be tolerated. Although the kinetic products described herein react with any water present in the reaction medium, additional amounts of reagents can easily be added to compensate for the loss due to hydrolysis. It is preferred to use conventional laboratory techniques for drying solvents used and to exclude water reaction media.

Suitable solvents include hydrocarbons, they are aliphatic and aromatic, including pentane, 1 'hexane diisocyanate, 1' of heptane, octane, cyclohexane, cyclopentane, benzene, toluene, O -, m-xylene - or P -, mesitylene, andc...; ethers, cyclic and acyl such as diethyl ether, the ethyl or butyl, tetrahydrofuran, dioxane, the 1.2 to-dimethoxyethane, andc...; carboxylic acid esters such as ethyl acetate, methyl formate, methyl acetate, amyl acetate, n-butyl acetate, s-butyl acetate, methyl propionate, methyl butyrate, andc...; nitriles as 1' acetonitrile derivative, propionitrile, butyronitrile, andc...; halogenated hydrocarbons, they are aromatic or aliphatic, such as chloroform, methylene chloride, carbon tetrachloride, the 1.2-dichloroethane (ethylene dichloride), the 1, 1, 2 trichloroethane, the 1 ,l-dibromo 2 a-chloroethane, the 2 a-distinguishing marks, the 1 a-chlorobutane, the chlorobenzene derivatives, fluorobenzene, o -, m-chlorotoluene - or P -, O -, m-bromotoluene - or P -, dichlorobenzene, andc...; and nitrated compounds such as nitromethane, nitroethane, 1 - or the 2 a-nitropropan, nitrobenzene, c...

The particular inert organic solvent as the medium for the preparation of the compounds kinetic triaryl phosphite/halogen or as a medium for use in the present proédés is not critical but, however, should be given in selecting the most appropriate solvent properties as the polarity of the solvent, the melting point or boiling, and ease of separation of products.

Preferred solvents for the preparation of the kinetic product and for the present methods described below are hydrocarbons, in particular the aromatic hydrocarbons, and halogenated hydrocarbons. Preferred significantly halogenated hydrocarbons other than chloroform. Methylene chloride is the most preferred solvent.

Is allowed to stand in solution a compound derived from the reaction kinetics of a triaryl phosphite and chlorine or bromine, or isomerizes ilil.se transforms in compound stable thermodynamic corresponding to variable speeds dependent, inter alia, the nature of the triaryl phosphite, solvent, halogen and the temperature of the solution. The experimental data have also shown that the presence of an acid (the HX) or an excess of triaryl phosphite will increase the rate of transformation of the kinetic and thermodynamic product.

Using the magnetic resonance spectroscopy

31

nuclear of P, it is determined that the period (half-life) of the product reaction kinetics phosphite triphënyle and chloride in methylene chloride at room temperature is about 8 hours. There is a period of about 39 hours for the complex kinetic triphenyl phosphite/bromine under the same conditions.

As aforesaid, the period observed (transformation rate) for any complex kinetics described herein can be affected by the solvent and by the presence of a hydrogen halide (HX from) or an excess of triaryl phosphite. Thus, for example, it should be noted for a shorter time than when the solvent for preparing the complex kinetics is not rigorously dried; 1' hydrogen acid produced by the reaction of the complex kinetics with water present in the solvent will increase the rate of transforming to the stable form. Table I provides a summary of various properties of the product kinetic and thermodynamic of the product of the reaction of the phosphite triphënyle and chlorine.

1. NMR³¹ W (HM₂ C1₂ ) - 3.7 ppm *

2. ^T- l/2= 8 h at room temperature

in methylene chloride

3. an IR (HM₂ C1₂ 1120 - 1190 (ft), 1070 (ft),

1035 (f.), 1010 (ft), 990 (ft), 640 (meters)

625 (meters), 580 (AF), 510 (F.), 465 (AF) **

4. Is hydrolyzed by giving HCl and

(1 PhO)₃ IN.

5. Reacts with n tBuOH giving HCI,

n BuCl and phc>₃ IN.

1. NMR³¹ w (HM₂ C1₂ ) + 22.7 ppm *

2. Stable at room temperature

3. an IR (HM₂ C1₂ ) 1130 - 1210 (ft), 1065 (ft), 1035 (F.), 1010 (ft), 980 (ft), 625 (a TFA) 590 (meters), 505 (F.), 460 (F.) **

4. Sec * hydrolysis by giving inter alia HCI, Streptococcus (phenol) and (1 PhO)₂ PC1

5. Reacts with n tBuOH giving HCI, Streptococcus (phenol), n BuCl and (1 PhO)_has (Blockpolymers) ^ p0c1_G where a, b., C., =0, 1, 2 or 3 and a + b + c=3

31

Against P of h3po4; (+) indicates a displacement to the strong fields

(-) indicates a downfield.

a Tf=very strong

f.=strong; the m=means; AF=low.

j-j-T-T-VBE1 VBE1 expression "kinetic product" is a term of the technique that, when 1' used by referring to reactions giving two or more products, denotes the product formed as quickly, regardless of its thermodynamic stability. If such a reaction is stopped well before the products reach thermodynamic equilibrium, the reaction is referred to kinetic control since more of the product formed more quickly will be present.

In some cases, comprising reacting triaryl phosphites with chlorine or bromine, the rate of product formation kinetics and rate of thermodynamic equilibrium are such that the product kinetics can be prepared and used before a significant amount of the kinetic product occurs only or does isomerizes in stable thermodynamic product.

Maximize the production and the stability of the kinetic product, reaction conditions are chosen so as to minimize the potential for the thermodynamic equilibrium of the reaction mixture. More simply, conditions are obtained for the regulation kinetics by lowering the reaction temperature and the product temperature kinetics after it is formed, and by minimizing time allowed for thermodynamic equilibrium, e.g. using the kinetic product in a subsequent reaction shortly after its preparation.

Typically, the reactants are combined, a triaryl phosphite and chlorine or bromine, in a substantially inert organic solvent at a temperature below about 30 °c. Although the products kinetic form at higher temperature, such conditions favor the formation of thermodynamic products. Preferably, derivatives are prepared triaryl phosphite/halogen at temperatures of about 30 °C. or below. The minimum temperature for the reaction is obviously determined by the freezing point of the solvent used for the preparation. The reaction temperatures are from about substantially preferred -70 °c to about 0 °c.

It has been found that the triaryl phosphite itself reacts to a certain degree with its kinetic reaction product with chlorine or bromine, significantly increasing the rate of conversion into corresponding thermodynamic product. Therefore it is preferred, but this is not necessary, that an excess of halogen is maintained in the reaction mixture peridant formation kinetic compounds. This can be achieved in practice by adding the triaryl phosphite to a solution of an equivalent amount of the halogen or adding the halogen and triaryl phosphite concurrently with a quantity of inert organic solvent at the desired temperature. The simultaneous addition of reagents is carried out at a speed such that the color of the halogen persists in the reaction media until the last drop of triaryl phosphite such color will disappear. Or, it can eliminate the excess halogen using binding agents known as acetylenes halogen, or olefins comprising the alkenes, dienes, the cycloalcênes, or the bicycloalcenes. A preferred attachment agent is an alkene in 2 ^ ^ 6'P^{aRs exeni} W - * -^I ethylene, propylene, butylene or the amylëne.

The triaryl phosphite complex kinetic/halogen used in the method of the present invention are stabilized in solution by the addition of about 10 to about 100 moles of I into a tertiary amine having a pKa of about 6 to about ^ 10. If, for example, about 50% mole added pyridine to a solution of the product reaction kinetics triphenyl phosphite or chlorine in methylene chloride, only traces of product thermodynamic equilibrium by NMR³¹ w, extended periods of time at room temperature. The tertiary amine may be added to a solution of the complex triaryl phosphite/halogen freshly prepared, or it can be used in the reaction mixture of triaryl phosphite and halogen to obtain a stabilized solution of the kinetic product used in the present invention.

During the reduction process of the present invention, chlorine or bromine (according to the complex triaryl phosphite/halogen used) is formed as by-product. To prevent undesired side reactions between this byproduct and cephalosporin sought, a fixing agent is used halogen in the reaction mixture that reacts or inactive chlorine or bromine as soon as it is formed. The expression "halogen fixing agent" as used herein in the description of the present invention, denotes the organic substances that readily react with chlorine or bromine that do not react with the complex triaryl phosphite/halogen used as a reducing agent in the present method. Examples of halogen binding agents that can be used in the present method are alkenes, cycloalkenes, the bicycloalcenes, dienes, the cyclodienes, the bicyclodienes, the alkynes and substituted aromatic hydrocarbons that readily undergo electrophilic substitution by bromine or chlorine, for example the monophenols and ethers and esters of monophenols and polyphenols. Examples of binding agents include halogen alkenes^C 2^{- (} lo /~^as ethylene, propylene, the butene-1, the butene-2, isobutylene, the pentene-1, the pentene-2, the 2 a-methylbutene-L-, the 3 a-methylbutene-L-, hexene and 1, heptene L, octene and 1, the nonenes isomers, andc...; cycloalkenes having 5 to 8 carbon atoms in the ring such as cyclopentene, cyclohexene, cycloheptene and cyclooctene the ; the dienes and cyclodienes c ^ GC - 5 to 8 having carbon atoms in the ring, e.g., pentadiene, hexadiene, 1' heptadiene, cyclopentadiene, cyclohexadiene, cyclooctadiene, the 2.3 and dimethylbutadiene, the 1.3 and isoprëne, andc...; the alkenes having from 2 to 6 carbon atoms, such as acetylene, methyl acetylene, ethyl acetylene, dimethylacetylene, pentyne with over 1, pentyne with-a 2, the hexynes isomers, the 3 a-méthylbutyne L, the 3.3-dimethyl-butyn-a 1, and acetylenes similar in which the acetylenic bond quickly will add chlorine or bromine (it has been found that the phenylacetylene is not a fixing agent chlorine. satisfactory) ; bicyclic unsaturated hydrocarbons such as pinene and camphene; and ethers of phenols, ethers and esters of substituted phenols alcanoylic lower phenols represented

by the formula

wherein R is an alkyl group ^ ^ - ^ c-c or alkanoyl c2 c, -, the R and £RG are independently hydrogen atoms or alkoxy groups in c - ^ - ^ C., alkanoyl in c₂ ~Dc. the Cj-c-alkyl or ^. Examples of such derivatives include monomethylic ether of 1 'of hydroquinone, dimethyl ether of 1' of hydroquinone, anisole, phenetole, m-dimethoxybenzene, veratrole, phenyl propionate, phenyl acetate, the diacëtate resorcinol, and the esters and ethers of phenols like that readily react with chlorine and bromine.

The fastening agents preferred are halogen alkenes such as ethylene, the propylene copolymers, butylene, amylene is described, the cyclopentene or cyclohexene.

As theoretically at least 1 molar equivalent of halogen is produced for each equivalent of sulfoxide reduced in the present method, uses at least a molar equivalent amount of fixing agent of halogen in the process of reduction of sulfoxides cephalosporin for each equivalent of the starting cephalosporin sulfoxide. Typically, about 1 to about used 3 molar equivalents of halogen fixing agent for each equivalent of starter substances; it may, however, be used greater amounts of fixing agent halogen without changing the reduction process.

The 7 a-acylaminocéphalosporines and 6 a-acylaminopénicillines origin for the present halogenation process are all known compounds, or they may be obtained from known compounds according to conventional procedures. The chemical literature and patent literature is very abundant in the preparation of derivatives of penicillins and cephalosporins which can be used in the present method. For example, the derivative s 3 a-exométhylènecéphams are described in the patents of E.U.A. no. 3.932.393, 4.052.387 and 4.060.688. Derivatives 2-methyl 3 a-cephem compounds are described in Journal of of Chemical Society in, 97 5020 (1975) and 98 ^, 2342 (1976). The book Penicillins NDA Cephalosporins, EH Flynn to, ed., Academy press assembly, York, 1972, also describes a variety of penicillins and cephalosporins and their preparations.

The starting materials for the present process can be represented by the general formula

IR ^

R7conh -||FWD

I

COOH

VI

1, 7

wherein R, and R, R and Y are as defined above. Provided that there was not any amino groups, hydroxyl, carboxyl or other unprotected protonic substituents on the starting materials, the nature of the variables of R, the R ^, Y and R ^ is not decisive compared to the present method. It is the amido function in c 6 or c-7 which is niodifiée under the conditions of the present method, the X

in passing from the formula - CONE - the formula c=n - wherein X is chlorine or bromine. The R, the R ^, the R ^ and remain there typically unmodified. Of course, as with most other chemical processes, yields the imino-halide or ester "nuclear" thereof may vary from one substrate to another.

The 7 a-acylaminocéphalosporine starting for the present method may be a compound 1 a-oxa déthiacéphem of formula

COOH

wherein R, and R ^ are as defined above and m is the c - ^ - a or b as defined above. This are also known compounds or they can be obtained from known compounds by conventional procedures. These compounds, as well as the 1 a-carba-to-déthiacéphems and 1 aza-déthiacéphems corresponding which can also be used in the present method, are described in the Patent of E.U.A. № 4.123.528.

Each of the embodiments of methods previously described is carried out in the presence of a tertiary amine. Used typically from about 1.0 to about 1.2 equivalents, preferably about 1.0 and equivalent of a tertiary amine, for each equivalent of halogenating agent.

Tertiary amines preferred for the method and the combination halogenation enol/halogenation of imino group described below are those having a pKa of about 1 to about ^ 10. Substantially preferred are tertiary amines having a pKa of about 6 to about ^ 10. Examples of tertiary amines suitable for use in the present invention are trialkylamines such as trimethylamine, triethylamine, tri-n-propyl amine, 1 'éthyldiméthylamine, the benzyldiéthylamine, andc...; the dialkylarylamine as dimethylaniline, diethylaniline the, N, N-diethyl-4-methylaniline, n-methyl-Néthylaniline, N, N-dimethyltoluidine, andc...; tertiary amines cyclic and bicyclic pyridine, collidine, quinoline, 1' isoquinoline, the 2.6 to-lutidine, the 2.4 a-lutidine, the 1.5 and the diazabicyclo [4.3 .0lnonène and 5 (DBN is), the 1.5 and the diazabicyclo [5.4 .0lundécène and 5 (cyanoethyl), the triethylene ' diamine derivatives, andc...? and tertiary amines basic polymers as the copolymer formed from divinyl benzene and vinyl pyridine described by Hallensleben and Wurm in Anqew. Mal. Int. DE. JAMA., 15, 163 (1976). The pyridine is a preferred tertiary amine.

The present method is generally applicable to

the reduction of any of a wide variety of known cephalosporin sulfoxides. Examples of sulfoxides cephalosporin optional reduction in cephalosporin derivatives are the corresponding sulfoxides cephalosporin of formula

In so far as it is not so unprotected amino groups or hydroxy or enolic on these starting materials, the nature of the variables of R ^, r2, the R ^ and Y is not decisive. The groupings of Rj, R.₂ , and Y are generally not affected by the present method. Of course, as with most other chemical processes, yields cephalosporins searched in the present methods will vary cephalosporin another.

The sulfoxides used in this embodiment have been described in patents of E.U.A. with reference to the above formula XII as, compounds in which a is a {^ the Cj-c-alkoxy) carbonyl or (c ^ haloalkoxy) carbonyl are described in the Patent of E.U.A. no. 3.953.436. Sulfoxides 3-hydroxy 3 a-cephem and sulfoxides 3 a-exométhylènecépham are described in the patents of no. 3.917.587 E.U.A. and 4.052.387. The sulfoxides in which a is a C alkanesulphonyloxy - ^ - ^ c-group or a phenyl - or phenyl substituted-sulfonylxoy are prepared by the method described in the Patent of E.U.A. № 3.985.737. The 2-methyl 3 a-cephem compounds are described in Journal of of Chemical Society in, 97, 98 and (1975) 5020, 2342 (1976). Further, the Patent of E.U.A. № 3.647.786 describes a method generally applicable to the synthesis of sulfoxides of cephalosporins.

A preferred group of sulfoxides of cephalosporin in the present method comprises the sulfoxides having the above formula wherein:

The R ' is a protecting group of the carboxylic acid group;

is hydrogen;

R₂ is hydrogen and is an acyl group of formula - RyCO wherein R₇ an aralkyl group is of the formula

^K <- DEGREES⁰⁾₁ the n -^C. LQ^Q 2 -

where r° is a group 2-thienyl, phenyl or substituted phênyle, Q is an oxygen atom, m is 0 or 1, and Q₁ and Q₂ are hydrogen; and Y is a divalent radical of formula

vBE1 VBE1

ii or f

Α ¾

wherein a is as defined above.

When using carboxylic acids of cephalosporin in the present method, the yields significantly inferior because the complex kinetic reacts not only with the, part sulfoxide but also with carboxy group to form the corresponding acid halide which, under conditions of normal isolation of the product, is hydrolyzed to the acid. Preferably, the carboxy function in C-4 sulfoxide cephalosporin is protected prior to reduction in the present method. For the increase of the reduction when using acids of sulfoxides of cephalosporin in the present method, there may be additional equivalent of the complex kinetics. A water treatment of the reaction medium will isolate the corresponding cephalosporin acid.

The expression "protected amino" as used in the definition above refers to an amino group substituted by one of the blocking of the amino group commonly used as the t-butoxycarbonyie (T-BOC-), benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenxyloxycarbonyl, 2, 2, 2 a-trichloroéthoxvcarbonyle, or the grouping of L-carbomethoxy-2-propenyl formed with 1' methyl acetoacetate. It will be that are suitable protective groups of amino group similar as those described by J.W. the Barton in Circuit protective groups in an in-Biologique joining technology, J G W mcomy, Ed., plenum which press assembly, York, Υ Ν.., 1973, Chapter 2.

