CA1319682C - Process for the preparation of new oximes derivated from 7-aminothiazolylacetamidocephalosporanic acid - Google Patents

Abstract

PRECISION OF DISCLOSURE

The subject of the present invention is a method of preparation of new oximes derived from 7-amino acid thiazolyl acetamido cephalosporanic of general formula (I):
(I) in which R represents a hydrogen atom, R 'represents a hydrogen atom, or a saturated or unsaturated alkyl radical turé having from 1 to 4 carbon atoms, A represents either a hydrogen atom equivalent to alkali, alkali metal earthy, magnesium or an amino organic base, the trait wavy means that the OR 'group is in the syn position. These new oximes have antibio-ticks.

Description

~ 3 ~

The subject of the present invention is a method of preparation of new oximes derived from 7-amino acid thiazolyl acetamino cephalosporanic of general formula I:
NH-R
o (I) # 11 ~, ~
OR 'CO2A 2 ~ 3 in which R represents a hydrogen atom, R 'represents smells of a hydrogen atom or a saturated alkyl radical or unsaturated having 1 to 4 carbon atoms, A represents either a hydrogen atom being an equivalent of alkali metal, alkaline earth, magnesium or an amino organic base, the wavy line means that the group OR 'is in the syn position.
Among the other values of R ′, we can cite methyl, ethyl, propyl, isopropyl, butyl radicals, sec-butyl, tert-butyl, vinyl, propenyl, butenyl, ethynyl and propargyle.
Among the values of A, we can cite in particular an equivalent of sodium, potassium, lithium, calcium or magnesium; among the organic bases that can be represented by A, mention may be made of trimethylamine, tri-thylamine, methylamine, propylarnine, N, N-dimethyl-thanolamine, tris- (hydroxymethyl) aminomethane, arginine or lysine.
The compounds of formula I, defined as having the syn isomer form, can be represented schematically-by the following general formula:

. ~
: `", j 1 3 ~ 2 NH-) ~. O

'' .. NH \, S

~ Z \ `CH20 CCH3 L! invention relates more particularly to a process for preparing the products of formula I, in which R represents a hydrogen atom, R 'represents a hydrogen atom, or an alkyl, saturated or unsaturated raidcal, having 1 to 4 carbon atoms and A represents an atom of hydrogen, a sodium atom or an equivalent of diethylamine.
Among the products of formula I, there may be mentioned in particular the products described below in the examples and particularly:
- 3-acetoxymethyl acid 7- ~ 2- (2-amino 4 thiazolyl)

2-methoxy imino acetamid ~ ceph-3-eme 4-carboxylic;

- The sodium salt of 3-acetoxymethyl acid 7- l2- (2-amino 4-thiazolyl? 2-methoxy imino acetamid ~ ceph-

3rd 4-carboxylic;
r - 3-acetoxymethyl 7- L2- (2-amino 4-thiazolyl) acid 2-methoxy imino acetamido¦ ceph-3-eme 4-carboxylic isomer syn, ~ 3 ~ 8 ~

- The sodium salt of 3-acetoxynethyl acid 7- ~ 2- (2-ar ~ o

4-thiazolyl) 2-methoxy imino acetamido1 ceph ~ 3- ~ me 4-carboxylic, i ~ syn omer;

- 3-acetoxymethyl 7 {2- (2-amino 4-thiazo-lyl) 2-methoxy imino acetamido] ceph-3-eme 4-car ~ oxylic, tel that obtained by] .e process described in example 4;
- The sodium salt of 3-acetoxymethyl acid 7- [2- (2-amino 4-thiazo.lyl) 2-methoxy imino acetamido ~ ceph-3-eme 4-carboxylic, as obtained by the process described in Example 7;
- The sodium salt crystallizes from 3-aceto- acid xymethyl 7- ~ 2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido ~
ceph-3eme 4-carboxylic, syn isomer;

- 3-acetoxymethyl acid 7- [2- (2-amino 4-thia-zolyl) 2-ethoxy imino acetamido] ceph-3-eme 4-carboxylic, syn isomer and its salts with alkali and alkaline metals earthy, magnesium or organic amino bases;

-L'aclde 3-acetoxymethyl 7- [2- (2-amino 4-thiazo-lyl) 2 - ((2-propenyl) oxymino) acetamido] ceph-3-eme ~ -car-boxylic, syn-isomer and its salts with alkali metals, alkaline earth, magnesium or amine organic bases;

- 3-acetoxymethyl 7-L2- (2-amino ~ -thia-zolyl) 2 - ((1-methyl ethoxy) imino) acetamido ~ ceph-3-eme 4-carboxylic, syn-isomer and its salts with alkali metals `lin, alkaline earth, magnesium or organic bases amines.

It is understood that the products of formula I pre-previously cited may exist:

- either in the form indicated by the said form-mule I, - either in the form of products of formu ~ I:
- Z

~ ~.

R ~ 3 NOT .

-H
S
(Iz) ~ R '~ N ~ CT ~ 2-O ~ C1 - in which R, R 'and A have the abovementioned meaning.

The process for the preparation of formulated products the I, as defined above, subject of the invention, is characterized in that 7-amino acid is reacted cephalosporanic formula:

.

~ L ~ J`CH2-O ~ H3 -with an acid of formula IIc: `
NH-Rd `20 ~ -~ -C02H (IIc) . ~ R ~ d isomer ~

or a functional derivative of this acid, formula IIc, in which Rd represents an easily eliminated grouping ble by acid hydrolysis or by hydrogenolysis or a group chloracetyle and R'd represents an easily eliminated grouping free by acid hydrolysis or by hydrogenolysis, a group 13 ~ 9S ~ ~

chloracetyl or a saturated or unsaturated alkyl radical having ~
1 to 4 carbon atoms, it being understood that when R'd repre- I
feels a chloracetyl group, it is the same for Rd, to obtain a form product] .e Ic::

NH-Rd ~ O ~ I
~ N ~ S ~ (Ic) OR'd ~ ~ CH2-O-cO-cH3 C ~ 2H

in ~ where Rd and Rd have the meaning indicated above, product of formula Ic which is hydrolyzed in an acid medium or hydrogenolysis, or treats with thiourea according to the values of Rd and R'd to obtain a product of formula Ib:

i ~ ~ S ~ (Ib) OR ~ ~ CH2-O-CO-CH3 (~ 2H

in which R represents a hydrogen atom or a radical saturated or unsaturated alkyl having from 1 to 4 carbon atoms and corresponding to a product of formula (I) in which A re-has a hydrogen atom, a product of formula Ib which saLifie possibly according to the usual ~, e ~ hodes.

The process for the preparation of for-mule I, as defined above, also subject to the invention is characterized in that the acid is reacted 7-amino cephalosporanic formula:

- 5 ~

~ 3 ~

~, ~ S`j / i N, ~ `CH -oc-cH

with an acid of formula II:

NH-Rl (II) / ~
SN
\ _! C ---- CO211 NOT
OR'l syn isomer or a functional derivative of this acid, formula II in which Rl represents a group which can be easily eliminated by hy-acid drolysis or by hydrogenolysis and R'l represents a group easily eliminated by acid hydrolysis or by hydro-negolysis or a saturated or unsaturated alkyl radical having from 1 to 4 carbon atoms, to obtain a product of formula Ia:
NIHRl `~ (Ia) SN
`CC-NH` ~ ~ S ~ ~
NO / 'N ~ \
OR 'CH -OC-CH

in which Rl and R'l have the meaning indicated above product of formula Ia which is hydrolyzed in an acid medium or hydrogenolysis to obtain a product of formu: The defined Ib previously and that we salify? if desi.r ~.
In the pr ~ -cédem ~ lerlt described compounds, the groups-easily removable by acid hydrolysis or by hydro-genolysis is chosen from the group made up of groups tert-butoxycarbonyl, trityl, dibenzyl, trichloro-thyle pements and carbobenzyloxy.
, ~
~ ,, ~

131g ~

In a preferred embodiment of the process for preparing the products of formula I, we ~ 3 ~

treats 7 amino cephalosporanic acid with an Eonc- derivative tional acid of formula IIc or fI, such as an anhydride or acid chloride, the anhydride can be formed in situ by the action of isobutyl chloroformate or dicyclohexylcar-bodiimide on aci.de. We can also use other halides or other anhydrides formed in situ by action of other alkyl chloroformates, of a dialkylcar-bodiimide or another dicycloalkyl carbodiimide. We can also use other acid derivatives such as azide acid, the active acid amide or an active acid ester forms ~ ar example with hydroxy succinimide, paranitrophenol or 2-4 di-nitrophenol. In case the acid reaction 7-amino cephalosporanique is carried out with a halide of the acid of general formula IIc or II or with a formal anhydride me with an isobutyl chloroformate, we proceed preferably in the presence of a basic agent. As a basic agent, we can choose for example an alkali metal carbonate or a base tertiary organic such as N-methyl morpholine, pyridine or a trialkylamine such as triethylamine.

As the acid hydrolysis agent to which we subject, where appropriate, the products of formula Ic or Ia, we can cite formic acid, trifluoroacetic acid or acetic acid.
These acids can be used anhydrous or in aqueous solution.
se. As a hydrolysis agent, the system can be included zinc-acetic acid.

A hydrolysis agent is preferably used acid such as anhydrous trifluoroacetic acid or acids formic or aqueous acetyl to eliminate groupings tert-butoxy carbonyl or trityl.

We use. preferably the zinc ~ acid system ., ~ --7 acetic for eliminex the trichloroethyle group and hydro-catalytic generation ~ to eliminate benzyles groups, di-benzyles and carbobenzyloxy.

The reaction of thiourea on the product of formula Ic, in which Rd represents a chloraceous group-tyle and R'd represents a chloracetyl group or a radical alkyl, saturated or unsaturated, having from 1 to 4 carbon atoms, is carried out, preferably in a neutral or acidic environment. This type of reaction is described by Masaki / JACS, 90, 4508 (1968) /.

The products of formula Ic, Ia or Ib can be salified according to the usual methods. Salification can, for example, be obtained by action on these acids of a base mineral such as for example sodium hydroxide or po-tassium or sodium bicarbonate, or an acid salt substituted or unsubstituted aliphatic canboxylic acid, such as diethylacetic acid, ethyl hexanoic acid or, more specifically cially, acetic acid.

The preferred salts of the acids previously cited are the sodium salts.

Salification can also be obtained by.
action of an organic base such as triethylamine.

For the preparation of the salts, the solvates of free acids can also be used as products starting in place of free acids. We can quote, by example the solvates obtained with water, ~ ormic acid or an alcohol.

The solvates with an alcohol, more particular-ment ethanol, can also be obtained, for example, by ~ 319 ~
, treating with a mixture of alcohol and water the solvate formed with formic acid, this treatment being followed by a concentration of the solution.

This salification is carried out preferably in a solvent or a mixture of solvents, such as water, ethyl ether, methanol, ethanol or acetone.

The salts are obtained in amorphous or crystalline form tallized according to the reaction conditions used.

The crystallized salts are preferably prepared by reacting the free acids or their solvates formed, for example, with formic acid or ethanol with one of - salts of the aliphatic carboxylic acids mentioned above, preferably with sodium acetate.

~ In the preparation of a sodium salt, the reaction tion is carried out in a suitable organic solvent, such as for example methanol, a solvent which may contain small quantities of water.

It is also possible to transform salts amorphous in their crystallized form. For this purpose, an amor-sodium phe, which can be in the form of a solvate withj by example, 0.5, 1 or 1.5 mole of water, can be dissolved in a suitable organic solvent, preferably a low alcohol molecular weight, such as methanol; crystallization can then be carried out directly or by addition of other sol-for example, ethanol, isopropanol, n-butanol, acetone, ~ thers and, in general, organic solvents - miscibl ~ s with methanol.

If the starting material, the solvent or both constituents contain water, the crystallized salt can be obtained in the form of h ~ drate. For example, sodium salt ~ 9 ~

. crystallized 3-acetoxymethyl acid 7- ~ 2- (2-amino 4-thia-zolyl) 2-methoxyimino acetamidoJ ceph ~ 3-th 4-carboxylic syn isomer could be isolated at ~ ec, for example, 0.5, l or l.5 mole of water.

- The invention also relates to a variant of the process for preparing the products of formula Ib:

~ O

\ = ~ _ ~ HS ~ Ib) OR ~ ~ ~ CH2_o ~ C_CH3 isomer syn and their pharmaceutically acceptable salts, formula Ib in which R represents a hydrogen atom or a radical saturated or unsaturated alkyl having from 1 to 4 carbon atoms and corresponding to a product of formula I in which A
represents a hydrogen atom characterized in that either an salt of a product of formula Ic is treated with an acid in which Rd represents an easily eliminable grouping by acid hydrolysis and R'd represents a group easily eliminable by acid hydrolysis or a saturated alkyl radical or unsaturated having from 1 to 4 carbon atoms to obtain a pro-duit of formula Ib or else it is treated with a hydro-genolysis a salt of a product of formula Ic in ~ uelle Rd represents a group easily eliminated by hydrogen lysis and R'd represents a group that can be easily eliminated by hydrogenolysis or a saturated or unsaturated alkyl radical having the 4 atoms of carhone to obtain a salt of a product of L ~

1319 ~ 2 formula Ib or else we treat with thiourea a salt of product of formula Ic in which Rd represents a group-chloracetyl and R'd represents a chloracetyl group or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon to obtain a salt of a product of ~ ormule Ib.

The invention also has ob ~ and a variant of the process for preparing the products of formula Ib:

N / A

~ NH ~ ~ ~ (Ib) ~ R ~ I CH -O-CO-CH

and their pharmaceutically acceptable salts, formula Ib in which R represents a hydrogen atom or a radical cal saturated or unsaturated alkyl, having 1 to 4 carbon atoms and corresponding to a product of formula I, in which A
represents a hydrogen atom, characterized in that either, an salt of a product of formula Ia is treated with an acid, in which R1 represents an easily eliminated grouping ble by acid hydrolysis and R'l represents an easy grouping-I

ment eliminable by acid hydrolysis or an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, to obtain hold a product of formula Ib, or else, we treat with a hydrogenolysis agent a salt of a product of formula Ia t in which Rl represents an easily eliminated grouping by hydrogenolysis and R'l represents a group easily eli-shabby by hydrogenolysis or a saturated or inert alkyl radical saturated, having 1 to 4 carbon atoms, to obtain a salt `: -] .1 -. ..

~ 319 ~
of a product of formula Ib.

The acid used to hydrolyze the salts of products of formula Ic GU of formula Ia, in which Rd and Rl represent a group which can easily be eliminated by acid hydrolysis and R'd and R'l. represent an easy grouping Lely eliminable by acid hydrol.yse or an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, is, preferably formic acid. We can however use trifluoroac ~ tic acid or acid . . _ , ~ 3 ~ 8 ~ J

acetic. These acids can be used anhydrous or in solution aqueous.
As a hydrogenolysis agent, to which the salts are omitted products of formula Ic or of formula Ia, in the ~ which Rd and R1 represent a group easily removable by hydro-genolysis and R'd and Rl1 represent a group easily eliminable by hydrogenolysis or an alkyl radical, ~ aturated or unsaturated, having from 1 to 4 carbon atoms, there may be mentioned catalytic hydrogenation.
A subject of the invention is also a process for preparing tion of the products of formula IIc, as defined above, characterized in that a product of formula IVo is treated N (IV) C02alc GOLD' in which R 'represents a hydrogen atom, a group easily removable by acid hydrolysis or hydrogenolysis or an alkyl radical, saturated or unsaturated, having from 1 to 4 atoms of carbon, and alk represents an alkyl radical having from 1 to ~ atoms of carbon, either by a functional derivative of an easy grouping-ment eliminable by acid hydrolysis or by hydrogenolysis ~ so.it, when R 'represents a hydrogen atom or an alkyl radical saturated or unsaturated having from 1 to 4 carbon atoms pax a derivative functional of the chloracetyl group to obtain a product of formula Vc:.
N ~ l-Rd S ~ N (Vc) ~ ~ 02alc OR'd 13 ~ 8 ~ D
~ in which Rd represents an easily removable tooth group by acid hydrolysis or by ~ hydrogenolysis or a group chloracetyl and R'd represents an easily removable group by acid hydrolysis or by hydrogenolysis; a chloracetyl group or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon, it being understood that when R'd represents a group chloracetyl, it is the same for Rd, product of formula Vc that it is treated with a base and then with an acid to obtain a product of formula IIc:
NH-Rd `- == '- T 2 (IIc) ~ R'd in which ~ d and R'd have the meaning indicated above.
A subject of the invention is also a process for preparing tion of the products of formula II ~ as defined above, characterized in that a product of ~ ormule IV is treated:

(IV) ~ = ~ co2alc GOLD' in which R 'represents a hydrogen atom, a group easily removable by acid hydrolysis or hydrogenolysis or a saturated or unsaturated alkyl radical having from 1 to 4 atoms carbon and alc repre ~ ente an alkyl radical having from 1 to ~ atorne ~
carbon ~, by a functional derivative of a gxoupage easily eliminable by acid hydrolysis or by hyd: rogénoly, se pour o ~ HOLD
a product of formula V:

J ~

- ~ ~, 3 ~ 8, ~ i ~

NH-R

SN (~
\ = / - ~ co2alc ~ 1 in which R1 represents an easily eliminable group by acid hydrolysis or by hydrogenolysis and R ~ represents Im group easily removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated alkyl radical having 1 to ~ carbon atoms, product of formula V which is treated with a base, then with an acid to obtain a product of formula II:

N ~ -R1 S ~ N (II) \ == ~ C02H ~;

~ R'1 in which R1 and R'1 have the meaning indicated above.
In one embodiment of the process for preparing ~
prod ~ its of formula IIc or products of formula II, the derivative functional group easily removable by hydrolysis acid or by h ~ drogenolysis is preferably -trityl chloride used in the presence of triethylamine, or other amino bases tertiary such as other ~ trialcoylamine ~ t methylmorpholine or pyridine You can also use other functional samples grouping ~ easily eliminated by acid hydrolysis or by hydrogenation. Among this ~ derivatives, there may be mentioned chloroformate of tert-butyl prepared in situ or tert-butyl azidoformate ~
trichloroethyl or benzyl cAloroformate, anhydride ~ 3 ~

mixed formyl-acetic prepared in situ9 chloride or another benzyl or dibenzyl halide, phthalic anhydride or N-carbethoxy phthalimide.
The functional derivative of the chloracetyl group is, preferably chloroacetic anhydride or a halide, such as than monochloroacetyl chloride.
Dan ~ s the case where the reaction to obtain a product of formula Y5 is carried out with a chloroacetyl halide, operates preferentially ~ ent in the presence of an identical basic agent to those mentioned above.
~ based which is used to saponify the product of formula V or formula Vc e ~ st, preferably soda, but we can also use other bases, such as potash or the barite.
The acid that is used to isolate the acid of formula II
or of formula IIc is preferably dilute hydrochloric acid, but acetic acid or form acid can also be used mique.
~ The invention also relates to a method of preparation of products of formula IV, as defined above demment, characterized in that the thiourea is made to act on a product of formula III:

Cl-CH2 ~ -C02alc (III) GOLD' in which R 'represents a hydrogen atom, a group easily eliminated by acid hydrolyae or by hydrogenol ~ e or a saturated or unsaturated alkyl radical having from 1 to 4 atoMes of carbon and alc repre ~ ente an alkyl radical aya ~ t of 1 to 4 atoms of carbon, to obtain after treatment with a ba ~ e, a product of formula IV:

~ 3 ~ the) g ~

C02alc (IV) ~ ' in which R 'and alc have the abovementioned signi.fication.
In a preferred embodiment of this process, the base which is used to obtain the product of formula IV is potassium acetate. We can however use carbonates and acidic alkali carbonates, soda or potash diluted.
~ The invention also relates to a variant of process for the preparation of products of formula V, process described previously.
This variant for the preparation of formula Vb:
N ~ IR1 ~ N
~ co2alc (Vb) OR "b in which R1 represents an easily removable group by acid hydrolysis or by hydrogenolysis, R "b represents a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon and alk represents an alkyl radical having from 1 to 4 atoms of carbon, and corresponding to a product of formula V, such as ~ ue defined above, in which R1 represents a group easily removable by acid hydrolysis or by hydrogenolysis and R'1 represents an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, is caracté.ri ~ ée in that we treat a 0 ~, '1 ,. - ~

~ 3 ~ 9 ~
product of formula IV ":

SN
~ Ozalc (IV ") OH

by an equivalent of a functional derivative of an easy grouping-ment eliminable by acid hydrolysis or by hydrogenolysis, to obtain a product of formula X:

NHR

~ (X) C02alc ~ H

which is treated with an alkylating agent, to obtain the expected product of formula Vb.
Danff a mode of execution of this process, the derivative functional group easily removable by hydrolysis acid or by hydrogenolysis is; preferably, chloride trityle. We operate alorff preferably with a base triethylamine ~ We can also use other bases ~, such as other trialkylamines, methyl morpholine or pyridine.
We can also use other ~ functional derivatives easily removable groups ~ by acid hydrolysis or hydrogenol ~ e, such as chloroformate or azidoformate tert-butyl, trichloroethyl chloroformate or dibenzyl, mixed formyl acetic anhydride prepared in ffitU, chloride or another benzyl or dibenzyl halide, the anhydride 1 3 ~
phthalic or N-carbé-thoxy phthali ~ nide.
~ 'alkylating agent that we u-tillse to prepare the products of formula Vb e ~ t, preferably a halide alkyl, such as alkyl iodide or an alkyl sulfa-te.
The invention also relates to a variant of the process for the preparation of products of formula IV, process described previously.
This variant for the preparation of the products of formula IVa:

N (IVa) ~ / C02alc o Ra dan ~ s which alk represents an alkyl radical having from 1 to 4 carbon atoms and R'a represents a saturated alkyl radical, having from 1 to 4 carbon atoms9 and corresponding to a product of formula IV, as defined above, in which R 'represents ~ ente a saturated alXyl radical having from 1 to 4 carbon atoms7 is characterized in that a product of formula VI is treated:

CH3-CC-C02-alc ~ ~ (Vl) OH

in which alc has the previous ~ ignification, by an agent of alkylation, to obtain a prodult of fo; rmu: Le V ~

: CH -CC-CO alc 3 ~ ~ 2 (VII) ~ R'a ~ ``. q , ~ ~ ~ \ _ product which is treated with a brominating agent, to obtain a product of formula VIII:

BrCH -CC-CO alc 2 11, ~ 2 s (VIII) OR'a product on which we act the thiourea, then a base, to obtain a product of formula IVa.
In one embodiment of this method, the agent alkylation that we use to transform products of formula VI into products of formula VII is preferably an alkyl halide, such as chlorur ~, bromide or alkyl iodide or a sulfate of alkyl having 1 to 4 carbon atoms.
The preferred brominating agent is to transform the products of formula VII into products of formula VIII is bromine. '' The base ~ ue we use after action of the product of formula VIII on thiourea is preferably a carbonate or an acidic alkali metal carbonate. We can however use diluted soda or potash or potassium acetate.
It was found that the configuration of the products of formula I 'and formula I was related to the configuration of the products of formula IV, because the confi-guration of the products obtained from the products of formula IV can be maintained during the synthesis.
This is also of course the case for products obtained from products of formulas IVa and IV ", since these are included in formula IV.
The configuration of the products of formula IV depends of a certain number of parameters brought into play during the preparation of these products.
This is how we found that when the action of ,. . . :

,:,:. '' : - ~ 3 ~
thiourea on fo.rmule products; it is self-driving in an aqueous solventJ such as aqueous acetone ~ e or ethanol aqueous, or at room temperature, by acting a quantity substantially stoichiometric of thiourea and for a duration fairly short of the order of 1 to 3 hours, or finally when all the previous conditions are met, we obtain the isomer syn.
~ A present invention therefore also relates to a pr ~ assigned to prepare products of formula IV, such as defined above, in the syn form, characterized in that we react the thiourea, then a base on a product of formula III ':

~ -CH -CC-C0 alc 2 ~ 2 0 ~ ~ III ') OR'b in which] e X represents a chlorine or bromine atom and R'b represents a hydrogen atom, a group easily eliminable by acid hydrolysis or by hydrogenolysis or a radical alkyl, saturated or unsaturated, having from 1 to 4 carbon atoms when X represents a chlorine atom, or R'b represents a hydrogen atom or a saturated alkyl radical having from 1 to 4 carbon atoms when X represents a bromine atom and in what, for the reaction of thiourea, either we operate in an aqueous solvent, either operating at room temperature, presence of a substantially stoichiometric amount of thio-urea and driving the reaction in a ternps limited to a few hours, either we operate by bringing together all the ~ cond.ition ~
set out above.

~ 0 ~ 'invention also pou.r subject a method of preparation of form IV products, as defined previously, in the form ~, which consists in reacting the ~. . .

