CA1132575A - 2-(2-amino-4-thiazolyl)2-hydroxyimino acetic acid derivatives and preparation process of same - Google Patents

Abstract

The subject of the invention is acids of general formula: (III) in which R2 represents a group which can be easily eliminated by acid hydrolysis or by hydrogenolysis or a chloroacetyl radical, R3 represents either a CO2R "1 group in which R" 1 represents a radical alkyl having from 1 to 3 carbon atoms, or an ester group easily removable by acid hydrolysis or by hydrogenolysis, either a nitrile radical or a carbomoyl radical - CONH2, R 'and R ", identical or different, represent an atom of hydrogen or an alkyl radical having from 1 to 3 carbon atoms, the group being in the syn position. The invention also relates to a process for the preparation of these acids which are in particular usable as intermediates in the preparation of derivative oximes 3-acetomethyl 7-amino thiazolyl acetamido cephalosporanic acid for antibiotic use on gram (+) and gram (-) bacteria.

Description

7 ~
This request is a di ~ ision of the request of Bre ~ and No. Z99.661 filed March 23, 1978.
~ has now inven, tion has for object of new ~ waters acids of formula genera ~ e:
~ R2 SN II

N \ IR ' R "

in which R2 represents an easily eliminated grouping free by acid hydrolysis or by hydrogenolysis or a radical chloroacetyle, R3 represents either a CO2R "1 group in which R "1 represents an alkyl radical having from 1 to 3 carbon atoms, or an easily removed ester group free by acid hydrolysis or by hydrogenolysis, either a nitrile radical, that is to say a carbamoyl radical, e -CONH2, R 'and R ", identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atom, the group R 'being in the -o - C - R3 R "
position ~ X ~
The invention also relates to a method of preparation of these new acids of general formula (III).
Among the preferred values of R3, we can cite carbamoyl radicals -CONH2 and nitrile.
The acids of general formula III are usable.
as intermediaries in the preparation of new oximes derived from 3-acetoxymethyl 7-amino thiazolyl aceta-mido cephalosporanique, of general formula:

- 1 ~ '~' - ~ \
~ 3 ~
, ~
s ~ ~ ~ H ~ / S (I) ~, 1 o, ~ 1 ~
I CH2 ~ 0-11 CH3 CO2 ~

in which Rl represents a radical -CO2R'l in which R'l represents an alkyl radical having from 1 to 3 atoms of carbon, a hydrogen atom or a metal equivalent alkaline, alkaline earth, magnesium, ammonium, or a amino organic base, or Rl represents a nitrile radical, either R1 represents a carbamoyl radical CONH2, A represents a hydrogen atom, an equivalent of alkali metal, alkaline-earthy, ammonium magnesium, or an organic base aminee, R 'and R ", identical or different, represent a hydrogen atom or an alkyl radical having 1 to 3 atoms of carbon, the group R 'being in the position OC-Rl R "
~ y ~, it being understood that in the case where ~ Rl represents a radi-cal CO2R'l in which R'l represents a hydrogen atom, A represents a hydrogen atom, and when Rl represents a radical CO2R'l in which R'l represents an equivalent of alkali, alkaline earth metal, magnesium, ammonium, or of an organic, amino base, A represents the same equi.-are worth of alkali metal ~ alkaline earth, magnesium, ammonium, or an amino organic base ~
Among the values of ~ '1 in the general formula (I) the following values may be mentioned: methyl, ethyl, propyl, isopropyl.
Among the preferred values of R'l we can cite -~ 3 ~ 57 ~
egaleme ~ t é ~ ui ~ around sodium, potassium, lithium, calcium or magnesiumi among the organic bases, we can cite trimethylamine, diethylamine, triethylamine, methylamine, propylamine, N, N-dimethyl ethanol amine, tris (hydroxy methyl) amino methane, arginine or lysine.
A can represent any one, equivalents alkali, alkaline earth metals, magnesium, ammonium, or of an amino organic base mentioned above for R'l.
R 'and R'l can represent the methyl radicals, ethyl, propyl or isopropyl.
Among the products of general formula (I), one can cite in particular the products of general formula (I) such than ~ inie above in which Rl represents a radical CO2R'l in which R'l represents an alkyl radical having 1 to 3 carbon atoms, a hydrogen atom or equivalent of alkali, alkaline earth metal, magnesium, ammonium or of an amino organic base, e ~ R 'and R "represent each a hydrogen atom.
Among the products of general formula (I3 we can cite more particularly the products described below in the examples, and more particularly:
- acid 7- [2- (2-amino thiazol-4- ~ 1) 2-carbethoxy methyl oxyimino àcetamido ~ 3-acetoxymethyl ceph-3-eme 4-carboxylic, isomer ~ y ~;
- acid 7- ~ 2- (2-amino thiazol-4-yl) 2-hydroxy carbonyl methyl oxyimino acetamido ~ 3-acetoxymethyl ceph-3-th 4 ~ carboxylic, syn isomer;
- 3-acetoxymethyl acid 7-C2- (2-amino thiazol-4-yl) 2- ~ (cyano-methyl) oxyiminoJ acetamid_lceph-3-eme 4-carboxylic, isomer syn;
- 3-acetoxymethyl acid 7- ~ 2- (2 ~ amino thiazol-4-yl) 2- ~ (amino carbonyl ~ methyl oxyimin ~ acetamido ~ ceph-3-th 4-carboxylic, isomer ~ y ~;