The expression "protected hydroxy" refers to the groups that 1' and which can be easily cut are formed on a hydroxy group, a formyloxy group as the, chloroacétoxy, a benzyloxy, benzhydryloxy, trityloxy, 4 a-nitrobenzyloxy, trimethylsilyloxy, phenacyloxy, tert-butoxy, methoxymethoxy, tetrahydropyranyloxy, andc.... other protecting groups of hydroxy group, including those described by B.C. Reese in Circuit protective groups in an in-Biologique joining technology, the supra, Chapter 3, are to be considered as part of the expression "protected hydroxy" as used herein.

The expression "protective group of the acidic group carbôxyligue" refers to protecting groups commonly used to block or protect the carboxylic acid functionality while the reactions are carried out on other functional sites of the compound. Such protective groups are noticed for their easy cleavage methods of hydrolysis or hydrogenolysis into the corresponding carboxylic acid. Examples of protective groups forming carboxylic acid esters include methyl, tert-butyl, benzyl, 4-methoxybenzyl, alkanoyloxymethyl c2 in^- GC, 2 a-iodoethylisopropylcarbonate, 4-nitrobenzyl, diphénylmëthyle (benzhydryl), phenacyl, 4 a-halophénacyle, dimethylallyl, 2, 2, 2 a-trichloroethyl, sorting (C alkyl ^ - ^ C.) silyl, succinimidométhyle ester forming groups and the like. In addition to the protection of the carboxy groups by ester groups, these carboxy groups may also be protected in the form of a mixed anhydride, such as that formed with acetyl chloride, propionyl chloride, the isobutyryl chloride acid chlorides and the like, in the presence of a tertiary amine. Other protecting groups known carboxy groups as those described by e. Haslam in Circuit protective groups in an in-BiologiqueChemistry, the supra, Chapter 5, will be recognized as appropriate. The nature of such groupings forming ester is not decisive.

In the foregoing definitions, the protecting groups of the hydroxyl, amino and carboxy are not exhaustively defined. The role of these groups is to protect the reactive functional groups during the present methods and can thereafter be removed at any later point in time without disrupting the remainder of the molecule. A large number of protective groups are known in the field, and the use of other protective groups which are not mentioned specifically above may also occur for the substrates used in the methods of the present invention.

The complexes triphenyl phosphite/halogen (z=h) halogenating agents are the preferred halogenating in the methods of the present invention. The complex kinetic triphenyl phosphite/chlorine is far preferable for the present methods. For the halogenation process of enols, better results have been observed when using about 1.1 to about 1.2 equivalents of halogenating reagent enolic per equivalent of substrate. For the enol halogenation method/halogenation of amino group in combination, use is preferably about 2.2 to about 2.4 equivalents, and much more preferably about 2.3 equivalents, halogenation of compounds for each equivalent of the enolic substrate.

Preferably performed with the halogenation processes of this invention at a temperature of about 0 °c or below. It is preferred that a well defined reaction temperature of about -10 °c or less. Generally, not carried the present methods to a temperature below about

- 70 °C. Preferred very much a reaction temperature of about - 10 to about - 70 °c. It should be noted that the present chlorination processes can be carried out, although this is not advantageous, at temperatures above and below - 70 °c 30°. The freezing point of the reaction medium and the solubility of the substrate are the factors limiting at low temperatures while the stability of the halogenating agent is thermodynamically unstable primary account in the choice of reaction temperatures of above. Of course, if the halogenating agent has been stabilized in solution with a tertiary amine as described above, the range of temperatures for the present method becomes a variable much less critical; temperatures above could easily be employed without significant loss in halogenating agent and without detrimentally affecting the halogenation process itself.

The embodiment of forming of imino-to-halogênures present methods is generally carried out at a temperature of about 30 °c or less. The present process is preferably carried out at a temperature of about 0 °c or less, and more preferably around -10 °c or less. Generally, the process is not performed at a temperature below about confectioneries -70 °c. It is preferred by many times a temperature range from about -10^{the O} C. at approximately -70 °c.

It should be noted that the embodiment forming imino halides of the method of the present invention can be carried out at temperatures above and below a - 70 degrees to 30°. The freezing point of the reaction medium and the solubility of the substrate are the factors limiting possible at low temperatures while the stability of the halogenating agent thermodynamically unstable and imino halides products are the major considerations to avoid choosing higher reaction temperatures. Of course, if the halogenating agent has been stability in solution with a tertiary amine as described above, the range of temperatures for the present method becomes a variable less critical; can be used at a higher temperature without significant loss in halogenating agent and without detrimentally affecting the halogenation process itself.

The embodiment of reduction method

the present invention is carried out in an inert organic solvent essentially anhydrous. Such solvents have been described and exemplified above for the description complexes/halogëne triaryl phosphite.

Preferred solvents for the present method are hydrocarbons, in particular aromatic hydrocarbons and halocarbons. Halogenated hydrocarbons other than chloroform are much preferred. Methylene chloride is the solvent yet more preferred.

This embodiment is generally carried out at a temperature of about 30 °c or less. It is preferably carried out at a temperature of about 10 °c or less.

It is not generally performed at a temperature less than about -50 °c. It is preferred by many times a temperature range from about to about 0° -30 °c.

It should be noted that the embodiment of reduction method of the present invention can be performed at temperatures above 30 °c and less than -50 °c. The freezing point of the reaction medium, the solubility of the substrate and reaction rates are the factors limiting possible at low temperatures whereas complex stability triaryl phosphite/halogëne thermodynamically unstable and cephalosporin obtained is the. main consideration to avoid the choice of reaction temperatures of above. Of course, if the complex triaryl phosphite/halogëne was stabilized in solution by a tertiary amine as previously described, the range of temperatures for the present method becomes a variable least criticized; higher temperatures can easily be used without significant loss of the reducing agent and without affecting the reduction itself.

Typically, the embodiment of reduction method is performed simply by adding the cephalosporin sulfoxide as a solid or in solution to a mixture of the triaryl phosphite complex/halogëne (about 1 to about 1.3 molar equivalents per equivalent of the sulfoxide) and a fixing agent halogen (about 1 to about 3 molar equivalents per equivalent of sulfoxide) in an inert organic solvent at the desired temperature. One can follow the course of the reaction, for example by chromatography comparative thin film.

The reduction is generally complete after about 30 minutes to about 2 hours in the preferred reaction conditions. The isolation and purification of the cephalosporins obtained can be done using conventional laboratory techniques including, for example, extraction, crystallization and recrystallization, filtration and crushing. The cephalosporins obtained are known compounds which are useful as antibiotics (after removing protective groups) or as intermediates leading to other derivatives of cephalosporins.

The triaryl phosphite/halogen complex used as the reducing agent in the present method are also potent halogenating agents. They can be used to transform the enolic hydroxyl groups and corresponding vinyl chlorides, in the presence of a base, for transforming the amide groups in the imino-corresponding halides. The reactivity of versatile complex kinetic triaryl phosphite/halogen is operated in each of the embodiments of the present invention. The present invention therefore also includes the reduction/halogenation sulfoxides of cephalosporin. These additional aspects of the present invention are illustrated and summaries by the reaction schemes I and II:

Scheme I; The enol Rëductlon/halogenation

Scheme-II: Reduction/halogenation of imino group

Scheme-III: Reduction/halogenation of 1'/enol halogenation of imino group

0

_R7C0NH ^ / VBE1

the R<■VBE1 */

the I

COOH

VBE1

/

^R7 vBE1/VBE1 rTTlI

X-VBE1 - / -

I

COOH

In the above formulae, R is a protecting group of the carboxyl group and R ^, r2, ^ / R. 1 X and Y are as defined above, provided that, when Y is

radical of formula

A is not a group

hydroxyl. The imino halides obtained in the reactions described in the schemes II and III may be isolated or converted by procedures known (by alcoholysis via 1 'imino-to-ëther) esters corresponding nuclear

ΗΧ·Η ε ΐ

respectively.

1

REDUNDANTABLE COCR COCR XXI.

In the reduction/halogenation'd ' ënols illustrated by scheme I above, prepared 3-halo cêphalosporine by reacting a sulfoxide 3 hydroxy-cephalosporin with about 2 to about 3 equivalents of the triaryl phosphite complex kinetic/halogen in the presence of at least 1 molar equivalent of a fixing agent in an essentially anhydrous inert organic solvent at a temperature of about 30 °c or less.

With reference to the scheme II above, representing another embodiment of the present invention, imino-book upwardly is prepared by reacting cephalosporin sulfoxides of 7 acylamino-cephalosporin with about 2 to about 3 equivalents of complex kinetic triaryl phosphite/halogen in the presence of at least 1 equivalent of fixing agent of halogen and from about 1.0 to about 2.0 equivalents of a tertiary amine in an organic solvent substantially free of water at a temperature of about 30 °c or less.

The scheme III above represents a preferred embodiment of the present invention by preparing an imino halide 3 a-halocêphalospôrine by reacting a - 7 acylamino * 3 a-hvdroxy-cephalosporin with about 3 to about 5 equivalents of complex triaryl phosphite/halogen, in the presence of at least 1 equivalent of a fixing agent of halogen and from about 2 to about 5 equivalents of a tertiary amine in an essentially anhydrous inert organic solvent at a temperature of about 30 °c or less. We found the best results for the method of scheme III-when using about 4.4 equivalents of complex kinetic triaryl phosphite/chlorine and about 3.8 equivalents for each equivalent of pyridine sulfoxide 7 acylamino-3 a-hydroxycéphalosporine starting, using methylene chloride as solvent.

The embodiments of methods_{in a} ee single step and more effects of the present invention, illustrated by the schemes I to III above, are carried out in substantially the same conditions as those detailed above for the overall reduction of sulfoxides cephalosporin using triaryl phosphite complexes/halogen. With the exception of particular structural requirements for the reactants cephalosporin sulfoxide, the necessity of the presence of a tertiary amine in the processes of schemes II and III, and the stoichiometry for the different particular methods to a plurality effects, all reaction parameters for the methods has several effects schemes I to III are identical to those described for the basic process of this invention. This comprises the intervals mentioned temperatures, solvents, the triaryl phosphite complex kinetic/halogen, the halogen binding agents and the particular conditions' preferred above.

The cephalosporins obtained in the present methods may be isolated and purified by standard laboratory techniques including, for example, extraction, crystallization and recrystallization and trituration.

As the imino halides obtained are sensitive to the alcoholysis or hydrolysis to acid catalysis and attack nucleophilic, certain precautions must be taken during product isolation avoid exposing the products to conditions under which such reactions of 1' ininohalogénure might otherwise result. For example, in neutral conditions obtained by holding a fixing agent concentration of a non-nucleophilic acid such as propylene oxide, which can be washed with solutions of the imino halides obtained with water and brine and evaporate them, generally under reduced pressure, to obtain the product in essentially pure form.

As the principle use of imino halides obtained is their use as intermediates 7 a-aminocéphalosporires giving the corresponding, reacted preferably the imino halides obtained in the present method, without isolating them from the reaction mixture of reduction/halogenation, confectioneries with excess' an aliphatic alcohol in^C 1~^C 15^and>P^{the R} ^ ^ f.^conference '^a 3-substituted primary aliphatic alcohol or a 1, 2 - or 1.3-diol to form esters corresponding nuclear.

The alcoholysis improved imino halides cephem through an imino ether intermediate using aliphatic alcohols (^ - substituted and the 1, 2 - or 1.3 diols to give esters nuclear cephem is described in the Patent of e.ü.a. no. 3.845.043.

It is preferred for 1 'imino-etherification and the subsequent alcoholysis of imino halides primary aliphatic alcohol β-substituted c ^ - ^ /. C.^a 1/3 diol aliphatic in the Cj-C.₁₅ 1.2 diol or an aliphatic^C 2^{- C.} 12

The primary aliphatic alcohols suitable β-substituted compounds of formula

^{THE RX} ^ CHCHaOH

Said RY

wherein Rx and Ry each is an alkyl group as the primary aliphatic alcohol has from 6-substituted 4 to about 12 carbon atoms, or Rx and Rx are taken together with the carbon atom to which they are bonded to form a cycloalkyl group having from 5 to 8 carbon atoms.

Examples of such alcohols are 1 'butanol, the 2 a-methylbutanol, the 2 a-ethylbutanol, the 2 a-ethylhexanol, the hydroxyméthylcyclopentane, 1' hydroxyméthylcyclohexane, the 2 a-nbutyloctanol, the 2 n-propylhexanol alcohols and the like. Of 1, 2 - or 1.3 diols suitable are those of formulae

HOCH-to-CHOH and ^ c CHOinHOCH

I-it!

A RW Rz of the RC rd.

wherein Rc and Rd are hydrogen atoms or alkyl groups so that the 1.2 diol has from 2 to 12 carbon atoms and Ou RW and Rz are hydrogen atoms, or methyl or ethyl groups, and each of re and RF is a hydrogen atom or a hydrocarbon group such that the 1.3 diol has from 3 to 15 carbon atoms. Examples of 1.2 diols are the 1.2 and propylene glycol, the 2.3 and butane diol, the 1.2 to-butane diol, the 3.4 to-pentanediol and 3.4 to-hexane diol. Examples of 1.3 diols are the 1.3 methylpropanediol, the 1.3 to-butane diol, the 1.3 and pentanediol diisobutyrate, the 2.2-to-dimêthyl L, 3 methylpropanediol, the 2.2-to-diëthyl-to-1.3 methylpropanediol, the 2.4 a-pentanediol and 2.2-diphenyl-L-, 3 methylpropanediol. The alcohols or diols clearly preferred for cleavage of iriino alkali metals present methods are 1' butanol, the 1.2 methylpropanediol and 1.3 methylpropanediol.

Is carried out with excess alcohol or diol for cleavage of imino halides obtained in the methods of the present invention. The amount of alcohol or diol excess is not decisive. Upon utilizing the 1.2-or 1.3 diols mentioned, an excess of 2 to 3 times will suffice.

When utilizing a primary aliphatic alcohol grams-disubstituted, preferred are generally an excess of about 3 to 6 times. Of course, greater amounts of alcohol or diol can be used without altering the flow of the ' reaction. Often utilized an excess of 10 confectioneries 15 times alcohol or diol preferred. In general, it is preferred an excess of 3 to 15 times alcohol or diol.

When using aliphatic alcohols other than those listed above as being preferred for cutting the imino halides of the present method, preferred are typically large excess, of about 10 to 100 times.

Generally, the alcohol or diol is added to the reaction mixture siplement halogenating wherein prepared 1 'imino-halide according to the method of the present invention.

The alcoholysis of 1 'imino-halide (via the formation of an imino ether) is by acid catalysis. The reaction mixture is for itself generally acidic enough that the alcoholysis occurs by addition of alcohol or diol without adding acid to the reaction mixture. However, alcoholysis to enhance speed and hence the speed of formation of the ester nuclear, acifie is preferably the reaction mixture with, for example, hydrochloric acid after adding the alcohol or diol to the reaction mixture. This can be done simply by bubbling HCl gas into the reaction mixture for a short period of time. It is possible however to use other acids, organic and inorganic. Typically, at least about added 1 equivalent of hydrochloric acid to the reaction mixture to promote the formation of the ester nuclear.

Nuclear esters obtained can often be isolated as crystalline hydrochlorides, simply by filtering the crystallized product from the reaction mixture. Nuclear non crystalline esters produced by the inventive procedure may be isolated from the reaction mixture using conventional laboratory techniques. Or, may be reacted (acylating) nuclear esters in solution, without isolating them. Acylation of the esters nuclear laboratory techniques are well known to give esters 7-acylamino cephalosporins which may be dêestérifiés to give antibiotics known or which may be used as intermediates for further chemical modifications.

By combining the reduction process/halogenation enol-imino-described above (scheme III above), using a complex triaryl phosphite/chlorine, with the subsequent alcoholysis of 1 'imino chloride resulting, achieved an improved process for preparing acid esters 7-amino 3-chloro 3 a-cephem-to-4-carboxylic acids from sulfoxides acid esters 7 acylamino-3~hydroxy and 3 a-cephem-to-4-carboxylic acids. Before this invention, the total conversion of 3 functions were performed in 3 separate steps, it is to say reduction, chlorination and interruption of the side chain, or in two steps, or by combining the reduction and chlorination (see Patent no. 3.115.643 E.U.A. of) with a subsequent cut the side chain or by combining the chlorination and severing the side chain after reduction of the sulfoxide, for example using the method described in the Patent of E.U.A. no. 4.044.002. With the discovery of the present method, the transformations of reduction, chlorination and cutoff can be performed with excellent yields in a single reaction vessel without isolation of the intermediates.

Nuclear esters 3 a-halocéphems are known compounds. They can be acylated using conventional acylation techniques and déestérifiés then to give compounds known antibiotics. Is particularly important utility of these esters nuclear intermediates in the preparation of the acid 7 - (d 2 phenyl 2 amino) acetamido-3-chloro 3 a-cephem-to-4-carboxylic, an antibiotic relatively important novel clinically.

In a preferred embodiment of the method of the present invention, prepared a hydrochloride acid ester 7-amino 3-chloro 3 a-cephem-to-4-carboxylic acid of formula

FORM XIX

a) reacting a sulfoxide acid ester 7 acylamino-3-hydroxy 3 a-cephem-to-4-carboxylic acid with about 4.0 to about 5.0 equivalents of the product reaction kinetics of equivalent amounts of phosphite triphênyle and chlorine in an essentially anhydrous inert organic solvent, in the presence of about 3.5 at approximately 4.0 equivalents of pyridine and from about 1 to about 3 equivalents of an alkene in c ^ - ^ C. in an inert organic solvent essentially anhydrous, at a temperature of about -10° to about -30 °c. ;

b) about 3 to about by adding 15 equivalents of isobutanol, of 1.3 methylpropanediol or 1.2 methylpropanediol reaction mixture, after the end of the formation of 1 'imino-chloride 3-chloro 3 a-cephem; and

c) by acidifying the reaction mixture with hydrochloric acid.

A particularly preferred inert organic solvent is methylene chloride.