~ ~ ~ r ~

~ niourée on a p: product of formula III, as defined previous ~ emment and is characterized in that 9 is one operates in an aqueous solvent, it is operated at ambient temperature, presence of a substantially stoichiometric amount of thiourea and driving the reaction in a time limited to a few hours9 either we operate by meeting all the conditions set out above.
~ The invention has enfi.n for a method of preparation products of formula IVa, as defined above, which consists in making the thiourea act on a product of formula VIII, as defined above, and is characterized in that, either one operates in an aqueous solvent, if one operates at rature room, in the presence of a substantially stoe-chiometric of thiourea and driving the reaction in a time limited to a few hours, or we operate by bringing together all of the above conditions.
This is how the products of formula IV obtained in examples 3,8,10,12, and 21 have the syn configuration.
~ es products of general formula I '9 including those of general formula I and particularly those which in the form syn, have very good antibiotic activity on the one hand on gram (~) bacteria, such as staphylococci, streptococci, in particular penicillin-resistant staphylococci, on the other hand, on gram (-) bacteria, especially bacteria coliforms, Klebs ~ ella, Salmonella and Proteus.
This ~ properties make suitable said pharmaceutical products-ceutically acceptable to be used coml ~ e drugs in the treatment of diseases with sensitive germs and in particular in that of staphylococcal diseases, such as septicemales staphylococci, malignant staphylococcal infections of the face or skin, pyoderma, septic or suppurative wounds, carbuncles, phlegmons, erysipelas, acute staphylococcal disease ~ s primitive or post influenza, - ~ 3 ~ 9 ~ 8 ~
Dronchopneumonles, pulmonary suppurations.
These pharmaceutically acceptable products can also be used as medicine ~ in the treatment of collibacillosis and associated infections, in infections with Proteu3, in Klebsiella and Salmonella and in other a ~ fection ~
caused by bacteria ~ to gram (-).
~ es products of formula I pharmaceutically acceptable can be used ~ for the preparation of pharmaceutical compositions ceutiques containing, as active ingredient, at least one desdit8 products and in particular one of those of syn structure described in the examples.
Among these compositions, it is necessary to mention more particularly the pharmaceutical compositions containing, to as active ingredient, at least one of the products of formula general I, in which R represents, a hydrogen atom, R ' represents a hydrogen atom or an alkyl radical, saturated or unsaturated turé, having from 1 to 4 carbon atoms and A represents an atom dihydrogen or sodium.
Pharmaceutical compositions must also be mentioned.

ceutiques containing, as active ingredient:
- ~ 3-acetoxymethyl acid 7- [2- (2 ~ amino 4-thiazolyl) 2-methoxy imino acetamido ~ ceph-3-th 4-carboxylic, isomer syn; this product is in particular described in example 4, 6, 20 or 22, - or the sodium salt of 3-acetoxymethyl acid 7-[2- (2-amino 4-thiazolyl) 2-methoxy imino acetarnido ~ ceph-3-th 4-carboxylic, i ~ omer ~; this product is not described in example: 7, - or the ~ el of sodium crystallizes from 3-acetoxy acid-methyl 7- [2- (2-arnino 4 - thiazolyl) 2 ~ methoxy imino acetamido]
ceph-3-èmë 4-carboxylic, syn-isomer, or at least one of the following products:

- 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) acid . . .

~ 3 ~

2 ethoxy imino acetamido ~ ceph-3-èrne 4-carboxylic, isomer syn and its salts with ~ alkali, alkaline earth metals, magnesium or base ~ organic amino, pharmaceutically acceptable, - Acid 3 acetoxymethyl 7 ~~ 2- (2-a ~ nino 4 ~ thiazolyl) 2 - ((2-propenyl) oxymino) acetamido ~ ceph 3-th 4 - carboxylic9 syn isomer and its ~ els with alkali metals, alkaline earth metals, magnesium or organic amino bases, pharmaceutically acceptable, - 3-acetoxymethyl 7-¦? - ((2-amino 4-thiazolyl) acid 2 - ((1-methyl ethoxy) imino ~ acetamido ~ ceph-3-th 4-carboxylic, i ~ omer ~ _ and its salts with the ~ alkali metals, alkaline-earthy, magnesium or organic amino bases, pharmaceu-tically acceptable.
This ~ compositions can be administered by the buccal rectal, parenteral or locally applied topically on the skin and mucous membranes.
They can be solid or liquid and present themselves in pharmaceutical forms commonly used in medicine human, such as tablets, simple or coated, capsules, granules, suppositories, preparations injectables, ointments, creams, gels; they are prepared according to the usual methods. ~ e or the active ingredients can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fat of animal or vegetable origin, the paraffinic derivatives, the glycols, diver ~ wetting, di ~ persisting or emulsifying agents, conservatives.
~ a dose administered is variable depending on the condition treated, subject, route of administration and product ~ 3 ~
considered, It can be, for example ~ nple9 between 0.2 ~ 0 g and 4 g per day, orally in the hom ~ e with the product described in example 4 or 7 or between 0.500 g and 1 g, three times daily, intramuscularly.
- Does the invention make it possible to obtain, as products new industrial products, products of general formula:

S ~
~ / C02H

OR ~ 2 dan ~ which R2 represents a hydrogen atom or a group easily removable by acid hydrolysis or by hydrogenolysis and R'2 represents a hydrogen atom, a group easily eliminable by acid hydrolysis or by hydrogenolysis or a radical alkyl, saturated or unsaturated, having from 1 to 4 carbon atoms, being understood that R'2 cannot represent a hydrogen atom, when R2 represents a group which can easily be eliminated by acid hydrolysis or by hydrogenolysis, as well as the products of general formula:

Cl- ~ H2-C ~ - ~ -C02alc R'1 in which R'1 represents an easily removable group by acid hydrolysis or by hydrogenolysis or an alkyl radical, saturated or unsaturated, having from 1 to ~ carbon atoms and alk represented has an alkyl radical having from 1 to 4 carbon atoms.
The invention also makes it possible to obtain from 1 3 ~

new industrial products, the products of formula Ic, such as defined above, useful for repairing products of formula Ib, as defined above.
~ es products of formula III which are not known can be prepared from ~ -chloro ~ -oximinoacetylacetate ethyl described in J. of Medicinal Chernistry 1973, Vol. 16, no 9, as shown below.
We obtain the products in which R 'represents a group easily removable by acid hydrolysis or by hydrogenolysis by conventional reactions ~ using derivatives functional groups.
We obtain the products in which R 'represents a alkyl radical, saturated or unsaturated, having from 1 to 4 atoms of carbon by action on ethyl ~ -chloro ~ -oximinoacetylacetate corresponding halides or alkyl sulfates.
~ es products of formula III ', in which X represents a bromine atom and R'b represents a hydrogen atom can be obtained by treatment with a brominating agent of the products of formula VI:

(VI) ~ H

under ~ conditions identical to those described for the treatment of ~ q products of formula VII.
In addition to the products described in the examples, the following products make up of ~ additional substances can be obtained ~ ues by the invention:

- ~ '3-acetoxynlethyl 7-¦2- (2-amino 4-thiazolyl) acid 2-propyl-oxy imino acetamido ~ ceph-3-th 4-carboxylic, isornere syn and its salts with alkaline ~, alkaline-earth, magnesium or organic bases ~ nines;

_ ~ _ i` ~ 3 ~ 8 ~

~ ~ '3-acetoxy acid ~ thyl 7- ~ 2- ~ 2-arn: ino ~ -thla ~ olyJ.) 2-butyloxy imino acetamido] ceph-3-èrne 4-carboxylic, isomer syn and its salts with alkali and alkaline earth metals, magnesium or arnine organic bases;
- 3-acetoxymethyl 7-L2- (2-amino 4 - thiazolyl) acid 2- (2-methyl propyloxy imino) ac ~ tamido ~ ceph-3-th 4-carboxylic acid, syn isomer and its salts with alkali and alkaline earth metals, magnesium or amino organic bases;
- ~ 3-acetoxynnethyl acid 7-] 2- (2-amino 4-thiazolyl) 2- (1,1-dimethyl ethoxy imino) acetamido ~ ceph-3-soul 4-carboxylic, syn isomer and its salts with alkali, alkaline earth metals, magnesium or amino organic bases;
- ~ 'acid 3-acetoxymethyl 7-¦2- (2-amino 4-thiazolyl) 2- (2-butenyloxy imino) acetamido3 ceph-3-th 4-carboxylic, syn isomer and its salts with alkali and alkaline earth metals, magnesium or amino organic bases;
- 3-acetoxymethyl 7- [2- (2-amino 4-thiazolyl) acid 2- (3-butenyloxy imino) acetamid.o ~ ceph-3-th 4-carboxylic, sYn isomer and its salts with alkali, alkaline earth metals, magnesium or amino organic bases;
- ~ 'acid 3-acetoxymethy1 7- ~ 2- (2-amino 4 - thia ~ olyl) 2- (2-butynyloxy imino) acetamido ~ ceph-3-th 4-carboxylic acid, syn isomer and its salts with alkali and alkaline earth metals, magnesium or amino organic bases;
- 3-acetoxymethyl 7- L2_ (2-amino 4-thiazolyl) acid 2- (3-butynyloxy imino) acetamido ~ ceph-3-th 4-carboxylic acid, syn isomer and its salts with alkali and alkaline earth metals, magnesium or amino organic bases;

~ 1 B

- ~ 3; ~
- ~ '3-acetoxymethyl acid / -L2- (2-amino ~ --thiazolyl) 2- (1-propenyloxy imino) acetarllido] ceph-3-th ~ -carboxylic, s ~ isomer and its salts with alkali metals, alkaline earth metals, magnesium or amino organic bases;
- ~ 3-acetoxymethyl acid 7- [2- (2-amino 4-thiazolyl) 2- (1-propynyloxy imino) acetamido] ceph-3-th 4-carboxylic acid, isomer ~ and its salts with alkali and alkaline earth metals ~
magnesium or organic amino bases;
- 3-acetoxymethyl acid 7- ~ 2- (2-amino 4 thiazolyl) 2- (1-butenyloxy imino) acetamido] ceph-3-th 4-carboxylic acid, syn isomer and its salts with alkali, alkaline earth metals, magnesium or organic amino bases;
- 3-acetoxymethyl 7-L2- (2-amino 4-thiazolyl) acid 2- (1-ethynyloxy imino) acetamido] ceph-3-th 4-carboxylic acid, i ~ omère s ~ n and its salts with alkali and alkaline earth metals9 magnesium or amino organic bases;
- ~ '3-acetoxymethyl acid 7- ~ 2- (2-amino 4-thiazolyl) 2- (2-propynyloxy imino) acetamido ~ ceph-3-th 4-carboxylic acid, s ~ n isomer and its salts with alkali metals, alkaline earth metals, magnesium or the organi ~ ues amino bases;
- ~ '3-acetoxymethyl acid 7- ~ 2- (2-amino 4-thiazolyl) 2- (l-butynyloxy imino) acetamido ~ ceph-3-th 4-carboxylic acid, syn isomer and its salts with alkali and alkaline earth metals, magnesium or organic amino bases.
The following examples9 illustrate the invention without however limit it.
Example 1: Acid 3-acetoxYmeth ~ yl 7t2- (2-t ~ ritylamin ~ 4-thiazolyl ~
2-tritylhydroxyimino acetamido] ceph-3-th ~ -carboxylic.
Stage A: 2- (2-amino 4-thiazolyl)? -Hydlox, ~ mino acetate d'É-t ~
2 g of ~ ethyl chloro-oximinoacetylacetate are placed in 5 cm3 of ethanol and 0.76 g of thiourea and stirred thoroughly rature ambient sei ~ e hours in all, the hydrochloride crystallizes, - ~

11 3 ~
diluted with 5 cm3 of ~ ther9 spins, rinses with eth ~ lol-ether (1-1) then with ether and obtains 1.55 g of hydrochloride.
The 1.55 g of hydrochloride obtained are dissolved in 40-50C in 8 cm3 of water then neutralizes juice ~ u'à p ~ I 5-6 by addition of sodium acetate. ~ 'Free amine crystallizes. We ice then wring, wash with water, dry and obtain 1222 g of the isomer anti F = 154C.
The mother liquors and washing liquids from several tests are combined, concentrate, resume with water, wash with ether, add carbonate sodium acid, wring, wash with water obtains 1 9 g of product comprising two tasks in thin layer chromatography, purifies by chromatography on silica by elution with ether. We combines the pure fractions of the isomer ~ _ concentrates, ether, wring, dry and obtain ~ nt 50 mg of this isomer.
Stage B: 2- (2-trit ~ lamino 4-thiazol ~ ll 2-trityl ~ drox ~ irnino-ethyl acetate.
_____________ __ To a solution of 5.4 g of product prepared in Stage A
in 54 cm3 of chloroform and 7.5 cm3 of triethylamine, the following is added at + 10C a solution of 15 g of trityl chloride in 30 cm3 chloroform. ~ almost an hour of rest, wash with 40 cm3 water 20 cm3 of water containing 4 cm3 of normal hydrochloric acid, decante, dry and concentrate dry.
The residue is taken up in 10 cm3 of ether, 50 cm3 are added methanol stirred, wrung, washed with methanol and obtained in two jets 14.2 g of expected product.
Stage C: acid 2- (2-trit ~ lamino 4-thiazol ~ ll 2-trit ~ lh ~ drox ~~
_______ .._______ ______ ____ .__________ ~ _ _______ __ __. _ _ imino acéti ~ ue.
___________ __, 10.5 g of ester obtained with Satde B are suspended in the neighborhood ~ reflux age in 55 cm3 of dioxane. We add slowly 17 cm3 of 2N soda. We continue a slight reflux, cools and wring out the salt. I ~ e salt is taken up in 60 cm3 of chloride methylene, 20 cm3 of water and 2 cm3 of acetic acid. We wring out the acid, ~ q _ ~, _ ~ 3 ~
wash with water and obtain a first jet of 7 g of acid ~
The dioxane is evaporated from the mother solution, we add 20 cm ~ of methylene chloride7 10 cm3 of water and 1 cm3 of acid acetic. A second 1.5 g jet of the same product is isolated.
A total of 8.5 g.
Analysis: CHO, NS 0.5 HO
~ 3 33 ~ 3 2 Calculated: C 75.85 H 5.03 N 6.17 S 4.7 Found: 75.8 4.9 5.9 4.6 ~ tade D: 3-acetox acid ~ methyl 7 ~ 2- (2-t _tylamino 4-thiazolyl) 2-tritylhydroxyimino acctamido ~ ceph- ~ -ème 4-carboxylic.
A suspension of 8.5 g of acid prepared with Stage C in 50 cm3 of methanol and add 5 cm3 of N-methyl morpholine ~ Stir ten minutes at 30C9 add 30 cm3 of chloride of methylene, concentrate, add 100 cm3 of ether, break up, e3sore, wash with ether, dry and obtain a first spray of 7.2 g of salt.
Concentrate to dryness, take up in ether and obtain a second jet of the same product.
Is suspended under agitation sou ~ inert gas 4.24 g of the above morpholine salt in 60 cm3 of chloride methylene.
Stir five minutes, ref ~ oidit at -5C and add 6 cm3 of a ~ molar solution of isobutyl chloroformate in methylene chloride. We lai ~ se fifteen minutes sou ~ agitation at -5C, cools to -20C and adds a 1.36g solution 7-amino cephalosporanic acid dan ~ 25 cm3 chloride methylene and 1.4 cm3 of triethylamine. We leave it an hour at room temperature, wash with 50 cm3 of water containing 10 cm3 hydrochloric acid N, e ~ sore, decanted, washed with water and concentrated to dryness. We grind in ether, wring, wash with octher and obtains 4.5 g of crude product, The crude product is stirred for one hour at ~ 10 ~ in 10 cm3 methylene chloride. ~ 'in ~ oluble e ~ te ~ soré and rinoé au methylene chloride ~ 50 cm3 of ether are added to the fil-trat, stirred, . ~

`. ~ 3 ~

drain the precipitate, wash with ether and obtain 2.29 g of product expected.
We still get a second spray of 0.856 g aoit 3.146 g of expected product.
Example 2: 3-acetox ~ methyl 7-L2- (2-amino 4-thiazolyl) acid 2-hydroxyimino acetamido ~ cePh-3-em_ 4-carboxylic.
2.29 g of product obtained in Example 1 are suspended in 18.4 cm3 of 50% aqueous ormic acid. We wear under bright stirring fifteen minutes at 55C ~
~ We cool, add 10 cm3 of water, wring, wash with water, concentrate in vacuo, add acetone, spin dry, add 30 cm3 of ether, stir, spin, wash with ether and obtain 0.665 g of product. Another 0.123 g of product is obtained which crystallizes either 0.78 ~ g.
0.735 g of the product is dissolved in 7.5 ml of ethanol and 7.5 cm3 of acetone. 70 mg of carbon black are added, drained, removes solvents, disintegrates in ethanol, washes with ethanol and obtains 0.450 g in a first spray then 0.105 g in a second spray.
Infrared _ ~ = o 1774 cm (B-lactam) 1740 crn 1 1676 cm 1 C = C NH2 1630 cm 1 NH 1520 cm 1 Example 3: Acid 3-acetox ~ hyl 7 L2- (2-tritylamino 4-thiaæol.Yl) 2-methoxyimino acetamido1 ceph 3-th 4-carbox li ue.
J .Y_ q S-tade A: 2- (2-amin_ 4-thiazol ~ l ~ 2-met-hox ~ mino eth acetate ~ le.

1 g of ~ -chloro a-methoxyrrlino acetylacetate is introduced ethyl ~ 3cm3 of absolute ethanol and has ~ 0 ~ 42 g of thiourea crushed. The mixture is stirred at ambient temperature for approximately two hours. We ~ diluted with 60 cm3 of ether the hydrochloride obtained crystallizes, stir, eseore, wash, dry and obtain 685 mg of hydrochloride. We `~ 3 ~ 8 ~, -dissolves them in 4 crn3 of water at 50 (', add potato acetate ~ iurn up to pH 6, the released amine crystallizes. We cool, e ~ eore, wash with water, dry and obtain 270 mg of the expected product. ~ '= 161C.
~ e product obtained at configuration ~
NMR (CDC ~ 3 60MHZ) ppm: 4 (N-OCH3), 6.7 (proton of the cycle thiazolic).
Stage B: 2- (2-trit ~ lamino 4-thiaz_l ~ l) 2-methox ~ vimino acetate of eth ~ le, _____ __ 4.6 g of product prepared according to the previous stage are below 30C in 92 cm3 of methylene chloride. We cool to -10C, add 2.9 cm3 of triethylamine, cool again to -35C, add in fifteen minutes 6.1 g of trityl chloride, leave return to room temperature, a total of two and a half hours.
Wash with water, then with 0.5N hydrochloric acid and aceta-te sodium in water. Dry, concentrate, resume with ether ~
concentrate again9 dissolved in methanol, add water and ether9 leaves to crystallize, spin, wash with ether and 6.15 g of expected product is obtained. F = 120C.
The product obtained has the configuration s.yn, Stage C: acid 2- (2-tritylamino 4-thiazol ~ l) 2-metho3 ~ imino acéti ~ ue.
_____ __ 7.01 g of ester obtained in the ~ stage are dissolved in 35 cm3 dioxane. It is brought to 110 in an oil bath and added in five minutes 9 cm3 of 2N sodium hydroxide, leaves for thirty minutes at reflux under agitation. ~ e crystallized sodium salt ~ eO We cool 9 spin, wash with dioxane then with ether and obtain a first jet of

5.767 g of salt. We concentrate the ~ mother olution and get a second 1.017 g spray or a total of 6.7 ~ 4 g of salt.

3 ~ 06 g of salt are placed in 65 cm 3 of chloride of methylene and 6.5 cm3 of 2N hydrochloric acid, washed with water, 3èche and concentrated to dryness to quantitatively obtain the free acid.
~ e product obtained at the configuration ~ _ ~ 3 ~

~ L 3 iL ~

XMN (DMSO, 60MHZ) pp ~ m: 3.68 (N- ~ CH3) 6. ~ (proton ~ u cycle thiazolic).
Stage D: 3-acetoxymethyl acid 7 ~ 2- ~ tritylamino 4 = -thiazo ~ yl) 2-methoxyimino acé-tamido] ceph- ~ -ème 4-carboxyli ~ eu.
I. the dry acid obtained in Stage C is dissolved in 30 cm3 of dry methylene chloride. We have ~ all 0.78 g of dlcyclohexylcarbo-diimide and stir for one hour at room temperature. We wring the dicyclohexylurea formed, cools to -10C, adds a solution 1.01 g of 7-amino cephalosporanic acid in 13 cm3 of chloride of methylene and 0.9 cm3 of triethylamine. We let come back at room temperature, add 1 cm3 of acetic acid, spin dry, wash with water containing hydrochloric acid, with water, dry, concentrate dry, take up with 10 ml of dioxane, add 1 cm3 of water and 3 cm3 of saturated solution of sodium hydrogen carbonate. We shake, wring, washing and concentrating to dryness - use is made of methylene chloride ~
washes with 10 cm3 of water and 5 crn3 of normal hydrochloric acid, decanted, washed with water ~ dry disintegrates in ether and obtains 1.747 g of crude product ~ ue is purified by dissolution dan ~
ethyl acetate followed by precipitation with ether. We obtain 1.255 g of pure product.
The product obtained has the configuration ~
R-chloro a-methoxymino ethyl acetylacetate used from Example 3 was prepared as follows:
22.5 g of y-chloro a-oxirnino acetylacetate are placed ethyl in 100 cm3 of methylene chloride.
Place on an ice bath and add slowly under stirring a ~ olution ~ riache of diazomethane (at 21.6 g / l) or 275 cm ~. We leave five minutes ~ in cbntact and destroys the excess of diazomethane with a little alumina. Concentrate then purify by ~ 0 elution s ~ r silica with methylene chloride. 11.93 g are obtained of expected product. ~ e 2- (2-amino 4-thiazolyl) 2-methoxyimino ethyl acetate used in Example 3 also prepared ~ 3 ~
as following:

Stage a: 2-acet ~ l 2-methox ~ imino eth acetate ~ le.
_______ ______ __________ _________ ______ ~ __ __ We introduce 180 gd ~ 2-acetyl 2-hydroxyimino acetate crude ethyl in 900 cm3 of pure acetone. At 1-C so ~ s nitrogen, we add 234 g of potassium carbonate; we then introduce ~ 03 cm3 of dimethyl sulphate. Stir 3 hours at temperature room, add ice, pour into 4 liters of water, extract with methylene chloride9 washes with water, dries and distills solvents. 185 g of expected product are obtained ~
Stage ~: 4-bromo 2-methox ~ imino acet, eth acetate, yle.
_______ ________________ __________ _____________ __ 197 g of product obtained as in stage a are placed in 1 liter of methylene chloride and add 200 mg of acid sulfonic paratoluene. At 20C, 1 / 1Oe of the solution is introduced 191 g of pure bromine in 200 cm3 of methylene chloride.
When the reaction is started, the rest of the solution is introduced bromine in one hour around 20C. Then let rise to 25C
to complete the reaction. Washed with ice water, extracted with methylene chloride, dries and distils the solvent. We obtain 268 g of expected product.
Stage y: 2- (2-amino 4-thiazol ~ 1) 2-methoxyimino acetate eth.
______ ___.________________ __________ ___________________ __ 80 g of thiourea are introduced into 270 cm3 of ethanol and 540 cm3 of water. 268 g are introduced under nitrogen in half an hour of product obtained in the ~ stage in 270 cm3 of ethanol, Shake one hour around 20C. It is cooled to 15C and introduced by small portions of potassium hydrogen carbonate up to pH 5. We spin, wash with water, dry and obtain 133.8 g of the expected product.
~ e product obtained is identical to that obtained in stage ~.
Example 4: 3-acetoxymeth acid, yl 7 ~ 2- (2-amino 4-thiazolyl) 2-methox.yimino acetamido] ceph-3-th 4-carbox ~ lique.
0.975 g of the product obtained in Example 3 are stirred ten minutes at 55C in 4 cm3 of 50% aqueous formic acid. We add 4 cm3 of water, wring, concentrate to dryness under vacuum. We declare 3t 1 3 ~

in 2 cm3 of ethanol, drain, wash with ethanol then with ether and obtains 0.428 g of pure product.
AnalySe: Cl 61 ~ 1 77N5S2 Calculated: C% 42.19 H% 3.76 N% 15.- ~ 7 S% 14.08 ~ found: 42.3 4.1 15.2 13.8 The product obtained has the syn configuration, NMR (DMSO 60MHZ) ppm 2.03 (-C CH), doublet 9 58 J = 8HZ (~ ONH) 6.76 (pro-ton thiazolic cycle).
Example 5: Diethylamine salt of 3-acetoxy methyl acid 7- ~ 2-(2-tritylamino 4-thiazolyl) 2- (methoxyimino) acetamido ~ ceph-3 rd 4-carboxylic.
3-acetoxy methyl acid 7- ~ 2- (2-tritylamino 4 ~ thiazolyl) 2- (methoxyimino) acetamido ~ ceph-3 rd 4-carboxylic obtained as indicated in Example 3 from the condensation of the acid 2- (2-tritylamino 4-thia ~ olyl) 2-methoxyimino acetic ~ or form anhydride prepared using dicyclohexyl carbodiimide and 40.8 g of 7-amino cephalosporanic acid, is dissolved in 350 cm3 of dioxane. 350 cm3 are added slowly with stirring.
sulfuric ether pUi9 33 ¢ m3 of diethylamine. We stir for 20 minutes, wring out the diethylamine salt of 2- (2-tritylamino acid) 4-thiazolyl) 2-methoxyimino acetic which crystallized. We wash this salt twice per 30 cm3 of the above dioxane-ether mixture and 62.6 g are obtained ~ The filtrate is concentrated to consistency syrupy and add about 2.5 liters of sulfuric ether. We stir and spin, 110.3 g of the desired diethylamine salt are obtained.
The product obtained has the configuration ~
Example 6: Acid 3-acetoxy meth, yl 7 ~ 2- (2-am1no ~ -th azol ~ l) 2- (methoxymino) acetamidol ce ~ h-3 èrne ~ -carboxYllclue ~ 6 g of product obtained in Example 5 are added to 180 cm3 50 "aqueous formic acid maintained at 50C. Stir 20 minutes at 50C, wring out the triphenyl carbinol formed. 180 cm3 are added S