- 3-acetoxymethyl acid 7- ~ 2- (2-amino thiazol-4-yl) 2 ~ car-boxy l-methyl ethyl) oxyimino ~ acetamido ~ ceph-3-th 4-carboxylic, syn isomer, as well as their salts with alkali metals, alkaline earth, magnesium, ammonia and organic bases ques aminees, and more secially:
- the disodium salt of acid 7- ~ 2- (2-amino thiazol-4-yl)

2-hydroxy carbonyl methyl oxyimino acetamidoJ3-acetoxymethyl ceph-3-th 4-carboxylic, syn isomer;
- the sodium salt of 3-acetoxymethyl acid 7- ~ 2- (2-amino thiazol 4-yl) 2- ~ (cyanomethyl) oxyimino ~ acetamido ~ ceph-3-eme 4-carboxylic, syn isomer, - the sodium salt of 3-acetoxymethyl acid 7- ~ 2- (2-amino thiazol 4-yl) 2 ¦ (amino carbonyl) methyl oxyimino ~ acetamido ~
ceph-3-th 4-carboxylic, syn isomer and, - the disodium salt of 3-acetoxymethyl 7 r2- (2-amino thiazol 4-yl) 2- ~ (lOcarboxy l-methyl ethyl) oxyiminoJacetamidoJ
ceph-3-th 4-carboxylic, syn-isomer.
It is understood that the products of formula (I) previously cited may exist:
- S _ in the form indicated by said formula (I);
- Or in the form of products of formula (Iz):
NH

S ~ H ~ ~

N ~ ~ (Iz) The compounds of general formula (I) are obtained by treating a product of formula (II):
~ 1 2N S

O ~ ~ CH2_0-ll-cH3 (II) .575 in which A 'represents a hydrogen atom or a group ment ester easily elim, in, able by hydrol ~ Se.acide ou ~ a, r hydrogenolysis / by an acid of formula (III) selo ~ ention as previously defined, to obtain a pxoduct of formula (I '):

NH -R

SN o `- '~ ~, (I') R ~ ~ f S ~

OC-R3 N ~ CH -O- ~ -CH 3 R "O2A ' in which R2, R3, R '' R "and A 'have the meaning indicated above, which is handled by one or more agents chosen from the group formed by acid hydrolysis agents, of hydrogenolysis and thiourea according to the values of R2, R "1 and A 'to obtain a product of formula (Ia):
~ 2 SNO