Preferred substrates sulfoxides 3-hydroxy 3 a-cephem are those carrying the groups carboxamido-conventional and cephalosporin in position 07. A particularly preferred group of sulfoxides 3-hydroxy 3 a-cephem are those bearing acylamino r° of formula - (Q-^ ^ ^ - QC theS r° CONE - where is a group 2 a-thiënyle, phenyl or substituted phënyle, O is an oxygen atom, m is 0 or 1 and Q and₂ are hydrogen atoms. Clearly preferred for economic reasons and not necessarily to their reactivity with the substituents at 07 phenylacetamido, phênoxyacëtamido and 2 a-thiénylacétamido. Similarly, the 4-nitrobenzyl group is a preferred protecting group for the carboxyl group in the preferred embodiment of the present process because of the nature of crystalline hydrochloride obtained and thus the ease of separating high purity nuclear ester.

The following examples are given to further illustrate the present invention. It will be understood that this invention is not limited by any of these examples.

In the examples and the following preparations, the nuclear magnetic resonance spectra are abbreviated with NMR. The nuclear magnetic resonance spectra were obtained on a Varian model spectromëtre Associates to T 60 using tetramethylsilane as reference standard. The chemical shifts are expressed in parts per million by concerns (p.p.m.) and the coupling constants (j pieces) are expressed in Hz.

Example 1 7 - (l-chloro-2 a-phényléthylidëne) imino 3-methyl 3 a-cephem-a 4 -4 carboxylate¹ - nitrobenzyl

In 50 ml of methylene chloride confectioneries -15 °c, chlorine gas is bubbled while simultaneously adding dropwise to the solution 3.2 ml (12.3 mmol) of triphenyl phosphite (Vpp). Combined chlorine and TPP at such a rate that the color light yellow chlorine can be detected in the reaction mixture during the entire simultaneous addition. Near the end of the addition TPP, stopping the addition of the chlorine. Then adding pyrophosphate until the couleuf yellow reaction mixture is dissipated. Then added additional chlorine and the remainder TPP to the reaction mixture until the last drop TPP dissipates the color of chlorine.

With the resulting solution of complex kinetic triphenyl phosphite/chlorine thus prepared (a TPP/C.) to

-15 °c, added 4.68 grams (lg mmol) of 7 a-phenylacetamido-3-methyl 3 a-cephem-to-4-carboxylate and 4-nitrobenzyl, dropwise in 12 min, a solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of methylene chloride. The reaction mixture was stirred at a temperature of 15 to -10 -15 °c during additional minutes, then added 2.1 ml of propylene oxide. The cooling bath is removed and the reaction mixture was stirred for 15 additional minutes while the temperature to about 0 °c. The reaction mixture is washed with 25 ml of water, dried over calcium chloride dihydrate and 1' vacuum evaporated to a syrup which then crystallizes. Pulverizing the resulting product in 25 ml of diethyl ether containing six drops of propylene oxide, the mixture is filtered, washed with ether and dried in vacuum at room temperature, yielding (94.2) 4.58 g of the title product as white crystals of snow, 132 and 133 °f.w..

NMR (CDCl ^, pyridin-d 5) δ 2.18 (O, 3), 3.37

(ABq, 2, j=16 Hz range), 3.96 (e, 2), 5.05 (d derivatives, 1, j=5 Hz range), 5.37 (e, 2), 5.5 (d derivatives, 1, j=5 Hz range), 7.3 (e, 5, aromatic hr), and 7, 4 - 8, 4 (the m, 4, H-aromatic).

^ ^ ^ Analysis calculated for ^ ^ R4II Oj is a-IBS^:

C., 56.35; hr, 4.15; n-, 8.65; e, 6.60; LC, 7.30. Found:~the c, 56.60; hr, 4.25; n-, 8.83; e, 6.49; LC, 7.07. Example 2 6 - (l-chloro-2 a-phényléthylidëne) imino methoxalyl of 2', 2', 2¹ - trjchloroéthyle

A solution is prepared of about 12.3 mmol of the complex triphenyl phosphite/chlorine in 45 ml of methylene chloride according to the procedure described in the example 1. To this solution to -30 °c, added 4.66 grams

(10 mmol) of 6 in-phénylacétamidopénicillinate uu .1^! , 2 ', 2' trichloroethyl. Used additional 5 ml of methylene chloride to introduce the ester of penicillin by washing in the reaction mixture. To the resulting solution, is added dropwise in 20 minutes a solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of methylene chloride. The reaction mixture was stirred at a temperature of about 15 to -20 -30 °c min, after which added 2.1 ml of propylene oxide for destroying any HCl or any excess chlorinating reagent remaining in the reaction mixture. After allowing the reaction mixture to warm up to about 15 minutes at 0 °c during, washed the solution with 25 ml of ice water and dried over calcium chloride dihydrate.

Vacuum evaporation of the dried solution gives 11 g of an oil which crystallized by adding about 1 ml of diethyl ether. Crystallized product added 25 ml of diethyl ether containing 4 drops of propylene oxide. After stirring at room temperature for 5 min, the white crystallized product is filtered, washed with 25 ml of diethyl ether and dried under reduced pressure at room temperature. 2.52 G of the product obtained title, 84 and 85.5 ° f.w..

There is obtained a further collection of 1.06 g of the title product by evaporating the filtrate under vacuum up to a suspension of 12 grams is diluted with 20 ml of a 1:1 mixture of ether and hexane. Total yield, 74%.

NMR (CC1₄ ) 6, 1.56 (o, 3), 1.68 (O, 3), 3.96 (e, 2), 4.57 (O, 1), (e, 2) 4.8, 5.3 (e, 1, j=4 Hz to), 3.93 (d derivatives, 1, j=4 Hz range) and 7.3 (e, 5).

Analysis calculated for^C. ;] 8.^H i8^NR 2⁰ 3^CS ^ 4:

C., 44.65; hr, 3.75; the n, 5.78; e, 6.62; LC, 29.29. Found: C., 44.76; hr, 3.84; the n, 5.90; e, 6.71; LC, 29.06. Example 3 7 - (l-chloro-2 a-phénoxyéthylidëne) imino 3-chloro 3 a-cépham and 4 -carboxylate 4'-nitrobenzyl

Prepared according to the procedure described in the example 1 a solution of about 12.3 mmol of the complex ohosphite triphenyl/chlorine in 45 ml of methylene chloride. To this solution to -15 °c, added 5.04 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl introduced by washing the reaction mixture with additional 5 ml of methylene chloride. Immediately, added dropwise in 15 minutes reaction mixture a solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of methylene chloride. After stirring the reaction mixture for 15 minutes at a temperature of -10 to -15 °c, added 2.1 ml of propylene oxide. The cooling bath is removed and allowing the temperature of the mixture up to about 0 °c in 15 min, after which the reaction mixture is washed with 25 ml of ice water, dried over calcium chloride dihydrate and is then evaporated in vacuum up to about 20 grams of crystals. Not observed after addition of about 50 ml crystals of diethyl ether to the residue obtained. After decanting the ether of the residue obtained, ôn dry the residue more thrust in vacuum up to 11 g of a thick oil. This residue is washed three times with 50 ml portions of 1:1 mixture of ether and hexane. The trituration of the resulting thick oil with 25 ml of diethyl ether causes crystallization of the product. The crystallized product is filtered, washed with ether and dried in vacuum at room temperature, yielding 3.58 grams (68.6%) of the title product as crystals of light color; f.w. 94 and 97°.

NMR (CDC1₃ , pyridin-d 5) 6, 3.56 (ABq, 2, j=18 Hz range), 4.8 (e, 2), 5.13 (d derivatives, 1, j=5 Hz range), 5.3 (e, 2), 5.53 (d-wide, 1, j=5 Hz range) and 6, 8 - 8, 3 (the m, 9).

Analysis calculated for^C 22^H 17^NR 3 °6^CS ^ 2:

C., 50.59; hr, 3.28; the n, 8.04; e, 6.14; LC, 13.57. Found: C., 50.32 the R Hr, 3.36; the n, 8.20; e, 5.92; LC, 13.57. Example 4 6 - (l-chloro-2 a-phenoxyethylidene) iminopénicillate of 4'nitrobenzyl

Dried over calcium chloride dihydrate for about 15 minutes a solution of 9.71 grams (20 mmol) of 6 in-phênoxyacétamidopënicillinate of 4'-nitrobenzyl in

75 ml of methylene chloride. The solution is filtered and is evaporated to about 40 ml for adding to the preparation a TPP/C.. A solution is prepared of about 24.3 mmol of the complex triphenyl phosphite/chlorine in about 50 ml of methylene chloride at a temperature of -15 -20 °c according to steps described in the example 1. The solution is cooled TPP/c to -40 °c and the solution is added ester penicillin prepared previously. The temperature of the reaction mixture rises to about -22 °c.

Then added dropwise in 15 minutes reaction mixture, at a temperature of -20 to -30 °c, a solution of 2.02 ml (25 mmol) of pyridine in 8 ml of methylene chloride. After stirring the mixture for about 15 min, added 4.2 ml of propylene oxide (60 mmol).

After allowing the reaction mixture to warm up to 0 °c in about 15 min, washed with 50 ml quickly. ice water and dried over calcium chloride dihydrate. The solution is filtered and dried under reduced pressure evaporates up to about 27 g of solution. And then successively added 50 ml of ether and 20 ml of twice■carbon tetrachloride ; in each case, the resulting solution is evaporated under vacuum to an oil product.

The nuclear magnetic resonance spectrum of the crude product shows that it is the title product contaminated with triphenyl phosphate.

NMR (CDC1₃ ) 6, 1.33 (o, 3), 1.46 (O, 3), 4.46 (O, 1), (e, 2) 4.8, (e, 2) 5.2, 5.3 (d derivatives, 1, j=4 Hz range), 5.57 (D., 1, j=4 Hz range), and 6, 7 - 8, 3 (the m, 9).

Example 5 7 - (1-chloro-L-phénoxyéthylidëne) imino 3-acetoxy-3 a-cephem-a 4 -4 carboxylate¹ - nltrobenzyle

- Bubbled chlorine gas in 45 ml of methylene chloride cooled to -10 °c, while simultaneously adding dropwise 3.16 ml (12 mmol) of triphenyl phosphite. The verification of simultaneous addition of these reagents to maintain a light yellow color (excess chlorine) throughout the preparation until the last drop phosphite added dissipates the yellow color. To the resulting solution, is added 5.28 (10 mmol) of g to 7 a--phenoxyacetamido-to-3-acetoxy-3 a-céphem~4-carboxylate 4'-nitrobenzyl introduced ^ by washing the reaction mixture with 5 ml of methylene chloride. Then adding drop confectioneries drop in to the reaction mixture at 15 minute -10 °c 1.01 ml (12.5 mmol) of pyridine in 5 ml of methylene chloride. After stirring the mixture for 15 additional minutes s - 10 °c, is added 2.1 ml (30 mmol) of propylene oxide. After stirring for 10 minutes at 0 °c, the mixture is washed with 50 ml of ice water, dried over calcium chloride and is evaporated under vacuum to an oil. The crystallization trials of the product in ether are unsuccessful.

After evaporation under reduced pressure of all solvents the residue obtained; added 25 ml of carbon tetrachloride and is evaporated again to dryness the resulting solution. A NMR spectrum of the unpurified product shows that it is 1 'imino chloride title.

NMR (CDClj) 6, 2.06 (O, 3), 3.41 (ABq, 2, j=18 Hz range), 4.83 (e, 2), 5.05 (d derivatives, 1, j=5 Hz range), 5.28 (e, 2),

5.56 (d-wide, 1, j=5 Hz range) and 6, 8 - 8, 3 (m-, aromatic hr).

Example 6 7 a-1l-chloro 2 - (2-thienyl) éthylidëne] imino 3-methyl 3 a-cephem -4 carboxylate 4' a-nitrobenzvle

Following the procedure described in the example 1, a solution of about 12 mmol of the complex phosphite triphénylé/chlorine in 45 ml of methylene chloride. To this solution to -10 °c, added 4.74 grams (10 mmol) of 7 - (2 a-thiénylacêtamido) - 3 methyl-3 a-cephem-to-4-carboxylate 4'-nitrobenzyl introduced by washing the reaction mixture with additional 5 ml of methylene chloride. After 5 min, added dropwise in 20 - 30 minutes at 1.01 ml (12.5 mmol) of pyridine in 5 ml of methylene chloride. The reaction mixture was stirred for about 30 min to -10 °c, then allowing the reaction mixture to warm up to room temperature and stirred for about 2 hours.

To the reaction mixture, then added 2.1 ml (30 mmol) of propylene oxide. After 10 min, the mixture is washed with 50 ml of ice water, dried over calcium chloride dihydrate and is evaporated under reduced pressure to an oil. The oil obtained is crystallized by adding a 1:1 mixture of methylene chloride and ether. Filtering the crystallization mixture gives 2.03 grams (41.3%) of the title product, 129 and 132 °f.w.. Obtained 1.95 g of additional (39.6%) of the product title, by evaporation of the filtrate of the crystallization mixture. Total yield:

80.9%).

NMR (CDC1₃ )<5, 2.16 (O, 3), 3.33 (ABq, 2, j=18 Hz range), 4.16 (e, 2), 5.03 (d derivatives, 1, j=4 Hz range), 5.33 (e, 2), 5.5 (d-wide, 1, j=4 Hz range), and 6, 8 - 8, 4 (w, H-aromatic).

Analysis calculated pôut c21^H i8^NR 3 °5^S 2^C1 :

C., 51.27? HR, ' 3.69; N-, 8.54; E, - 13.03.

Found: C., 51.30; hr, 3.72; n-, 8.31; e, 12.91.

Example 7

7 - (tDC-chlorobenzylidene) imino 3-methyl 3 a-cépbem and 4 -4 carboxylate¹ - nitrobenzyl

A solution is prepared of the complex triphenyl phosphite/chlorine in 45 ml of methylene chloride using 3.16 ml (12 mmol) phosphite detriphênyle selonselon.le procedure described in the example 1 above.

To this solution to -10 °c, added the g (10 mmol) 4.14 of 7 a-benzamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl 1.01 ml (12.5 mmol) and pyridine. The reaction mixture is removed from the ice bath and it rises immediately to 0 °c. After stirring the reaction mixture for about 3 min, 1 'imino chloride begins to crystallize.

After one hour at room temperature, the reaction mixture is filtered to give a crystalline product washed with 1' ether * and Qu is dried. Isolated 2.28 grams (48.3%) of the title product, f.w. 175 °c.

Diluted, with methylene chloride filtrate obtained previously and washed successively with diluted hydrochloric acid and a dilute solution of sodium chloride then dried over calcium chloride dihydrate. Vacuum evaporation of the solution dried resulting gives an oil which, by trituration with ether diéthyligue, gives a second crop of crystals of the title product is filtered, washed with ether 50

and is dried. Thus isolated due. 1.72 grams (36.4%) filtrate product title. Total yield: 84.7%.

NMR (CDC1₃ ) δ 2.20 (O, 3), 3.43 (ABq, 2, j=8 Hz range), 5.15 (d derivatives, 1, j=5 Hz range), 5.37 (e, 2), 5.75 (d derivatives, 1, j=5 Hz range) and 7, 2 - 8, 4 (w, H-aromatic).

Analysis calculated for^C 22^H 18^NR 3 °5^CS '⁵ '^:

C., 55.99; hr, 3.84; n-, 8.90; e, 6.79; LC, 7.51. Found: C., 56.16; hr, 4.06; n-, 9.00; O, 6.54; LC, 7.67. Example 8

7 - (l-chloro-2 a-phénoxyéthylidëne) imino-L-methyl-3 a-cephem-a 4 -4 carboxylate¹ - nitrobenzyl

A solution is prepared of the complex triphenyl phosphite/chlorine in 45 ml of methylene chloride from 3.95 ml (15 mmol) of triphenyl phosphite and chlorine according to the procedure described in the example 1.

With this solution, added 4.84 (10 mmol) of g to 7-phenoxy-benzylamide 3-methyl 3 a-cêphem-to-4-carboxylate 4' nitrobenzyl which is introduced in the reaction mixture by washing with 5 ml of methylene chloride. Then, added dropwise in 30 minutes reaction mixture to -10 °c 1.3 ml (15.6 mmol) of pyridine in 8 ml of methylene chloride. The reaction mixture followed by removal of the ice bath and allowed to stirred for 30 min, then added 2.1 ml (30 mmol) of propylene oxide. After 10 min, the reaction mixture is washed with 50 ml of ice water, dried over calcium chloride dihydrate and is evaporated in vacuo to an oil which crystallized by addition of 50 ml of diethyl ether. The filtration gives 3.44 grams (68.6%) of the title product: f.w. 110 degrees and 111 degrees Celsius.

NMR (CDC1₃ , pyridin-d 5) 6, 2.16 (O, 3), 3.26 (ABq, 2, j=18 Hz range), 4.83 (e, 2), (5.01 (d derivatives, 1, j=5 Hz range), 5.28 (e, 2), 5.52 (d-wide, 1, j=5 Hz range) and 6, 7 - 8, 2 (m-, aromatic hr).

Example 9 7 - (l-chloro-2 a-phénoxyéthylidëne) imino 3 a-méthylènecépham-to-4-carboxylate 4 '-nitrobenzyl/hydrochloride 7-amino 3 a-méthylënecépham-to-4-carboxylate 4'-nitrobenzyl

A solution is prepared of about 12.3 mmol of triphenyl phosphite compound/chlorine according to the procedure described in the example 1. With this solution, added 4.84 (10 mmol) of g to 7 a--phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4'-nitrobenzyl and dropwise in 15 minutes a solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of methylene chloride. The mixture is stirred for about 15 minutes at a temperature of -10 to -15 °c before adding 2.1 ml (30 mmol) of propylene oxide.

After 15 min, the reaction mixture is washed with 25 ml rapidly water-ice, dried over calcium chloride dihydrate for about 5 minutes and evaporated under vacuum, resulting in about 11 g of a thick oil is dissolved in 25 ml of carbon tetrachloride. The NMR spectrum of the product obtained by evaporating the solution of carbon tetrachloride shows that the product is the imino chloride title contaminated only by triphenyl phosphate.