1 3 ~
ethanol, concentrated to dryness under reduced pressure. We resume residue by a mixture of 100 cm3 of water and 20 cm3 of ethan ~ l and focus again. It is taken up in 100 cm3 of water, stirred for 15 minutes.
te ~ at 15C, wring it out, re ~ with water and then with ether to obtain 15.6 g of expected product.
The product is identical to that obtained in Example 4.
EXAMPLE 7 Sodium Salt of _'a_de 3 ~ acé-toxyméthyl 7 L2- (2-amino 4-thiazolyl) 2- (rneth ~ xyimino) acetamido ~ ceph-3-th 4-carboxylic 45.55 g of 3-acetoxymethyl 7L2- (2-amino 4-thiazolyl) acid lO 2- (methoxyimino) acetamido ~ ceph-3-th 4-pure carboxylic obtained according to the ~ process ~ of examples 4 or 6 are added to 100 cm3 distilled water. Gradually add 3 g of acid carbonate sodium by adding about 20 cm3 of ethanol.
80 cm3 of ethanol, 4.5 g of charcoal are added.
active, shakes for 5 minutes, filters, rinses with ethanol and concentrates dry vacuum. It is taken up in 100 cm3 of ethanol, concentrated to dryness and dissolves the residue in 100 cm3 of methanol. We add 2 liters of acetone, shakes violently, wrings, rinses with acetone, then ether. After drying sou ~ vacuum, 43.7 g of a product are obtained 20 white which rehydrates in air to reach a final weight of 45.2 g / o </ 20 = ~ 55 + 2 (at 0.3 ~ in water).
Analysis:
Calculates: C% 40.24 H ~ 3.38 N% 14.67 S 5'o 13.43 Na% 4.81 Found: 40.3 3.8 14.4 ~ 3.3 4.84 The product obtained has the configuration s ~ yn, NMR (60MHZ D20) ppm: 2.0 ~ (COCH3) doublet at 9.53 J = 8HZ (NHCO) 6.75 (thiazolic proton).
Example 8 Acid 3-acetoxymethvl 1 [? - ~ 2 t ~ lamino ~ thiazol ~
2 - ((2-propenyl) oxyimino) acetamido ~ ceph 3-th 4 - carbox.ylic.
~ 0 Stage A: 2- (2-amino 4-thiazol ~ li 2- ~ 2-; ~ ro; eén ~ yl ~ ox ~ ymino ~ acetate _______ __ ____ ____________ _ ___ _ __ __ _ ___ ____ ___ .. ___ of eth ~ le _____ __ a) 9.7 g of 2 hydroxyimino 4-chloro acetyl ethyl acetate, 1 ~ _3G

~ 0 cm3 of acetone and 9.15 cm3 of 3-iodopropene are cooled dan ~
ice and add 27.5 cm3 of 60ude 2Ng and leave for one hour and a half at room temperature;
b) 3.8 g of thlouree are added to the reaction medium, heat at 60C for 15 ~ inu-tes, then 45 minu-your at temperature room, flushes acetone, adds methyl chloride ~ ne, water, potassium carbonate, stirred decanter, methylene chloride, ~ dries, concentrated to dryness, obtains 9.75 g of residue which is chromatographed on silica eluting with ether, isolates 2.7 g of product which is taken up in isopropyl ether, wring out the crystals, rinse and dry. 783 mg of product are obtained expected.
F = 100 ~. ~ e product obtained at configuration ~ 0 Stage B: 2- (2-tritYlamino 4-thiazol ~ l) 2 - ((2- ~ ro ~ enYl) oxyimino) _______ __________________________ ____ ___ __ ________ _ ~ .____ eth acctate:
_ ____ __ __ __ __ _ _ _ 511 mg of product prepared in stage A is mixed, 0.92 cm3 of dimethylformamide, 1.8 cm3 of methylene chloride and 0.29 cm3 of triethylamine. Cool to -15C and add 615 mg trityl chloride. We leave at room temperature a hour and a half, add 2 cm3 of 1N hydrochloric acid, then 5 cm3 of water, decanted, dried, concentrated to dryness and obtained 1.28 g of product gross.
~ e product obtained in the syn configuration.
Stage C: Acid 2- (2-tritylamino 4-thiazol ~ l) 2- (~ 2- ~ ro ~ enyl) ox ~ -_______ ________ ______ ________________ _ ___ __ _ __ _ ___ imino) acéti ~ eu:
_____ _ _____ __ We heat at 120C. 1.28 g of product obtained in Stage ~,

6.2 cm3 of dioxane and 3 cm3 of 2N sodium hydroxide. We bring to re ~ lux a hour, the sodium salt crystallizes, it is wrung, rinsed with the mixture ether-dioxane, dries and isolates 805 mg of product.
It is taken up in 10 cm3 of methylene chloride and 3 cm3 of 1N hydrochloric acid, stirred until dissolved, decanted, dried, concentrated to dryness, resumed with ether, wrung out and `` 1 3 ~
obtains 715 mg of stretched product. F = 170C.
~ e product obtained in the syn configuration.
Stage D: Acid 3-acetoxymeth ~ l 7-L2- (2 - tritylamino 4-thiazolyl) 2 - ((2-pro ~ enyl) o ~ yimino) acetamido7 ceph-3-th 4-carboxyli ~ eu 470 mg of product prepared in stage C is mixed, 5 ~ m3 of methylene chloride and 130 mg of dicycloh ~ xylcarbodiimide, we rinse with a little methylene chloride and wash ~ se ~ ou agitation one hour at room temperature9 wring out the dicyclohexylurea formed, cools the filtrate and adds 90U ~ inert gas7 136 mg of 7-amino cephalo ~ poranic acid in solution in 2.4 cm'S
methylene chloride and 0.14 cm3 of triethylamine. We leave a hour and a half at room temperature, add 2 cm3 of chlorine acid 1 N hydric and water, agitates ~ decant, washes with water, dries, concentrate and obtain 610 mg of crude product.
The product obtained has the configuration ~
Example 9: Acid 3-acetoxymeth ~ rl 7l2- ~ 2-amino 4-thiazolyl) 2 - ((2-pro ~ en ~ l? Oxyimino) acetamidoJ ceph-3-th 4-carboxJylic We bring the 610 mg of product obtained in Example 8 and 3 cm3 of aqueous formic acid at 50 ~, at 60C for 15 minutes ~, add 4 cm3 of water, stir, es ~ ore triphenyl carbi ~ ol, rinse with water, concentrates dry ~ or ~ empty, resumes with water, disintegrates, spins, rinses and obtains 120 mg of sought acid, ~ ~ 160C.
Specter_Ultra-Violet:
Dan ~ ethanol: max 2 ~ 6 nm E = 375 ~ - 18,000 inflection 252 nm E = 316 inflection 295 nm E = l38 ~ = 6,600 In an ethanol-hydrochloric acid N / 10 mixture:
max 263 nm E = 380 ~ = 18,300 inflection 280 nm E - 317 NMR (DMSO'90 MHZ) ppm: 2.02 (OAo) 6.68 (thiazolic proton).
~ e product therefore has the syn configuration.
'Example 10: Acid 3-acet_xy_ ~ hiazolrl ~

c ~

~. 3 ~
~ - (ethoxy imino) acetamido ~ ceph-3 - èrne 4-earboY. ~ lique Stage A: 2- (2-amino 4-thiazol ~ 1) 2-ethox ~ imino ethyl acetate:
_______ _____________, _______ _ ________ __________________ _ __ a) 19.4 g of ~ -chloro ~ -oxyimino acetoacetate are placed ethyl in 60 cm3 of acetone and 14.3 cm3 of diethyl sulfate.
Cool 10 minutes ~ in an ice bath and add in ~ 0 minutes, 55 cm3 of 2N sodium hydroxide, stirred 40 minutes;
b) 7.6 g of thiourea are added to the reaction medium, brought to 55C for 20 minutes, flushes out acetone, resumes at ethyl acetate, add 6.9 g of potassium carbonate, stir, decanted, re-extracted with ethyl acetate, dried and concentrated to dryness.
17.4 g of residue are isolated and chromatographed on silica in eluting with ether. The expected product is collected, resumed at isopropyl ether, spin, rinse, dry and obtain 2.8 g of expected product.
F = 129C. ~ e product obtained in the syn configuration.
Stage B: 2- (2-trit ~ lamino 4-thiazol ~ l) 2-ethox ~ imino acetate _______ __ ______ ________________ __________ ______________ of ethyl:

3.16 g of product obtained are placed under inert gas.
stage A, 6 cm3 of dry dimethylformamide. 12 cm3 of chloride methylene and 1.89 cm3 of triethylamine. We cool to -15C and slowly add 3098 g of trityl chloride. We let it rest half an hour, the temperature rises to + 10a, then maintains 3.5 hours at room temperature. 13 cm3 of acid are added hydrochloric 1 N, stirred, decanted, washed with hydrochloric acid l N, pui ~ with water. Extracted with methylene chloride, dried, concentrated to dryness and obtains 7.89 g of crude residue.
The product obtained has the configuration ~
Stage C: ~ cide 2- (2-trit ~ lamino 4-thiazol ~ l ~ 2-ethox ~ iMino ace-_______ _______________ ________________ _ ~ ___.-___ ___________ ti ~ ue:, ~ 0 We bring to 110C, 7.89 g of product obtained in stage B, 40 cm3 of dioxane and 19.5 cm ~ of 2N sodium hydroxide for one hour. We wring, rinses with an ether-dioxane mixture, then ~ with ether alone ~ 3 ~
and dry. 6.25 g of ~ sod1uln salt are obtained, which is taken up in 60 cm3 of methylene chloride and 20 cm ~ of hydrochloric acid that 1 N ~ the two phases are stirred, add 20 cm ~ of methanol, decant, wash ~ water / extract with methyl chloride mixture ~ ne-methanol, dry, concentrate and isolates 5.85 g of 2- (2-trityl-amino 4-thiazolyl) 2-ethoxy imino acetic pure.
~ e product obtained in the syn configuration.
Stage D: 3-acetoxy meth acid, ~ l -7-¦ 2- ~ 2-trit ~ l mino 4-thiazolyl) 2- (ethoxy imino ~ _acetamld ~ ceph-3-th 4-carboxylic We place ~, ~ 3 g of aclde 2- (2-tritylamino 4-thiazolyl) 2-ethoxy imino acetic prepared in stage C in 34 cm3 of chloride of methylene, cools the suspension and adds 970 mg of dicyclo-hexylcarbodiimide, rinses with methylene chloride and shakes a hour at room temperature. The dicyclohexylurea is drained.
We ref ~ oidit the filtrate at -20C and add in one go, a solution re ~ stiffness at ~ ZO C of 1.02 g of 7-amino cephalosporanic acid in 18 cm3 of methylene chloride and 1.06 cm3 of triethylamine.
Let it warm up for an hour and a half, add 1.8 cm3 of acetic acid, add 9 cm3 of 1N hydrochloric acid, stir, decant, wash with water, extract with methylene chloride, dry, concentrate and obtain 4.56 g of the expected product.
~ e product obtained in the syn configuration.
Example 11 -: Acid 3-acetox ~ meth! Yl 71 2- (2-amino 4 - thiazolyl) 2-(ethoxv imino) acetamido7 cePh-3-th 4-carboxylic AT _ _. ~.,.
The 4.56 g of product obtained in Example 10 are placed in 23 cm3 of aqueous formic acid at 50 ~, brings 15 minutes to 55C, diluted with water (30 cm3), wring out the triphenyl carbinol. We concentrate dry filtrate, take up with water, stir, spin, rinse, dry and obtains 116 mg of impure product. We obtain a deu ~ th jet of ~ 0 ~ 74 mg of product crystallized by concentration of the filtrate, i.e.

altogether 790 mg.
The following purification is carried out:

S 8 ~

We paste in ~ 5 cro ~ of water, 1 06 ~ g of raw product, bring to 70C for 5 minutes, cool, stir for half an hour, spin, rinse, dry and isolate 815 mg of purified product. These 815 mg are taken up in 2 cm3 of water and 3 crn3 of acetone, the mixture is heated slightly wring out the insoluble matter ~ add 3 cm3 of water, heat to 60C
and flushes acetone by bubbling nitrogen through, wring out the grain ~
formed, rinsed with water, then with ether and isolates 438 mg of product expected.

l ~ naly8e: C1 7H1 97N5S2 calculated: C% 43.49 H ~ 4.08 N% 14.92 S% 1 ~ 66 Found: 44.5 4.4 14.8 13.3 The product has the syn configuration NMR (60MHZ DMSO) ppm: 2005 (OAc) 6.75 ~ proton of the cycle thiazolic).
Example 12: 3-acetox acid, ymethyl-7r2- (2-tritAylamino 4-thia30lyl) 2 ~ meth ~ l ethox ~ imino) acetamido] ceph 3-th 4-carboxylic.
Stage A: 2-acet ~ l 2- (1-methyl ethoxyi ~ ino) eth acetate ~ le.
_______ ______ ______ ____ _______ _____________ ______ __ 39.8 g of 2-acetyl 2-hydroxyimino acetate are placed ethyl in 200 cm ~ of pure acetone. Cool in the bath ice and add 52 g of potassium carbonate ~ æium, then, in one half hour, 25 cm3 of 2-iodopropane. Then stirred for 2 hours ~, add 800 cm3 of water and 500 cm ~ of methylene chloride, stir, decant, methylane chloride extract, dry, e ~ sore con-center and isolate 41.5 g of expected product.
Stage B: 4-bromo 2- (1-meth ~ l ethoxyimino2 acet ~ eth lacetate ~ le.

The ~ 1.5 g of product obtained in the previous stage are placed in l90-cm3 of methylene chloride with traces of acid sulfonic paratoluene. Shake and introduce in one hour, at ~ 0 room temperature, a solution of 11.9 cm ~ of bromine in 50 cm ~

methylene chloride. Stir, add ice water, remove cante, extract with chloride of m ~ thylene, wash ~ ice water, D ~ ~ ' ~ 9 ~ 2 dry, concentrate and i ~ ole 55 g of expected derivative.
Stage C: 2- (2-amino 4-thiazol ~ l) 2- (1-meth ~ 1 é-thox ~ imino) _______ ____________________ ____ ~ ____ ~ _ __ ~~ __ ~ _____ ~
ethyl acetate.
___ __ __ __ ____ _ _ 14.9 g of thiourea are placed in 55 cm3 of ethanol and 105 cm3 of water and add in 40 minutes a variation of the 55 g of product prepared in stage B in 55 cm3 of ethanol. Shake 2 hours and a half at room temperature, add 220 cm3 of acid carbonate sodium at 10 ~ o in water, stir, spin, rinse, dry and isolate 42.15 g of crude product which is chromatographed on silica in eluting with ether, collects the product-rich fractions waited, concentrated, takes up the crystals with isopropyl ether, wring, rinses and obtains 10.75 g of the expected product.
~ e product obtained in the syn configuration.
Stage D: 2- (2-trit ~ lamino 4-thiazol ~ 1) 2_ (1-meth ~ l éth_xyim-n_) ethyl acetate.
_____________ __ 11 g of product obtained in the ~ stage are placed in 20 cm 3 of dry dimethyl formamide, 40 cm3 of methylene chloride and 6.2 cm3 triethylamine. The mixture is re-stiffened and added slowly 13.2 g of trityl chlorine, stirred for 2.5 hours, added 43 cm3 of normal hydrochloric acid, stirred, decanted, relave with 40 cm3 of water, extract with methylene chloride, dry, spin dry, concentrated to dryness and obtains 27.7 g of the expected product, ~ e product product obtained has the configuration s ~ n.
Stage E: Acid 2- ~ 2-tritylamino 4-thiazol ~ l) 2 ~ meth ~ l _______ ________ ______ _ ____._________ _ ___ ___ ~ __ _ ethoxyimino) acéti ~ ue.
_____ _____ ______ __ A mixture of 27.7 g of product obtained is brought to the stage D, 150 cm3 of dio ~ anne and 65 cm3 of 2N sodium hydroxide at reflux for two o'clock. ~ e sodium salt crystallizes, cooled, wrung, rinse with ether-dioxane mixture (1-1), dry and obtain 16 ~ 5 g crude sodium salt. We di ~ sout 15.9 g of this sodium salt in 15.9 g of dimethyl ~ ormamide, 100 cm3 of water and about 500 cm3 of methanol. ~ 0 cm3 of 2N hydrochloric acid is added, flush the . - * ~

~ 3 ~ 8 ~
methanol, diluted with water, wrung, rlnce, ~ èc ~ le, takes up the ~ 9.8 g of viscous product obtained in 220 CM ~ of a mixture of chloride methylene methanol (50-50), concentrate at 3ec, resume with ether, disintegrate, wring out the crystals, rinse and dry. We get 4.9 g acid sought. F -170C, An analytical sample is obtained in dissolv ~ nt 300 mg of crude product in 2 cm3 of methylene chloride and 1 cm3 of methanol, diluted with water and methylene chloride, stirred, es ~ ore cirsitals, rinse with methylene chloride and water7 dries and isolates 230 mg of pure product for analysis.
Anal, yse:
calculated: C ~ 0 68.77; II ~ v 5.34; N ~ 8.91; S ~ 6.8 ~ rou ~ é: 68.6 5 ~ 5 8.8 6.8 ~ e product obtained in the syn configuration.
Stage F: 3-acetoxymeth acid, vl 7- ~ 2- (2-tritylamino 4-thiazolyl) 2 ~ me-th ~ l ethoxyimino) acetamido7 ceph-3 rd 4-car-~ J
boxylic.
4.89 g of acid obtained in the Edans stage are placed under argon 13.5 cm3 of dimethyl ~ ormamide. After dissolution, we cools in an ice bath and adds-1.62 g of dicyclohexyl-carbodiimide in 16 cm ~ of methylene chloride. The dicyclo-hexylurea crystallizes. Shake in an ice bath. wring, rinses with methylene chloride, dries and isolates 1.424 g of dicyclohexylurea. Cooled in a methanol ~ ice bath and add a solution of 1.41 g of 7-amino cephalosporanic acid in 30 cm3 of methylene chloride and 1.45 cm3 of triethylamine. We stir 3 hours at room temperature, add 20 cm3 of acid normal hydrochloric, stirred, decanted, chloride extract methylene, dry, spin and obtain ~ .05 g of product mixture expected- ~ initial product. It is taken up in methylene chloride, primer, leaves to crystallize with stirring, es ~ ore le ~ crystals, rinses, dries, obtains 1.6 g of pure initial product ~ concentrated at '~ 3 1 ~ 1'3 ~ 8? J
dry ~ takes up the residue in the ether ~ i ~ opropylic ~ n ag: i tant vigorously and isolates 4.91 g of insoluble viscous product which is the expected product.
~ e product obtained at the configuration Example 13: Aclde 3-acetoxymethYl 7-L2- (2-amino 4-thiazolyl) 2-(1-meth, yl ethoxyimino) acetamido ~ ceph-3 rd 4-carbox, yli ~ eu.
4.91 g of crude product obtained in Example 12 are placed in 30 cm3 of 50% aqueous formic acid, stirred in a bath of water at 60C, diluted with water, wring out the triphenylcarbinol formed, rinse with water, dry and isolate 1.39 g of triphenylcarbinol. We concentrates dry, resumes with water, disintegrates, wrings, rinses with water, s ~ che and obtains 800 mg of the expected product.
A sample for analysis is obtained by dissolving 972 mg of crude product in 4 cm3 of methanol, diluted with 20 cm3 of ether, wring out the insoluble matter, rinse, dry and obtain 404 mg of pure acid expected. F -200C.
Analysis:
Calculated: C ~ 44.71; H ~ 4.38; N% 14.48; S% 1 3, 26 Found: 44.5 4.5 14.1 13.2 ~ e product at confi ~ lration sYn NMR (60MHZ DMSO) ppm: 2.01 (CH3CO); doublet at 9.46 J = 8HZ (CONH); 6.7 (proton of the thiazolic cycle).
Example 14: Acode 3-acetoxy ~ eth ~ yl 7- [2- ~ 2-tritylamino 4-thiaæolyl) 2-ethoxy imino acetamido ~ ceph-3-th 4-carboxylic Stage A 2- (2-trit ~ lamino 4-thiazol ~ l) 2-hydroxy imino acetate _______ ______.__ ________________ _ ____ ____ ______________ eth ~ le, anti isomer:
_____ __ _____________ 32.2 g of 2- (2-amino 4-thiazolyl) 2-hydroxy are introduced imino ethyl acetate, anti isomer prepared according to Stage A of Example 1 in 90 cm3 of dried dimethylformamide and add 24 cm3 of tritéhylamine, Cooled to -30C pUi3 is introduced by small por-in half an hour, 47.6 g of trityl chloride, give up spontaneous warming ~ 3 ~ 8 ~
for two and a half hours, add 150 cm3 of hydrochloric acid 2 ~ and 600 cm3 of water. Shake 15 minutes, spin, stack 3 times ~
with ether, taken up in a mixture of methanol, triethylamine and of water, stir, spin, rinse with aqueous methanol ~ dry and isolate 60.2 g of expected product. 3.4 g of crude product are recrystallized ~ é ~ dan ~ a mixture of methylene methanol chloride. We get 3g pure product. ~ 3,260C.
Stage B: 2- (2-trit ~ lamino 4-thiazolyl) 2-ethox ~ imino acetate _______ __ _____ ________________ ______ ___ ______________ ethyl, anti isomer:
_____ __ _____________ 11.5 g of product obtained in previous Stage A are introduced and 5.85g of potassium carbonate in ~ 25 cm3 of dimethylformami-from ~ due. Cool to 15C and add 16.7 cm3 of ~ ulf ~ te ethyl, let ~ e 4 hours at room temperature, auout 420 cm3 of water and 250 cm3 of ethyl acetate, stirred ~ decanted ~ washed with water ~
extract with ethyl acetate, dry filter, evaporate to dryness, takes ethanol, leaves crystalli ~ er, rinses with ethanol, paste with petroleum ether, dry and obtain 6.6 g of the expected product.
F = 165C ~ This product can be recreated as tall:
797 mg dan3 is dissolved in a 50-50 mixture of chloride meth ~ lene and ethanol, spin, concentrate to evaporate the chloro methylene rure and let ~ e recrystallize the product, es ~ ore, rinses with ethanol, dries and isolates 596 mg of pure product.
Stage C: Acid 2- (2-trit ~ lamino 4-thiazolyl ~ 2-ethox ~ imino ______ ________ ______ ________________ ________ ______ acéti ~ eu, anti isomer:
_____ __ _____________ 7.29 g of product prepared at the ~ previous stage are introduced.
tooth in 45 cm3 of dioxane and 9 cm3 of 2N sodium hydroxide. We bring to water bath at 50C under agitation for 1 hour 50 minutes, re froze ~ starts the cry ~ tallisation dan ~ ice water, es ~ ore, rin-this with ether and obtains 4.2g of ~ el of ~ odium, We resume the ~ el dan ~ 50 c ~ 3 of methylene chloride, 40 cm3 of water and 11 cm3 of aci ~
normal hydrochloric, stirred, decanted 9 chloride extract methylene, wash with water, dry, e ~ 30re, concentrated at ~ ec, resumes the residue with 50 cm3 of ether, stir, e ~ sore the ~ crystals, rinse ~ 3 ~
.

with ether and obtains 3.27 g of the expected product.
F = with decompogition 200 ~ approx.
NMR ~ 60 MHZ CDC13) ppm = 7.66 (proton of the t cycle, hiazo-lic)