NH ~ S (I a) ~ --C - R5 ~ 1 R "O ~ CH -OC -CH 3 in which R4 represents a radical C02R "1 in which R "2 represents an alkyl radical having from 1 to 3 atoms of carbon or a hydrogen atom, either R4 represents a nitrile radical, ie R ~ represents a carbamoyl radical CONH2 and R 'and R "have the meaning indicated above, and corresponding to a product of formula (I), in which Rl has the meaning of R4 and A represents a hydrogen atom, product of formula (Ia) which is alified, if necessary, to obtain the products of formula (Ib):

~ `

~ 3 ~ 5 ~ O

1 ~ Rl NH \ S (Ib) ~ 0-C-R5 ~ ~
R "~ ~ CH2 ~ O-ll C ~ 3 C02A "

in which R5 represents either a CO2R "3 radical in which Rl'3 represents an alkyl radical having from 1 to 3 carbon atoms or a ~ equivalent of alkali metal, alkaline earth; magnesium, of ammonium, or of an amino organic base, ie a nitrile radical, or a carbamoyl radi.cal CONH2 A "represents an equivalent of alkali, alkaline earth metal, magnesium, ammonium, or a amino organic base, it being understood that if R5 represents a group pement CO2R "3 in which R" 3 represents an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium, or a base or ~ ani ~ eu amine, A "represents the same equivalent of alkali metal, alkaline earth, magnesium, ammonium, or an organic base amino, R 'and R "have the meaning indicated above and corresponding to a product of formula (I) in which] .e R ~ a la value of R5 and A that of A ".
As a group which can be easily eliminated by acid hydrolysis or by hydrogenolysis which R2 can represent, we may mention the tert-bu-toxy carbonyl, trityl, benzyl groups, benzhydryl, trichloroethyl, carbobenzyloxy, formyl, trichloro-ethoxy carbonyl or 2-tetrahydropyrannyl.
Among the easily removable ester radials by acid hydrolysis or by hydrog ~ nolysis that can represent R "l there may be mentioned the benzhydryl, tert-butyl, benzyl, para-radicals m ~ thoxybenzyle and trichloroethyl.

~ Z57 ~
A 'can represent any of the ester radicals easily removable by acid hydrolysis or hydrogenolysis mentioned above for R "l.
In a preferred mode of execution of the process, treats the product of formula ~ II) with a functional derivative of ormule (III) acid, such as anhydride or chloride acid, the anhydride can be formed in situ by ac-tion of isobutyl chloroformate or dicyclohexylcarbodiimide on acid. It is also possible to use other halides or still other anhydrides formed in situ by the action of others alkyl chloroformates, a dialkoylcarbodiimide or another dicycloalcoylcarbodiimide. We can also use other acid derivatives, such as acid azide, acid amide or a active acid ester forms, for example, with hydroxy succinimide, paranitrophenol or 2-4 di-nitrophenol. In the event that the reaction of the product of formula (II) is effected with a halide acid of general formula (III) or with an anhydride formed preferably with isobutyl chloroformate, presence of a basic agent.
As the basic agent, one can choose, for example, a alkali metal carbonate or a tertiary organic base, such as that ~ -methyl morpholine, pyridine or a trialcoylamine, such as triethylamine.
The transformation of the products of formula (I ') into products of formula (Ia) aims to replace the substituent R2 by a hydrogen atom, does not replace the substituent Rl'1 when that this represents an easily eliminable ester grouping by acid hydrolysis or by hydrogenolysis by the radical R "2 represents presenting a hydrogen atom, and replacing the substitute A 'when this ~ represents an easily elicable ester group shabby by acid hydrolysea or by hydrogenolysis by an atom hydrogen ~

~ 3 ~ 575 ....