NMR (CC1₄ ) δ 3.4 (ABq, 2), (e, 2) 4.87, 5.30 (w, 3), (e, 2) 5.45 and 6, 7 - 8, 4 (w, H-aromatic).

1 'imino chloride is dissolved in 50 ml of unpurified methylene chloride and treated by 5.1 ml (55 mmol) of isobutanol and hydrogen chloride. The temperature of the reaction mixture rises from about 20 to about 30 °c is observed before the crystallization mixture in a cooling bath. After two hours at ambient temperature, the product is filtered, washed and dried, yielding 3.58 grams (92.7%) of crystals near white hydrochloride 7-amino 3 a-méthylènecépham-to-4-carboxylate 4'-nitrobenzyl, 180 and 181 °f.w..

NMR (DMSO to d 6) δ 3.67 (e wide, 2), 5.0 (D., 1, j=5 Hz range), 5, 35 - 5, 53 (m, 6) and 7, 6 - 8, 4 (w, H-aromatic)

Example 10

hydrochloride 7-amino 3 methyl-3 a-cëphem-to-4-carboxylate 4'-nitrobenzyl

To a solution of 4.1 ml of isobutanol (44 mmol) in 40 ml of methylene chloride at 25 °c, is added 2.89 grams (8 mmol) of 7 - (L-chloro-2 a-phenylethylidene) imino 3 a-mêthyl and 3 a-cépham -^, 4 carboxylate 4' - nitrobenzyl prepared in the example 1. The resultant solution is treated by hydrochloric gas flow for about 1 minute and moderate 15 seconds. The ester hydrochloride nuclear title begins to precipitate as a gelatinous solid that crystallizes rapidly and fills the solution as a paste. As stirring is inefficient ., the reaction mixture is diluted with additional 40 ml of methylene chloride. Was stirred at room temperature for 2 hours the mixture alcoholysis resulting diluted and then filtered, giving 2.52 grams (81.6%) of the title product; f.w. 183.5 °c.. When treated by HCl gas, the filtrate gives 0.47 g of additional product title (pp.f, 183.5 °c). Combined yield for the alcoholysis: 96.8%.

NMR (DMSO to d 6) δ 2.21 (O, 3), 3.65 (ABq, 2, j=16 Hz range), 5.18 (Q-, 2, j=4 Hz to, H of the β-lactam), 5.41 (e, 2) and 7, 6 - 8, 4 (w, H-aromatic).

Example 11

Hydrochloride 7-amino 3 a-m3thvl-a 3 - cephem-to-4-carboxylate 4'-nitrobenzyl

(Has) from the 7-a-phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4' - nitrobenzyl.

A solution is prepared of the complex triphenyl phosphite/chlorine by bubbling chlorine in a solution of 2.89 ml (11 mmol) of triphenyl phosphite in 50 ml of methylene chloride at -15 °c. With this solution, added 5.02 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl 0.85 ml (11.5 mmol) and pyridine. The reaction mixture was stirred for 1 hour at a temperature of to -15 -10 °c, then added 6.0 ml (64.8 mmol) of isobutanol. The cooling bath is removed and the reaction mixture is allowed to warm to room temperature in 2 hours.

Filtering the ethyl ester hydrochloride nuclear title, which begins to crystallize after approximately 15 min, washed with methylene chloride and dried.

Obtained a total of 3.55 grams (92%) of the title product as white crystals; f.w. 189 °c with decomposition.

(D) from the 7 a-heptanoylamido-to-3 ~méthyl and 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl

Repeating the experimental procedure described in paragraph (has) above in detail, using 4.61 grams (10 mmol) of 7 a-heptanoylamido and 3 methyl-~céphem 3 and 4-carboxylate 4¹ - nitrobenzyl as substrate. Isolated a total of 6.32 grams (93.8%) of the ethyl ester hydrochloride nuclear white snow as crystals, f.w. 188.5 °c with decomposition.

(C.) from the 7 a-phënoxyacétamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl in tetrahydrofuran

A solution is prepared of the complex triphenyl phosphite/chlorine by bubbling chlorine in a solution of 11 mmol of triphenyl phosphite in tetrahydrofuran (UHF) to -10 °c. With the solution, is added 4.84 (10 mmol) of g to 7 a-phénoxyacëtamido-to-3 ~méthyl and 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl. The reaction mixture is then added 0.95 ml (11 mmol) of pyridine. And then allowing the reaction mixture under stirring at -10 °c for one hour, after which it is allowed to warm to room temperature and stirred for 2 hours additional. Then adding 6.0 ml (65 mmol) of isobutanol. After 2 hours, reaction mixture is filtered. Washed with THF and dried the ethyl ester hydrochloride nuclear resulting crystalline. Total yield: 3.03 grams (78.5%); f.w. 151-to-153 °C with decomposition.

(D.) from the 7-a-phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4 '-nitrobenzyl in 1' acetonitrile derivative

A solution is prepared of the complex triphenyl phosphite/chlorine by bubbling chlorine in a solution of about 11 mmol of triphenyl phosphite in 45 ml of acetonitrile to -10 °c. With this solution, added 4.84 (10 mmol) of g to 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl and 0.95 ml

(11 mmol) of pyridine -10 °c. After allowing the reaction mixture stirred for 2 hours at -10 °c, is removed from the ice bath. After 2 additional hours, the reaction mixture is 6.0 ml (65 mmol)

54

of isobutanol. After seeding, the product crystallizes and, after one hour of stirring, the mixture is filtered, washed with 1' acetonitrile and dried; obtained in total 2.55 grams (66.1%); f.w. 184 °c with decomposition.

(I) from the 7 a-phénoxyacëtamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4' a-nitrobenzylenitrobenzyle.dans ethyl acetate

It follows the same procedure as that described in paragraph (d-) above but using ethyl acetate as a solvent for the formation of the reactive triphenyl phosphite/chlorine and for the cut-off method. Obtained total 2.48 grams (64.2%); f.w. 177-to-179 °C with decomposition.

(F.) from the 7-a-phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4¹ using the complex - nitrobenzyl phosphite to tri-O-tolyl/chlorine

Prepared as follows a solution of the complex tris-tri-O-tolyl/chlorine: added 3.91 grams (11 mmol) phosphite tri-O-tolyl to 45 ml of methylene chloride cooled down to -10 °c under nitrogen atmosphere.

Chlorine gas is bubbled into the solution until the yellow color persists. Then adding about 0.5 mmol phosphite tri-O-tolyl to remove the yellow color. With the solution, is added 4.84 (10 mmol) of g to 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl 1.01 ml (12.5 mmol) and pyridine. The reaction mixture is removed from the cooling bath and stirred for 10 min, then added 5.1 ml (55 mmol) of isobutanol. The product begins to crystallize about 5 minutes after which was bubbled hydrogen chloride in the reaction mixture. After 90 min, reaction mixture is filtered. The product is washed with 25 ml of methylene chloride and dried under reduced pressure. Obtained a total of 3.46 grams (89.6% yield);

f.w. 184 °c with decomposition.

(Grams) from the 7 a-phénoxvacétamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl using as a basis the divinylbenzene-vinyl pyridine copolymer

A solution is prepared of the complex kinetic triphenyl phosphite/chlorine in 50 ml of methylene chloride at -10 °c by first bubbling chlorine in the solution and then adding dropwise triphenyl phosphite at such a rate that the yellow chlorine still persists. When the dropwise addition of triphenyl phosphite is almost completed, stopping the addition of the chlorine. Then added triphenyl phosphite to discoloration of the solution. Used a total of 3.0 ml (11.4 mmol) of triphenyl phosphite. With this solution, added 5.0 grams (10.3 mmol) of 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4' and then immediately nitrobenzyl 5.0 g of divinylbenzene-vinyl pyridine copolymer. The reaction mixture is removed from the cooling bath and stirred for 2 hours at ambient temperature. The polymer is filtered and washed with about 20 ml of methylene chloride. Treatment of the filtrate by 6.0 ml (64.8 mmol) of isobutanol. Then HCl gas is bubbled into the mixture for about 2 min. The hydrochloride of the product begins to crystallize into nuclear about 3 minutes and, after one hour, the mixture is filtered, washed with methylene chloride and dried. Isolated a total of 2.98 grams (75%) of the ethyl ester hydrochloride nuclear; f.w. 183 °c with decomposition.

(Hr) from the 7-a-phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl using the complex phosphite (p-methoxyphenyl) sorting/chlorine.

Prepared as follows a solution of the complex phosphite (p-methoxyphenyl) sorting/chlorine: added dropwise to 45 ml of methylene chloride at a temperature of from 20° -10 4.6 grams (11.5 mmol) of " sorting phosphite (pméthoxyphényle) in about 5 ml of methylene chloride, with simultaneous addition of chlorine to an endpoint colorless. After the addition of all the reagent the phosphite, additional chlorine added to impart color light yellow; the color of excess chlorine is quickly dissipated without the addition of more phosphite. To the resulting solution, is added 4.84 (10 mmol) of g to 7 a-phënoxyacétamido and 3 a-mêthyl and 3 a-cephem-to-4-carboxylate 4' -

56

nitrobenzyl is washed in the reaction mixture with 5 ml of methylene chloride. Is then added dropwise to the reaction mixture in 15 minutes a solution of 1.01 ml (12.5 mmol) pyridine in 4 ml of methylene chloride. After stirring the reaction mixture for 15 minutes to -10 °b, reaction mixture is 5.1 ml (55 mmol) of d¹ butanol. HCl gas is bubbled into the reaction mixture, and shortly after, the cooling bath is removed. After 2 hours at ambient temperature, reaction mixture is filtered and the obtained 0.89 gm (23%) of the ethyl ester hydrochloride 173 and 174° nuclear f.w..

(I in) from the 7 a-phënoxyacétamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl, using the triëthylamine as a basis.

A solution is prepared of the complex kinetic triphenyl phosphite/chlorine by adding chlorine gas together 3.16 ml (12 mmol) of triphenyl phosphite to 45 ml of methylene chloride at -10 °c. A light yellow color persists over the entire preparation. Added 0.5 mmol additional triphenyl phosphite to dissipate the yellow color of chlorine. To the resulting solution, is added 4.84 (10 mmol) of g to 7 a-phênôxyacétamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4' nitrobenzyl are added to the mixture by washing with 5 ml of methylene chloride. After 5 min, 15 min added 1.8 ml (.13 mmol) in 8 ml of triëthylamine methylene chloride. After stirring the reaction mixture for 15 minutes to -10 °c, the cooling bath is removed from the reaction mixture and added 5.1 ml (55 mmol) of d * butanol. Then HCl gas is bubbled into the reaction mixture for about 3 min. The reaction mixture is seeded and allowed to warm to room temperature. After 2 hours to. room temperature, reaction mixture is filtered and the obtained 1.28 grams (33.2%) of the ethyl ester hydrochloride nuclear, f.w. 180.5 °c with decomposition.

(D) from the 7 a-phénoxvacétamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl using DBU as base.

It follows the same experimental procedure as described in paragraph (I-) above but using, instead of the triêthylamine, 1.95 ml (13 mmol) of 1.5 and the diazabicyclo [5.4 .cQundéc-to-5-ene (cyanoethyl). Isolated 0.59 grams (15.3%) of the ethyl ester hydrochloride nuclear; f.w. 181 °c with decomposition.

(K.) from the 1-oxide of 4 of 6 a-phénoxyacêtamidopénicillanate¹ - nitrobenzyl.

Is heated at reflux for 4 hours a solution of 5.02 grams (10 mmol) of the 1-oxide 6 a-phénoxyacétamidopénicillanate of 4¹ - nitrobenzyl 0.25 grams (1 mmol) of pyridinium dichlorométhanephosphonate 88 ml of 1, 1, 2 trichloroethane in. The reaction mixture is evaporated under vacuum to a volume of about 44 ml.

A solution of 12 mmol of the reagent triphenyl phosphite/chlorine by bubbling chlorine gas into a solution of 3.15 ml of triphenyl phosphite in 44 ml of 1, 1, 2 trichloroethane to -10 °c. The chlorine gas is bubbled into the solution until a yellow color persisted. And then flushing the yellow color by adding a drop of triphenyl phosphite.

And then adding the solution of the first paragraph above to the solution (to -10 °c) of the reagent triphenyl phosphite/chlorine. And then added to the reaction mixture to

-10 °c 0.89 ml (11 mmol) of pyridine. After 30 minutes at this temperature, the reaction mixture is removed from the ice bath and allowed réchaqffer to room temperature. After 30 min, added 0.42 ml (5 mmol) additional pyridine. After stirring the reaction mixture for 30 minutes, added 9.25 ml (100 mmol) of isobutanol. The product crystallizes while the reaction mixture was stirred overnight. The filtration gives 2.67 grams (69.2%) of the

The Chl•' ôrhydratë * nuclear ester; f.w. 183 °c with decomposition.

(I) from the 1-oxide 6 a-phénoxvacétamidopénicillanate of 4'-nitrobenzyl, using the 2.6 to-lutidine as base

It follows the same procedure experimental that in paragraph (a K) above, but instead of pyridine 1.25 ml (11 mmol) of 2.6 to-lutidine. Also bubbled hydrogen chloride in the reaction mixture for about 60 seconds after the addition of 1' butanol. The product begins to crystallize about 2 to 3 minutes after 1^{* 1} adding hydrogen chloride.

Isolated a total of 2.47 grams (64%) of the di-hydrochloride nuclear; f.w. 173 °c with decomposition.

Example 12

Hydrochloride 7-amino 3-methoxy-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl

Is obtained by bubbling chlorine in an agitated solution of 0.4 ml (1.5 mmol) of triphenyl phosphite in 10 ml of methylene chloride at -10 °c up to persistence of the yellow color light green of excess chlorine. A small drop of triphenyl phosphite fact totally disappear the color. To the resulting solution, is added 0.5 grams (1 mmol) of 7 a--phenoxyacetamido-to-3-methoxy-3 a-cephem-to-4-carboxylate 4'-nitrobenzyl 0.12 ml (1.5 mmol) followed by pyridine. The reaction mixture is removed from the cooling bath and stirred one and a half hours at room temperature, then added 0.6 ml (6.4 mmol) of d¹ butanol. The hydrochloride of the title nuclear product begins to crystallize in the reaction mixture in 5 minutes after addition of the alcohol. After 1 hour and a half, reaction mixture is filtered and the obtained 0.3 grams (75%) of the title product as white crystals dirty; f.w. 185 °c with decomposition.

NMR (DMSO to d 6) 6, 3.92 (e wide, 2), 4.0 (O, 3),

5.02 (d derivatives, 1, j=5 Hz range), 5.32 (D., 1, j=5 Hz range), 5.45 (e, 2) 7, 6 - 8, 4 and (w, H-aromatic)

Analysis calculated for c ^ ^ ^ ^ H-O-n-SCLs - ':

C., 44.84; the H, 4.01; n-, 10.46; LC, 8.82; e, 7.98. Found: C., 44.69? Hr, 4.17; n-, 10.34; LC, 9.05; e, 7.77.

Example 13

Hydrochloride 7-amino 3 a-méthylènecépham-to-4-carboxylate 4' - nitrobenzyl

To a solution of 5.02 grams (10 mmol) of 1-oxide 7 a--phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4' nitrobenzyl 2.4 ml (22.5 mmol) in 50 ml amylene methylene chloride to 15 °c, is added dropwise in 10 minutes at 1.67 ml (22.5 mmol) of acetyl bromide.

The reaction mixture is cooled to 0 °c, 25 ml of ice water is added and the mixture stirred for 30 minute reaction. Separating the layer of methylene chloride, then washed successively with 25 ml of water and with 25 ml of a dilute solution of sodium chloride, dried over anhydrous sodium sulfate and evaporated under vacuum to a volume of 25 ml.

A solution is prepared of the complex kinetic triphenyl phosphite/chlorine by bubbling chlorine gas into a solution of 2.89 ml (11 mmol) of triphenyl phosphite in 25 ml of methylene chloride at -10 °c up to persistence of the yellow color. Is added to the solution to remove the yellow color 0.12 ml (0.46 mmol) of additional triphenyl phosphite. With the resulting solution to -10 °c, added the solution prepared according to the preceding paragraph. Then added 0.93 ml (11.5 mmol) of pyridine. Then the reaction mixture is removed from the ice bath and allowed to warm to room temperature. After one hour, the reaction mixture is 5.1 ml (55 mmol) of isobutanol. The product begins to crystallize in the reaction mixture after about 10 mins. After stirring the reaction mixture 90 minutes at room temperature, the mixture is filtered and is obtained (82.1%) of 3.17 g of ethyl ester hydrochloride nuclear title; f.w. 182 °c with decomposition.

NMR (DMSO to d 6) 6, 3.6 (e wide, 2), 4.95 (D., 2,

J=5 Hz range), (w, 6) 5, 33 - 5, 7, and 7, 6 - 8, 4 (w, H-aromatic).

Example 14 7-amino 3 a-acetoxymethyl and 3 a-cephem-to-4 carboxylate of the benzhydryl

To a solution of 1.39 grams (1.5 mmol) of the ester of the 2.4 a-dichlorobenzoylcéphalosporine dibenzhydrylic C as :.?: 10 ml of methylene chloride at -35 °c, 0,484 ml is added pyridine (6 mmol). To the resulting solution, a solution of the reagent is added triphenyl phosphite/chlorine -10 °c prepared from 1.57 ml (6 mmol) of triphenyl phosphite and chlorine in 10 ml of methylene chloride. After 150 minutes to about 18 °c, the reaction mixture is cooled to -5 °c and treated by 3.0 ml of isobutanol. The reaction mixture is allowed to heat to a temperature of about 20 °c, after which the solvent evaporated from the reaction mixture, thereby leaving a dark brown syrup. The residue is dissolved in 20 ml of resulting methylene chloride and 10 ml of water. Is adjusted to 0.9 with hydrochloric acid the pH of the aqueous layer.