7 ~ 36 (proton of the grouping trityle) Stage D: Acid 3 ~ acetox ~ meth ~ 1 7- ~ - (2 ~ tri ~ 1amino 4-thiazolyl ~
____ ___ ______________ ___ ____ _. ~ ____ ________________ _ 2-ethox ~ imino acetamido1 ce ~ h-3-th 4-carbox ~ eu ~ i ~ anti omer:
Sou ~ q inert gas mixture 4.1g of acid obtained in Stage C
previous, 36 cm3 of tetrahydrofuran, 27 cm3 of methyl chloride thylane and 0.99 cm3 of N-methyl morpholine ~ Cooled to -20 ~ a and introduced, drop by drop, 1.17 cm3 of chloro ~ ismi ormiate butyl. We wash ~ 3 minutes at this temperature, cools to -35C
and has ~ a solution of 2.45g of 7-amino cephalo acid ~ poranic dan ~ 4.5 cm3 of methylene chloride and 2.52 cm3 of triethylamine.
We give up to warming ~ pontane for 2 hours 8 and a half 9 flushes the solvent ~, resumes with a mixture of methyl chloride lene, dleau and normal hydrochloric acid ju ~ qqu'à p ~ l 1 2. We extract with methylene chloride, wash with water, ~ dry, es ~ ore, co ~ -center, take up in ethyl acetate, diluted with iqopropyl ether, shake, eqsore, rinse with isopropyl ether, dry and obtain 4.87g of expected product, i ~ anti omer. ~ a purification e ~ t obtained as ~ uit:
We say ~ out the ~ 4.87g of product above ~ dan ~ 10 cm3 ethyl acetate chau ~ fant, dil ~ e slowly with ether isopro-pylic, stir, wring, rinse, isopropyl ether9 ~ dry and obtains 4.53 g of purified product.
Example 15 ~
2-ethoxy imino acetamido ~ ceph-3-èm _4-carbox ~ eu, i ~ anti omer The 4 27g of purified product, obtained in Example 14, are placed ~ q in 20 cm3 of aqueous ormic acid (50-50). We wear the mix in a 60 ~ water bath, stir 20 minutes, cool and dilute with water, stir 10 minutes ~, e ~ ore triphenyl carbinol, rinse with , 13. ~ g ~
water and get ~ 44g. Ethanol is added to the filtrate, con empty center. The residue is taken up in ethanol, chaase à nou empty 80U9 calf, add 30 cm3 of water to the residue, stir for one hour on mixture formed in ~ an ice water bath ~ e ~ wring, rinse with water aè-che and obtains 2.06g of expected product. The purificatio ~ e ~ t obtained like 8Ui t:
We die ~ out the 2.06g below ~ us dan ~ 5 cm3 of bicarbonate 10% aqueous sodium and 5 cm3 of water. We are ~ ore the trouble9 rinses to water, add, drop by drop, pure ormic acid up to pH 3-4, wring out the crystals obtained after 12 hours at te ~ temperature room, rinse with water, dry and get 1.73 of pure product ~
F = 200C approximately with decompo ~ ition.
RM ~. (60 MHZ, DMSO) ppm = 2.04 (CH3CO) 705 (proton of the thiazolic key).
Example? 6: ~ d ~ ~ ~ J ~ ~ Ya) 2 ~ meth ~ lethoxy _ino) acetamido ~ ceph-3-th 4-carboxYliq ~ e ~ isomer anti - Stage A: 2- (2-trit ~ lamino 4-thiazol ~ l) 2 ~ meth ~ lethoxx imino Eth acetate ~ the ~ i ~ anti omer:
_____________ __ ___________ ~ _ 80US inert gas 6.86g of 2- (2-tritylamino 4-thiazolyl) 2-hydroxy imino ethyl acetate, anti isomer prepared according to stage A of Example 14, 3 ~ 51g of potassium carbonate in 15 cm3 of dimethyl formamide and 7.7 cm3 of i ~ opropyle iodide.
We leave ~ e ~ or stirring 4 hours and a half, add 250 cm3 of water di ~ tilled and 150 cm3 of ethyl acetate, stirred, decanted, the ~ e water, extracted with ethyl acetate, dried, wrung, concentrated to dryness, resumes with ethanol, laiese cri ~ talliser after priming, e ~ sore, rinses with ethanol, emp ~ te with petroleum ether and obtains 3.26 ~ of expected product. F ~ 182C.
Stage B: Acid 2- (2-trit ~ amino_4-thiazol ~ l ~ 2- ¢ 1-meth ~ lethoxx imino acéti ~ eu ~ iso ~ re anti:
___________ __ ____ _______ 6.8g of product obtained in the preceding stage A is mixed, 41 cm3 of dioxane and 8.15 cm3 of ~ or 2N. We bring to the water bath at 55C for 2 hours, cools, adds 9.5 cm3 of acid ~ 31 ~

hydrochloric 2N, obtains a pH of 2 - 3, cha ~ e dioxane, lai ~ se ~ crystallized, diluted with water, a ~ ite, esgore, rinCe ~ water ~ emp ~ te with ether, dry and obtain 5.87 g of the expected product.
= 240 ~ C with decomposition ~ ition.
NMR (CDC13 60 MHZ) p. p, m. _ 7.66 (proton of the thiazolic cycle) 7.31 (trityle grouping).
Stage C: Ac_de 3-acetoxymethyl 7- ~ - (2-trlt ~ lamino_4-thia ~ ol ~ l) 2- (1-meth ~ lethoxy imino) acetamido ~ ce ~ h-3-th 4-carbox ~ eu, __ ______ ______ ______ ________, 1 ___ ____.____________ __ __ anti isomer:
____________ Introducing 5.66g of acid obtained in ~ tade B above dan ~ a mixture of 48 cm3 of tetrahydrofuran, 48 cm3 of chloride methylene and 1.32 cm3 of N-methyl morpholine. We heat ju ~ that dissolving, cooling to -20C and adding 1.56 cm3 of chloroformate d'i ~ obutyle, abando ~ ne 10 minutes between -20C and -10C, pUi9 cool said at -35C and suddenly introduced 3.26g of 7-amino cephalospo- acid ranic in 60 cm3 of methylene chloride and 3.36 cm3 of triene -thyl amine 8ec. We let it warm up and stir 3 hours 30 minutes, removes solvents, resumes with ethyl acetate, observes a ~ total solution, diluted with ether i ~ opropylic, agitate, spin dry, rinse this with isopropyl ether, ~ che and obtains 5.42g of product wait ~ u.
The product is purified by dissolving hot 5.82g of pro-duit obtained according to the process below ~ us dan ~ 20 cm3 d ~ ethyl acetate-the, we dilute with 200 cm3 of opropyl ether, wring, dry and -isolates 4.82 g of expected product.
: 3-acetox acid ~ meth ~ l 7- ~ 2- (2-amino 4-thiazolyl) 2- (1-methylethoxy imino) ac ~ tamid ~ ceph-3-soul 4-carboxylic, anti lsomer 3.62 g of product obtained in Example 16 are introduced into 16 cm3; aqueous formic acid 50 - 50. The mixture is brought to 60C
for 20 minutes ~, cools ~ to -20C, adds 16 cm3 of water, shakes, wring out the triphenyl carbinol, rinse it with water, dry and gets 1.23g, 'g ~

Concentrate to seo under vacuum, rep ~ end with ethanol as then chaase sou3 empty, take up with water, stir, initiate the crystallization while cooling 9 spin the crystal-gum mixture obtained rinsed with water, dried and isolated 1.68g of expected raw product.
A pure sample is obtained by operating as follows:
Dissolve 2 g of product dan8 5 cm3 of bicarbonate of sodium in ~ aqueous solution at 10 ~ and 5 cm3 of water, stirred lO minu-test, wring, rinse with water, add formic acid to the filtrate ju ~ u'at pH = 3, stir for one hour in a ~ lace bath, essore9 rinse with water, say ~ out the gum dan ~ 10 cm3 of ethanol by heating, cooling says dan ~ ice water, wring, rinse with ethanol, pui ~ with ether.
748 mg of purified product are obtained. We also observe the forma-tion of a crystalline deposit in the filtrate, diluted with ether without precipitating, wring out the crystals, rinse with an etha- mixture nol-ether, then with ether. 177 mg of pure product are thus obtained crystallized, anti isomer.
F = 200C approximately with decomposition.
NMR (DMSO 60 MHz) ppm = 7.46 (cyano-thiazolic proton) 4.43 (group tertiary proton isopropyl).
Example 18 Acid 3-acetoxymethyl 7- [2- (2-tri ~ ylamino 4-th zolyl) 2- (2-propenyl oxymino ~ acetamid ~ ceph -3-eme 4-carbox.Ylique ~ isomer anti , ~
Stage A: 2- (2-trit ~ lam-no 4-thiazol 1) 2- (2-Eropén ~ lox ~ im no) acetate_d'eth ~ le, anti isomer:
We mix ~ or inert gas 6.86g of 2- (2-tritylamino 4 thiazolyl) Z-hydroxy imino ethyl acetate, anti isomer prepared according to stage A of Example 14, 3.51 g of potassium carbonate, 15 cm3 of dimethyl forma ~ ide and 7 cm3 of allyl iodide. We shake 5 hours at room temperature, add 250 cm3 of water and 150 cm3 ethyl acetate, stirred, decanted, washed with water, extracted with acetate dry ethyl tate, spin dry, concentrate to dryness, take up with ethanol, ~ 9 ~ 3 ~ 'i6 ~

initiates crystallization, cools in ice water, leaves crystallize with stirring for half an hour, es ~ ore, rinse the ethanol crystals and obtains ~ t 4.72 g of the expected product, ~ e product is purified as follows:
215 mg of the above product are dissolved in ~ 2 cm3 ethanol and 2 cm ~ of methylene chloride. We concentrate the filtrate, diluted with ethanol and allowed to crystallize in ice water, wring, rinse ~ étha ~ ol, know and obtain 70 mg of purified product ~
F = 90C (pasty); F = 160C (frank).
Stage_ ~: Acid 2- (2- rit ~ lamino 4-thiazol ~ l) 2- (2- ~ ro ~ en ~ loxy imino) acéti ~ ueL anti isomer:
_____ ______ __ _____________ 3.71 g of product obtained in stage A are introduced.
yield in 22 cm3 of dioxan ~ e and 4.5 cm3 of 2N sodium hydroxide. We bring to water bath ~ 55C for one hour 50 minutes, re ~ oidit, add 5.25 cm3 2N hydrochloric acid to pH = 2, flush the dioxane, obtains a gum which is diluted with water, cools in ice water, wring, rinse with water, then empfite with ether 3 times ~.
2.85 g of expected product are obtained.
F = 198C (decomposition).
NMR (CDC13 90 MI ~ z) ppm = 7.64 (proton of the thiazolic cycle) 7.27 (proton of the trityle).
Stage C Acid 3-acetox ~ meth ~ l 7- ~ 2- (2-tritylamino 4-thiazolyl _______ ______________ ____ .___ __ ______ _____, ___________ _ ~ - (2-pro ~ en ~ lox ~ imino ~ acetamidol ce ~ h-3-èrne 4-carbox ~ eu, __ __ __ __ ___ ______ __________ ~ ___ _ __ ___________ __ __ anti isomer:
__ ____ _ __ __ 2.82 g of the acid obtained in Stage B above are introduced.
in 24 cm3 of dry tetrahydrofuran and 24 cm3 of chloride methylene, then after dissolution, 0.66 cm3 of N-methyl is added morpholine. Cool to -20C and add 0.78 cm3 of chloro-formate ~ 'isobutyle.
The mixture is stirred for 3 minutes at -20C, then cooled to -35C and introduces a solution of 1.63 g of 7-amino cephalosporanic acid in 30 cm3 of methylene chloride and 1.68 cm3 of triethylamine.

~ '~ 7 1 ~ i l L ~; `
., 13 ~ g2 We lai ~ reheat ~ er for 3 hours 3, chase the ~ olvants, resumes with methyl chloride ~ only add 50 cm3 of water and 15 crn3 of acid normal hydrochloric. Agitate, decant, wash with water, extract with methylene chloride, ~ dries, e ~ ore, rinses with methylene chloride, concentrated to dryness, taken up in diethyl acetate, diluted with iso- ether propyllic, agitate, wring, rinse with ether i ~ opropyliqus and obtains 3.08 g of expected product.
The purification is obtained as 9Uit:
We say ~ out 3.59g of product obtained as below ~ u ~ in 15`cm3 d ~ ethyl acetate, diluted with isopropyl ether ~ stirred, wring out the precipitate, rinse with isoprop ether ~ lique and i901e 3.33g of purified product.
Example 19: 3-Acetox.ymethyl 7- (2- (2-amino 4 thiazol! Yl) 2- (2-~ ropenyloxy lmino) aceta ~ id ~ ceph-3-eme 4-carb-oxyl eu, i30mère anti 2.53 g of product obtained in Example 18 are placed in ~
11.5 cm3 of aqueous for ~ ic acid 50 - 50.
The mixture is brought to 60C for 20 minutes, diluted to water, cools to room temperature, e ~ Yore, rinses with water, 3rd che the triphenyl carbinol formed and obtie ~ t 963 mg.
Concentrate the mother liquors ~ dry 90U ~ empty, add ethanol, then the eye ~ e, resumes gum dan ~ 15 cm3 of water, deli-te, e ~ sore, rinse with water, ~ dry and get 1.275g of product expected.
~ e product is purified as follows:
We put in ~ uspension 1.63g of raw product dan ~ 15 cm3 ethanol, brings to re ~ lux, e ~ ore ~ rinses with ~ ethanol, recovers 877 mg of insoluble product. 20 cm3 of ether1 eY- are added to the filtrate sore in ~ insoluble, rinse with an ethanol-ether mixture 1-1, dry, i ~ ole 9;? mg of an insoluble second part. We concentrate half the filtrate, observe the crystallization of the product, es ~ ore, rinoe first with ethanol then with ether, dry and isolate 162 mg of pure product, anti isomer. F = 180C (pasty ~ e).
NMR (~ MSO 60 MHz) ppm = 7.48 (proton of the thiazole cycle);
æ ~

~ 3 ~
~ .04 (protons of the acetyl group).
Example 20: 3-acctoxymé-th ~ [2- ~ 2-amino ~ -thiazolyl acid) 2-methoxy imino_acétamidol ce ~ -3-th ~ -carbox, ylique, isomer s ~ n Stage A: 2- (2-chloracetamido 4 ~ thla ~ olyl) 2-mcthoxy iMino acetate ethyl ~ syn isomer;

45.8 g of 2- (2 amino 4-thiazolyl) 2-methoxy are mixed imino ethyl acetate, syn isomer prepared according to stage A of Example 3 in 200 cm3 of methylene chloride, distilled 20 cm3 to dry, cools to 10C and adds 50 cm ~ of pyridine.
41 g of monochloroacetic anhydride are added and the mixture is slightly heated until dissolved ~ 6 hours left at 20C under nitrogen, add 5 cm3 of water, stir and pour into 300 cm3 of 2N hydrochloric acid ice. Decanted, extracted with methylene chloride, washed with water with sodium bicarbonate, water, dry, go black, concentrate and add 300 cm3 of isopropyl ether. The product crystallizes. We concentrate until a thick paste is obtained, ice, spin, wash, with isopropyl ether, dry and obtain 45.4 g of product, F = 113C.
A pure sample is obtained by recrystallization in a mixture of methylene chloride and isopropyl ether.
F = 118C, NMR (CDCl3 60 MHz) p (d) HN- ~ -CH2Cl (c) (a) ~ I ~ O-CH2-(e) b CH3 (b) (a) tripl ~ t centered on 1.38 ppm J = 7 Hz;
(b) singlet 4.05 pp m ,;
(c) quadruplet centered on 4.44 pp M,, j = 7 Hz;
(d) singlet 4.33 ppm;

5 ~
~ _ . .

131 ~
~ e) singlet 7.27 pp m O;
(f) singlet 9.95 ppm Stage B: Acid 2- ~ 2-chloracetamido 4 - thiazol ~ vl) _2-methox ~ imino aceti ~ eu, isomer 9 ~ n:
___ __ _ _ __.__ __ ____ _ 46 g of product obtained at Stage A are introduced.
yield in 230 cm3 of absolute ethanol. We add ~ 20C under nitrogen, 30 cm3 of pure soda lye. ~ e product dissolves, the salt of sodium begins to crystallize, then the medium solidifies.
After 16 hours, the product is filtered and washed with ethanol. The salt obtained is dissolved in water, ice, add 100 cm3 of hydrochloric acid ~ e 2N, saturated with sodium chloride, extracted with ethyl acetate co ~ tenante 10% dléthanol, One dries. goes black. distills under vacuum, entered ~ does the water with benzene, resumes with methylene chloride, dry distilled, taken up in methylene chloride, ice, wrung, la-ve with methylene chloride, dries and obtains 34.5g of product at-tense. ~ -200C. about. The product is purified by recrystallization dan ~ an acetone-isopropyl ether mixture.
Analysis: C8H804N3ClS = 277.68 Claculé: C% 34.60 H% 2.90 N% 15.13 Cl ~ 12.77 S ~ 11.55 Found: 34 8 2.8 14.8 12.6 11.5 NMR (DMSO 60 MHz) 11 (b) HNC-CH a (e) ~ 2 H ~ `d /
(d) OCH3 (a) , ~ 0 (a) singlet ~ .92 ppm;
(b) singlet 4.38 ppm;
(c) singlet about 5 ppm;

~ 3 .li ~

~ 3 ~ 2 (d) singule-t 7.58 pp ~ n .;
(e) singlet 12.6 pO p, m.
Stage C: Acid 3-acetox ~ methyl 7- ~ 2- (2-c ~ lloracetamido ~ -thiazol ~ l) _______ ___________.___ ____ ____ __ __________________________ _ 2-methoxy imino acetamido ~ ce ~ h-3-èrne 4-carbox ~ eu, isomer s ~ n:
____ ~ ___ ________________, ~ ___ ________________ __ __ _________._ _ 15 ~ g of product obtained in previous stage B are introduced.
in 80 cm ~ of methylene chloride. At 5C, 8 crn3 of triethylamine. At 0C under nitrogen, 3.8 cm3 of chloride are introduced of thion ~ le and 26 cm3 of methylene chloride. We let 15 minutes at 0C, then add 7 cm3 of triethylamine. We introduce at 0C under nitrogen, 13.6 g of 7-amino cephalosporanic acid in 100 cm3 of methylene chloride and 14 cm3 of triethylamine. We let re ~ onter at 20C, then stir for one hour. This solution is dry distilled SOU8 empty around 30 - 35C. We dissolve the residue in 250 cm3 of water, turns black, adds 50 cm3 of acid hydrochloric 2N. The precipitate is drained, washed with water. ~ e crude product obtained is suspended in 80 cm3 of ethanol.
At ~ 5C, 7 cm 3 of triethylamine are added. We add only one blow with stirring at + 5DC ~ 15 cm3 of 4N sulfuric acid, the product crystallizes ~ After 15 minutes, it is wrung, washed with ethanol by mashing, then with ether, dried under vacuum and obtains 18.6 g of expected product.
/ ~ / D = ~ 26 1 (at 1% in dimethyl formamide).
NMR (D ~ SO 60 MHz) Q (c) HNC-CH Cl (e) t 2 s / ~ rl ~ - ~ J ~

~ CI ~ (a) ~ 0 (b) I-I2-OC-CH ~
CO2lI has ~ J

1 ~ 3 1 ~

(a) singlet 2.03 ppm;
(b) singlet 3.90 pO pm;
(c) singlet 4.38 ppm;
(d) singlet 7.45 pp ~.
Stage D: 3-acetoxymethyl acid 7-r2- ~ 2-amino 4-thia ~ olyl) 2-methox ~
imino acetamido ~ ce ~ h-3-th 4-carbo ~ eu ~ syn isomer:

5.32 g of acid obtained in Stage C are suspended previous in 10.6 cm3 of water and 912 mg of thiourea. At 20C, we add 1 g of potassium acid carbonate. After dissolution, we stirred for 6 hours around 20C under nitrogen. Ba gummy precipitation starts after an hour and about a half. We add 30 cm3 of water and 3 cm3 of formic acid. Cool to 5C. We wring, wash with water containing 10% formic acid. We dissolve the residue around 5C in 30 cm3 of water containing triethylaulin.
At 5C, 3 cm3 of formic acid are added, the precipitate is drained, washing by mashing with water containing formic acid. We removes dark brown gum. The aqueous phases are combined and treated with black. We get a light yellow solution which we saturated with ammonium sulphate. We wring out the precipitate, water, wring,] with water and obtain a precipitate A.
~ es mother liquors are saturated with ammonium sulfate, which gives a precipitate which llon wrings, washes 3 laws with a minimum water ~ t obtains precipitate B.
Precipitates A and B are combined. We resume at Ethanol, stirred one hour at 20C and lai ~ 16 hours at 0C. We spin, wash with ethanol, ether, dry in vacuo and obtain 3.47 g of expected product, i ~ omer ~

S ~ N
~ ~ NH (c) (d) OCH3 ~ / ~ H (a) (b) ~ CH2-0 ~ -CH3 (~ 02H O

NMR (DMSO 60 MHz) (a) singlet 2.03 ppm;
(b) 3.55 ppm singlet;
(c) doublet 5.19 ppm J = 5 Hz;
(d) singlet 6.8 ppm This product is identi ~ ue to that obtained in the examples 4 and 6.
Example 21: Dieth salt, ylamine of _'a of 3-acetoxymeth, yl 7- {2-(2-tritylamino 4-thiazol ~ l) 2-methoxy imino acetarnido} ceph-3-th 4-carboxylic, syn isomer Stage A 2-acetyl 2-methox ~ imino acetate eth ~ vle:
_______ ______ _____ ____ __________ _________ __ 4.69 kg of 2-acetyl 2-hydroxy imino acetyl are introduced ethyl acetate corresponding to 4.21 Kg of pure product in 21 liters anhydrous pure acetone. At 20 - 25C, 6.1 Xg of carbonate is added potassium. The suspension is stirred for 10 minutes, then added at 20 - 25C, 3.72 Kg of dimethyl sulfate. Shake for 3 hours at 20 - 25C. We then pour into 126 liters of mineralized water, extracted using 4 times 5 liters, then 2 liters of chloride methylene. Wash with 10 liters of demineralized water. We dry, wring, rinse with 2 liters of methylene chloride. We distill sou ~ empty and obtains 4.88 Kg of expected product.
Rf = 0.7 (in thin layer chromatography on silica; cluan-t:
methylene chloride - ethyl acetate 9 - 1), ~ 6 `~ .1 ~
',. ~

~ 3 ~ 682 ~ e product is identical to celul ob-teml to s-tade has the example ~.
Stage B: ~ -bromo 2 methox ~ imino acét ~ l acéta-te d'eth le:
_______ ________________ ___________ _______________ __ 3.53 kg of product obtained in stage A above are introduced.
tooth in 18.6 liters of methylene chloride and 3.5 g of acid sulfonic paratoluene. We add to the previous solution in 30 minutes maintaining the temperature at 22C + 1C, a solution of 2.96 Kg of bromine in 3.5 liters of chloride methylene. There is a release of hydrobromic acid after 15 minutes of introduction. Stir 45 minutes at 22C, wash with 2 times 14 liters of ice-cold demineralized water.
The washes are extracted with 2 times 3.5 liters of chloride methylene. It is dried, filtered, rinsed with methylene chloride and distills under vacuum. 4.7 ~ Kg of expected product are obtained.
This product is identical to that obtained in the ~ stage of Example 3.
Stage C: 2- (2-amino 4-thiazcl ~ yl) 2-methox ~ imino acet_te éth ~ le, _______ _________________ __ ___._______ _ s ~ n isomer:
_________ _ 1.43 kg of thiourea are introduced into 3.55 liters ethanol and 7.1 liters of demineralized water. Shake 10 minutes at 20C, PU9 adds at 20 - 25C, 4,730 Kg of product prepared at Previous stage B in 3.55 liters of ethanol. Shake 3 hours at 20 - 25C. Cool to 15 - 20C and neutralize to pEI 7 a ~ ec about i.6 liter of 22Bé ammonia.
stir for another 15 minutes at 20 - 25C. We wring, wash with 5 times 1.8 liters of demineralized water, dries and obtains 2.9 ~ 7 Kg of expected product ~ F = 162C, ~ e product is identical to that obtained in stages ~ and from example 3.
Sta ~ e D: 2- ~ 2-trit ~ aamin_ ~ __hiazolya) 2-metho ~ _imino_a_eta_e of eth ~ le, isomer s ~ n:
On i ~ troduit 3.41Kg of product obtained in the previous stage C

~ 57 --58. ~ -i3lS ~ r; ~ 2 in 17 liters of methylene chloride and 2,275 liters of triethylamine. We stir 15 minutes, add in one hour under stirring and nitrogen at 20 - 25C, 4.55 Kg of -trityl chloride.
The mixture is stirred for 20 hours at 20 - 25C under nitrogen, there is crystallization triethylamine hydrochloride.
Wash with 10 liters of acid 0.5N hydrochloric ice-cold and 2 x 10.2 liters ~ of demineralized water icy. The washes are extracted with 1.7 liters of methylene chloride, dried, filtered, rinsed with 1.7 liters of 10 methylene chloride. Dry distllle ~ or vacuum at a temperature-less than 50C.
8.425 Kg of crude product are obtained.
This product is redissolved at 20 - 25 ~ in 8.4 liters methanol, added in one hour to 20 - 25 ~ with stirring by initiating crystallization, 2.8 liters of demineralized water.
Stir another hour, ecsore, paste with 2 times 1.7 liters of methanol at 25% water, dries to 40 ~ and obtains 1.165 Kg of product expected.
~ e product is identical to that obtained in stage B of Example 3.
Stage E: Sodium salt of acid 2- (2-trit ~ lamino 4-thiazol; yl) _______ __________________________________ __________._____ _ 2-methox ~ imino acetamido, syn isomer:
________ ________________ __________ _ 4.175 kg of product obtained in stage D are introduced previous in 20.9 liters of ethanol. We bring to reflux SO'lS
agitation and nitrogen. A total di.ssolution is obtained from 55o ~.
5.235 litles of ~ oude about 2N, There is rapid crystallization. We act you hour reflux sou ~ nitrogen. We arnene at 20 - 25 ~ (~ and maintains 30 two hours at this temperature. We spin, wash with 4 Iois Z.1 liters of ethanol, dry and obtain 4.02 Kg of expected product.