To do this, we use one or more agents acid hydrolysis when R2 represents a group ~ acilely eliminable by acid hydrolysis, R3 does not represent a group CO2R "l in which R" l represents an ester group easily ~ can be removed by hydro ~ enolysis, ~ 'represents ~ a hydrogen atom or an easily ester group ~ removable by acid hydrolysis.

One or more hydrogenolysis agents are used when R2 represents a group easily eliminated by hydro-genolysis, R3 does not represent a CO2R "L group in which R"
lQ represents an ester group which can easily be eliminated by hydrolysis acid and A 'represents a hydrogen atom or an ester group easily removable by hydrogenolysis.
The product of formula (I ') is treated with one or more a number of acid hydrolysis agents and one or more agents hydrogenolysis, when at least one of the substituents-R2, R "l and A 'represents a group which can be easily eliminated by hydrolysis acid and at least one of these groups represents a group easily removable by hydrogenolysis.
The product of formula (I ') is treated with thiourea, and optionally by one or more acid hydrolysis agents or hydrogenolysis according to the values of R "l and A 'when R2 represents smells of a chloroacetyl radical.
As the acid hydrolysis agent to which we are subject the products of formula (I ′), mention may be made of the acid form mique, trifluoroacetic acid or acetic acid. These acids can be used anhydrous or in aqueous solution. We can also use the zinc-acetic acid system.
We use, pre ~ erence, an acid hydrolysis agent, such as anhydrous trifluoroacetic acid or formic acids or aqueous acetic, to remove tert-butoxy carbonyl groups or trityl which can represent the radical R2 or the groups benzhydryl, tert-butyl or paramethoxy benzyl which may represent ~:. ., 5t ~ S

feel A 'and R "l.

Preferably, the zinc-acetic acid system is used, to eliminate the trichloroethyl group which may represent R2, R "l and A'-Preferably, a hydrogenolysis agent, such as hydrogen in the presence of a catalyst, is used to remove the ~ benzhydryleetcarbobenzyloxy groups that can be presented R2et benzyl which can represent R "l and A '.
`The reaction of thiour ~ e on the product of formula (I ') in which R2 represents a chloroacetyl group, is preferably carried out in a neutral or acid medium. This kind of reaction is described by MASAKI (JACS, 90, 4508 (1968)).
The salification of the products of formula ~ Ia) can be carried out according to the usual methods. Salification can, by example, ~ be obtained by action on these acids of a mineral base, such as, for example, sodium hydroxide or potassium hydroxide or sodium bicarbonate or a salt of an alicarboxylic acid substituted or unsubstituted phatic, such as diethylacetic acid, ethyl hexano acid ~ eu or, more specifically, acetic acid ~

The preferred salts of the acids mentioned above are sodium salts.
Salification can also be obtained by action ammonia or an organic base such as triethylamine, diethylamine, trimethylamine, propylamine, N, N-dimethyl ~ thanol amine or tris (hydroxy m ~ thyl) amino m ~ thanc. I ~ lle pout also be obtained by the action of arginine or lysine ~

For 1 ~ preparation of salts, the solvates of the acids.
free pcu can also be used ~ s co ~ e products from ~
instead of free acids.

This salification is r ~ performed pre ~ erence in a solvent or a mixture ~ of solvents, such as water, ether ~ thy-lique, methanol, ~ thanol or acetone.

25 ~
The salts are obtained in amorphous or crist ~ llisée form according to the reaction conditions used.
The crystallized salts are preferably prepared in ~ ease reacting free acids with 1 ~ one of the salts of aids aliphatic carboxyls mentioned above, preferably, with sodium acetate.
In the preparation of a sodium salt, the reaction is carried out in a suitable organic solvent, such as for example, lc m ~ thanol, solvent which may contain small amounts of water.
The acids of formula (III) according to the invention can be prepared by making a ~ ir in the presence of a strong base su ~
a product of formula (IV) S ~; N `
--l - C02H (IV) NOT