Then mutually separating the methylene chloride layer is decided and extracted with water at pH 7.5. And then dried methylene chloride layer over magnesium sulfate and evaporated in vacuo to about 3.5 g of a very dark brown syrup is dissolved in 3.5 ml of a solution 3:7 ethyl acetate and toluene and applied to the surface of 40 g of silica gel in a column of 9 mm.

Chromatography using initially a mixture of eluent 3:7 ethyl acetate and toluene eluent 1:1 and then a mixture of toluene and ethyl acetate gives a total of 0.24 grams (36%) of the title product.

Example 15

Acid 7-amino 3 a-acetoxymethyl and 3 a-cephem-to-4-carboxylic (7 a-AAC).

With a suspension of 2.94 grams (5 mmol) of 2.4 and dichlorobenzoylcéphalosporine C., 0.16 ml (1.34 mmol) of quinoline and 2.39 ml (15 mmol) of n, N-diethylaniline in 30 ml of methylene chloride at room temperature, is added 2.45 ml (34.5 mmol) - acetyl chloride. After cooling the reaction mixture to

-25 °c, added 0.6 ml (3.75 mmol) of a solution of the reagent and diethylaniline triphenyl phosphite/chlorine obtained from 3.68 ml (14 mmol) of triphenyl phosphite in 15 ml of methylene chloride. And then removing the reaction mixture from the cooling bath and allowed to warm to room temperature

2 hours. After cooling the mixture to -15 °c, added 8.5 ml (116 mmol) of propylene glycol. The reaction mixture was stirred for about half an hour to 20 °c, after which it is cooled to -15 °c then combines with 25 ml of ice water. The aqueous layer which is separated from the pH is adjusted to 3.5 with 3.3 ml of ammonium hydroxide.

After shaking for 1 and a half hours in an ice bath, the solution is filtered and the obtained aqueous 0.4 grams (29%) of 7 a-AAC.

Example 16

Acid 7-amino 3 methyl-3 a-cephem-to-4-carboxylic (7 a-DCAA).

With a suspension of 3.40 grams (10 mmolesj acid 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylic, 0,158 ml (1.34 mmol) of quinoline and 2.38 ml (15 mmol) of n, N-diethylaniline in 30 ml of methylene chloride at room temperature, added 2.46 ml (34.5 mmol) of acetyl chloride. The reaction mixture is left under stirring for about 6 hours at a temperature of 18 to 22 °c. Then the reaction mixture is cooled to

-15 °C. Then added 0.6 ml (3.75 mmol) of n, N-diethylaniline and a solution of the reagent triphenyl phosphite/chlorine from 3.68 ml of triphenyl phosphite and chlorine in 15 ml of methylene chloride. And then removing the reaction mixture from the cooling bath and allowed to warm up to room temperature during the almost 7 minutes thereafter. Then the reaction mixture is cooled to -20 °c and added 10.7 ml (116 mmol) of isobutanol. Removed again the reaction mixture of the cooling bath. About 45 minutes after the addition of the alcohol, noted an abundance of a solid precipitate. After an additional half hour at room temperature, the reaction mixture is cooled to 0 °c and filtered, yielding 1.95 grams (73%) of 7 a-DCAA. Few impurities are visible on a NMR spectrum of the product.

Example 17

Acid 7-amino 3 a-acetoxymethyl and 3 a-cephem-to-4-carboxylic (7 a-AAC)

With a suspension of 4.18 grams (9.76 mmol) of 7 a--phenoxyacetamido-a 3 a-acetoxymethyl and 3 a-cephem-to-4 carboxylate sodium, 0,154 ml (1.31 mmol) of quinoline and 2.91 ml (18.2 mmol) of n, n diéthylanilihë in 29 ml of methylene chloride at room temperature, added 2.40 ml (33.6 mmol) of chloride acëtyle. After 1 hour and 15 minutes at room temperature,, the reaction mixture is cooled to -35 °c. To this mixture, a solution of the complex added kinetic triphenyl phosphite/chlorine prepared from 3.6 ml (13 mmol) of triphenyl phosphite and chlorine in 15 ml of methylene chloride. The reaction mixture was stirred at a temperature of -25 to -20 °c during ' about 60 min, thereafter adding 10.5 ml of isobutanol. The mixture is allowed to warm up to 0 °c, temperature at which is stirred for 2 hours. The reaction mixture is then added to a mixture of 50 g of ice and water. The aqueous layer is separated and adjusting its pH to 3.5 confectioneries. Then the solution is stirred 1 hour aqueous during in an ice bath under nitrogen stream. Filtering the aqueous solution gives 2.7 grams (78%) of 7 a-AAC.

Example 18

Acid 7-amino 3 a-acetoxymethyl and 3 a-cephem-to-4-carboxylic (7 A-AAC)

Suspended is 4.55 g of the sodium salt of cephalosporin c in 142 ml of chloroform inhibited by amylene. The solution is distilled to a volume of 67 ml. Then it is cooled 26 °c the suspension of sodium salt of cephalosporin c in chloroform. With this solution, added 0,464 ml (3.94 mmol) of quinoline, 6.95 ml (43.5 mmol) of diethylaniline and 9.30 ml (131 mmol) of acetyl chloride.. and then heated with stirring to the mixture to about 35 °c in 7 min, after which the heat source is removed. After 2 hours of stirring, reaction mixture is filtered through hyflo using a hard glass paper in a Buchner funnel.

Ôn adds a solution of the reagent of triphenyl phosphite/chlorine -20 °c prepared by adding chlorine and triphenyl phosphite (8.9 ml, 34 mmol) simultaneously with 35 ml of chloroform, to a mixture of the filtrate obtained previously to -30 °c and 3.2 ml (20 mmol) of diethylaniline. The reaction mixture is stirred at a temperature of from 60 to -20 -15 °c during minute, after which it is cooled to -35 °c. Then adding 15 ml of propylene glycol.

After stirring the reaction mixture for 2 hours at 0 °c, then you're 51 g of ice. The chloroformic layer is separated and is re-extracted with 5 additional grams of ice water. One joins the aqueous extracts and adjusting the pH thereof to about 3.5 with 7.5 ml of ammonium hydroxide. Then to the aqueous solution for 60 minutes in an ice bath with a stream of air blown across the surface to flush residual chloroform. The suspension is filtered off and washed sequentially with the product 6 ml of water, 15 ml of methanol and 5 ml of acetone.

Obtained total 1.87 grams (73%) of 7 a-AAC(air dried).

Example 19

Acid 7-amino 3 a-acetoxymethyl and 3 a-cephem-to-4-carboxylic (7 A-AAC)

(Has) is ' 4.8 grams (10 mmol) of the sodium salt of cephalosporin C dihydrate suspended in 80 ml of methylene chloride (stabilized by cyclohexane, dried over molecular sieves 4a). Added 7.4 grams (8 ml, 50 mmol) of diethylaniline dried on KOH and 4.7 grams (4.3 ml, 60 mmol) of acetyl chloride. The mixture is stirred in an ice bath to 30 - 40 °c for one hour and then at room temperature for 2 hours. Filtration removes 1.65 g of undissolved material. The reaction solution is cooled in an ice bath before adding alcohol to a solution of the compound kinetic triphenyl phosphite/chlorine prepared as follows: added 6.8 grams (5.8 ml, 22 mmol) of triphenyl phosphite to 100 ml of dry methylene chloride cooled down to the temperature ice-alcohol before adding chlorine gas to persistence of a yellow coloration. The addition of a few drops of triphenyl phosphite gives a colorless solution. After mixing the two solutions described previously to the bath temperature ice-alcohol, is added dropwise in 10 minutes at 3.3 grams (3.5 ml, 22 mmol) in 20 ml of diethylaniline dry methylene chloride. The reaction mixture was stirred at cold for 2 hours, and then cooled. again to about -35 °c and treated by 6.0 grams (7.4 ml, 80 mmol) of isobutanol dried on molecular sieve 3a. Subsequently passed into the reaction mixture for about 30 seconds a stream of dry hydrogen chloride. It refrigerates the reaction mixture overnight. Then the OH adds 20 ml of water to the solution of methylene chloride. Vigorously shaken for 5 minutes the mixture to 2 phase resulting. Separating the methylene chloride layer washed with 20 ml of water. One joins the aqueous layer and wash water, washing them with ethyl acetate followed by adjustment to pH 3.8 with a saturated solution of ammonium bicarbonate.

After 30 minutes at the temperature of the ice bath, the aqueous suspension is filtered and the obtained 1.5 grams (vacuum-dried, 83%) of 7 a-AAC.

(B.) is 4.8 grams (10 mmol) of sodium salt dihydrate of cephalosporin C 80 ml suspended in tetrahydrofuran (dried over molecular sieve 5a). Added 7.4 grams (8.0 ml, 50 mmol) of diethylaniline dried on KOH and 4.7 grams (4.3 ml, 60 mmol) of acetyl chloride. The mixture is stirred in a water bath to about 30 - 40 °c for one hour, then at room temperature for about 2 hours and demiç.. the filtration removes 5.7 g of undissolved material. The reaction solution is cooled in an ice bath before adding alcohol to a solution of the complex triphenyl phosphite/chlorine prepared as in paragraph (has) above, but using tetrahydrofuran as solvent in place of methylene chloride. After mixing the two solutions, added dropwise in 10 minutes a solution of 3.3 grams (22 mmol) of in 20 ml tetra * diethylaniline dry tetrahydrofran. The reaction mixture was stirred cold for 2 hours, cooled further to about -35 °c, then^C. the BN treated by 16 ml of propvlèneglycol. Is passed through the reaction mixture for about 15 seconds a stream of dry hydrogen chloride. It refrigerates overnight the reaction solution. The treatment as described in paragraph (has) which precedes provides 1.2 gm (45%) of 7 a-AAC.

(C.) is 3.3 grams (5 mmol) of salt monohydrate of n-chloroacétylcéphalosporinequinolëine c into suspension in 40 ml of methylene chloride (stabilized by cyclo hexane and dried over molecular sieve 4a). Added 3.0 grams (20 mmol) of KOH and 1.9 diëthylaniline dried on the g (1.8 ml, 25 mmol) of acetyl chloride. The mixture is stirred at room temperature for 1 hour. The reaction solution is cooled in an ice bath before adding alcohol to the complex triphenyl phosphite/chlorine which we prepared a solution as in paragraph (has) above, using 3.4 grams (11 mmol) of triphenyl phosphite.

After mixing the two solutions described in the previous paragraph, is added dropwise in a solution of 10 dab 1.6 grams (11 mmol) in 10 ml of diëthylaniline dry methylene chloride. The reaction mixture was stirred at cold for 2 hours, and then cooled more thrust to about - 35 °c and treated by 3.7 ml of isobutanol (dried over molecular sieve 3a). A current is passed hydrogen chloride in the reaction solution for about 15 min. Then cools the reaction mixture overnight. After the treatment procedure described in paragraph A above, 730 mg (54%) is isolated of 7 a-AAC.

Example 20

Hydrochloride 7-amino 3 methyl-3 a-cëphem-to-4-carboxylate 2¹ , 2¹ , 2¹ - trichloroethyl, in benzene.

(Has) simultaneously added chlorine gas and 3.16 ml (12 mmol) of triphenyl phosphite to 10 - 15 °c to 45 ml of benzene. A light yellow color is maintained in the reaction mixture until the last drop phosphite added to clarify the solution. With this solution, added 4.64 gm (10 mmol) of 7 a-phênylacétamido-to-3-methyl 3 a-cephem-to-4~carboxylate of 2¹ , 2¹ , 2¹ - trichloroethyl. After stirring the reaction mixture for 5 minutes at 10 and 15 degrees Celsius, added 15 minutes a solution of 1.1 ml (12.5 mmol) of pyridine in 8 ml of benzene. After stirring the reaction mixture for a total of 45 min, added 5.1 ml (55 mmol) of isobutanol, and HCl gas is bubbled into the reaction mixture for about 90 seconds. The product crystallizes during queque.l title ' the reaction mixture was stirred at room temperature for 2 hours. The filtration gives 3.5 grams (91.6%) of the ethyl ester hydrochloride nuclear title; f.w. 179 °c with decomposition.

NMR (DMSO to d 6) 6, 2.27 (O, 3), 3.6 (ABq, 2, j=16 Hz range), 5.00 (e, 2), and 5.12 (Q-, 2, j=4 Hz range) H of the 8-lactam).

(D) repeating the same procedures as in paragraph (has) of the example 20 but all preparation is carried out at room temperature (20 and 25 degrees Celsius) instead of 10 and 15 degrees Celsius. Isolated a total of 3.26 grams (85.4%) of the ethyl ester hydrochloride nuclear title; f.w. 179 °c with decomposition.

Example 21

Hydrochloride 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl

Chlorine gas is bubbled into a solution of 2.63 ml (10 mmol) of triphenyl phosphite in 50 ml of methylene chloride at 0 and 5 degrees Celsius until a yellow color. Dissipate 1' excess chlorine, outlined by the yellow color of the solution, by adding triphenyl phosphite dropwise until disappearance of the yellow color. This requires additional 0.47 ml (1.8 mmol), resulting in a solution of 11.8 mmol of the complex kinetic triphenyl phosphite/chlorine. With this solution, added 5.04 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4-nitrobenzyl and a solution of 1.01 ml (12.5 mmol) of pyridine in 2 ml of methylene chloride. With the addition of the pyridine solution, the temperature of the reaction mixture changed from 5 to 12 °c. Then allowing the solution under stirring at room temperature for 2 hours, then added 5.1 ml (55 mmol) of isobutanol. In 10 min, the title hydrochloride begins to crystallize in the reaction mixture. After one hour and half ^ mixture is filtered and the obtained, after drying, 3.71 grams (91.4%) of the title product as crystals near white;

f.w. 180-to-181 °C with decomposition.

NMR (DMSO to d 6) 6, 3.7 (e wide, 2), 5.33 (Q-, 2, H of the 8-lactam), 5.46 (e, 2) 7, 5 - 8, 4 and (H-aromatic).

Example 22

Hydrochloride 7-amino 3 methyl-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl

Chlorine gas is added to a solution of 2.89 ml (11 mmol) in 50 ml of phosphite triphënvle of methylene chloride at 0 and 5 °C to persistence of a yellow color in the reaction mixture. And adding additional 0.17 ml (0.65 mmol) of triphenyl phosphite to remove the yellow color. To the resulting solution, to 0 and 5 degrees centigrade, added 4.84 (10 mmol) of g to 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl introduced by washing the reaction mixture with 5 ml of methylene chloride. The reaction mixture is then 1.01 ml (12.5 mmol) of pyridine, resulting in a temperature increase of 10 °c to 5°. Then the mixture is allowed to warm to room temperature and stirred for 2 hours, then added 5.1 ml (55 mmol) of isobutanol. After about 20 min, is bubbled through a trace of hydrogen chloride in the reaction mixture. The product begins to crystallize immediately. After 2 and one half hours, reaction mixture is filtered and the obtained, after drying, 3.29 grams (85.3%) ester hydrochloride of the title, f.w. 177 °c with decomposition.

0.32 Is isolated additional G title product after processing the previous filtrate. additional with hydrogen chloride. The total yield product title is 93%.

Example 23

Chorhydrate of 7-amino 3 methyl-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl

Chlorine gas is bubbled into a solution of 2.89 ml (11 mmol) of triphenyl phosphite in 50 ml of methylene chloride and 5 and 10 °C until the solution becomes a pale yellow indicating the presence of an excess of chlorine. Added two drops of triphenyl phosphite for removing color. With the resulting solution to 5 and 10 °, added 4.67 gms (10 mmol) of 7 a-phenylacetamido-3 a-mêthyl and 3 a-cêphem-to-4-carboxylate 4' nitrobenzyl, 0.85 ml (10.5 mmol) followed by pyridine. The solution is allowed to warm to room temperature.

After 2 hours, the mixture is cooled to 15 °c before adding 5.1 ml (55 mmol) of isobutanol. Then, the reaction mixture was stirred during 2 hours at room temperature, during which time the product crystallizes.

The filtration gives, in 3 crops, a total of 3.5 grams (90.6%) of the title hydrochloride; f.w. 188 °c with decomposition.

Example 24

Hydrochloride 7-amino 3 methyl-2 a-cephem-to-4-carboxylate 4'-nitrobenzyl

Using the same procedure as that of the example 23 below but is used as the substrate 7 a--phenoxyacetamido-to-3-methyl 2 a-cephem-to-4-carboxylate 4' nitrobenzyl, 4.84 grams (10 mmol). Isolated a total of 3.27 gm (84.7%) of the title hydrochloride; f.w. 184 °c with decomposition.

NMR (DMSO to d 6) δ 1.96 (e,), 5.12 (e wide, 2),

5.4 (meters), 6.34 (e wide, 1) 7, 6 - 8, 4 and (H-aromatic) Example 25

Hydrochloride 7-amino 3 a-willwill méthylënecéphara-to-4-carboxylate 4¹ - nitrobenzyl

It follows the same procedure as that of the example 23 above, but is used as the substrate 7 a--phenoxyacetamido-a 3 a-méthylènecêpham-to-4-carboxylate 4' nitrobenzyl, 4.83 grams (10 mmol). Isolated a total of 3.58 grams (92.8%) of the title hydrochloride; f.w. 176.5 degrees-a 177 °C with decomposition. The NMR spectrum of the product is identical to that described for the product in the example 9 above.

Example 26

Hydrochloride 7-amino 3-acetoxy-3 a-cephem-to-4-carboxylate 4-nitrobenzyl

Chlorine gas is bubbled into a solution of 2.89 ml (11 mmol) of triphenyl phosphite in 50 ml of methylene chloride at 5 and 10 °C to persistence of the yellow color of chlorine. And then flushing the color by adding 3 drops of triphenyl phosphite. By removing the cooling bath before adding 5.28 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-acetoxy-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl (10.5 mmol) and 0.85 ml pyridine. Then the reaction mixture was stirred at room temperature for 2 hours, then added

6.0 ml (64.8 mmol) of isobutanol. In the 8 min, the product begins to crystallize in the reaction mixture. After 2 hours, the mixture is filtered and obtained 2, 57g (59.9%) of the title hydrochloride as crystals brilliant white; f.w. 160 °c with decomposition.