Stage F: Acid 2- (2-tritylamino 4-thiazolyl ~ 2-rnethox; y irnino aceti-_, ~

~ 3 ~ 2 aue lsomere svn:
500 g of product obtained at the preceding stage E are introduced.
tooth corresponding to 440 g of product ~ ec in 2.5 liter ~ of chlo-methylene rure. It is added in 2 minutes to 20 - 25C SOU9 stirred tion and nitrogen, about 2 liters of normal hydrochloric acid. We shakes for two hours ~ at 20 - 25C under nitrogen. We decant the phase chloromethylenic and washed with 3 times 2 liters of demineralized water achieved. The washing water is extracted with 1 liter of chloride methylene. On ~ dry, add 25 g of black, e ~ qore, rinse with methylene chloride, dry di ~ and obtains 481 g of product gross. They are taken up in 2.1 liters of isopropyl ether. We wring, washed with twice 420 cm3 of isopropyl ether. We dry under vacuum until constant weight and obtains 42 ~ .6 g of product expected.
The product is identical to that obtained in stage C of Example 3.
Stage G: Diethylamine salt _ 3_acetox acid ~ meth ~ 1 7 ~ 2- ~ 2-trit ~ lamino 4-thiazol ~ l) 2-methox ~ imino acetamido ~ ce ~ h-3-th ____ ________ ______ _ ____.____ _______ ~ ________ 1 .___ ________ 4-carbox ~ isomeric l ~ n:
________ __ __ ~ __________ _ ~ 200 g of 2- (2-tritylamino 4-thiazolyl) acid are introduced 2-methoxy imino acetic obtained in the previous stage F in 1200 cm3 methylene chloride. The suspension is brought to reflux under stirring and under inert gas, pui ~ distilled at ordinary pressure 600 cm3 of methylene chloride. We bring to 18 - 20C, then intro-'' while maintaining at this temperature 54 g of dicyclohexyl carbon diimide in 54 cm3 of methylene chloride. We shake for an hour at 18 - 20C under inert gas, then it is added in 15 minutes to this temperature an extemporaneously prepared solution of 61.4 g of acid 7-amino'cephalo ~ poranic in 900 cm3 of methylene chloride and 63 cm3 of triethylamine. Shake for one hour and thirty minutes at 20C
(pH = 6.5 - 7). 50 cm3 of acetic acid are added in ~ uite, leaves 15 minutes with stirring at 20C, then es ~ ore to remove the starting 7-amino cephalosporanic acid. We ~ ~ q ..

~ 3 ~ 8 ~

rinse with 4 times 200 cm3 of methylene chloride. ~ at 30lution organic is washed with 3 times ~ 400 cm3 of demineralized water, then dried over magnesium sulfate. We wring, rinse with 2 faith ~
200 cm3 of methylene chloride, dry distilled 30U8 pressure r ~ -pick and under inert gas. The oily dry extract is dissolved at 20 -25C 80U9 stirring and ~ ou inert gas dan ~ 700 cm3 of dioxane. We distills 90U8 empty and ~ or inert gas at a lower temperature at 30C, 300 cm3 of a dioxane-methylene chloride mixture. We brings to 20C + 2C, pUi8 adds 500 cm ~ of sulfuric ether. We added te 52 cm3 of diethylamine. After about 10 minutes, the salt 2- (2-tritylamino 4-thiazolyl) 2-methoxy acid diethylamine Imino acetic crystallized. Leave for one hour under inert gas at 20C. It is drained, rinsed with 3 times 100 cm3 of a solution of dioxane-ether, the recovered diethylamine salt is dried and gets 113.6g. ~ a ~ organic solution is precipitated e ~ 30 minutes SOU8 stirring in 3.25 liters of isopropyl ether. We leave 15 minutes 80U ~ stirring, then spin under vacuum. We rinse with 2 times 400 cm3 of isopropyl ether, dries 80U ~ empty and obtains 182g of product identical to that obtained in Example 5.
Example 22: Acid 3-acetoxymeth ~ l 7- ~ 2- (2-amino 4-thiazolyl? 2-methoxy imino acetam_dolceph-3-th 4-carboxylic, syn isomer 182g of the product obtained in example 21 above ~ have in-stirred and ~ or ~ ga ~ inert products at 28 - 30C, in 347 cm3 of formic acid and 87 cm3 of demlnérali water ~ éeO There are dis ~ olution total and crl ~ tallization of t ~ iphenyl carbinol. We leave it under agi ~ ation under inert gas 2 hours 30 minutes at 28 - 30C, then pre-cipite in 15 minutes ~ with stirring in 1740 om3 of water d ~ mineralized ~ e and 847 g of ~ ammonium ulfate. We lai ~ e 30 minutes sou ~ agitatlon.
We esso ~ e, rinsed with 2 times 174 cm3 of demineral water] i ~ ee, ~ che 90U9 empty at 25 - 30a and obtains 147g of a mixture of product and triphenylcarbinol. The raw product is pasted for one hour at 18 - 20C in 735 cm3 of ether. We e ~ sore, ~ - -D ~ ~

1 3 ~ 2 ~,.
~ ince with 2 times 147 crrl3 of ethe ~, s ~ che ~ 25 ~ 30 ~ and obtlent 89 g expected product ~
This product is ernpaté 80US agitated and s ~ us nitrogen in 445 cm3 of ethanol. ~ A suspension is brought to 45-50C under agitation-tion and maintained for one hour under these conditions. Then we stick one hour at 18-20C. We are ~ ore, rinse with 2 times 45 cm3 ethanol, dried under vacuum at 20C and obtained 76.85 g of product expected.
This product is placed in the presence of 230 crn3 of acid acetic. Stir 15 minutes under nitrogen, then add 77 cm3 of water demineralized. Then about 700 cm3 are added to this solution.
of water. Leave to stir for one hour at 18-20C, then add in 10 minutes about 269 g of a ~ monium sulfate, leave 1 ~ minutes, then add 3.85 g of black. We leave 15 minutes with stirring, wring, rinse with 77 crn3 of demineralized water 25% acetic acid. Is added at 18-20C with stirring, 154 cm3 of formic acid, add a primer of final product, then promotes crystallization by scraping, We leave 2 hours under stirring at 18 - 20C, then ~ two hours at 0 + 5C ~ We wring, washing with 4 laws 77 cm3 of demineralized water at 5C ~ o of formic acid.
It is dried at 20 - 25C under vacuum. 49.45 g of product are obtained in the form of formate.
~ e formate obtained is mashed with stirring for one hour at 45 - 50C in 250 cm3 of ethanol, then leave for one hour at 18 - 20C. It is drained, rinsed with 2 times 50 cm3 of ethanol. We dries at 20C under vacuum, then 10 to 15 hours at 30 - 40C. We obtains 45.45 g of expected product. / a / D - + 64.5 (C = 0 ~ 5 ~ in water at 0.5% NaHCO ~, ~ e product is identical to that obtained in Examples 4, 6 and 20.
Example 23 Salt of ~ odium of 3-acetoxyrnethYl acid 7- ~ 2- (2-arnino `4-thiazolyl) 2-methoxy imino_acétarnido3 ceph- ~ -eMe ~ -carboxYlique ~ ~ l 1 3 ~ 2 crystallized, syn-isomer Dissolve 19.8 g of 3-acetoxyrnethyl acid r ~ - (2- (2-amlno 4-thiazolyl) 2-methoxy imino acetamido ~ ceph- ~ -erne 4-carboxylic, syn isomer obtained according to example ~ 9 6, 20 or 22 in 65 cm3 of molar solution of sodium acetate in m ~ thanol. We let it crystallize for 35 minutes at room temperature, add in hour, 40 cm3 of ethanol, continues 2 hours 30 minutes stirring ice water bath, wring, wash twice with 10 cm3 of a methanol-ethanol mixture (1 - 1); twice using 10 cm3 ethanol, pUi9 twice using 20 cm ~ ether ~ After drying, 2 hours at 45C under vacuum and 48 hours under desiccator under sulfuric vacuum, 16,191 g of crystallized product are obtained.
By operating in avoidance of all contact with humidity atmospheric, we obtain a product whose physical constants are given below:
H20 (Karl Fischer) - 0.2alo Methanol ~ 0.1a ~ 0 ~ Determination by chromatography Ethanol: 0.45 ~ ~ in vapor phase Analog C16H167N5S2Na = 477-5 ~ Calculated: C% 40.24 H ~ 3.38 N% 14.67 S% 13.43 Na otO 4081 Found: 39.9 ~ .5 14.5 13.1 4.8 ~ e product left in the air rehydrates.
The X-ray spectrum (Debye Scherrer) allowed to confirm the crystalline nature of the product obtained.
You can also use i ~ opropanol instead of ethanol to obtain the crystallization of the expected product ~
EXAMPLE 24 Sodium Salt of Acid ~ -acetoxYmeth ~ l 7-L2- (2-amino 4-thia7oly]) 2-rnetlloxy imino acetamido ~ ceph-3-èrne 4 ~ carboxyli ~ eu crystallizes isomer syn.
`~ 0 Stage A: Solvate between ~ ~ -amino 4-thiaæolyl) 2-methoxy imino_acétamido ~ ceph- ~ -ème 4-carbox.yliclue lsomer syn and acid ~ ormi ~ eu -s ~~~
''J; ~

~ 3 ~ 3 2 We add in small quantities and with stirring 87.2 g diethylamine salt of iodine 3-acetoxymethyl 7- ~ 2- (2-tritylamino 4-thiazolyl) 2-methoxy imino acet ~ nido ~ ceph-3-th 4-carboxylic, prepared according to Example 5, in a mixture of 220 cm3 of acid pure formic and 220 cm ~ of water. Shake 30 minutes ~ at 50C, cools, eliminates by filtration 30.1 g of triphenyl carbinol.
Pour into the filtrate 450 cm3 of water, remove with charcoal a slight precipitate and concentrate at 40C under vacuum until a precipitation forms. 200 cm3 of anhydrous ethanol are added9 cools with ice, filter ~ wash with ethanol and ether and dry sou ~ vacuum.
31.1 g of expected product are obtained, ~ naly ~ e: C16H17N57S2 'HC2H' 2 Calculated: C ~ 0 39.3 H% 4.08 N% 13.48 S ~ 0 12.34 H20 ~ ~ .46 Found: 39.2 4.1 13.2 12.8 4 ~ 15 Stage B Sodium salt crystallizes 15 g of freshly prepared solvate obtained according to the Stage A are dissolved in 75 cm3 of methanol, the solution is treated with 4.5 g of sodium acetate and 3 g of activated carbon. After filtration, there is; joust 5 cm3 of isopropanol while stirring. After 16 hours at 0, the crystals are isolated, washed with ethanol and ether and dries for two hours under high vacuum at 50C.
7.95 g of expected product are obtained.
~ e product then briefly stays in the open air.
The following analysis is obtained: C16H16N5NaO7S2 1 H20 = 495.5 Calculated: c% 38.78 H ~ 0 3.66 ~ ~ 14.14 Na ~ 4.64 S ~ 12.94 Found 38.6 3.7 13.8 4.6 13.2 ~ xample 25: Sodium salt of 3-ace-tox acid, yllle-thyl / - ~ 2- (2-amino 4-thiazolyl) 2-methox, y imino acetamido ~ ceph-3-th 4-carboxyl ~ eu amorphous i ~ syn omer.
Stage A: Solvate between 3-acetox ~ methyl acid 7- ~ 2- (2 ~ amino 4-thiazol, yl) 2-methox ,, v_imino acetamido Lceph-3-th 4-carbox, ylique , ~ ~ 3 ~ 3 ~
syn isomer and ethanol We dissolve 52 g of solvate with the Iorroic acid obtained in Stage A of Example 24, in a mixture of 3 liters of ethanol at 96% and 350 cm3 of water. Concentrate under vacuum (until obtained with a volume of approximately 300 c ~ 3. ~ e solvate begins to crystallize during the concentration. Cool for an hour in the bath ice, filter, wash with a little ethanol and vacuum dry at room temperature in the presence of concentrated sulfuric acid.
4 ~ g of expected product are obtained.

lysis C16H17N57S2 0.8 mole C2H50H = 492.3 Claculé: C% 42.94 H ~ 4.46 N% 14.23 S% 13.02 Found: 43.0 4.4 14.1 12.9 B) Amorphous sodium salt 3 g of solvate are placed with the ethanol obtained in Stage A
in 60 cm3 of water at 0C and added with stirring 0.504 g of sodium hydrogen carbonate dissolved in 6 cm3 of water. We filter the ~ neutral solution and lyophilized immediately. ~ e product stays then briefly in the open air.
The following analysis is obtained: C16H16N5NaO7S2, 1.5 ~ 0 H20 = 504.47 Calculated: C ~ 38.09 H ~ 3.8 N% 13.88 Found: 38.2 ~ .9 13.6 Example 26 Sodium salt of 3-acetoxvmethvl acid 7- ~ 2- (2-amino 4-thiazolyl) 2-methox ~ imino acetamido ~ ceph-3-th 4-carbox ~ eu crystallized, syn-isomer 4.95 g of 3-acetoxymethyl 7- ~ 2- (2-amino acid are added to 4-thiaæolyl) 2-methoxy imino acetamido ~ ceph-3-th 4-carboxylic, syn isomer obtained ~ u according to Example 4, 6, 20 or 22, 5cm3 of ethanol, then under ~ stirring in an ice-water bath, 10 cm3 of a mo-aqueous sodium carbonate (1M), Apxès dissolutLonJ on adds 15 cm3 of ethanol, concentrated to 30 ~ under vacuum, resumes with etha ~ nol, ~ dries at constant weight. We get a poudx that we take with 15 cm3 of methanol ~ We begin crystallization and abandon a D. ~
6 ~

1 3 ~
~ uit at ref ~ igator. On i ~ ole 3. ~ 0'7 g crLstaLlis product key ~ -.

Example 27: Sodium salt of aclde 3-acetoxymethyl 7- ~ - (2 ~ amino 4-thiazolyl ~ 2-m ~ thoxy imino acetamido ~ ceph-3-th 4-carbox ~ lique crystallized, syn-isomer We dissolve 0.5 g of arnorphic sodium salt o'btenu selo ~
Example 25, in 2 cm3 of methanol, adds slow ~ nt with stirring 0.25 cm3 of n-butanol and cools for 48 hours in the refrigerator-kill at around 6C. The crystals are washed with a little methanol cold and dried for 3 hours under vacuum at 40C in the presence of acid concentrated sulfuric, 0 ~ 2 g of crystallized product is obtained.
~ e product ~ then briefly stays in the open air.
Analysis: C16H16NsNaO7S2 '5 Calculated: C% 38.09 H% 3.8 N ~ 0 13.88 0% 26.96 ~ found: 38.4 3.8 13.8 27.1 By operating with similar operating conditions, slightly different crystalline forms are obtained containing, by example7 0.5 mole of water or 1 mole of water and 1 mole of methanol.
X-ray spectra (Debye Scherrer) of products obtained above confirm the crystalline nature of the products obtained.
Example 28:
We prepared a preparation for injection of formula:
- ~ cide 3-acetoxymethyl 7- ~ 2- (2-amino 4-thiazolyl) 2-hydroxy imino acetamido ~ ceph-3-th 4-carboxylic ........ ......... 500 mg - Sterile aqueous excipient ......... ~ ......................... ~ qs ~ p. 5 cm3 ~ xample 29:
We prepared a preparation for injection of formula:
- 3-acetoxymethyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imlno acetamido ~ ceph-3-eme 4-car ~ oxyli (read ....... ......... 500 mg Sterile aqueous excipient .................... qs 5 cm3 ~, _ ~ S

~ xample ~ O:
We prepared for injection of formula:
- Sodium salt of 3-acetoxymethyl acid 7 ~ r- (2-amino 4-thiazolyl) 2-methoxyimino acetamido ~ ceph-3-th 4-carboxyli than .............. ,............................ ,..... ...... ....... 500 mg;
- Sterile aqueous excipient .........., ..................... qs 5 cm3 Example 31:
We prepared a preparation for injection of formula:
- 3-acetoxymethyl acid 7- ~ 2- (2-amino 4-thiazolyl) 2-(l-methyl ethoxy imino) acetamid ~ ceph-3-th 4-carboxy-lique ,,,,, ......., ...., ..., ........ ,, .... 0 ........., .. .............. 500 mg;
- Sterile aqueous excipient .......... ~ .sp 5 cm3 Example 32:
We made capsules corresponding to the formula:
- 3-acetoxymethyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetarnid ~ ceph-3-th 4-carboxylic .................. 250 mg;
- Excipient q, s. for a capsule finished at L ~ 400 mg.
Example 33:
We made capsules answering ~ the formula:
- Sodium salt of 3-acetoxymethyl acid 7- C2- (2-amino 4-thiazolyl) 2-methoxy imino acetamid ~ ceph-3-th 4-carboxyli-that ......... ...................................... ~. .......... 250 mg;
- Excipient qs for a capsule terminated at ..... 400 mg.
Example 34:
We made capsules corresponding to the formula:
- 3-acetoxymethyl acid 7- ~ - (2-amino 4-thiazolyl) 2- (1-methyl ethoxy imino) acetamid ~ ceph-3-th 4-carboxyli-than ................................................. .......... 250 mg;
- Excipient q. ~. for a capsule terrninée at .... 400 mg.
Pharmacological study of the products of the invention.

Activity in vltro Method of dilutions in the middle:

'~, -6 ~

~ 3 ~ 3 ~, We prepax a series of tubes in which we distribute the same amount of sterile nutrient medium. We distribute in each tube increasing amounts of the product to be studied and then each tube is seeded with a bacterial strain.
After twenty-four or forty-eight hour incubation in the oven at 37C, the inhibition of growth is appreciated by transill? ~ mination, which determines the concentrations minimum inhibitory (C, M, I. expressed in ~ g / cm3).
I. the following results were obtained:
(The product called product A is 3 acetoxy acid methyl 7 2- (2-amino 4-thiazolyl) [2-methoxyimino acetamido] ceph-3-th Anti-isomer 4-carboxylic).

.; -. ~ '~
? ~

~ 3 ~ 2 Acid 3-ac ~ ymethyl 7- C2 ~ 2-amino 4-thiazol ~ l ~ 2-hydroxy imino ketamido ~ ceph-3-th_4-ca b ~ eu, anti isomer MIC in ~ u ~ / ml STRAINS _ _ . . ___. ............... ... _ _. _. _ _.
Staphylococcus aureus UC 1061 Pen-Sensible 5 5 . . . .......... .. _ .. ~ _ Staphylococcus aureus UC 1128 Pen - Resistant 10 10 ~ __. __.
. Staphylococcus aureus Exp. N 54 146 5 10 . ~ ._ _ _. __ ~.
Pyogenic Streptococcus A 561 0.5 0.5 - __. . . ~. ._ _. .
Bacillus subtilis ATCC 6633 2 5 ~ ____ ___. _ __ __ _ Escherichia Coli ST UC 1020 3 3 ____ .__ ._ __ .. ___. _ .. .. _.___ .. _ ._ ._.__. __. , _ ~ _,.
Escherichia Coli RT UC 1261 1 . _. __, . ~: scherichia Coli Exp. T026B6 2 2 __ __ ~. ~~~ __ _. _ _ ~.
Escherichia Coli RG R55 123D 5 10 _ _ .. ........ __ __ _ _ Klebsiella pneumoniae Exp. 52 145 0.6 0.6 __. __._._.______._ .__ .. ... _ ....
Klebsiella pneumoniae 2536 R 20 40 - - - ._. ~ .-Proteus mirabilis (indol-) A 235 2 2 _._ Salmonella typhimurium 420 2 2 , ..,.
Enterobacter cloacae 681 - 40 40 _ ._ _ ~. _ _ _ .. ~

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at . ~ ___ __ ~ _ _._ ... __ ._. _ ~

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_ _ ___ _ _. ~ _ ____ ____ .. ___ .. _._ ____ . . ~. . . . . . .
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MIC in u ~ / ml _____ L 24 Tl 48 H
__ _________ ~ _ ~ __ ~ ___ _ _ ~ _._._. ,, ___ Staphylococcus aureus ATCC 5 638 Pen-Sen ~ ible ................. O .................. 1 2 Staphylococcus aureus UC 1 128 Pen-Resistant ............................... 2 2 _ ___ _ _, _ ___ Staphylococcus aureus exp. N 54 146 2 2 _. _ Resistant Staphylococcus aureus Co 15 C ~ phalexin .............................. 10 20 _ __ ___ Streptococcus pyog ~ nes A 561 ............ 0.02 0.02 _ ~ ._ ____._ Streptococcus ~ aecalis 5 432 ............ 2 10 , _ _ _ _ _ ~ __ Bacillus subtilis ATCC 6 633 ............ 1 1.
~ _______ _ ~
Escherichia Coli Sensitive Tetracycline ATCC 9,637 .............................. 1 1 . . ~ _ Escherichia Coli Resistant Tetracycline ATCC 11 303 ............................. 0.1 0.1 _ ~ __. __. _._ Escherichia Coli Exp. TO26B6 ............ 1 __ __ ___ __ _ _ _ Escherichia Coli Resistant Gentamicin, Tobramycin R 55 123 D .................. 1 _ _ ~
Klebsiella pneumoniae Exp. 52 145 ........ 0.05 0.1 _ _ Klebsiella pneumoniae 2,536 Resistant Gentamicin .............................. 2 5 _ ____ _ __._ ___. _ _. ~. . ~

Prote ~ s m.irabilis tindol-) A 235 ....... 0.2 0.2 : ~
~. . ~ __ __ ~ __ ~ _ ~ 3 1 ~

Product of _exemplQ 9 CMI STRAINS in ~ g / ml 24 H ¦ 48 ~ 1 _. ___ _ I ___ Proteus vulgaris (indol +) A 232 ............. 2 10 . _ ._ _____. ._ ~. ._._.___ Salmonella typhimurium 420 ................. 1 10 ~ ___ _.___ ~ _____ Providencia Du 48 ~ ............... ~ 3 5 __ ._ __ __....................... _ ........ __. __ _____ __ Pseudomonas 3 935 Exp. SG ~ .............. ......... 20 20 _ _ _ _. _ _.__. __ _ Serratia ~ Gentamicin resistant 2,532 ............ 0.4 1 .

- ~ ~ 3 ~

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~ 3 ~
Experimental infection with_Escherlchia 11ol_ ~ 26E36 A) The action of the product of Examples 4 was studied, 6, 20 and 22 on an experimental infection of Escherichia Coli of the mouse. We infested batches of ten male mice with mGyen weights of 21.5 g by intraperitoneal injection of 0.5 cm3 of a culture of twenty-four hours in nu-tritive broth of the Escherichia strain Coli (~ r) 026B6 from the Pastuer institute diluted 1 / 6th with water distilled.
Dermal or oral SOU5 injection was administered hour, five hours and twenty-four hours after the injection a specified quantity of product.
Mortality was noted for eight days.
The results were as follows:

... . .. ... ..

~. . . _ -. . _.
. MOR ~ ABITE AFTER Surviving Mice POSO ~ OGIE .... .. ._ _ on the 8th day.
21 ~ 30 28 H 30 32 H
... _ _. _. ._.___._ ..

. .. _ __ .. _ .__. __ 0.05 mg subcutaneous 10/10 .. _. _ _. ~ ____ ..... _ 0.1 mg 90US skin 10/10 ... _. _ ~
0.25 mg subcutance 10/10 . ... ___. _..... .. _.
0.1 mg per os 1 9/10 ._. ... _ ~.
0.25 mg orally 10/10 ... - -. ~ ......... .... .. ...
0.5 mg per OB. . - _. ____ B ~ By operating under similar conditions and infestan of ~ mice with an average weight of 22.5 g per inaection intraperitoneal from a culture of twenty-four hellre ~ of the strain Escherichia Coli (~) 026B6 di.lué to 1 / 5th.
D. ~ -~ 9 ~

~ 3 ~ g ~

We obtain the following result3 with the p: ~ oduit of -examples 4, 6, 20 and 22.

'8Q q ~ 3 ~

. ~ _ . ~ g o ~ ooooo ~ o , ~ ~ ~ ~ ~ ~. .-0, ~ ~

.O _ ~ ~ ON _ O
. ~ _ _ C ~ D _ .- _ ~ 0. C ~ l _ _ ~ _ _ _ U ~ :: ~. N ~ `J
- _ _ ~ ¢ i ~ _ F'l ~; o e ~ N Ir ~ = - ---- = _ _ ON = N = = ~, _ =
~ ~ oa) c ~ l ~
. ~ ~ _ ~ _ _ _ _. .
~ t _. _ ~
~ ~ o ~ VVC ~ C ~ Cq C ~ U ~
U ~ ~ V ~ U ~ OOO
. ~
., ~ __ _,.

F ~ _ ~ '' ~, OHO 13 ~ 3 ~) ~) ~ jO E ~
C ~ ~ _ C ~ l Lr ~ ll ~ L
~ jX ~: :) OOO ~ _ ~ U
E ~ OOOOOO
~ _. _ ~ _. .
. ~, ~ `~ 3 ~ ~ 3 ~ 2 Experimental Salrnonel Infection: Typhirnurium .
We studied the action of the product of e ~ .ample 7 on a experimental Salmonella typhimuriurn infection in mice.
We infested lots9 of 10 mice with an average weight of 20.5 g by intraperitoneal injection of 0.5 cm3 of a culture of 24 hours ~ in oxoid broth of the strain of Salmonella typhimurium 5210 diluted 1/75 with distilled water.
We administered by subcutaneous injection for one hour, 4 hours, 8 hours, 24 hours ~ and 32 hours after the injection a determined quantity of product.
The results were as follows:
, ~ t _ _. '..