. ' 0 ~
in which R2 represents a group which can easily be eliminated by acid hydrolysis or by hydrogenolysis or a chloroacetyl radical, and the OH group is in the syn position, a product of formula (V): R ' I-lal C - R3 (V) R "
in which Hal represents a halogen atom, R 'and R "identi-that ~ or different ~ represent a hydroy ~ ne atolllc or a radical alkyl having 1 ~ 3 carbon atom, and R3 represents either group C02R "1 in which R" l rcpr ~ scnte an alkyl radical ayatlt do 1 ~ 3 atom3 dc because ~ onc or a glollpcmcnt; Lacilcmcot; ~ limited nable by acid hydrolysis or by hydrog ~ nolysis, either. R3 represents a nitrile radical, 50it R3 represents a carbamoyl radical -CO ~ 2, to obtain a product of formula (III):

3 ~ 7S

~ I-R2 , ~
SN

R '~ III) \ 0-C-R3 expected.
In a preferred embodiment of the process below above, the strong base that we use is tert-butoxide of potassium sodium hydride or alcoholic potash. The halo-genure used is b ~ omure preferably, but we can also use chloride or iodide.
It should be noted that the products of formula (I ') syn isomer, as defined above, can also be obtained by a process characterized in that it acts in -presence of a base a product of formula (V):
R ' Hal - C - R3 (V) R "
in which Hal represents a halogen atom and R ', R ", and R3 have the above meaning, on a product of formula (VI) somère ~, S ~ N
\ IJ ~
NH \ ~ S (VI) OH ~ N ~ CH2OCCH3 in which R2 and Al have the previous signification for ob-hold a product of formula (I '), syn isomer.
In a preferred embodiment of the process below , ~, `G

above, the base in the presence of which the product is made to act of formula (V) on the product of formula (VI) .is chosen in the group formed by triethylamine, pyridine or silver oxide.
The solvent in which the reaction is carried out is preferably rence, chosen from methylene chloride ', benz ~ ne, aceto-nitrile, ethyl acetate, tee ~ rahydrofuran, dioxane, chloroform or dimethylformamide.
The products of formula (VI) can be prepared in ~ making ayir.l'isopropényl m ~ thyl ether of formula:

H2C = C
\ C ~ 13 on a product of formula (IV) isomer syn NllR2 SJ ~

~ CO2H (IV) I ~

NOT

. OH

formula in which R2 represents a group Eacilely eli-shabby by acid hydrolysis or by hydrogenolysis or a radical chloroacetyl to obtain a product of formula (VIII):

/ ~ (VIII) SN

/ C ~ 3 acid of formula VIII, or functional derivative of this acid, with which a product of formula (II) is treated:

~ ~ "~ ,.

112 ~ S ~

N ~ CH2OCCH3 (II) CO2 ~

formula in which A 'represents a hydrogen atom or a ester group easily removable by acid hydrolysis or by hydrogenolysis to obtain a product of formula (IX):

SN ¦¦
\ / (IX) S

~ CH3 I CH2OCCH3 OCH3 CO2 ~ ' in which R2 and A 'have the previous meaning, product of formula (IX) in which A 'represents a hydrogen atom which esterification, if necessary, to obtain the form products mule tIX) in which A 'represents an easy ester grouping ment eliminable by acid hydrolysis or by hydrogenolysis, product of formula (IX) which is treated with an acid under conditions moderate to obtain the product of formula (VI):

SN ll (VI) ~ -1 J ~
NH ~ S ~

OH O ~ N ~ CH2OCCI-13 C02 ~ ' The action of isopropenyl methyl ether on the product of formula (IV) is optionally carried out in the presence of a acid, for example in the presence of para-toluene sulfonic acid.