Noting the occurrence of additional product in the filtrate but none isolation test thereof was performed.

NMR (DMSO to d 6) 6, 2.2 (O, 3), 3.93 (s-wide, 2),

5.45 (meters) and 7, 6 - 8, 4 (H-aromatic).

Example 27

Hydrochloride 7-amino 3 methyl-3 a-cephem-to-4-carboxylate 4¹ using the complex - nitrobenzyl phosphite to kinetic sorting (p-chlorophenyl)/chlorine

With 5.17 grams (12.5 mmol) phosphite sorting (p-chlorophenyl) and 0.27 ml (3.28 mmol) of pyridine in 25 ml of methylene chloride at -70 °c, added chlorine gas. Added 0.40 ml amylene to disappear the excess chlorine. To the resulting solution, is added 2.42 grams

(5 mmol) of 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl (9.22 mmol) and 0.79 ml pyridine in 4 ml of methylene chloride, dropwise in 11 min. After 3 hours, the cooling bath is removed and added 6.94 ml of isobutanol. After heating the reaction mixture to about -10 °c, HCl gas is bubbled into the mixture for about 1 min. After 15 min, reaction mixture is filtered and the obtained 1.86 gm (96%) of the title product as a white solid; 184 and 185 °C with f.w. decomposition.

Example 28

7 - (l-chloro-2 a-phenylethylidene) imino 7-methoxy-3-acetoxy -methyl 3 a-cephem-to-4-carboxylate benzyl

To a solution of the complex phosphite triphênyle/chlorine prepared from chlorine and 12.3 mmol of phosphite in the presence of 0.1 ml triphênyle pyridine in 45 ml of methylene chloride confectioneries -15 °c, added 5.11 grams (10 mmol) of 7 a-phénylacêtamido-to-7-methoxy-3-acetoxy-methyl-L-cephem-to-4-carboxylate and benzyl, dropwise in 10 min, a solution of I, 01 ml (12.5 mmol) of pyridine in 4 ml of methylene chloride. After 50 min confectioneries and at a temperature of from 10° -15, added 2.1 ml (30 mmol) of propylene oxide. After 10 additional minutes (reaction temperature at 0 °c), the reaction mixture is washed with 25 ml of ice water, it is dried on the CAC ^ and is evaporated under vacuum until 11 g of syrup. The triturate the product 3 times in carbon tetrachloride and then resumes in 50 ml of ether. The concentrated ethereal solution of 0.5 g of precipitate, and then evaporated under vacuum to about 25 ml. RN obtains an oil product when the solution is diluted with 25 ml of hexane resulting ethereal. Oil is washed twice with a 1:1 mixture of ether and hexane, then 1 'évapore-to-vacuum to a foam twice from solutions in carbon tetrachloride, and obtained 2.5 g of the title product:

AN IR (CHC1₃ ) and 1780 1730 cm^-1 .

NMR (CDC1₃ , pyridin-d 5) 6, 1.96 (O, 3), 3.3 (ABq), 3.43 (e, 2), 3.93 (e, 2), 4.86 (ABq), 4.93 (O, 1),

5.25 (o, 1) and 7.3 (H-aromatic).

Example 29

The hydrobromide 7-amino 3 methyl-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl

To a solution of ' 25.4 ml of triphenyl phosphite complex prepared by reacting bromine/6.67 ml (25.4 mmol) phosphite triphênyle and 1.30 ml (25.4 mmol) of bromine in the presence of 2.10 ml (26 mmol) of pyridine in 100 ml of methylene chloride at a temperature of

-10 to -15 °c, added the g (20 mmol) 9.67 of 7 a--phenoxyacetamido-to-3-methyl 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl.

After one hour at a temperature of to -15 -10^Q C., the reaction mixture is removed from the cooling bath and added 13.88 ml (150 mmol) of isobutanol. After 2 hours of stirring at room temperature, reaction mixture is filtered and the obtained 4.76 grams (55.3%) of the title product, 179 and 181 °C with f.w. decomposition.

Analysis calculated for c ^ ^ ^ ^ n-RO-to-RBS:

C., 41.87; hr, 3.75; n-, 9.77; e, 7.45; brr, 18.57. Found: C., 42.04; hr, 3.57; n-, 9.54; e, 7.54; brr, 18.37.

NMR (DMSO to d 6) 52.2 (O, 3), 3.65 (s-wide, 2),

5.27 (m-, 2, H of the 8-lactam), 5.42 (e, 2) 7, 6 - 8, 4 and (the m, 4, H-aromatic)

Example 30

7 - (has-chloro 4 a-méthylbenzylidënimino) - 7 a-methoxy-L - (1-methyl 1, 2, 3, 4-tetrazol-5 a-ylthio) methyl-L-dethia L-oxa 3 a-cephem-a 4 -benzhydryl carboxylate.

To a solution of 200 mg of 7 - (4 a-methylbenzamido) - 7 methoxy 3 - (1-methyl-L, 2, 3, 4 a-tëtrazol-a 5 a-ylthio) methyl-1-dethia L-oxa 3 a-cephem-to-4-carboxylate in 10 ml benzhydryl nitroaniline at a temperature of 0 to -15 °c, added in a few hours 4 equivalents of complex triphenyl phosphite/chlorine (prepared in the usual manner) and 4 equivalents of pyridine. The great excess of pyridine complex is required presumably because of the presence of impurities in the oxa-to-cephem starting. The precipitation of salts and impurities with cc1₄ in ether followed by evaporation of the solvent gives an oil. A NMR spectrum of oil from 1' has ethereal extract signals corresponding to the triphenyl phosphite in addition to those corresponding to the title product.

NMR (CDC1₃ ) E 2.25 (O, 3), 3.53 (O, 3), 3.65 (O, 3), 4.16 (e, 2) ., 4.53 (e wide, 2) and 5.16 (O, 1, H c 6).

Example 31 7 a-phenylacetamido-3-chloro 3 a-cephem-to-4-carboxylate 4'nitrobenzyl

Is bubbled into a solution of chlorine

2.89 ml (11 mmol) of triphenyl phosphite in 50 ml of methylene chloride at -15 °c up to persistence of the yellow color indicating an excess of chlorine. And then removes the color by adding 2 drops of triphenyl phosphite. With the resulting solution of triphenyl phosphite reagent/chlorine, added 4.54 grams (10 mmol) of 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4' nitrobenzyl, dropwise in 40 min, a solution of 0.89 ml (11 mmol) of pyridine in 8 ml of methylene chloride. During the addition of the pyridine solution, the temperature of the reaction mixture to a value -15 to -10 °c. Then the reaction mixture was stirred at a temperature of 60 to -15 -10 °c during additional minutes, after which the reaction mixture is removed from the cooling bath. Then adding 1 ml of concentrated hydrochloric acid to the mixture to effect hydrolysis of the small amount of imino chloride which has formed. After stirring the reaction mixture for 30 minutes at room temperature, the mixture is diluted with 100 ml of ethanol 3a, stirred for 15 minutes at is, and then filtered, to give 2.67 grams (54.7%) of the title product as white crystals; f.w. 214 °c with decomposition. Obtained a second crop of the title product by concentrating the filtrate under reduced pressure in a volume of about 50 ml. Is isolated (31.1%) 1.52 g of additional product title. Total yield: 85.8%.

NMR (DMSO to d 6) δ 3.62 (e, 2), 3.94 (ABq, 2, j=18 Hz range), 5.3 (d derivatives, 1, j=5 Hz to], 5.52 (e, 2), 5.82 (Q-, 1, j=5 and 8 Hertz) and 7, 2 - 8, 4 (H-aromatic).

Analysis calculated for c ^ ^ ^ ls ôgscl:

C., 54.16; hr, 3.72; n-, 8.61; LC, 7.27; e, 6.57. Found: C., 53.91; hr, 3.92; n-, 8.44; LC, 7.27; e, 6.55. Example 32 7 a--phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4' nitrobenzyl

Following the procedure of example 31, prepared the product kinetic triphenyl phosphite/chlorine from 6.31 ml of triphenyl phosphite and chlorine in 45 ml of methylene chloride at -15 °c. To this solution at a temperature of from 10° -15, added 5.24 grams

(10 mmol) of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl and introduced into the reaction mixture by washing with 5 ml of methylene chloride. Then added dropwise to the solution in confectioneries drop 30 minutes at 1.01 ml (12.5 mmol) of pyridine in 8 ml of methylene chloride. After stirring the reaction mixture for 2 hours at -10 °c, added 1 ml of concentrated hydrochloric acid. After 30 minutes of stirring, the reaction mixture is washed with 100 ml portions of three water, dried over magnesium sulfate and evaporated under vacuum to an oil that crystallizes out then in 100 ml of ethanol 2b, yielding 4.19 grams (83.2%) of the title product; f.w. 142.5 and 146°.

NMR (CDC1₃ ) 6, 1.7 (ABq, 2, j=l8 Hertz), 4.60 (e, 2), 5.12 (d derivatives, 1, j=5 Hz range), 5.4 (e, 2), 5.91 (Q-, 1, j=5 and 9 Hz range), and 6, 8 - 8, 4 (H-aromatic).

Analysis calculated for £22 ^ ^ ^ 3 7 8 ΐ ^ ^:

C., 52.44; hr, 3.60; n-, 8.34; e, 6.36; LC, 7.04. Found: C., 52.67; hr, 3.73; n-, 8.12; e, 6.15; LC, 6.95. Example 33 7-a-phenoxyacetamido-to-3-chloro 3 a-cëphem-to-4-carboxylate 4' nitrobenzyl using the complex phosphite sorting (O.tolyl)/chlorine.

Chlorine gas is bubbled into a solution of 3.91 grams (10 mmol) phosphite tri (o-tolyl) in 45 ml of methylene chloride at -10 °c up to persistence of a yellow color. Then eludes the color by adding about 0.5 mmol of the phosphite. With the resulting solution to -10 °c, added 5.4 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4' nitrobenzyl is washed in the solution with 5 ml of methylene chloride. Then adding 1.01 ml (12.5 mmol) of pyridine. After allowing the reaction mixture stirred for 90 minutes at -10 °c, the reaction mixture is added 1 ml of concentrated hydrochloric acid. After stirring for 30 minutes, the reaction mixture is washed successively with two portions of 25 ml water and 25 ml of a dilute solution of sodium chloride, dried over sodium sulfate and evaporated under vacuum to an oil which crystallizes in 50 ml of ethanol 2b giving 3.35 grams (66.5%) of the title product. A NMR spectrum of the product is identical to that of the product obtained in example 32.

Example 34 7 a-phénoxyacétaroido-to-3-chloro 3 a-cephem-to-4-carboxylate 4'nitrobenzyl

(HAS) Baseless chlorination. A solution is prepared of the reagent triphenyl phosphite/chlorine as in example 31 above from 2.89 ml of triphenyl phosphite in methylene chloride to -10 °c. With this solution, added 4.86 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl. The reaction mixture was stirred during 2 hours to -10 °c. A TLC comparison shows that after about 2 hours the chlorination is completed to about 50%; noted also the presence of a little of imino chloride.

(B.) 2.6-to-lutidine. The reaction mixture described in paragraph (has) above, added 1.2 ml (10.5 mmol) of 2.6 to-lutidine. After the reaction mixture at 60 min during -10 °c, added 1 ml of concentrated hydrochloric acid. And then removing the reaction mixture from the cooling bath and stirred 30 minutes, and thereafter is washed successively with two portions of 100 ml water and 100 ml of a dilute solution of sodium chloride. Then the reaction mixture is dried over magnesium sulfate and evaporated under vacuum to an oil which crystallizes in 75 ml of ethanol 2b giving 3.83 grams (76%) of the title product;

124 and 126 °f.w..

Example 35

Hydrochloride 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl

(Has) methylene chloride, pyridine derivatives

Chlorine gas is bubbled into a solution of 6.31 ml (25 mmol) of triphenyl phosphite in 45 ml of methylene chloride at -10 °c up to persistence of the yellowness of the excess of chlorine. And then flushing the color by adding more drops triphenyl phosphite. To this reagent solution triphenyl phosphite/chlorine to -15 °c, added 4.86 grams (10 mmol) of 7-acetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl. Is then added dropwise to the reaction mixture at 40 min 2.02 ml (12.5 mmol) of pyridine in 8 ml of methylene chloride. After stirring the reaction mixture for 30 minutes to -10 °c, added 9.25 ml (100 mmol) of isobutanol. And then flushing the reaction mixture of the ice bath and treated by HCl gas for about 30 seconds. Although the product begins to crystallize after 5 min, the reaction mixture was stirred during 2 hours to about 20° and then filtered, yielding 3.33 gm (82%) of the ethyl ester hydrochloride nuclear title; f.w. 181 °c with decomposition.

NMR (DMSO to d 6) 6, 4.06 (e wide, 2), 5.33 (Q-, 2, j=4, 5 Hertz, H of the 8-lactam), 5.5 (e, 2), 7, 8 - 8, 3 (H-aromatic) and about 8.6 (e very wide, the NH - ^).

(B.) 1.2-dichloroethane, pyridine derivatives

It follows the same procedure as in example 35 (has) above but replacing the methylene chloride by the 1.2-dichloroethane as a solvent. Isolated a total of 3.10 grams (76.4%) of the title product.

(C.) methylene chloride, quinoline

It follows the same procedure as in paragraph (has) above but replacing pyridine by the quinoline. Isolated a total of 3.2 grams (79.8%) of the title product; f.w. 181 °c with decomposition.

(D.) methylene chloride, isoquinoline

It follows the same procedure as in paragraph (has) above, but used 1' isoquinoline instead of pyridine. The reaction mixture is markedly darker than in the previous experiments.

Isolated a total of 2.29 grams (56.4%) of the title product; f.w. 18l °C with decomposition.

(I) methylene chloride, n-, dimethylaniline followed the same procedure as in paragraph (has) above but wherein N, N-dimethylaniline in place of pyridine. Isolated a total of 0.91 grams (22.4%) of the title product; f.w. 182 °c with decomposition.

(F.) acetonitrile derivative, pyridine derivatives

Chlorine gas is bubbled into a mixture of 7.9 ml (30 mmol) in 45 ml of phosphite triphënyle'd¹ acetonitrile derivative to -10 °c. As the mixture solidifies, it is allowed to warm up to 10 °c where the reaction mixture liquefies again. To proceed with the addition of chlorine gas to persistence of a yellow color in the mixture. Then adding 0.1 ml of phosphite triphënyle decoloring the solution (about 30.4 mmol of the compound kinetic triphenyl phosphite/chlorine are formed). With this solution, added 5.4 grams (10 mmol) of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cêphem-to-4-carboxylate 4¹ - nitrobenzyl. Then added dropwise in 30 min 2.42 ml (30 mmol)' in 8 ml of pyridine acetonitrile, the temperature of the reaction mixture being 0 to 10 °c.

After stirring the reaction mixture for 1 hour, the cooling bath is removed and the reaction mixture is left under stirring at room temperature for 90 mins. Then adding 9.25 ml (100 mmol) of isobutanol. After 90 minutes at room temperature, reaction mixture is filtered and the obtained 0.95 grams (23.4%) of the title hydrochloride; f.w. 186 °c with decomposition.

(Grams) from the 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl

A solution of the compound prepared kinetic triphenyl phosphite/chlorine according to the procedure described in paragraph 35 (has) above by using chlorine and 2.89 ml (11 mmol) in 45 ml of phosphite triphënyle methylene chloride. With this solution, added 2.3 grams (5 mmol) of 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl. Then added dropwise with stirring at a temperature of -15 to -10 °c, 15 minute in, a solution of 0.89 ml (11 mmol) of pyridine and 5 ml of methylene chloride. After stirring the reaction mixture for one hour and a half at -15 to -10 °c, the cooling bath is removed and added 6 ml (64.8 mmol) of isobutanol.

While the slurry is agitated during the next hour, this mixture on warming to 23 °c, the product crystallizes.

Filtering the mixture to give 1.59 grams (78.3%) of the title hydrochloride as white crystals? f.w. 188 °c with decomposition.

(Hr) using the complex kinetic phosphite (o-tolyl) sorting/chlorine

Chlorine gas is bubbled into a solution of 9.24 grams (26 mmol) phosphite sorting (o-tolyl) in 45 ml of methylene chloride at -10 °c up to persistence of a yellow color. Then adding about 0.5 mmol of phosphite with mixture for consuming excess chlorine. With the solution, is added (10 mmol) 5.44 grams of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl which is introduced in the reaction mixture by washing with 5 ml of methylene chloride. Is then added dropwise to the reaction mixture to -10 °c 30 minutes a solution of 2.58 ml (32 mmol) of pyridine in 8 ml of methylene chloride. After stirring the reaction mixture for 30 minutes to -10 °c, added 9.25 ml (100 mmol) of isobutanol. The reaction mixture followed by removal of the ice bath and is bubbled HCl gas for about 60 seconds. And then allowing the reaction mixture stirred at room temperature for 90 min, after which the mixture is filtered, yielding 3.31 grams (81.5%) of the title hydrochloride; f.w. 183 °c with decomposition.