W ~

_ ~ N

w ~ =
I ~: -1-: ~

H ~ _ _ _ = = =
~: ~ ~
ON _. ~. ___. _ ~ _ .__. ~ ____._ _ ___ __.___ _ ~

W _ _ .. _ _ I ~ ~
Cl ¦ __ .___ __ ~ __ _ ol ~ ~ ~ LS ~ ~ o Pl El OOO ~ N
Dl __ -`` `` ~ 3: ~ 9 ~
Proteus Mirabilis exJ ~ ectional infection.
We studied the action of the products of examples 11 and 15 on an experimental Proteus Mirabilis infection in mice.
We infested lots of ten medium-weight mice 22 g by intraperitoneal injection of 0.5 cm3 of a culture of 24 hours in oxoid broth of Proteus Mirabilis A strain 23 diluted 1/4.
It was administered by subcutaneous injection for one hour, five hours and twenty-four hours after the injection a quantity determined product.
The results were as follows:

`~, 83 .i _ ~ _ ~ 3 ~ 82 ~ C oo CCC ~ ~
., 1 ~, a) h ~, _ ~, _ ~ ~ ~ ~ _ h ~ ~ ~ OOO Lr ~ ~ OOOOO
_ ~ _ ~ _ _ _ _ _ _ _ _ __ __ ~ DNN
: ~ _ __ ___ _ _ a ~ __ _, _ NOT_ __ _ _ ___ U ~ ~ NN
N__ _.___ _ ~ ___ .. __ N ~ ~
H_ N _ ~ _ ___ _ _ I _ NOT _ _ _ .--NOT _ NOT
'' U ~ _ N ~, _ NOT _ _ . _ ~ ~ ~ ~ Lr ~
~ _ _, _ _ l . _ ~ ~ __ ~ _ ~ ~ _ ~
., Q) ~ a) a ~ a ~ a ~ a) a) . XEX ~ -) ~ X ~ i XEXXE ~
~ Z; U ~ ~ Ir ~ Ll ~ ~, r H ~ N ~ O ~ ~ - + ~ N ~. ~ ~ 1 ~
~ 0 ~ O ~ O ~ O ~ O ~ O ~ '' ~ O ~ ~
~ ~ 0 ~ ~ ~ ~ ~ ~ ~ ~
E ~ ooo OO oo O
~~ ~ ~ ~ P ~ ~ _ - ~ -`! . __ _ ~ _ _ _ _ `` `~, ~

~ 3 ~ 8 ~ J
tOXlCl study i ~ u ~ che ~ la ~ ouris intravenously ~ has acute toxicity ~ of the product of Example 7 is determined in female mice from 19 to 21 g, Swiss CDI mouse Specific Pathogen ~ ree (Elevage CH. River - ~ rance), on lots from 8 to 10 animals per dose of the compound.
The animals are kept for the 4 days of the observation period in a protected pet store (temperature 21C + 1C, constant humidity, room with air overpressure) with food and drinking water "ad libitum''O
~ The product of Example 7 is dissolved in the concentration of 100 mg / ml in sterile distilled water nonpyrogenic. It is injected into a tail vein, under a volume variable, at a speed of 1 ml / min.

. . . _ _.__, ...................... ___ DOSES mg / Kg MOR ~ A ~ ITE AU JOUR MOR ~ ALITE TO'IA ~ E
____________________ _________. ______________ _ .__________._______ 1,000 0/10 2,000 to 0 / ~

~ a lethal dose is greater than 2,000 mg / kg, Symp-tomatolo ~
No symptoms of intoxication were noted during injection or during the observation period.

~ 5 '~, ~ 3 ~ 8 ~

OVERFLOW DISCLOSURE ~ Irr ~ IRE

In the main disclosure, the Company requests ~
resse has described and claimed new oximes derived from 7-amino thiazolyl acetarnido cephalosporanic acid, their preparation process and their application as medicaments.

This primary disclosure describes the products of formula I:

HR
(I) S ~ ~ S ~

OR '~ CH2 ~ ~ 3 in which R represents a hydrogen atom, R 'represents a hydrogen atom, or a saturated or unsaturated alkyl radical having from 1 to 4 carbon atoms, A represents either an atom hydrogen equivalent to an alkali metal, alkaline earth metal red, magnesium or an amino organic base, the trait undulates means that the OR 'group is in the position syn.

It is understood that the products of for ~ ule I, previously as mentioned, may exist:

- either under the ~ elm indicated 2ar said formula I:
- either in the form of products of formula Iz:

"` ~ 3 ~ 2 R
N (Iz) J ~
S NH

\ CC-NH ~

(jl CH2-0-C-CH3 co2 ~
in which R, R 'and A have the abovementioned meaning.
The main disclosure also relates to a process for the preparation of products of general formula I, characterized in that the 7-amino cephalos acid is reacted poranic formula:

\\ / s ~

0 / ~ \ CH2-0_ 1C-CH3 O

with an acid of formula II:
INH-Rl S / ~ N (II) \ C - C02H
NOT

OR ~ 1 syn isomer ~ 3 ~ 2 or a functional derivative of this acid, of: Formula II in the-which Rl represents a group easily eliminated by acid hydrolysis or hydrogenolysis and R'l represents a groUpelnent easily removable by acid hydrolysis or hydrogenolysis or an alkyl radical, saturated or unsaturated, ayan-t of the 4 atoms of carbon, to obtain a product of formula Ia:

INH-Rl, ~ SN (Ia) ~
CC-NH

No.

O ~ \
C2H o in which Rl and R'l have the meaning indicated above, product of formula Ia which is hydrolyzed in an acid medium or hydrogenolysis or treatment with -thiourea according to the values of R
and R'l to obtain a product of formula Ib:

"~
SN

(Ib) CC-NH
~ ~ ~ / S ~

OR ~ ~

O ~ C112-O-1-C113 C2 ~ 1 in which R represents ~ n hydroc1ene atom o ~ n radical alkyl, saturated or unsaturated, having ~ carbon ator11es ., ~, 7, 3 ~ 87J
and corresponding to a product of formula I, in which A
represents a hydrogen atom produced by formula Ib which is salifies if desired according to the usual methods.

The main disclosure also relates to a process, characterized in that the products of formula II
are prepared by acting the thouree on a product of formula III:

Cl-CI-I -CC -CO alc (III) ON ~ _ OR ' in which R 'represents a hydrogen atom, a group easily removable by acid hydrolysis or by hydrogenolysis, or an alkyl radical, saturated or unsaturated, has 1 to 4 atoms of carbon and alk represents an alkyl radical having from 1 to 4 carbon atoms to obtain, after treatment with a base, a product of formula IV:

NM
1 2 (IV) S ~
~ --- h ~ C02alc N _ OR ' in which R 'and alc have the abovementioned meaning, does of formula IV which is treated with a functional derivative of a group easily removable by acid hydrolysis or by hydrogenolysis, to obtain a product of formula V:

NH-Rl , ~
N (V) C02alc N ~ A-OR ' ~ 3 ~? ~

in which Rl represents an easily eliminable group by acid hydrolysis or hydrogenolysis, and R'l represents a group-Easily eliminable by acid hydrolysis or by hydrogenolysis or an alkyl radical, saturated or unsaturated, ayar.t of 1 to 4 atoms of carbon, product of formula V that the ORL treats with a base, then with an acid to obtain a product of formula II:

N ~ I-Rl SN
(II
~ = ~ C02 ~ 1 N _ ~ OR ' syn isomer The main disclosure also concerns the application cation as medicaments of products corresponding to the formula rale I and extends to pharmaceutical compositions which contain these substances as an active principle.
In the main disclosure, the Company request-described and claimed products conforming to formula I, a process for the preparation of these products, their application as medicines, as well as new industrial products needed res for the preparation of these products.
The Applicant Company has also described and claimed qué products conforming to formula I, a process of preparation tion of these products, their application as medicamen-ts, new industrial products needed for preparation of these products, as well as variants of the process described in the main disclosure.
The Applicant Company has described and claimed confon products (the forrllule I,: their a ~ lication collune [llc'dicd-new industrial products necessary for the pre-paration of the products of formula IB as well as variants of the process described in the main disclosure.

1 3 ~

In particular, the main disclosure do I have a variant of the proclcle for preparing the procluits of formula Vb:

NH - R

SN (Vb) --T ~ co2alC
SN
~ R "b in which Rl represents a group easily eliminated by acid hydrolysis or by hydrogenolysis, R "b represents a radical saturated or unsaturated alkyl having from 1 to 4 carbon atoms and alk represents an alkyl radical having from 1 to 4 carbon atoms, characterized in that a product of formula IV is treated:

~ ~ (IV ") SN co2alc NOT
OH
by an equivalent of a functional derivative of an easy groupell ment eliminable by acid hydrolysis or by hydrogenolysis, preferably trityl chloride in the presence of tri-thylamine for obtain a product of formula X:

NH-R
/ '~; (X) SN

co2alc ~ 1 NOT
~ I

';

- ~ 3 ~ ~ f3 ~ 2 which are treated with an alkylating agent, preferably a alkyl halide, to obtain the expected product Vb.
The primary purpose of this additional disclosure is object to illustrate with new examples, the general formula I.
It concerns 7-f2 (2-amino 4-thiazolyl) 2-hydroxyimino acetamido7 3-acetoxy methyl ceph-3-th 4-carboxylic, syn isomer and its salts with alkali and alkaline earth metals, magnesium or organic amino bases, and more specifically 7-12 (2-amino 4-thiazolyl) 2-hydroxyimino acetamido7 3- acid acetoxy methyl ccph-3-th 4-carboxylic, syn-isomer, and salt sodium 7-l2 (2-amino 4-tlliazolyl) 2-11ydroxyimino acetami ~ o / 3-acctoxy methyl ceph-3- ~ me 4-carboxylic, isomer syn, as well as 7- ~ 2 (2-tritylamino 4-thiazolyl) 2-trityl acid hydroxyimino acetamido73-acetoxy methyl ceph-3-th 4-carboxylic, syn isomer.
The above products can be prepared according to the above process recalled, described and claimed in the application main.
This additional disclosure also relates to a variant of the process for preparing the products of formula Ib:

/ ~
SN 0 (Ib) NH ~ ~ S ~.

NOT
o ~ 0 ~ ~ CI ~ 2 -0-C-CI ~ 3 in which R represents an llydrogerle atom or a radical alkyl, saturated or unsaturated, having from 1 to 4 carbon atoms and corresponding to a product of formula I, in which A
represents a hydrogen atom, characterized in that one makes - ~ 3 ~
react a derivative of the cephalosporanic acid 7-amirlo of formula:

2 ~

O ~ CII2 ICj CI13 C ~ l in which Al represents an easily eliminated grouping by acid hydrolysis or by hydrogenolysis with an acid of formula II:

NH-R

S / N (II) ~ l ~ f C 2 H
NOT

syn isomer OR'1 or a functional derivative of this acid, formula II in which Represents a group easily eliminated by hydrolysis acid or by hydLogenolysis or a radical ch: Loracetyle, and R ' represents a group easily removable by hydrolysis acid or by hydrogenolysis, a chloracetyl radical or a radical alkyl, saturated or unsaturated, having from 1 to 4 carbon atoms, for obtain a product of formula XI:

INH-Rl O (XI) ~ Nl ~ l ~

~ CI-12 -OC -CI-I 3 OR 'C02Al O

in which Rl, R'l and Al have the meanings indicated above, ~;

~ 3 ~ 8 ~
that are treated with one or more acid hydrolysis agents, with a or more hydrogenolysis agents, by thiourea, or by one or more of the foregoing agents to obtain a product of formula Ib ~

Among the groupings easily eliminated by acid hydrolysis or by hydrogenolysis, which can represent Rl and R'1 ~ we can cite the groupemen-ts -tert-bu-toxy carbonyl, trityl, benzyl, dibenzyl, -trichloroetllyl, carbobenzyloxy or tetrallyclro ~ yra ~ yle.

Among the values of Al, we can cite the radicals benzhydryl, tert-butyl, benzyl, paramethoxy benzyl and triehloroethyl.

In a preferred embodiment of the process, we treat the product of formula:

H2N r ~ s 1 ~ N ~ CH ~ -OCC ~ 13 by unclérivé function ~ of the acid of formula II, -telclue the anhydride or acid chloride, the anhydride can be formed in situ by action of isobu-tyle ehloroformate or dicyclohexylcarbodii-mide on acid. We can also use other halo ~ é-nures or eneore of other anhydrides formed in situ by action other alkyl chloroformia, a dialkoylcarbodiimide or another dicycloalkyl earbodiimide. We can also use other acid derivatives, such as acid azide, the activated aid amide or an activated aid ester formed, ~ ar example, with hydroxy succinimide, paranitrophenol or 2-4 di-nitrophenol. In case the reaction is carried out 1 3 ~ 2 with a halide of fo ~ mu] e general acid II or with an anhydride formed with an iso- chloroformate butyl, preferably proeede in the presence of an agent basic.
As the basic agent, one can choose, for example, a carbona ~ e of alkali metal or a tertiary organic base, such as N-methyl morpholine, pyridine or a trialcolylamine, such as triethylamine.
The transformation of products of formula XI into pro-duits of formula Ib is intended to replace the substituents Rl, Al by hydrogen atoms. Similarly, when R'l represents a group ~ acilemen-t eliminable by acid hydrolysis or by hydrogenolysis, or a group t chloracetyl the transformation has also aim to replace it with a hydrogen atom.
To do this, the product of formula XI is treated with one or more acid hydrolysis agents when the substituents Rl and Al represent a group which can be eliminated by acid hydrolysis and R'l represents a group which can be eliminated by acid hydrolysis or an al ~ cyle radical.
We treat the product of formula XI with one or more hydrogenolysis agents when the substituents Rl and Al represent try a group eliminable by hydrogenolysis, and R'l represents a group which can be removed by hydrogenolysis or an alkyl radical.
We treat the product of formula XI with one or more acid hydrolysis agents, and by one or more hydrogenating agents nolysis when at least one of the substituents Rl, Al and R'l represents feels a group eliminable by acid hydrolysis, and one at less of these groupings represcnte a groupernerlt ~ ninable by hydrogenolysis.
Finally, the product of formula XI is treated with the thiouree and optionally by one or more hydrolysis agents acid or hydrogenolysis when any of the substituents ~, . ~ = `_i 3 ~

R1 and R'l represents a chloroacetyl group.
As an acid hydrolysis agent to which we subject the products of formula XI, mention may be made of acid formi ~ ue, trifluoroacetic acid or acetic acid. These acids can be used anhydrous or in aqueous solution. We can also use the zinc-acetic acid system.
Preferably, a hydrolysis agent is used.
acid, such as anhydrous trifluoroacetic acid or aqueous formic or acetic acids, to eliminate tert-butoxy carbonyl or trityl groups that can represent the radical R1 or R'1 or the groups benzhydryl, tert-butyl or paramethoxy benzyl ~ eu can represent A1.
The zinc-acid system is preferably used acetic, to eliminate the trichloroethyl group that can represent R1, R'1 and A1.
Preferably, a hydro-genolysis, such as hydrogen in the presence of a catalyst, to eliminate dibenzyl and carbobenzyloxy groups that can represent R1 and R'1 and benzyl that can represent R1, R'1 and A1.
The reaction of thiourea on the product of formula XI comprising at least one chloroacetyl group, is preferably carried out in a neutral or acid medium. This type of reaction is described by MASAKI (JACS, 90, 4508/1968).
This additional disclosure also relates to a process for preparing the products of formula II as defined above, characterized in that it is treated with a base then with an acid a product of formula IV:
1 ~ 12 . ~
SN
~ CO2alc NOT

i ~ omère ~ yn ~ ' '''X' ~ 3 ~ 82 in which R 'represents a hydrogen atom, a group easily eliminated by acid hydrolysis or by hydrogenolysis or an al ~ cyle radical, saturated or unsaturated, having from 1 to 4 atoms of carbon, and alk represents an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, to obtain a product of formula XII:

l H2 SN (XII) ~ '/ C2H
~ I

syn ~ R 'isomer in which R 'has the abovementioned meaning, which is treated by a functional derivative of a group which can easily be eliminated by acid hydrolysis or by hydrogenolysis or from the chloracetyl group to obtain a product of formula II:

NH-R

/ ~ (II) ,, C02H

NOT
syn isomer OR'l in which Rl represents an easily eliminable group by acid hydrolysis or by hydrogc? nolysis ~, or a grouperllerlt chl.ora ~
cetyl, and R'l represents an easily elimi.nable grouping by acid hydrolysis or by hydrogenol.yse, a chloraceous-tyle group or a saturated or unsaturated alkyl radical having from 1 to ~ atoms of carbon.

. . i ~ 3 ~
The base that we use to saponify the product of formula XII is preferably soda, but we can also use other bases such as potash or barite.
The acid that is used to isolate the acid from formula XI is preferably dilute hydrochloric acid, but can also use acetic acid or formic acid.
The functional derivative of a group easily eliminable by acid hydrolysis or by hydrogenolysis is preferably trityl chloride used in the presence of sorted-thy-lamin or other tertiary amino bases such as others trialcoylamines, methyl morpholine or pyridine.
We can also u-ti.lisc.r other functional descriptions-group nels easily removable by acid hydrolysis or.by hydrogenolysis. Among these derivatives we can cite the tert-butyl chloroformate prepared in situ, or azidoformate tert-butyl, trichloroethyl or benzyl chloroformate, the formyl-acetic mixed anhydride prepared insi-tu, the chloride or another benzyl or dibenzyl halide, the anhydride phthalic or N-carbetoxyph-talimide.

The functional derivative of the chloracetyl group is, preferably chloracetic anhydride or a halide such than monochloroacetyl chloride. In case the reaction is carried out with a chloroacetyl halide, the procedure is preferably mainly in the presence of a basic identical agent ~ ceu ~
mentioned above.
This Additional Disclosure!
relates to a process for the preparation of products of formula Vc:

_. .
. .

~ L 3 ~

INH_Rl , / ~
S
~ C02alc (Vc) syn isomer 5 R "c in which R1 represents an easily removable group by acid hydrolysis or by hydrogenolysis, or a chloro- group cetyl, R`'C represents a group which can be easily eliminated by acid hydrolysis or by hydrogenolysis, or a chloracety group the, different from Rl, and alc represent an alkyl radical having 1 to 4 carbon atoms, characterized in that a product of formula X:

NII-R
/ ~ (X) SN
\ = ~ co2alc . ~
NOT

isomer syn O ~ L
__.
in which Rl and alc have the abovementioned meaning by a functional derivative of the group easily eliminated by hydro-acid lysis or by hydrogenolysis or of the chloracetyl group R "C
to obtain the product Vc.
The group easily eliminated: The by acid hydrolysis or by hydrogen] .yse that represents R ~ is, preferably, the trityl grouping.
The functional derivative of an easily eliminated group free by acid hydrolysis or by hydrogenolysis which is made to act on product X is preferably dihydropyrannyl.

_ 99 _ , '~;

~ 3. ~ v ~

We can however use functional derivatives mentioned above.
This additional disclosure therefore has more especially for subject a process of preparation as described above, charac-terized in that R "C represents a tetra- radical hydropyrannyl.
~ es produi-ts, obje-t this present disclosure-like those in the main disclosure, have a very good activity ~ antibio-tick, on the one hand, on the bac-series gram (+), such as staphylococci, streptococci and no-tammen-t on penicillin-resistant staphylococci and other part, on gram (-) bacteria, especially bacteria coliforms, I ~ lebsiella, Salmonella and Proteus.
These properties make these products suitable for used as medicines in the treatment of ailments sensitive germs and in particular in that of staphylococcal diseases, such than s-taphylococcal septicemia, malignant s-taphylococcal face or skin, pyoderma, septic or suppurating wounds, carbuncles, phlegmons, erysipelas, primitive staphylococcal disease ai.gu ~ s or post-influenza, bronchopneumonia, pulmonary suppurations.
These products can also be used as a drugs to treat collibacillosis and infections associated, in injections with Proteus, I ~ lebsiella and .-Salmonella, and other conditions caused by bacteria to gram (-).
This additional disclosure therefore also has for subject, as drugs and notan ~ ent of m? dicamen-ts antibiotics, the following $ products of formula I.:
- L, 7-¦2- (2-arnino 4-thiazolyl) 2-hydroxyimino acid acetamid ~ 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer ~ y ~
and its salts with alkali, alkaline earth metals, magnesium sium or the amino organic bases, and more particularly:

. .

~ 3 ~

~ 7-¦2 (2-amino 4-thlazoly1) 2-hydroxyimino acid acetamido] 3-acetoxy methyl ceph-3-th ~ -carboxylic, isornere syn, whose activity, with regard to different germs, has been shown particularly remarkable, and:
- The sodium salt of acid 7- t2- (2-amino 4-thia-zolyl) 2- hydroxyimino acé-tarnido] 3-acetoxy methyl ceph-3-th 4-carboxylic syn isomer.
The invention extends to pharmaceutical correlations containing as active ingredient at least one of the drugs defined above.
These compositions can be administered by the ~ uccal, rectal, parenteral or locally applied topically on the skin and mucous membranes.
They can be solid or liquid and present themselves in the common pharmaceutical forms used in medicine human like, for example, simple or coated tablets, capsules, granules, suppositories, mixed preparations jec-tables, ointments, creams, gels, they are prepared according to the usual methods. The active ingredient (s) can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glyclos, the various wetting, dispersing or emulsifying agents, conservatives.
The dose administered is variable depending on the condition treated, the subject in question, the route of administration and the product considered. It can be, for example, between 0.500 g and 1 g, three times daily, intrarnuscularly, in humans with the product described in Example 1 or 2.

This disclosure suppk ~ [llcntairc a eg.llement ~; .
. . ~

- ~ 3 ~

for object, as new and notar ~ nent industrial products ~ title of intermediate products necessary for the preparation formuble Ib products defined above, the products of formula XI:
NH-R

J ~ (XI) SNO

¦ ~ 1 N
,, o- ~ ~ ~ CM2-O-I_CH3 in which Rl, R'l, and Al have the indicated meaning above.
These products, like the products of formula I, have antibiotic activity.
The following examples illustrate the invention without however limit it.
Example 35: Acid 7- ~ 2 t2-amino 4-thiazolyl) 2-hydroxyimino acetamido ~ 3-acetoxy methyl-ceph-3-th 4-carboxylic, syn isomer.
Stage A: 2 (2-amino 4-thiazolyl) 2-hydroxyimino ethyl acetate, syn isomer.
0.8 g of thiourea is dissolved in 2.4 cm of ethanol and 4.8 cm of water. The solution of 2 g of 4-chloro is added in 5 minutes 2-hydroxyimino acetyl ethyl acetate and stirred for one hour at full ambient rature. We hunt most of the ethanol under partial vacuum and neutralizes at pH 6 by adding acid carbona-te solid sodium. We ice, spin, wash with water, dry under vacuum at 40C. 1.32 g of expected product are obtained. F = 232C.

Analysis: C5 Hg O3 N3 S
calculated: C%: 39.06 H%: 4.21 N%: 19.52 S%: 14.9 found: 38.9 4.4 19.7 14.6 ~ 3 ~ 2 NMR (DMSO, 60 MHz) 1 2 () S ~ N
\ / (b) (a) ~ \ ~ ~ ~ CO2-CH2-CH3 (vs) \ H
(e) (a) triplet centered on 1.25 ppm J = 7 Hz (b) quadruplet centered on 4.27 ppm J = 7 Hz (c) singlet at 6.83 ppm (d) singlet at 7.11 ppm (e) singlet ~ 11.4 ppm Stage B: Acid 2 (2-amino 4 - thiazolyl) 2-hydroxyimino acetic, isomer ~ y ~.
21.5 g of product prepared according to stage A are introduced into 200 cm of absolute ethanol and 55 cm3 of 2N sodium hydroxide. We stir in a 45C water bath. After 30 minutes, place in a water bath frozen then brings to pH 6 with acetic acid. We observe a rush. It is drained, rinsed with ethanol at 50% water then with ether. After drying, 16.9 g of product are obtained expected.
Rf = 0.05 (eluent: ethyl acetate - ethanol - water 70-20-10).
Stage C: Sodium salt of acid 2 (2-tritylamino 4-thiazolyl) 2-trityl hydroxyimino acetic, isomer One mixes 16.9 g of acid prepared in the ~ stage, 50 Clll of dimethyl formamide and 42 cm3 of triethylamine. Shake for 15 minutes at ambient temperature and observes a total dissolution.
Is cooled ~ 20C, the salt of triethylaTnine crystal-partially read. We introduce in 15 mlnutes at - 20C, 54 g of ~, ~
~, i, -. . .

~ 3 ~ 2 trityl chloride in 100 cm3 of chloroform. We shake one hour leaving to rev ~ nir at room temperature. We pour into 200 cm3 of water containing 40 cm3 of acid hydrochloric 2N.
decanted, washed the organic phase by 2 times 200 cm3 of water, dries, spins, flushes solvents under pressure reduced, resumes with ethyl acetate.
100 cm3 of saturated carbonate solution are added sodium acid, stir, decant. Sodium salt crystallizes. Ice for 30 minutes, spin and rinse with ethyl acetate. 27 g of sodium salt are obtained expected. Rf = 0.33 (Ether).
Stage D: 7- [2 (2-tritylamino 4-thiazolyl) 2-tri-tyl hydroxyimino acetamido] 3-acetoxy methyl tert-butyl ceph-3-th 4-carboxylate, isomer s ~ n.
17.2 g of sodium salt of acid 2 (2-tritylamino 4-thia ~ olyl) 2-trityl hydroxyimino acetic, syn isomer obtained in stage C in 170 cm3 of chloroform, and 170 cm3 of hydrochloric acid N. Decanted, washed 5 times at the water. It is dried, wrung, flushed out the solvent.
The residue is taken up in 170 cm3 of chloride methylene. 2.8 g of dicyclohexyl carbodiimide are added.
it is acted for one hour and then wrung 1.9 g of dicyclohexylurea.
To the filtrate, 3.66 g of 7-amino 3-acetoxy are added tert-butyl methyl ceph-3-th 4-carboxylate.
Stir two hours at room temperature, wash with normal hydrochloric acid, then with water, with a 5% aqueous sodium bicarbonate solution then the water.
The organic phase is dried, wrung, chased solvent, take up in methylene chloride and elute on silica column with a mixture of methylene chloride 5% ether.

'''6.; ~ F' . ~, , i,, .
.

1,319 ~ 82 Interesting fractions (Rf - 0.78 in ether) are combined. The solvent is removed under pressure reduced and taken up in isopropyl ether.

104a ,:, Ji ~ j ~ 2 : `

On de: Li-te, wring and rinse with isopropyl ether.

5.8 g of product are obtained.

C ~ IO ~ IS Analysis calculated: C%: 69.7 H%: 5.2 N%: 7 ~ 1 S%: 6.5 found: 70.4 5.6 6.5 5.9 ~ N (CDC13 60 MHz) (d) ~ 3 ~ C \
~ -I
~

HN ~ I 1 - I ~ S \

(c) / N ~ `~ 1 (b) N 0 1 C ~ I2-O-ll_c ~ I3 O CO ~ tBu C - ~ (a) (d) (a): singule at 1 ~ 55 ppm (b): singlet at 2.06 ppm (c): singlet at 6.45 ppm (d): singlet at 7.31 ppm Stage E: Acid 7-L2 (2-amino 4-thiazolyl) 2-hydroxyi-mino acetamido ~ 3-acetoxy methyl ceph-3-th 4-carboxy-lique, isomer ~ y ~.

1 g of product obtained in stage D is placed in 3 cm of -tri- acid fluoro acetic. The mixture is stirred for 30 minutes at ambient temperature, then add 30 cm of isopropyl ether. The salt precipitates. We wring and rinse with isopropyl et'rler. We obtain: insi 0.652 g of 7-I2 (2-amino 4-thiazolyl) trifluoro acetic acid salt 2-tri-tyl hydroxyimino acetamido ~ 3-ac ~ toxy methyl ceph-3-th 4-carboxylic.
This ~ roduct is dissolved in 6 cm of -tetrahydrofuran, . . .

~ 3 ~ 2 3 cm3 of 50% aqueous formic acid are added. Shake 15 minutes at 50C, flushes out the solvents, resumes with ether, wring and rinse with ether. 0.441 g of formate of the expected product. The salt is crushed in 2 cm3 of water containing 3 drops of pyridine (pH 6). We wring, rinses with water, dries and obtains 0.136 mg of the expected product.
The filtrate e ~ t brought to dryness, then taken up in ethanol. We spin, rinse with ethanol and obtain 0.04 g of product additional.
NMR (DMSO, 6 0 MGZ) ( VS ) ~ 12 SN
~ J ~
H 11 'NH ~ _ ~ S ~

(b) OH ~ cH2-O-Icl-cH3 (d) CO; ~ HO

(a): singlet at 2.01 ppm (b): singlet at 6.67 ppm (c ~: singlet at 7.08 ppm (d): singlet at 11.3 ppm Example 36: Acid 7- [2 (2-amino 4-thiazolyl) 2-hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, syn-isomer.
Stage A: 2 (2-trityalmino 4-thiazolyl) 2-hydroxyimino ethyl acetate, isomer ~ y ~.

~ .` '~

~ 31 ~ 82 , 43.2 g of 2 (2-amino 4-thiazolyl) 2-hydroxyimino are introduced syn isomer ethyl acetate prepared in stage A of the example 35 in 120 cm3 of dimethyl formamide, dry.
Cool to -35C, introduce 32 cm3 of triethylamine, then in 30 minutes in fractions, 60 g of chloride f ,,.

. ~

X

~: 3 ~

trityle. Let the temperature rise, observe a dissolu-total tion, then heating up to 30C. After an hour, poured onto 1.2 1 of ice water containing 50 cm of acid hydrochloric 22 se.
Stir in an ice-water bath, wring, rinse with normal hydrochloric acid, ernpâ-te with ether ~
69.3 g of hydrochloride are obtained.
The free base is obtained by dissolving the product in 5 volumes of methanol added with 120% -trié-thylamine, then gently precipitating with 5 volumes of water.

Calculated: C%: 67.6 H%: 5.1 N%: 9.1 S%: 6.9 Found: 67.5 5.1 8.8 6.8 NMR (CDC13, 0 ~ -Iz) (d) ~ 3 - C-NII

S \ N (b) (a) ~ C02-CH2 - CH3 (vs) NOT

OH

(a): Triplet centered on 1.31 ppm J = 7 Hz (b): Quadruplet centered on 4.37 ppm J = 7 Jz (c): Singlet at 6.37 ppm (d): Singlet at 7.28 ppm Stage B: 2 (2-tritylamino 4 - thiazolyl) 2 - tetrahydro-pyrannyl oxyi, mino ethyl acetate, isom ~ re ~ y ~.

~ n place 5.6 g of product p.reparo au sl, cl ~ e A dar ~ s 5 ~ C`lll de 3 ~ redistilled dihydropyran. We place in an ice water bath, then add 2.4 y of para-toluene sulfonic acid.

Shake for an hour and a half, letting it rise to '' ~ 3 ~ 2 room temperature ~ We pour into a mixture of 100 cm3 of benzene, 100 cm of water and 2 cm of triethylamine.
Decant, wash with water, dry, spin, rinse with benzene, then flushes out the solvent. It is taken up in isopropyl ether.
that, begins the installation, abandons a night to the refrigerator, spin and rinse with isopropyl ether. 4.42 g of product - F = 184C.
Analysis: para-toluene sulfonic acid salt C3 ~ II39 07 N3 2 calculated: C%: 63; 9 H%: 5.5 N%: 5.9 S%: 9.0 found: 63.7 5.5 5.8 8.9 NMR (CDC13, 60 ~ -lz) (e) ~ 3 - C_N ~ I () / ~
SN
b) (a) H ~ ~ CO2-CH2-CH3 (c) N - '~
0, ~ J

(a): Triplet centered on 1.36 ppm (~): Qua ~ ruL ~ Iet against on 4.39 ~ pln (c): Singlet at 6.60 ppm (d): Singlet at 6.91 ppm (e): Singlet at 7.28 ppm.
Stage C: Acid 2 (2-tritylamino 4-thiazolyl) 2-tetra-hydropyrannyl oxyimino ace'tique,: isom ~ re syn.

4.56 g of product prepared at the stage r ~ dar-s ~ 5 cm are placed.
dioxane and 8.4 cm of 2N soda. We bring to refll] x during one half past one. The mixture is cooled in an ice-water bath, the salt precipitates.
It is drained, rinsed with aqueous dioxane then with ether, and obtains 4.66 g of sodium salt.

~ 108 -The 11 3 ~
The acid is obtained by dissolving the product in 50 cm of dioxane, acidifies with formic acid (pII5) and precipitates with 90 cm of water. F = 180 ~ C.
r ~ MN (CDC13, 60 ~ -Iz) 6.69 ppm (proton of the cycle thiazoli ~ eu), 7.31 (aromatic).
Stage D: 7- ~ 2 (2-tritylamino 4 - thiazolyl) 2-tetrahydro-pyrannyl oxyimino acetamido] 3-acetoxy methyl ceph-3-th tert-butyl 4-carboxylate, isomeric ~ y ~.
0.362 g of product prepared in stage C is added, 0.244 g of 7-amino 3-acetoxy methyl ceph-3-th 4-carbo ~ tert-butyl ylate and 0.280 g of dicyclohexylcarbodiirnide in 4 cm3 of dry chloroform.
We ac3ite 2 hours ~ ambient temperature ~. We wring out the dicyclohexy-luree for ~ o and chlorofoY-rllo rirlce.
'n removes the solvent from the filtrate under reduced pressure, dissolved in 1 cm of ~ ther then chroma-tography on column of silica, eluting with ether.
We gather the fractions of kf ~, 38, flush the solvent under reduced pressure, takes up in isopropyl ether, disintegrates, spin dry, rinse with isopropyl ether. We obtain 0.184 g of expected product.
ANALYSIS: C43 H4s 8 N5 2 calculated: C%: 62.7 II%: 5.5 N%: 8.5 S%: 7.8 found: 62.8 5.9 8.1 7.5 F ~ MN (CDC13, 60 M ~ Iz) (e) (~ 3 _ C-NII

SNO
Jl / S.

H ~ --NI-I ~
(d) ~ O ~ (c) ~ C ~ I2-O- ~ -CH3 (b) Y '' CO2tBu I (a) ~ 3 ~ S ~ 2 (a): 1.53 pprn (b): 2.07 ppm (c): 5.46 ppm (d): 6.67 ppm (e): 7.28 ppm Stage ~: Acid 7- ~ 2 (2-amino 4 - thiazolyl) 2-hydroxy-imino acetamidol 3-acetoxy methyl-ceph-3-th 4-carboxy-lique, isomer ~ y ~.
638 mg of ~? Roduct obtained according to stage D sor ~ t aCJi.teS 15 minutes at room temperature in 1.8 cm3 of tri ~ luoroacetic acid. We add 18 cm3 of isopropyl ether and wring 404 mg of product who rushed. These 404 mg are taken up and agitated for 15 minutes at 50C with 2 cm3 of 50% aqueous formic acid. We focus on dry under vacuum at 30C, take up in 1 cm3 of ethanol, add a drop of pyridine and wring out the expected product.
This product is identical to that obtained in Example 35.
~: Acid 7- ~ 2- (2 - tri-tylam: ino 4-thiazolyl) 2-trityl hydroxyimino acetamido ~ 3-acetoxy methyl ceph-3-th 4-carboxylic, syn-isomer.
Stage A: 2- (2-tritylamino 4-thiazolyl) 2-trityl hydro-xyimino ethyl acetate, isomer ~ y ~.
1.08 g of 2 (2-amino 4-thiazolyl) 2-hydroxyimino acé-ta-te are dissolved ethyl, isomer ~ y ~, prepared in Stage A of Example 35 in

8 cm of chloroform. We add 1.5 cm of triethylamine, then add to - ~ 5C in 25 minutes, the solution of 3 g of chloride trityl in 6 cm of chloroform, and stir for one hour at temperature ambient. Washed with 18 cm3 of water, 8 cm3 of hydrochloric acid normal and 3 times 20 cm of water. We dry, spin and concentrate dry. The product is re ~ taken up with isopropanol in which it crystallizes. 2.3 g of tender product are obtained. F - 140C.
Stage B: Sodium salt of acid 2- (2 - tritylarnino 4-thiazolyl) 2-trityl hydroxyimino acetic, syn isomer, . -~ 9fi ~

0.7 g of product obtained in the ~ stage is dissolved in 3.5 cm of hot dioxane. It is heated to 110C and added with stirring drop by drop, 1 cm 2N soda. We continue to stir for 1 hour 50 ~ a temperature close to reflux, cools and squeezes out the salt sodium which precipitated. Is this product identical ~ the one obtained in stage C of exernple 35.
Stage C: Acid 7- ~ 2- (2-tritylamino 4-thiazolyl 2-trityl hydroxyimino acetamido ~ 3-acetoxy methyl ceph-3-th 4-carboxylic, syn-isomer.
4.12 g of sodiurn salt obtained in stage B is placed in suspension in 50 cm of chloroform. 50 cm of hydrochloric acid are added.
than normal. Shake, decant, and wash three times with 50 cm of water. It is dried, wrung and concentrated to dryness. We thus obtain 2- (2-tritylamino 4-thiazolyl) 2-trityl llydroxyimino acid acetic, isomer s ~ n.
The acid obtained is dissolved in 50 ml of chlorurc from methylene. 1.6 g of dicyclohexyl carbodiimide, stirred one hour at room temperature, wring out the dicyclohexylurea, cools to -10C the solution, and adds 1.1 g of 7-amino acid cephalosporanic solution in 10 cm of methylene chloride and 1.2 cm of triethylamine. Stir 2 hours at temperature ambient, add 50 cm of normal hydrochloric acid, stir, decanted, washed with 3 times 50 cm of water, dried, wrung and concentrated dried up.
It is disintegrated with e-thanol, wrung 2.36 g of raw condensate.
This product is transformed into di ~ '? Ethylamirle salt of acid 7- ~ 2- (2-tri-tylamino 4-thiazolyl) 2-trityl hydroxyimino acetamido] 3-acetoxy mé-thyl cc ~) tl-3- ~ mc 4-carboxyliquo, isom ~ rc ~ y ~, by ac tiOIl of the diethylamine in ether.
The salt obtained is displaced by hydrochloric acid normal in the presence of metllylerlc chloride? until obtelltiol? of a acid pH. The solution is washed with water, dried and brought to dryness.

. ~

~ 3 ~

0.75 g of expected product is obtained, purified.
Example 38 Acid 7-L2- (2-amino ~ -thiazol ~ 1) 2-hydroxy--mino acé-tamido ~ 3-acetoxy methyl ceph-3-th 4-carboxylic, somère syn.
The ditrityl product obtained ~ Example 3 is dissolved in S cm of 50% aqueous formic acid. Shake for 15 minutes at 50C, remove solvents, take up in ether, spin dry and rinse with ether.
We thus obtain] e f-) roduit .sous ~ orllle do form: iate.
This formate is crushed in 3 cm of water containing a few drops of pyridine (pH 6). We spin, rinse with water, dries and obtains the product which is identical to that obtained in Examples 35 and 36.
EXAMPLE 39 Sodium Salt of 7- ~ 2- (2-Amino Acid) 4-thiazolyl) 2-hydroxyimino acetamido ~ 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer ~
0.613 g of acid obtained in Examples 35, 36 are dissolved or 38 in a mixture of 2 cm of distilled water, and 2 cm of a mola solution: sodium acetate in methanol. We add 60 mg of activated carbon, wring, rinse with 2 cm of methanol, concentrated to dryness under vacuum at 30C, resumed with ethanol and obtained, after wringing and drying, 0.432 g of expected sodium salt.
Example 40: Crystallized sodium salt of acid 7- [2--t2-amino 4-thiazolyl) 2-hydroxyimino acetamido ~ 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer ~ y ~.
1.78 g of methanol are suspended in 8 cm of methanol.
the acid obtained in examples 35, 36 or 38. 8 cm of molar solution of sodium ace-tate in methanol, expected sodium immediately cris-tallise. We have 15 minutes to complete the transformation, spin, wash with ethanol, then with ether. 1.53 ~ of white crystallized product is obtained.
ANALYSIS: Cls ~ 14 7 N5 2 ~ i `

~ 3 ~ 2 Calculated: C%: 38.88 H%: 3.04 N%: 15.11 S%: 13.8 ~ Na%: 4.96 Found: 38.8 3.1 15.1 13.8 ~, 85 Infrared (nujol) \ C = o 1753, 172 ~, 1683 crn 1 MH, OH, 3597 cm 1 NMR (DMSO, 60 MHz) Singlet at 2.01 ppm -C-CH3 Singlet at 6.65 ppm (proton of the thiazole cycle) Singlet at 7 ~ 6 ppm (amine group NM2) Exeln ~ le ~ 1:
We prepared a preparation for injection of formula:
- Acid 7- [2- (2-amino ~ -thiazolyl) 2-hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4- ~ arboxylic, syn isomer ......... 500 mg - Sterile aqueous excipient ......................... ~ ................ qs 5 cm Example 42:
We made capsules corresponding to the formula:
- Acid 7-L2- (2-amino 4-thiazolyl) 2-hydroxyimino acetamido ~ 3-acetoxy methyl ceph-3-th ~ -carboxylic, isomer ~ y ~ ......... 250 mg - Excipient qs for a capsule completed at .................. ~ 00 mg Pharmacological study of the product of the invention.
~ activity in vi-tro Liquid dilution method:
We prepare a series of tubes in which we distribute the same amount of sterile nutrient medium. We say tribe in each tube increasing amounts of the product to be studied and then each tube is seeded with a bacterial strain.
~ v ~ incubation of v: ingt - qualro or that ~ o ~ o ~ eight hours in the oven at 37C, the inhibition of growth is appreciated by transillumination, which allows to determine the concentrations inhibitories: CMI eXpril ~ l (`C. '; on g / cln).
The following results were obtained:

- 113 ~

:: `,`, i, j . ~ 3 ~ 'ig ~

- Produces examples 35, 36 and 38 -__ _ MIC in ~ lg / ml S 0 UCHES __________ ________.
24h 4 ~ 3h ___________________________________ ___________ ___________. .________. , Staphylococcus aureus ATCC 6 538 Pen-Sensible 0.5 0.5 _______________________________________________ ______ ____. .________, Staphylococcus aureus UC 1 12 ~ 3 Pen-Resistanl 1 Staphylococcus aureus exp. n 5 ~ 146 .............................................. ......... 1 ______________________________________________ ___________ ________. .
Streptococcus pyogens A 561 .............................................. ................. 0.02 0.02 ______________________________________________ ___________. ________.
Strep-tococcus faecalis 5 432 ............................................ .................. 5 5 ______________________________________________ ___________ ________ Streptococcus faecalis 99 F 74. ___________ ________ Bacillus subtilis ATCC 6 633 ............................................. .................. 0.5 ______________________________________________ ___________ ________, Escnerichia Coli Sensitive T-tracycline ATCC 9,637 ............................................... .................................. 0.05 0.1 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ _ ._ _ _ _ _ _ _ _ _ _ _ _. .
Escherichia Coli Resistant Tetracycline ATCC 11 303 ............................................... ................................. 0.1 0.1 ..

- 11 ~ -

9 ~; 3 ~

CM I in, ~ Jg / ml SOUC EI E S________ __________ Escherichia Coli Exp. TO26B6 ................ 0.05 0.1 ______________________________________________ ________ __________ ~
Escherichia Coli Resistant Gentamicin, Tobramycin R 55 123 D .................... 0.2 0.2 ______________________________________________ ________ __________ Itlebsiella pneumoniae Exp. 52 145 ........ 0.05 0.1 ________________________________________.______ _________ __________ Itlebsiella pneumoniae 2,536 Resistant Genta-micine ........ ...................... ..... 0.2 0.5 ______________________________________________ _________ __________ Proteus mirabilis (indol-) A 235 .......... 0.1 0.2 ________________ ~ _____________________________ _________ __________ Salmonella -typhimurium 420 ........ ..... 0.1 0.1 ______________________________________________ ________ ___ ______ Enterobacter cloacae 681 .................. .... 5 10 ______________________________________________ _________ __________.
Providencia Du 48 .......................... 2 2 ______________________________________________ _________ __________ Serratia Resistant Gen-tamicin 2 532 ...... 10

Claims (93)

1. Process for the preparation of the products of formula (I):

(I) in which R represents a hydrogen atom, R ' represents a hydrogen atom or a saturated alkyl radical or unsaturated having from 1 to 4 carbon atoms, A represents either a hydrogen atom or a metal equivalent alkaline, alkaline earth, magnesium or base organic amino, the wavy line means that the grouping OR 'is in the syn position, process characterized by what we react the 7-amino cephalosporanic acid of formula:
with an acid of formula (IIc):

(IIc) syn isomer or a functional derivative of this acid, formula (IIc), in which Rd represents a grouping can be eliminated by acid hydrolysis or by hydrogenolysis or a chloracetyl group and R'd represents a group easily removable by acid hydrolysis or by hydrogenolysis, a chloracetyl group or a saturated or unsaturated alkyl radical having from 1 to 4 carbon atoms, it being understood that when R'd represents feels a chloracetyl group, it is the same for Rd, to obtain a product of formula (Ic):

(Ic) in which Rd and R'd have the meaning indicated above, product of formula (Ic) which is hydrolyzed in an acid medium or hydrogenolysis, or treats with thiourea according to the values of Rd and R'd to obtain a product of formula (Ib):

(Ib) in which R represents a hydrogen atom or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon and corresponding to a product of formula (I) in which A represents a hydrogen atom, product of formula (Ib) which is salified if desired. 2. Process for the preparation of the products of formula (I) as defined in claim 1, characterized in what we react the 7-amino cephalosporanic acid of formula:
with an acid of formula (II):
(II) syn isomer or a functional derivative of this acid, formula (II) in which R1 represents a group easily eli-shabby by acid hydrolysis or by hydrogenolysis and R'1 represents feels a group easily removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated alkyl radical having from 1 to 4 carbon atoms, to obtain a product of formula (Ia):

(Ia) in which R1 and R'1 have the meaning indicated above above product of formula (Ia) which is hydrolyzed in medium acid or hydrogenolysis to obtain a product of formula (Ib) as defined in claim 1, product of formula (Ib) which is salified, if desired. 3. Variant of the method according to claim 1, for the preparation of the products (Ib):
(Ib) syn isomer and their pharmaceutically acceptable salts, formula (Ib) in which R represents a hydrogen atom or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon and corresponding to a product of formula I in la-which A represents a hydrogen atom characterized in that that either we treat with an acid a salt of a product of formula (Ic) in which Rd represents a grouping easily eliminable by acid hydrolysis and R'd represents a group easily removable by acid hydrolysis or an alkyl radical saturated or unsaturated having from 1 to 4 carbon atoms to obtain a product of formula Ib or else it is treated with a hy-drogenolysis a salt of a product of formula (Ic) in which Rd represents a group which can be easily eliminated by hydrogenolysis and R'd represents a group which can be easily eliminated by hydro-genolysis or a saturated or unsaturated alkyl radical having 1 to 4 carbon atoms to obtain a salt of a product of formula Ib or else we treat with thiourea a salt of product of formula (Ic) in which Rd represents a group chloracetyl and R'd represents a chloracetyl group or a saturated or unsaturated alkyl radical having from 1 to 4 carbon atoms bone to obtain a salt of a product of formula (Ib). 4. Variant of the method according to claim 2 for product preparation (Ib):
(Ib) and their pharmaceutically acceptable salts, formula (Ib) in which R represents a hydrogen atom or a radical saturated or unsaturated alkyl having 1 to 4 carbon atoms and corresponding to a product of formula (I), in which A represents a hydrogen atom, characterized in that, or, an acid is treated with a salt of a product of formula (Ia), in which R1 represents a group easily eliminable by acid hydrolysis and R'1 represents a group easily removable by acid hydrolysis or an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, for obtain a product of formula (Ib), or else, we treat by a hydrogenolysis agent a salt of a product of formula (Ia), in which R1 represents an easily removable group by hydrogenolysis and R'1 represents a group easily eliminable by hydrogenolysis or a saturated or incipient alkyl radical saturated, having 1 to 4 carbon atoms, to obtain a salt of a product of formula (Ib). 5. Method according to claim 1, characterized in that the products of formula (IIc) are prepared in processing a product of formula (IV) (IV) in which R 'represents a hydrogen atom, a group easily removable by acice hydrolysis or by hydrogenolysis or an alkyl radical, saturated or unsaturated, having from 1 to 4 atoms of carbon, and alk represents an alkyl radical having from 1 to 4 carbon atoms, either by a functional derivative of a group easily removable by acid hydrolysis or by hydrogenolysis, either, when R 'represents a hydrogen atom or a radical saturated or unsaturated alkyl having 1 to 4 carbon atoms per a functional derivative of the chloracetyl group to obtain a product of formula (Vc):
(Vc) in which Rd represents an easily eliminated grouping by acid hydrolysis or by hydrogenolysis or a chlorine group acetyl and R'd represents a group which can be easily eliminated by acid hydrolysis or by hydrogenolysis; a chloracetyl group or a saturated or unsaturated alkyl radical having from 1 to 4 atoms carbon, it being understood that when R'd represents a group-chloracetyl, it is the same for Rd, product of formula (Vc) which is treated with a base and then with an acid to obtain a product of formula (IIc):
(IIc) in which Rd and R'd have the meanings indicated above. 6. Method according to claim 2, characterized in what the products of formula (II) are prepared by processing a product of formula (IV):
(IV) in which R 'represents a hydrogen atom, a group easily removable by acid hydrolysis or hydrogenolysis or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon and alk represents an alkyl radical having from 1 to 4 carbon atoms, by a functional derivative of a group easily removable by acid hydrolysis or hydrogenolysis to obtain a product of formula (V):
(V) in which R1 represents an easily removable group by acid hydrolysis or by hydrogenolysis and R'1 represents a group easily removable by acid hydrolysis or by hydrogenolysis or a saturated or unsaturated alkyl radical, having from 1 to 4 carbon atoms, product of formula (V) which treated with a base, then with an acid to obtain a product of formula (II):