Example 36

7 - (l-chloro-2 a-phenoxyethylidene) imino 3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl

It follows the same procedure as in example 35 (has) but instead of adding 1' butanol reaction mixture, is added 4.2 ml of propylene oxide. Then, the reaction mixture is left under stirring for 15 min at 0 °c. Then the reaction mixture is washed with 50 ml of ice water, and is dried over calcium chloride dihydrate. Vacuum evaporation of the solution dried lbs

gives 21 g of a dark-colored syrup. The addition of ether diethylic (containing a few drops of propylene oxide) at residue by depositing a small amount of tar. Then, 5 ml is added to mixture of methylene chloride and the concentrated resulting solution of about 1 g of black tar. Vacuum evaporation of the solution gives a syrup that triturate in 50 ml of a 1:1 mixture of ether and hexane that is subsequently decanted three times, resulting in a semi-solid that, after storage at refrigerator for several days, is triturated in ether to give 1.08 g of a solid identified by NMR as the 7 a-phênoxyacétamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4 - nitrobenzyl *. Evaporation of the filtrate in vacuo gives a foam is dissolved in a few milliliters of methylene chloride. The resultant solution is diluted with a small amount and then with about 50 ml ether alcohol 2b (containing a few drops of propylene oxide). The imino chloride title (0.24 grams) crystallizes from the solution and has a melting point of 97 and 98 degrees Celsius.

The structure of the product is confirmed by NMR spectrum.

NMR (CDCl ^, pyridin-d 5) δ 3.56 (ABq, 2, j=18 Hz range), 4.8 (e, 2), 5.03 (d derivatives, 1, j=5 Hz range), 5.3 (e, 2), 5.53 (d derivatives, 1, j=5 Hz range) and 6, 9 - 8, 3 (H-aromatic).

Example 37

Hydrochloride 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl

(Has) a solution is prepared of about 25.5 mmol of the compound triphenyl phosphite/chlorine by bubbling chlorine gas into a solution of 6.31 ml (24 mmol) of triphenyl phosphite in 45 ml of methylene chloride at -10 °c up to highlight an excess of chlorine. Added triphenyl phosphite (about 1.5 mmol) additional for. removing the color yellow. With this solution, added 5.24 grams (10 mmol) of 7-phenoxy-benzylamide 3 hydroxy-r3-to-cephem-to-4-carboxylate 4¹ - nitrobenzyl which is introduced in the reaction mixture by washing with additional 5 ml of methylene chloride.

Then added dropwise in 40 minutes a solution of pyridine in 8 ml of 2.02 ml methylene chloride.

The temperature of the reaction mixture to a value -10° to -15 °c. After stirring of the reaction mixture during polymerization temperature i25 minutes, the reaction mixture is 9.25 ml of isobutanol (100 mmol). Immediately thereafter, the reaction mixture is removed from the cooling bath and HCl gas is bubbled into the mixture for about 30 seconds. Then the reaction mixture is seeded and allowed under stirring at 20 °c for about 2 hours.

The filtration gives 3.49 g of (86%) of the title hydrochloride as white crystals; f.w. 179-to-180 °C with decomposition.

(D) is substantially following the same procedures as described in paragraph (has) above but used 3.61 ml of 1.3 methylpropanediol instead of 1' butanol. Isolated a total of 3.25 grams (80%) of the title product;

f.w. 182 °c with decomposition.

Examples 38 - 50

Following the procedure of example 11 general experimental, carried out the following transformations using the halogenating compounds obtained from triaryl phosphite and halogen indicated.

Example 38. 7 a-phenylacetamido-3-chloro 3 a-cephem-to-4-carboxylate 2 ',', 2 2 'a-trichloroethyl from the 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 2', 2 ', 2' to-trichloroethyl; triphenyl phosphite/chlorine.

Example 39. 7 a-formamidopyrimidine-3 a-bromo 3 a-cephem-to-4 carboxylate of the benzhydryl from the 7 a-formamidopyrimidine-3-hydroxy 3 a-cephem-to-4 carboxylate of the benzhydryl; triphenyl phosphite/bromine.

Example 40. 7-acetamido-3-chloro 3 a-cephem-to-4 carboxylate T-butyl from the 7-acetamido-3-hydroxy 3 a-cephem-to-4 carboxylate T-butyl; sorting phosphite (4 a-méthoxyphény] 00)/chlorine.

Example 41. 7 a-benzamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4 '-methoxybenzyl from the 7 a-benzamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-methoxybenzyl; sorting phosphite (o-tolyl)/chlorine.

Example 42. 7-a-phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 2 a-iodoethylisopropylcarbonate from the 7-a-phenoxyacetamido-a 3 - hydroxy 3 a-cephem-to-4-carboxylate 2 a-iodoethylisopropylcarbonate; triphenyl phosphite/chlorine.

Example 43. 7-methoxy-7 a-phenylacetamido-3-to-a-brom>- 3 a-cephem-to-4-carboxylate 4 '-nitrobenzyl from the 7-methoxy-7 a-phênylacétamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4' nitrobenzyl; triphenyl phosphite/bromine.

Example 44. 2 a-phénylpropionamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4¹ - chlorophénacyle from the 2-phenyl-propionamido-linked-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4' a-chlorophénacyle; sorting phosphite (4 a-ethylphenyl)/chlorine.

Example 45. 7-methoxy-7 - (2-thienyl) acetamido-3-chloro 3 a-cephem-to-4-carboxylate benzyl from the 7-methoxy-7 - (2-thienyl) acëtamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate benzyl; triphenyl phosphite/chlorine.

Example 46. 7 - (5 a-tetrazolyl) acetamido-3-chloro 3 a-cephem-a 4 - carboxylate 4¹ from the 7 - nitrobenzyl (5 a-tetrazolyl) - benzylamide 3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; sorting phosphite (2-Ethoxyphenyl)/chlorine. Example 47. 7 thereof [2 tert-butoxycarbonylamino 2 a-phenylacetamido] and 3 a-bromo 3 a-cephem-to-4-carboxylate pivaloyloxymêthyle from the 7 thereof [2 tert-butoxycarbonylamino 2 a-phënylacétamido] and 3-hydroxy 3 a-cephem-to-4-carboxylate pivaloyloxymêthyle;

phosphite (P--propylphenyl) sorting/bromine.

Example 48.^: 7 - [2 - (4 a-nitrobenzyloxycarbonylamino) - 2 a-phenylacetamido] and 3-chloro 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl from the 7 - [2 - (4 a-nitrobenzyloxycarbonylamino) - 2 a-phenylacetamido] and 3-hydroxy 3 a-cephem-to-4-carboxylate 4' nitrobenzyl; triphenyl phosphite/chlorine.

Example 49. 7 thereof [2 a-chloroacetamidothiazol-a 5 a-ylacétamido] and 3-chloro 3 a-cephem-to-4-carboxylate 4 '-nitrobenzyl e from the 7 thereof [2 a-chloroacetamidothiazol-a 5 a-ylacétamido] and 3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; sorting phosphite (o-tolyl)/chlorine.

Example 50. 7-chloroacetamido and 3 a-bromo 3 a-cephem-to-4-carboxylate 2 ',', 2 2' a-trichloroethyl from the 7-chloroacetamido and 3-hydroxy 3 a-cephem-to-4-carboxylate 2 ^ ^ 2 - 2¹ - trichloroethyl; triphenyl phosphite/bromine.

Examples 51 - 59

Following the procedure of example 35 experimental (has), the hydrochloride of the prepared 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl from 3 to-hydroxycéphems indicated below using the chlorinating agent derived from chlorine and triarylphosphite indicated.

Example 51. 7 a-formamidopyrimidine-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; triphenyl phosphite.

Example 52. 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; sorting phosphite (o-tolyl). Example 53. 7 - (2 a-thiénylacétamido) - 3 hydroxy-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; triphenyl phosphite.

Example 54. 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl "; triphenyl phosphite.

Example 55. 7 a-benzamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; triphenyl phosphite.

Example 56. 7 a-phénylthioacétamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; sorting phosphite (o-tolyl). Example 57. 7 - [2 - (t-butoxycarbonylamino) - 2 a-phenylacetamido] and 3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; triphenyl phosphite.

Example 58. 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; sorting phosphite (pméthoxyphényle).

Example 59. 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; sorting phosphite (p-tolyl). Examples 60 - 67

By following the general procedure in example 35 (has), carried out the following transformations using the halogenating compound derived from chlorine or bromine and triarylphosphite indicated.

Example 60. 7-amino 3-chloro 3 a-cephem-to-4 carboxylate T-butyl from the 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4 carboxylate T-butyl; triphenyl phosphite.

Example 61. 7-methoxy-7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl from the 7-methoxy-7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; triphenyl phosphite.

Example 62. 7-amino 3 a-bromo 3 a-cêphem-to-4-carboxylate 2¹ , 2 ', 2' a-trichloroethyl from the 7-acetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 2¹ , 2¹ , 2' a-trichloroethyl;

the phosphite tri-O-tolyl.

Example 63. 7-amino 3-chloro 3 a-cephem-to-4-carboxylate from the 7 - benzyl (4 a-chlorophénoxyacëtamido) - 3 hydroxy-3 a-cephem-to-4-carboxylate benzyl; sorting phosphite (péthoxyphényle).

Example 64. 7 a-Methoxy-phenylazo 7-amino 3-chloro 3 a-cephem-to-4 carboxylate of the benzhydryl from the 7-methoxy-7-phenyl-acetamido-3-hydroxy 3 a-cephem-to-4 carboxylate of the benzhydryl;

triphenyl phosphite.

Example 65. 7-amino 3 a-bromo 3 a-cephem-to-4-carboxylate 4^T from the 7 - nitrobenzyl (3 a-nitrobenzamido) - 3 hydroxy-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; triphenyl phosphite.

Example 66.. 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4 'methoxybenzyl from the 7 thereof [2 a-a formyloxy-a 2 a-phenylacetamido] and 3-hydroxy 3 a-cephem-to-4-carboxylate 4'-methoxybenzyl; phosphite (m-tolyl) sorting.

Example 67. 7-amino 3 a-bromo 3 a-cephem-to-4-carboxylate 4' - nitrobenzyl from the 7 (2 a-thiénylacétamido) - 3 hydroxy-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl; triphenyl phosphite.

Examples 68 - 75

By following the general procedure of example 36, carried out the transformations of the following compounds, using a halogenating agent derived from chlorine or bromine and triarylphosphite indicated.

Example 68. 7-methoxy-7 - (α-chlorobenzylidëne) imino 3-chloro 3 a-cephem-to-4-carboxylate 4 '-nitrobenzyl from the 7-methoxy-7 a-benzamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; triphenyl phosphite.

Example 69. 7 - (l-chloro-2 a-phenylethylidene) imino 3-chloro 3 a-cephem-to-4-carboxylate benzyl from the 7-phenyl-acetamido-3-hydroxy 3 a-cephem-to-4-carboxylate benzyl? phosphite (o-tolyl) sorting.

Example 70. 7 thereof [the L-chloro 2 - (2-thienyl) ethylidene) the imino] and 3-chloro 3 a-cephem-to-4-carboxylate 2¹ , 2 ', 2' a-trichloroêthyle from the 7 - (2 a-thiénylacêtamido) - 3 hydroxy-3 a-cephem-a 4 - carboxylate 2 ', 22' a-trichloroêthyle; triphéyle phosphite.

Example 71. 7 - (1 a-chloroethylidene) imino 3-chloro 3 a-cephem-to-4-carboxylate 4 'a-mëthoxybenzyle from the 7 a-acétamido' 3-hydroxy 3 a-cephem-to-4-carboxylate 4' a-mëthoxybenzyle;

triphenyl phosphite.

Example 72. 7 - (l bromo 2 a-phenoxyethylidene) imino 3 a-bromo 3 - cephem-to-4-carboxylate 4¹ - nitrobenzyl from the 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4' nitrobenzyl; triphenyl phosphite.

Example 73. 7 - (l-chloro-2 a-chloroacétoxy and 2 a-phenylethylidene) imino 3-chloro 3 a-cephem-to-4 carboxylate T-butyl from the 7 - (2 a-chloroacétoxy and 2 a-phenylacetamido) - 3 hydroxy-3 a-cephem-to-4 - tert butyl carboxylate; phosphite (o-methoxyphenyl) sorting.

Example 74. 7 - (4 chloro-has-chlorobenzylidene) imino 3-chloro 3 a-cephem-to-4-carboxylate 4 '-nitrobenzyl from the 7 - (4 a-chlorobenzamido) - 3 hydroxy-3 a-cephem-to-4-carboxylate 4' nitrobenzyl; triphenyl phosphite.

Example 75. 7 - (l bromo 2 a-phenylethylidene) imino 3 a-bromo 3 a-cephem-to-4-carboxylate 4 '-nitrobenzyl from the 7 a-phenylacetamido-3-hydroxy 3 a-cephem-to-4-carboxylate 4' nitrobenzyl; triphenyl phosphite.

Example 76 7-a-phenoxyacetamido-a 3 a-bromo 3 a-cephem-to-4-carboxylate 4'nitrobenzyl; triphenyl phosphite/bromine.

To a solution of 2.30 ml (4.5 mmol) of bromine in 90 ml of methylene chloride at -70 °c, 12.22 ml is added (46.6 mmol) of triphenyl phosphite to remove the color of the bromine. With this solution, 10.6 grams is added (20 mmol) of 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cëphem-to-4-carboxylate 4¹ - nitrobenzyl which is introduced in the reaction mixture by washing with 10 ml of methylene chloride. The mixture is heated at a temperature of

-35 to -30 °c and added dropwise in 35 min, a solution of 3.64 ml (45 mmol) of pyridine in 16 ml of methylene chloride. After 4 ti_or AE.., the reaction mixture is 50 ml ' ice water. Is the resulting solution stirred for half an hour. The OH score ' 1¹ ^ occurrence of three layers. Washed there middle layer which is the, coated of methylene chloride with 50 ml of water and brine and dried over anhydrous sodium sulfate. The solvent evaporated under vacuum up to 29.7 grams. The addition of 150 ml methanol induces the crystallization of the title product;

3.78 grams (dried); pp.f, . h39-to 13.9 degrees Celsius.

NMR (DMSO to d 6) 6; 4) 0' (ABq, C.₂ ~Hr), 4.65 (e, 2, HM₂ the side chain), 5.28 (d derivatives, 1, j=5 Hz range), 5.47 (e, 2, HM₂ of the ester), 5.8 (Q-, 1, j=5 Hz and 8 Hz range) and 6, 9 - 8, 4 (H-aromatic).

Example 77 7 - (l-chloro-2 a-phenylethylidene) imino 7-methoxy-3-acetoxy -methyl 3 a-cephem-to-4-carboxylate benzyl.

To a solution of the complex triphenyl phosphite/chlorine prepared from chlorine and 12.3 mmol of triphenyl phosphite in the presence of 0.1 ml of pyridine in 45 ml of methylene chloride at -15 °c, added 5.11 grams (10 mmol) of 7 a-phenylacetamido-7-methoxy-3 a-acetoxymethyl and 3 a-cêphem-to-4-carboxylate and benzyl, dropwise in 10 min., a solution of 1.01 ml (12.5 mmol) of pyridine in 4 ml of methylene chloride. After 50 minutes at a temperature of to -15 -10 °c, added 2.1 ml (30 mmol) of propylene oxide. After 10 additional minutes (reaction temperature at 0 °c), the reaction mixture is washed with 25 ml of ice water, dried over calcium chloride and is evaporated under vacuum until 11 g of syrup. The triturate the product three times in carbon tetrachloride, and then resumes in 50 ml of ether. The concentrated ethereal solution of 0.5 g of precipitate, and then evaporated under vacuum up to about 25 ml. An oily product is obtained when the solution is diluted with 25 ml of hexane resulting ethereal. Oil is washed twice with a 1:1 mixture of ether and hexane, and then vacuum evaporated twice from solutions in carbon tetrachloride and a foam is obtained providing 2.5 g of the title product.

NMR (CDCl a-j, pyridin-d 5)<e 1.96 (O, 3), 3.3 (ABq), 3.43 (e, 2), 3.93 (s at, 2), 4.86 (ABq), 4.93 (O, 1),

5.25 (o, 1) and 7.3 (H-aromatic).

Example 78

Hydrochloride 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl, using the complex kinetics phosphite (p-chlorophenyl) sorting/chlorine.

With 10.34 g of phosphite (p-chlorophenyl) sorting and 0.53 ml (6.5 mmol) of pyridine in 50 ml of methylene chloride at -70 °c, chlorine added in 15 ml of methylene chloride. Added 0.52 ml amylene for consuming excess chlorine. With the resulting solution of complex sorting phosphite (P chlorophënyle)/chlorine, 5.28 g of added 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl using 10 ml of methylene chloride for introducing the substrate by washing in the reaction mixture. Then added dropwise in 33 minutes at 1.57 ml (19.5 mmol) of pyridine in 9 ml of methylene chloride. After 2 hours, the reaction mixture is allowed to warm up to 2 °c. Added 6.94 ml of isobutanol and HCl gas is bubbled into the mixture for 2 min. The mixture is evaporated under vacuum to a syrup which is added 50 ml of ethyl acetate.

By triturating the gum with about 100 ml of methanol. A white solid is filtered, phosphate sorting (p-chlorophenyl). evaporation of the filtrate under vacuum to dryness. At residue, added 15 ml of a 1:1 mixture of toluene and ethyl acetate and just sufficient methanol to dissolve the residue gummy. By rest for about 5 min, 0.97 g of the title product as a solid crystallizes white; 184 and 186 °C with f.w. decomposition.

Example 79 7 a-phenylacetamido-3 a-méthylënecépham-to-4-carboxylate 4'nitrobenzyl

With 75 ml of methylene chloride at -20 °c, added chlorine gas and 10 ml of triphenyl phosphite at such a rate that a green colored pale persists in the reaction medium during the addition. The temperature of the reaction medium to a value -20 to

-25 °C. Once the addition has ended, is added 3 ml amylene. Maintained -30 °c to the resulting solution.

complex kinetic triphenyl phosphite/chlorine (a TPP/C.).

Has an agitated mixture of 5.0 ml of the solution TPP/C. described above and 0.5 ml amylene, is added 500 mg of 1-oxide 7 a-phenylacetamido-3 a-méthylènecépham-to-4-carboxylate 4'-nitrobenzyl. After having stirred the reaction mixture at 10 °c during 45 min, added 2 ml of methanol. The mixture is evaporated to dryness under vacuum. Stirred the residue with ether and filtration gives 410 mg of the title product.

The nuclear magnetic resonance spectra for said product and the products examples 80 to 86 whose given in table II below.