(II) in which R1 and R'1 have the meaning indicated above. 7. Method according to claim 6, characterized in that that the products of formula (IV) are prepared by acting thiourea on a product of formula (III):
(III) in which R 'represents a hydrogen atom, a group easily removable by acid hydrolysis or hydrogenolysis or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon and alk represents an alkyl radical having from 1 to 4 carbon atoms, to obtain after treatment with a base a product of formula (IV):
(IV) in which R 'and alc have the abovementioned meaning. 8. Variant of the method according to claim 6, for the preparation of the products of formula (Vb):
(Vb) in which R1 represents an easily removable group by acid hydrolysis or by hydrogenolysis, R "b represents a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon and alk represents an alkyl radical having from 1 to 4 carbon atoms, and corresponding to a product of formula (V) as defined in claim 6, wherein R1 represents feels a group easily removable by acid hydrolysis or by hydrogenolysis and R'1 represents an alkyl radical, saturated or unsaturated, having from 1 to 4 carbon atoms, characterized in that a product of formula (IV ") is treated:
(IV ") by an equivalent of a functional derivative of a group easily removable by acid hydrolysis or by hydro-genolysis, to obtain a product of formula X:
(X) which is treated with an alkylating agent, to obtain the expected product of formula (Vb). 9. Method according to claim 5, characterized in that the product of formula (IIc) are prepared from of products of formula (IVa):
(IVa) in which alk represents an alkyl radical having from 1 to 4 carbon atoms and R'a represents an alkyl radical saturated having 1 to 4 carbon atoms, which correspond to the products of formula (IV) as defined to claim 5, in which R 'represents a radical saturated alkyl having from 1 to 4 carbon atoms, said carbon atoms products of formula (IVa) being prepared by treating a product of formula (VI):
(VI) in which alc has the previous meaning, by an agent alkylation, to obtain a product of formula (VII):
(VII) product which is treated with a brominating agent, to obtain a product of formula (VIII):
(VIII) product on which the thiourea is made to act, then a base, to obtain a product of formula (IVa). 10. Method according to claim 6, characterized in that the products of formula (II) are prepared for from products of formula (IVa):
(IVa) in which alk represents an alkyl radical having from 1 to 4 carbon atoms and R'a represents an alkyl radical saturated having 1 to 4 carbon atoms, which correspond to lay in the products of formula (IV) as defined in claim 6, in which R 'represents a radical saturated alkyl having 1 to 4 carbon atoms, said carbon atoms products of formula (IVa) being prepared by treatment of a product of formula (VI):

(VI) in which alc has the previous meaning, by an agent alkylation, to obtain a product of formula (VII):
(VII) product which is treated with a brominating agent, to obtain a product of formula (VIII):
(VIII) product on which the thiourea is made to act, then a base for obtain a product of formula (IVa). 11. Process for obtaining the products of formula (IV) as defined in claim 7 in syn form, charac-terrified in that we react the thiourea then a base on a product of formula:
(III ') in which X represents a chlorine or bromine atom and R'b represents a hydrogen atom, a group easily eliminable by acid hydrolysis or by hydrogenolysis or a radical saturated or unsaturated alkyl having from 1 to 4 carbon atoms, when X represents a chlorine atom or R'b represents a hydrogen atom or a saturated alkyl radical having from 1 to 4 carbon atoms, when X represents a bromine atom and in what for the reaction of thiourea, either we operate in a aqueous solvent, either operating at room temperature, presence of a substantially stoichiometric amount of thiourea and conducting the reaction in a time limited to a few hours, or we operate by meeting all the conditions-set out above. 12. The method of claim 11 for obtaining products of formula (IV) in the syn form which consists of react thiourea on a product of formula (III), such as defined in claim 7 and is characterized in that, either one operates in an aqueous solvent, or one operates at a temperature ambient rature, in the presence of a quantity substantially thiourea stoichiometric and driving the reaction in a time limited to a few hours, or we operate by bringing together all of the above conditions. 13. The method of claim 11 for obtaining products of formula (IVa) as defined in the claim tion 9 which consists in making the thiourea act on a product of formula (VIII) as defined in this same claim 9 and is characterized in that, either one operates in an aqueous solvent, either one operates at room temperature, in the presence of a quantity substantially stoichiometric of thiourea and while driving the reaction within a time limit of a few hours, or we operate by meeting all the conditions set out above. 14. The method of claim 1, of preparation tion of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, iso-syn mother, characterized in that 7-amino acid is reacted cephalosporanic with a product of formula IIc in which R'd represents a methyl radical. 15. The method of claim 2, of preparation 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) acid 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, isomer syn, characterized in that 7-amino acid is reacted cephalosporanic with a product of formula II in which R'1 represents a methyl radical. 16. The method of claim 3, of preparation tion of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, isomer syn, characterized in that an salt is treated with an acid product of formula (Ic) in which R'd represents a radical cal methyl. 17. Process for the preparation of 3-acetoxy acid methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido]
ceph-3-th 4-carboxylic, syn-isomer, characterized in that is reacted with 3-acetoxymethyl 7- [2- (2-trity-lamino 4-thiazolyl) 2-methoxyimino acetamido] ceph-3-th 4-carboxylic with formic acid. 18. The method of claim 4, of preparation tion of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, isomer syn, characterized in that an acid is treated with a salt of a product of formula (Ia) in which R'1 represents a methyl radical. 19. The method of claim 1, of preparation tion of the sodium salt of 3-acetoxy acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carbo-xylic, syn-isomer, characterized in that it reacts 7-amino cephalosporanic acid with a product of formula IIc in which R'd represents a methyl radical to obtain 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy acid imino acetamido] ceph-3-th 4-carboxylic, syn-isomer, that it is hydrolyzed in an acid medium and then salified. 20. The method of claim 2, of preparation tion of the sodium salt of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxy-lique, syn-isomer, characterized in that one reacts 7-amino cephalosporanic acid with a product of formula II in which R'1 represents a methyl radical to obtain the acid 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn-isomer, which is hydrolyzes in an acid medium and then salifies. 21. Method according to claim 17, characterized in that reacting 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2- (methoxyimino) acetamido] ceph-3-th 4-carbo-xylic, syn-isomer, with sodium hydrogen carbonate to obtain the corresponding sodium salt. 22. The method of claim 1, of prepa-ration of the crystallized sodium salt of 3-acetoxy acid methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido]
ceph-3-th 4-carboxylic, syn-isomer, characterized in that we prepare a solvate between 3-acetoxymethyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn isomer, and formic acid, then then salifies the solvate obtained. 23. The method of claim 3, of preparation crystallized sodium salt of 3-acetoxy methyl acid 7-[2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn isomer, characterized in that one treats an acid with a salt of a product of formula (Ic) in which Rd represents a methyl radical to obtain a pro-duit of formula Ib which is then reacted with the acetate te of sodium in a suitable organic solvent. 24. The method of claim 1 or 3, of pre-paration of the crystallized sodium salt of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn isomer, in hydrated or sol-vatée, characterized in that the diethyl salt is reacted 3-acetoxy methyl acid 7- [2- (2-tritylamino 4-thiazo-) lyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic with formic acid and then treat with acetate sodium in a suitable organic solvent. 25. The method of claim 1, character-se in that we prepare products of general formula I, as defined in claim 1, wherein R represents a hydrogen atom, R 'represents an atom hydrogen or an alkyl radical, saturated or unsaturated, having from 1 to 4 carbon atoms and A represents a hydro atom gene, a sodium atom or an equivalent of diethylamine. 26. Method according to claim 2, characterized in that products of general formula I are prepared, as defined in claim 2, wherein R represents smells of a hydrogen atom, R 'represents a hydrogen atom or an alkyl radical, saturated or unsaturated, having from 1 to 4 carbon atoms and A represents a hydrogen atom, an ato-me sodium or an equivalent of diethylamine. 27. The method of claim 2, of preparation 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-ethoxy acid imino acetamido] ceph-3-th 4-carboxylic, syn-isomer, and its salts with alkali metals, alkaline earth metals, magnesium sium or pharmaceutically acceptable amino organic bases bles, characterized in that the 7-amino acid is reacted cephalosporanic with a product of formula XI in which R'1 represents an ethyl radical which is then hydrolyzed in mid-acid place, then salify if desired. 28. The method of claim 2, of preparation tion of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2 - ((2-propenyl) oxymino) acetamido] ceph-3-th 4-carboxylic, syn isomer, and its salts with alkali metals, alkaline-earthy, magnesium or organic pharma-ceutically acceptable, characterized in that one reacts 7-amino cephalosporanic acid with a product of formula II in which R'1 represents a propenyl radical which is then hydrolyzed in an acid medium, then salified if desired. 29. Process according to claim 2, for preparing tion of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2 - ((1-methyl ethoxy) imino) acetamido] ceph-3-th 4-carboxy-lique, syn isomer, and its salts with alkali metals, alkaline earth, magnesium or organic bases pharmaceutically acceptable amines, characterized in that we react 7-amino cephalosporanic acid with a product of formula II in which R'1 represents a 1-methyl ethyl radical which is then hydrolyzed in the medium acid, then salify if desired. 30. A product of formula (I):
(I) in which R represents a hydrogen atom, R ' represents a hydrogen atom or a saturated alkyl radical or unsaturated having from 1 to 4 carbon atoms, A represents either a hydrogen atom or a metal equivalent alkaline, alkaline earth, magnesium or base organic amino, the wavy line means that the grouping OR 'is in the syn position. 31. A product of formula (IB):
(Ib) syn isomer and their pharmaceutically acceptable salts, formula (IB) in which R represents a hydrogen atom or a saturated or unsaturated alkyl radical having from 1 to 4 atoms of carbon, and its pharmaceutically acceptable salts. 32. 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn-isomer. 33. The sodium salt of 3-acetoxy methyl acid 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn isomer. 34. The crystallized sodium salt of acid 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn-isomer. 35. A product of formula (I), as defined in claim 30, wherein R represents an atom of hydrogen, R 'represents a hydrogen atom or a alkyl radical, saturated or unsaturated, having from 1 to 4 atoms carbon and A represents a hydrogen atom, an atom of sodium or an equivalent of diethylamine. 36. 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2-methoxy imino acetamido] ceph-3-th 4-carboxylic, syn-isomer, and its salts with metals alkaline, alkaline earth, magnesium or bases pharmaceutically acceptable organic amino. 37. 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2 - ((2-propenyl) oxymino) acetamido] ceph-3-th 4-carboxylic, syn-isomer, and its salts with metals alkaline, alkaline earth, magnesium or bases pharmaceutically acceptable organic amino. 38. 3-acetoxy methyl 7- [2- (2-amino 4-thiazolyl) 2 - ((1-methyl ethoxy) imino) acetamino] ceph-3-th 4-carboxylic, syn-isomer and its salts with metals alkaline, alkaline earth, magnesium or bases pharmaceutically acceptable organic amino. 39. Method of reaction of thiourea on .gamma.-halo-.alpha. isopropyloxyimino ethyl acetylacetate, isomer syn, halo meaning chlorine or bromine, followed, if applicable hydrolysis of the product to the corresponding acid dant. 40. A compound of formula:

syn isomer in which R represents hydrogen or an alkyl inferior. 41. Process for reacting thiourea on .gamma.-halo-.alpha.-methoxyimino acetyl ethyl acetate, syn isomer, halo meaning chlorine or bromine, followed, if applicable hydrolysis of the product to the corresponding acid dant. 42. A compound of formula:

syn isomer in which R represents hydrogen or an alkyl inferior. 43. Method of reaction of thiourea on the y-halo-.alpha.-ethoxyimino acetyl ethyl acetate (syn) halo meaning chlorine or bromine, followed, if applicable, hydrolysis of the product to the corresponding acid. 44. A compound of formula:

syn R represents H or lower alkyl. 45. Process for reacting thiourea on .gamma.-halo-.alpha. allyloxyimino ethyl acetylacetate (syn) halo meaning chlorine or bromine, followed, if applicable hydrolysis, to obtain the corresponding carboxylic acid laying. 46. A compound of formula:
syn R signifying hydrogen or a lower alkyl. 47. Process for reacting thiourea on .gamma.-halo-.alpha. ethyl propyloxyimino acetylacetate (syn) halo meaning chlorine or bromine followed, if applicable, hydrolysis to obtain the corresponding carboxylic acid dant. 48. A compound of formula:
syn R representing hydrogen or a lower alkyl. 49. Process for the preparation of compounds of formula (CIII):
(CIII) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base, for the action of an acid of formula:

syn isomer whose NH2 group can be conventionally protected-nelle, or its functional derivatives, on the acid:

or its esters or salts. 50. A compound of formula (CIII):

(CIII) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base. 51. Process for the preparation of compounds of formula (CIV):
(CIV) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base, for the action of an acid of formula:

syn isomer whose NH2 group can be conventionally protected-nelle, or its functional derivatives, on the acid:

or its esters or salts. 52. A compound of formula (CIV):
(CIV) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base. 53. Process for the preparation of compounds of formula (CV):
(CV) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal, or an amino organic base, by the action of an acid of formula syn isomer syn isomer whose NH2 group can be conventionally protected-nelle, or its functional derivatives, on the acid:
or its esters or salts. 54. A compound of formula (CVI):
(CVI) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base. 55. Process for the preparation of compounds of formula:
syn whose NH2 group can be conventionally protected-nelle, or its functional derivatives, on the acid:

or its esters or salts. 56. Compound of formula (CV):

(CV) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal, or an amino organic base. 57. Process for the preparation of compounds of formula (CVI):
(CVI) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base, for the action of an acid of formula:

in which R represents a lower alkyl by making react monochloroacetic acid or one of its derivatives on the corresponding 2-amino-thiazole compound. 58. A compound of formula:

syn in which R1 represents a hydroxy group, an alkyloxy lower or halogen. 59. Process for the preparation of compounds of formula (CXVI):

(CXVI) syn in which A represents hydrogen or a cation in causing the acid to react syn or its functional derivatives, on lactam or its esters or salts. 60. A compound of formula (CXVI):

(CXVI) syn in which A represents hydrogen or a cation. 61. Process for the preparation of the compounds of formula:

syn isomer in which R represents hydrogen or an alkyl lower, characterized in that the thiourea is made to act on the .gamma.-halo-.alpha. ethyl isopropyloxyimino acetylacetate, halo singling out chlorine or bromine, followed, if necessary, hydrolysis of the product to the corresponding acid. 62. Process for the preparation of the compounds of formula:
syn isomer in which R represents hydrogen or an alkyl lower characterized in that the thiourea is made to act on .gamma.-halo-.alpha.-methoxyimino acetyl ethyl acetate, halo meaning chlorine or bromine, followed, where appropriate, hydrolysis of the product to the corresponding acid. 63. Process for the preparation of the compounds of formula:

syn R representing H or a lower alkyl characterized in that that we make the thiourea act on the .gamma.-halo-.alpha.-ethoxyimino acetyl ethyl acetate, halo meaning chlorine or bromine, followed, where appropriate, by hydrolysis of the product to the corresponding acid. 64. Process for the preparation of the compounds of formula:

syn R signifying hydrogen or a lower alkyl characterized in that the thiourea is made to act on the .gamma.-halo-.alpha.-allyloxyimino ethyl acetylacetate, halo meaning chlorine or bromine, followed, if necessary, by hydrolysis, to obtain the corresponding carboxylic acid. 65. Process for the preparation of the compounds of formula:

syn R representing hydrogen or a lower alkyl charac-terrified in that the thiourea is made to act on the y-halo-.alpha.-ethyl propoxyimino acetylacetate, halo meaning chlorine or bromine, followed, where appropriate, by hydrolysis to obtain the corresponding carboxylic acid. 66. Process for the preparation of compounds of formula (CIII):

(CIII) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base, for the action of an acid of formula:
syn isomer the NH2 group of which is conventionally protected, or its functional derivatives, on acid:

followed by deprotection of the products obtained and a possible salification. 67. Process for the preparation of compounds of formula (CIV):

(CIV) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base, for the action of an acid of formula:

syn isomer the NH2 group of which is conventionally protected, or its functional derivatives, on acid:

followed by deprotection of the products obtained and a possible salification. 68. Process for the preparation of compounds of formula (CV):

(CV) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal, or an amino organic base, by the action of an acid of formula:

syn isomer the NH2 group of which is conventionally protected, or its functional derivatives, on acid followed by deprotection of the products obtained and a possible salification. 69. Process for the preparation of compounds of formula (CVI):
(CVI) syn isomer in which A represents hydrogen, an alkali metal, a alkaline earth metal or an amino organic base, for the action of an acid of formula:

syn isomer the NH2 group of which is conventionally protected, or its functional derivatives, on acid followed by deprotection of the products obtained and a possible salification.

CLAIMS SUPPORTED BY THE
ADDITIONAL DISCLOSURE 70. Variant of the method according to claim 1, for the preparation of the products of formula (Ib):
(Ib) in which R represents a hydrogen atom or a alkyl radical, saturated or unsaturated, having from 1 to 4 atoms of carbon, and corresponding to a product of formula (I), in which A represents a hydrogen atom, characterized in what we react a 7-amino acid derivative cephalosporanic formula:

in which A1 represents a group easily eliminable by acid hydrolysis or by hydrogenolysis, with a acid of formula (II):

(II) syn isomer or a functional derivative of this acid, formula (II), in which R1 represents an easily removable group by acid hydrolysis or by hydrogenolysis or a radical chloroacetyl, and R'1 represents a group easily eliminable by acid hydrolysis or by hydrogenolysis, a chloroacetyl radical or an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, to obtain a product of formula (XI):

(XI) in which R1, R'1 and A1 have the meanings indicated above above, which is treated by one or more agents acid hydroglyse, by one or more agents hydrogenolysis, by thiourea or by one or more aforementioned agents for obtaining a product of formula (Ib). 71. The method of claim 70, character-that the products of formula (II) are prepared in treating with a base then with an acid, a product of formula (IV):

(IV) syn isomer in which R 'represents a hydrogen atom, a group easily removable by acid hydrolysis or by hydrogenolysis or an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms, and alk represents a alkyl radical, having from 1 to 4 carbon atoms, for obtain a product of formula (XII):

(XII) syn isomer in which R 'has the abovementioned meaning, which one easily processed by a functional derivative of a group eliminable by acid hydrolysis or by hydrogenolysis or chloracetyl group, to obtain a product of formula (II):

(II) syn isomer in which R1 easily represents a group eliminable by acid hydrolysis or by hydrogenolysis or a chloracetyl group, and R'1 represents a group easily removable by acid hydrolysis or by hydrogenolysis, a chloracetyl group or a radical alkyl, saturated or unsaturated, having from 1 to 4 atoms of carbon. 72. Process for the preparation of formula (Vc):

(Vc) syn isomer in which R1 easily represents a group eliminable by acid hydrolysis or by hydrogenolysis, or a chloracetyl group, R "c represents a group easily removable by acid hydrolysis or by hydrogenolysis, or a chloracetyl group, other than R1 'and alk represents an alkyl radical, having from 1 to 4 carbon atoms, characterized in that a product of formula (X):

(X) syn isomer in which R1 and alc have the abovementioned meaning, by a functional derivative of the group easily removable by acid hydrolysis or by hydrogenolysis or of the group chloracetyl R''c to obtain the product Vc. 73. Process for the preparation of new products of formula (XI):

(XI) syn isomers in which R1 represents a hydrogen atom, R'1 represents a hydrogen atom or an alkyl radical, saturated or unsaturated, having 1 to 4 carbon atoms and A representing either has a hydrogen atom or an equivalent of metal alkaline, alkaline earth, magnesium or an organic base an amic picnic, said process being characterized in that one reacts a derivative of 7-amino cephalosporanic acid of formula:

in which A1 has the above meaning, with an acid of formula (II):

(II) syn isomer in which R1 and R'1 have the abovementioned meaning for obtain a product of formula (XI) desired. 74. The method of claim 72, character-laughed in that R''c represents a tetrahydropyrannyl radical. 75. Process for the preparation of compounds of formula (CII):

(CII) syn isomer in which A represents either hydrogen or a metal alkaline or alkaline earth is an amino organic base, by the action of an acid of formula:

syn isomer whose NH2 and NOH functions are protected in a way conventional, or its functional derivatives, on acid followed by deprotection of the products obtained and a possible salification. 76. Process for the preparation of compounds of formula (CII):

(CII) syn isomer in which A represents either hydrogen or a metal alkaline or alkaline earth is an amino organic base, by the action of an acid of formula:

syn isomer whose NH2 and NOH functions can be protected in a way conventional, or its functional derivatives, on acid or its esters or salts. 77. A compound of formula (CII):

(CII) syn isomer in which A represents either hydrogen or a metal alkaline or alkaline earth is an amino organic base. 78. Process according to claim 1, of preparation tion of 7- [2- (2-amino 4-thiazolyl) 2-hydroxyimino acid acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer syn and its salts with alkali and alkaline earth metals, magnesium or organic amino bases, characterized in that we treat 7-amino cephalosporanic acid with a derivative functional of the acid of formula IIc in which R'd represents te a trityl radical to obtain a product of formula Ic which is hydrolyzed in an acid medium and salified if desired. 79. Process according to claim 2, for preparing tion of 7- [2- (2-amino 4-thiazolyl) 2-hydroxyimino acid acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer syn and its salts with alkali and alkaline earth metals, magnesium or organic amino bases, characterized in what we treat 7-amino cephalosporanic acid with a functional derivative of the acid of formula II in which R'1 represents a 2-tetrahydropyrannyl radical to obtain a product of formula Ia which is hydrolyzed in an acid medium and salify if desired. 80. Process according to claim 3, for preparing tion of 7- [2- (2-amino 4-thiazolyl) 2-hydroxyimino acid acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer syn and its salts with alkali and alkaline earth metals, magnesium or organic amino bases, characterized in what is treated with an acid a salt of a product of formula (Ic) in which R'd represents a trityl radical for obtaining a product of formula Ib or else it is treated by an agent hydrogenolysis a salt of a product of formula (Ic) in the-which R'd represents a trityl radical to obtain a salt of a product of formula Ib. 81. Process according to claim 4, for preparing tion of the acid [7- 2- (2-amino 4-thiazolyl) 2-hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer syn and its salts with alkali and alkaline earth metals, magnesium or organic amino bases, characterized in what is treated with an acid a salt of a product of formula (Ia) in which R'1 represents a 2-tetrahydropyrannyl radical to obtain a product of formula (Ib) or else we treat by a hydrogenolysis agent a salt of a product of formula (Ia) in which R'1 represents a 2-tetrahydropyrannyl radical to obtain a salt of a product of formula (Ib). 82. Process according to claim 68, for preparing tion of acid 7- [2- (2-amino 4-thiazolyl) 2-hydroxyimino acé
tamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, isomer characterized in that an acid derivative is reacted 7-amino cephalosporanic with a functional derivative of an acid of formula II in which R'1 represents a trityl radical to obtain a product of formula XI which is treated with a acid hydrolysis agent to obtain a product of formula Ib. 83. Process according to claim 1, for preparing tion of the sodium salt of 7- [2- (2-amino 4-thiazolyl) acid 2-hydroxy imino acetamido] 3-acetoxy methyl ceph-3-th 4-car-boxylic, syn-isomer, characterized in that the acid is treated of 7-amino cephalosporanic by a functional derivative of the acid of formula IIc in which R'd represents a radical trityl to obtain a product of formula Ic which is hydrolyzed in an acid medium and then salified with sodium acetate in a suitable organic solvent. 84. Process according to claim 2, of preparation tion of the sodium salt of 7- [2- (2-amino 4-thiazolyl) acid 2-hydroxy imino acetamido] 3-acetoxy methyl ceph-3-th 4-carbo-xylic, syn-isomer, characterized in that the acid is treated 7-amino cephalosporanic by a functional derivative of acid of formula II in which R'1 represents a 2-tetrahydro- radical pyrannyl to obtain a product of formula Ia which is hyarolysed in an acid medium and then salifies. 85. Process according to claim 2, for the preparation 7- [2- (2-tritylamino 4-thiazolyl) 2-trityl hydroxy acid imino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, iso-mother syn, characterized in that the 7-amino acid ce-phalosporaniquw by a functional acid derivative of formula II in which R'1 represents a trityl radical to obtain a product of formula Ia which is then hydrolyzed in the medium acid to obtain a product of formula (Ib). 86. 7- [2 (2-amino 4-thiazolyl) 2- acid hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, syn isomer and its pharmaceutically salts acceptable with alkali, alkaline earth metals, magnesium or amino organic bases. 87. Acid 7- [2 (2-tritylamino 4-thiazolyl) 2-trityl hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, syn-isomer. 88. The sodium salt of acid 7- [2 (2-amino 4-thiazolyl) 2-hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic, syn isomer. 89. The crystallized sodium salt of acid 7-[2 (2-amino 4-thiazolyl) 2-hydroxyimino acetamido] 3-acetoxy methyl ceph-3-th 4-carboxylic acid, syn-isomer. 90. A product of formula (XI):

(XI) syn isomer in which A1 represents a group easily eliminable by acid hydrolysis or by hydrogenolysis;
in which R1 easily represents a grouping eliminable by acid hydrolysis or by hydrogenolysis or a chloroacetyl radical, and R'1 represents a group easily removable by acid hydrolysis or by hydrogenolysis, a chloroacetyl radical or a radical alkyl, saturated or unsaturated, having from 1 to 4 atoms of carbon. 91. Process for the preparation of the compounds of formula:

syn R representing H or a lower alkyl characterized in that that we make the thiourea act on the .gamma.-halo-.alpha.-hydroxyimino acetyl ethyl acetate, halo meaning chlorine or bromine followed, if necessary, by hydrolysis, to obtain the corresponding carboxylic acid. 92. Process for reacting thiourea on .gamma.-halo-.alpha.-hydroxyimino acetyl ethyl acetate (syn), halo meaning chlorine or bromine followed, if applicable, hydrolysis, to obtain the carboxylic acid corresponding. 93. A compound of formula:

syn R representing H or a lower alkyl.