Example 80 7-a-phenoxyacetamido-a 3 a-méthylënecépham-to-4-carboxylate 4'nitrobenzyl

the U - ^ According to the procedure in example 79, reduced the 500 mg 1-oxide 7 a--phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4'-nitrobenzyl and obtained 370 mg of the title product.

Example 81 7-a-phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4'nitrobenzyl

According to the procedure in example 79, reduced the 500 mg 1-oxide 7 a--phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl and 310 mg of the product obtained title.

Example 82

7 - (2 a-thiénylacétamido) - 3 methyl-3-methyl 3 a-cephem-a 4 -carboxylate 4'-nitrobenzyl

Following the procedure in example 79, is reduced 500 mg of 7 - 1-oxide (2 a-thiénylacétamido) - 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl and obtained 260 mg of the title product.

Example 83 7 a-heptanoylamino-to-3-methyl 3 a-cëphem-to-4-carboxylate 4'nitrobenzyl

According to the procedure in example 79, is reduced 500 mg of 1-oxide 7 a-heptanoylamino~3-methyl 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl and obtained 270 mg of the title product.

Example 84 7 - (2 a-thiénylacétamido) - 3 methyl-3 a-cephem-to-4-carboxylate 4'-methoxybenzyl

Following the procedure in example 79, is reduced 500 mg of 7 - 1-oxide (2 a-thiénylacétamido) - 3 a-cephem-to-4-carboxylate 4¹ - methoxybenzyl and obtained 470 mg of the title product.

Example 85

7 - (2 a-thiénylacétamido) - 3 methyl-3 a-cephem-to-4-carboxylate benzyl

By following the same general procedure that in the example 79, reduced 300 mg of 7 - 1-oxide (2 a-thiénylacétamido) - 3 methyl-3 a-cephem-to-4-carboxylate benzyl using 3 ml of the above solution of triphenyl phosphite complex/chlorine and 0.3 ml amylene to obtain 240 mg of the title product.

Example 86 7-a-phenoxyacetamido-a 3 a-méthylënecépham-to-4-carboxylate 2¹ , 2¹ , 2¹ - trichloroethyl

By following the same general procedure as described in example 79, 300 mg of the reduced 1-oxide 7 a--phenoxyacetamido-a 3 a-méthylènecépham-a 4 a-carboxylate of 2 ',', 2 2' a-trichloroethyl using 3 ml of the solution TPP/c and 0.3 ml amylene to obtain 80 mg of the title product.

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TABLE II

NMR (CDC1₃ ) S FOR THE PRODUCTS OF EXAMPLES 79 - 86

Example 87 7-a-phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4¹ using the TTP nitrobenzyl stability/C..

To a solution of 0.8 ml (10 mmol) of pyridine in 150 ml of methylene chloride confectioneries -20 °c, added chlorine gas and 20 ml of triphenyl phosphite at such a speed that a pale yellow persists throughout the addition. The temperature of the reaction medium to -20 °c. The resulting solution of complex kinetic triphenyl phosphite/stabilized chlorine, added 8 ml amylene and 19.13 g of 1-oxide 7 a-phënoxyacétamido and 3 a-méthylènecépham-to-4-carboxylate 4'-nitrobenzyl. The reaction mixture was stirred for about 1 hour at a temperature of -15° to -20 °c. Then heats the mixture to ambient temperature and concentrated in vacuo to a syrup. 40 Ml of methanol is added.

After 30 minutes of stirring, the solution is filtered, giving 11.58 g of the title product, which is confirmed by comparison with authentic material by NMR.

Example 88 7-a-phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'nitrobenzyl

A solution is prepared of the complex TPP/c by simultaneous addition of 6.1 ml of phosphte triphenyl and chlorine to 45 ml of methylene chloride at -15 °c. Triphenyl phosphite is added until the starch-iodide test is negative chlorine. With the resulting solution to -15 °c, is added 3 ml amylene and 10.6 g of 1-oxide 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4' orth. After 40 min, the reaction mixture is allowed to warm to room temperature and then filtered to remove the substance of unreacted starting material (5.08 grams). The filtrate is concentrated under vacuum to about 35 ml. After cooling the solution to 0 °c, is added 10 ml of acetic acid. The filtration gives, in two crops, 1.81 g of the acetic acid solvate of the title product.

NMR (CDC1)<5, 2.05 (e, 3, IC ^-COOH), 3.67 (e wide, 2), 4.53 (e, 2), 5.01 (d derivatives, 1, j=4 Hz range), 5.31 (ABq, 2),

5.65 (q-, 1, j=4 and 9 Hertz) and 6, 8 - 8, 4 (H-aromatic).

Example 89 7-a-phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4'nitrobenzyl

Following the procedure in example 88, used 17.1 ml of triphenyl phosphite to prepare the complex a TPP/c in 70 ml of methylene chloride at -20 °c. Added 2.2 ml amylene then 10.6 g of 1-oxide 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl. The temperature of the reaction mixture rises to -8 °c. After 45 min, is started by adding a solution of 3 ml of pyridine in 15 ml of methylene chloride, the addition is continued for 70 min. The temperature of the reaction mixture to a value confectioneries -10 -15 °c during 45 minutes when terminating the addition of pyridine. The reaction mixture is concentrated under vacuum to about 35 ml and 10 ml of ethanol is added (2b). Concentrated further of the solution and the addition of a few milliliters of acetic acid cause crystallization of 3.2 grams (in two crops) of the title product is isolated by filtration. The structure of the product is confirmed by NMR comparison with an authentic sample of the title product.

Example 90

Hydrochloride 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl

A solution is prepared of the complex kinetic triphenyl phosphite/chlorine by adding chlorine and triphenyl phosphite (36.8 ml, 3.5 equivalents per equivalent of sulfoxide cephem used below 22.3 grams) at the same time to 150 ml of methylene chloride at a temperature of about to about -20 -10 °c, by maintaining a pale yellow in the reaction mixture during the addition. With addition of the last drops of triphenyl phosphite in the mixture, there is obtained a negative starch-iodide test for chlorine.

After cooling the mixture to -25 °c, is added and then 5.1 ml of 22.3 g of amyiene 1-oxide 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl. After 25 minutes of stirring at a temperature of confectioneries -15 to -10 °c, first started dropwise addition of 11 ml (3.4 equivalents per equivalent of cephem sulfoxide) pyridine in 30 ml of methylene chloride. The addition of pyridine continues on 53 min. Fifteen minutes after terminating the addition of pyridine, added 37 ml (10 equivalents) of isobutanol and HCl gas is bubbled in the reaction mixture during 6 min. The product title crystallizes in the solution and is isolated by filtration, washed with 100 ml of methylene chloride and dried in vacuum. Obtained therefrom 6.4 grams (37%).

NMR (-DMSO Dc) 6, 4.06 (e wide, 2), 5.31 (Q-, 2, j=4, 5 Hertz, H (3-lactam), 5.5 (e, 2), 7, 8 - 8, 3 (H-aromatic) and about 8.6 (e very wide, the NH - *).

Examples 91 - 134

Is studied in detail the reaction described in the example 90 to optimize the reaction conditions. The table III summarizes the results of these studies. It follows the same general procedure as in example 90 using the amounts of reactants and reaction times indicated in the table. The substrate sulfoxide cephem and its amount (22.3 grams), the amount of methylene chloride used as a solvent for pyridine (30 ml) and the amount of isobutanol (37 ml) are held constant in each of the examples table.

90 - 134 RESULTS

*** Product ** Amylêne TBs pyridine derivatives (grams/(ml./ equiv *) (min) (ml air/equiv)% corrected)

Amylêne(ëquiv/ml. *)

5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 5,1/1.2 0 5,1/1.2 5,1/1.2 Product

Table III (result)

the tempsentredu cephem sulfoxide and the wave pyridine

périodelaquelle solution is added to the pyridine Example 135

7-amino 3-chloro 3 a-cephem-to-4 carboxylate 'of 4' - nitrobenzyl a solution is prepared of the triphenyl phosphite to die/chlorine complex (a TPP/C.) from 23 ml of triphenyl phosphite and chlorine in 100 ml of methylene chloride by the procedure described in example 90. To this solution at a temperature of to -10 -15 °c, 5.28 ml added cyclopentene (3.0 equivalents per equivalent of starting cephem sulfoxide), then 11.15 g of 1-oxide 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4' orth. Added dropwise in 60 minutes a solution of 6.2 ml of pyridine in 15 ml of methylene chloride while maintaining the temperature of the reaction mixture to a value of 15 °c to -10. Then adding 18.5 ml of isobutanol and HCl gas is bubbled into the mixture for about 3 min. And then allowing the reaction mixture to warm up to room temperature and, after ' 2 hours, the mixture is filtered to obtain the title product in a yield of 80.4%.

Examples 136 - 139

Used the same procedure and the same amounts of reagent (equivalents) that in the example 135, but varied the fixing agent of halogen, the table IV summarizes the results of examples 135. to 139.

.TABLE VI

SUMMARIZING EXAMPLES 135 - 139

Example 140

Hydrochloride 7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl (acetonitrile derivative)

(Has) by following the general procedure in example 90, the complex is prepared a TPP/C from chlorine and 23.0 ml phosphite triphény the in 100 ml of d¹ acetonitrile. With this solution, added 3.2 ml amylene and 11.15 g of 1-oxide 7 a--phenoxyacetamido-to-3-hydroxy 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl. Then added dropwise pyridine in 6.2 ml of 1' acetonitrile. After terminating the addition of pyridine, 18.5 ml of isobutanol is added. HCl gas is bubbled into the reaction mixture, and the temperature of the reaction mixture then rises to 40 °c. An ice bath is used to cool the mixture to about 25 °c. The product of the title crystallizes in the mixture to 28 °c and is isolated with a yield of 46.5%.

(D) using the same general procedure as in paragraph A above but reaction medium used is 100 ml of tetrahydrofuran. Added about 25 ml of methylene chloride to the mixture after the addition of 1' isobutanol and hydrochloric acid. Product yield of the title: 35.1%.

Example 141

7-amino 3-chloro 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl (room temperature).

A solution is prepared of the complex triphenyl phosphite/chlorine by adding chlorine and 22.9 ml of triphenyl phosphite simultaneously to a mixture of 100 ml of 0.93 ml of pyridine in methylene chloride at 21 and 25 degrees Celsius.

The reactants are added confectioneries such a speed that a green colored pale persists in the reaction mixture during the addition. With this solution, 4.2 ml added 11.2 g of amylene then 1-oxide 7 a--phenoxyacetamido-to-3-chloro 3 a-cephem-to-4-carboxylate 4-nitrobenzyl. The temperature of the reaction mixture rises at approximately 30 °c. Cooled to 22° before adding dropwise in 1 hour 5.3 ml of pyridine in 15 ml of methylene chloride. Fifteen minutes after completion of the addition of pyridine, 18.5 ml of isobutanol is added. HCl gas is bubbled into the solution for 5 min. There filtration after 2 hours gives 5.69 grams of the title.

Example 142

Hydrochloride 7-amino 3 a-méthylènecépham-to-4-carboxylate 4¹ - nitrobenzyl

The complex is prepared triphenyl phosphite/chlorine from chlorine and 31.6 ml of triphenyl phosphite by the procedure in example 90.

5.1 Ml added amylene and 19.13 g of 1-oxide 7 a--phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4' orth. After 30 min, first started dropwise addition of 6.3 ml of pyridine in 16 ml of methylene chloride. The addition continues for

1 hour. After 15 min, added 3.1 ml of pyridine in 8 ml of additional methylene chloride in half an hour. Fifteen minutes after the end of the last addition of pyridine, 37 ml of isobutanol is added. HCl gas is bubbled in the reaction mixture during 6 min. The filtration after 2 hours gives 10.5 grams (69.5%) of the title product.

NMR (DMSO in a-d₆ ) δ 3.67 (e wide, 2), 5.0 (D., 1, j=5 Hz range), 5, 35 - 5, 53 (the m, 6) and 7.6 - 8, the I (w, H-aromatic).

Example 143 7-a-phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4 'nj-to-trobenzyle. Complex kinetic triphenyl phosphite/bromine

(Has) a solution is prepared of the complex triphenyl phosphite/bromine by adding 19.9 ml of triphenyl phosphite to 3.9 ml of bromine in 150. ml of methylene chloride at -30 °c. Noting a pale color in the reaction mixture even when a test starch-iodide for bromine is negative. With this solution a - 45 °c, is added 8 ml amylene then 19.14 g of 1-oxide 7 a--phenoxyacetamido-a 3 a-méthylènecépham-to-4-carboxylate 4'-nitrobenzyl. A comparative thin layer chromatography indicates that the reduction is terminated after 20 min. The reaction mixture is allowed to warm to room temperature before concentrating in vacuo to about 40 ml.

To the resulting solution, 40 ml of methanol is added. Of crystals of the title begin to form in 30 seconds. The filtration gives 14.06 grams (76.8%) of the title product; the NMR data confirm its structure.

(D) it follows the same procedure as that described in paragraph (has) above, but the solution is cooled from the complex triphenyl phosphite/bromine to -60 °c before the addition of the sulfoxide alymene and 3 a-méthylènecépham. The reaction is carried out at a temperature of -40 °c to -45 °c. The thin layer chromatography that the reaction is complete after one hour. Isolated a total of 14.06 g of the title product.

Examples 144 - 153

Are reduced following cephalosporin sulfoxides according to the general procedure of example 79 using the complex triaryl phosphite/halogen indicated.

Example 144. 1-oxide 7 a-formamidopyrimidine-3 a-acétoxyméthylcéphem-to-4 carboxylate of the benzhydryl; complex triphenyl phosphite/chlorine.

Example 145. 1-oxide 7 - [2 - (2-thienyl) acetamido] and 3-chloro 3 a-cephem-to-4-carboxylate 4'-methoxybenzyl;

complex triphenyl phosphite/bromine.

Example 146. 1-oxide 7 a-chloroacëtamido and 3 a-bromomethyl 3 a-cephem-to-4-carboxylate 2 ', 2', 2¹ - trichloroethyl; complex phosphite (p-methoxyphenyl) sorting/chlorine.

Example 147. 1-oxide ' of 7 a-benzamido-to-3-methyl 3 a-cephem-to-4-carboxylate benzyl; complex triphenyl phosphite/chlorine.

Example 148. 1-oxide 7 a--phenoxyacetamido-a 3 a-cephem-to-4-carboxylate 4'-nitrobenzyl; complex triphenyl phosphite/chlorine.

Example 149. 1-oxide 7 - [2 - (2-furyl-) - 2 a-méthoximino-acetamido] and 3 - (1-methyl-L, 2, 3, 4-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4 carboxylate T-butyl; complex triphenyl phosphite/chlorine.

Example 150. 1-oxide 7 - (2 a-a formyloxy-a 2 a-phenylacetamido) - 3 - (1-methyl-L, 2, 3, 4-tetrazol-5 yl) thiomethyl-a 3 a-cephem-to-4 carboxylate of the benzhydryl; complex phosphite sorting (pchlorophényle)/chlorine.

Example 151. 1-oxide - 7 (4 a-nitrobenzyloxycarbonylamino) - 3 a-methoxymethyl-3 a-cephem-to-4-carboxylate 4¹ - nitrobenzyl complex phosphite (tolyl) sorting/chlorine or bromine/triphenyl phosphite complex.

Example 152. 1-oxide 7 a-phënylacétamido-to-3-acetylthio-methyl 3 a-cephem-to-4-carboxylate 4¹ - methoxybenzyl;

complex triphenyl phosphite/chlorine.

Example 153. 1-oxide 7 - [2 - (2-thienyl) acêtamido] and 3-methoxycarbonyl-3 a-cephem-to-4 carboxylate of the benzhydryl;

complex phosphite (P-methoxyphenyl) sorting/bromine.

Examples 154 - 163

According to scheme II of the foregoing description, are transformed sulfoxides 7 a-acylaminocéphalosporines used as starting materials in the examples 144 to 153, by first imino halides cephalosporin corresdants then esters 7 a-aminocephalosporin parties using the complex of triaryl phosphite/halogen indicated, pyridine as a base, and 1 'butanol, the 1.2 methylpropanediol or 1.3 methylpropanediol for the alcoholysis of 1 'imino-chloride.

Example 163 - 172

According to the general procedure in example 90 above, reacting the sulfoxide esters 7 acylamino-3 hydroxy-cephalosporin designated below in esters 7-amino 3 chloro-cëphalosporines corresponding using the reagents indicated.

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Example 173

Acid 7 - (2 a-thiénylacétamido) - 3 methyl-3 a-cephem-a 4 -carboxylic

A solution is prepared of the complex triphenyl phosphite/chlorine in methylene chloride at a temperature of -20 to -35 °c, by adding 10 ml of triphenyl phosphite to excess chlorine in 75 ml of methylene chloride. 3 Ml amylene is used for consuming excess chlorine.

To the solution of complex triphenyl phosphite/chlorine (30 ml, 12.9 mmol) at 0 °c, added 0.5 ml amylene and 0.90 grams (2, .2 mmol) sulfoxide acid 7 - (2 a-thiênylacétamido) - 3 methyl-3 a-cêphem-to-4-carboxylic acid. The sulfoxide dissolves after 5 minutes at 0 degrees and 5 degrees Celsius. The reaction mixture was stirred at that temperature for 25 min, during which time a precipitate. 0.1 Ml of water is added and the mixture is stirred for 5 mins. After adding 50 ml of ether, the product is collected by filtration. After drying (45 °c, 120 mm) during 2 days, 0.5 g of the sulfide is obtained.

NMR (DMSO to d 6) δ 8.21 (D., j=8 Hz range, the NH), 7.38 (m-), 6.96 (d-, j=4 Hz range), 5.67 (D., D., j=5, Z-8:00, hr_? ), 4.81 (d., j=5 Hz range, mmHg), 3.82 (e), 3.60 (Aβ, hr₂ ), 2.03 (e, methyl).