An acid salt can also be used as starting material . -13-`` t `~ 75 mineral of the product of formula (IV) such as the hydrochloride. In in this case the presence of an acid is not necessary and we obtain free amine by neutralization at the end of the reaction with a base such as pyridine.
Condensation of the product of formula (VIII) on the acid 7-amino cephalosporanic or one of its esters of formula (II) is carried out under the conditions described above for the action products of formula (III) on the same products of formula (II).
Possible esterification of formula products (IX) in which A 'represents a hydrogen atom takes place under the usual conditions. We can use for example a diazo derivative ~ such as diazodiphenylmethane.
The transformation of the products of formula (IX) into products of formula (VI) aims to divide the group ~ ent pro-lector of l-methyl oxime l-methoxy ethyl. This reaction is performed in an acidic environment under sufficiently mild conditions so that the protective groups R2 and A 'which can also ment being cleavable in an acid medium is not affected.
We operate to do this, for example, using aqueous hydrochloric acid about 1 or 2N, ~ room temperature for a time between about 30 minutes and a few hours.
The products of ~ ormule (III '), isomer ~ y ~:
N ~ IR2 SN (III ') \ == ~ C0 ll R ' N ~

in which R2, R 'and R "have the meaning indicated above 7 ~
and corresponding to the acids of formula (II ~) according to the invention as defined above in which R3 represents a radical carbamoyl C0NH2, can also be obtained by processing in presence of a base a product of formula (X), syn isomer:

~ HR2 (X) S / ~ l \ = ~ 1 ~ C02alk NOT

~ Oh formula in which alk represents an alkyl radical having 1

4 carbon atoms by a product of formula (V '):

R ' Hal-C-C02alkl - (Vl) R "
in which Hal, R 'and R "have the meaning indicated above and alkl represents an alkyl radical having from 1 to 4 atoms of carbon to obtain a product of formula (XI):
~ R2 SN (XI) CO2alk R ' O - C-C02alk R "
p.product which is treated with a base and then with an acid, to obtain hold a product of formula (XII):
N ~ R2 / C02alk .11 (XII) NOT

\ C-C02 ~ 1 product of formula (XII ~ of which a reactive derivative is first formed 3 ~ S

then treated with ammonia, to obtain the product of formula ~ XIII):

~ R2 ~ (XIII) SN
C02 at lk R ' NOT
`o ~ f _CONE ~ 2 R ~
product of formula (XIII) which is treated by a hase then by a acid, to obtain the expected product of formula (III ').
In a preferred mode of execution of the above process above, the reaction of the product of formula (VI) with the product of formula X is carried out in the presence of a base such as carbonate potassium. However, other bases such as than soda, potash or triethylamine.
The halide which is preferably used is the bromide, but chloride or iodide can also be used.
Transformation of the product of formula (XI) into a product of formula (XII) is carried out under mild conditions in order to do not saponify the CO2alk group. We can therefore operate by example in the presence of approximately one equivalent of a base such than soda, potash, or barium hydroxide and preferably temp ~ rature of an ice water bath for about an hour.

The acid that is used next is preferably aqueous hydrochloric acid. You can however use the acid dilute sulfuric or acetic acid.
The reactive derivative of the acid of formula (XII) which is preferably uses the mixed anhydride formed for example in situ by action of isobutyl chloroformate. We can however use other reactive derivatives such as esters activ ~ s form ~ s for example with hydroxy succinimide, para or ortho 132 ~ 7 nitro phenol or 2,4-dinitro phenol or symmetrical anhydride formed by the action of a carbodiimide such as dicyclohexylcarbodi-imide.
Saponification then reacidiflca ~ ion of the product of formula (XIII) are carried out under the usual conditions.
For example, soda is used as the base and it is re-acidified by hydrochloric acid.
On the other hand, the products of formula (III "), isomer syn:

~ IHR2 S ~ N (III ") ~ C02H
..
N ~ o - C -CN

R "
in which R2, R 'and R "have the meaning indicated above and corresponding to the acids of form (III) according to the invention as defined above in which the R3 represents a xad.ica.l nitrile, can be obtained by treating with a bases a product of formula (IV), isomer ~ y ~ :.
NH ~ 2 J ~
SN
~ ~ C02H (IV) 1 ~
~ Oh by two equivalents of product of formula (XIV):
~ I ' Hal - C ~ CN (XIV) ~ "

to obtain a product of formula (XV):

~. ~ 3 ~ 7 ~
N ~ IR2 ~ R ' SN
Co - C-CN
R '(Xv) -C _ CN
R7 ~
product of formula (XV) which is treated with a base and then with a acid to obtain a product of formula (III ") strained.
In a preferred embodiment of the process below above, the addition of the product of formula (XIV) to the product of formula ~ IV) is carried out in the presence of a base such as potassium carbonate. We can however use other bases such as soda, potash or triethylamine.
The saponification of the products of formula (XV) for to obtain the acids of formula ~ III ") is carried out in the normal saponlfication conditions followed by reacidification.
One can for example use soda followed by chlor-water.
The products of formula (III) according to the invention as defined above ~ can also be obtained by acting in the presence of a base on a product of formula (X) SN (X) C02alk N ~
OH
as defined above, a product of formula (V):
R ' Hal-C R3 (V) R "

in which ~ al, R ', R "and R3 are defined above, to obtain a product of formula (XVI):

SN (XVI) ~, / C02alk R ' NOT
~ 0 _ C _R3 product of formula (X ~ iI) which is treated with a base and then with a acid to obtain the expected product of formula (III) ~

J ~
SN
CO2 ~ l (III) R ' o - f - R3 R "
The base in the presence of which one performs the conden sation of the product of formula (V) sux the product of formula (X) is preferably potassium carbonate. We can however use other bases such as soda, potash or triethylamine.
The saponification of the product of formula (XVI) to obtain hold the product of formula (III) is performed so that the CO2R "1 group which R3 can represent is not itself saponified. We can use for example, as a potash base methanolic and re-acidify with hydrochloric acid.
We can finally notice that when the transformation, according to the process described above, products of formula (I ') in products of formula (Ia) is operated using an acid such as trifluoro ~ cetic acid, the products of formula ~ Ia) can be isolated as salts between the amine of the aminothiazole cycle 3 ~ 7 ~

and this acid. Examples of such products are described below.
in the experiential part, The free bases of the products are obtained, if desired of formula (Ia) per action of approximately one equivalent of a base such than pyridine.
The products of general formula (I) have a very good antibiotic activity, on the one hand on gram (~) bacteria, such as staphylococci, streptococci and especially on penicillin-resistant staphylococci and, on the other hand, on gram bacteria (- ~ especially on coliform bacteria, Klebsiella, Salmonella and Proteus.
These properties make said products suitable for formula (I) as defined above, pharmaceutically acceptable, to be used as medicaments and especially as antibiotic drugs, in the treatment of ailments sensitive germs and especially in that of staphylococcal diseases, such as staphylococcal septicemia, malignant staphylococcal face or skin, pyoderma, septic or suppurating wounds, carbuncles, phlegmons, erysipelas, primary acute staphylococcal disease or post influenza, bronchopneumonia, pulmonary suppurations ~ s.
These products can also be used as drugs in the treatment of collibacillosis and infections associated, in Proteus, Klebsiella and Salmonella and other conditions caused by bacteria gram ~
Among these drugs, there are preferably:
- acid 7- ~ 2- (2-amino thiazol-4-yl) 2-carbethoxy methyl oxyimino ac ~ tam.id ~ 7 3-ac ~ toxymC ~ tllyl CCpil-3 - ("lllo ~ -carboxyli (luc, i.90lll ~ rc .qyrl, - acid 7- ~ - (2-amino thiazol-4-yl) 2-hydroxy carbonyl m ~ thyl oxyimino ac ~ ta ~ id ~ 3-ac ~ toxym ~ thyl ccph-3- ~ rn ~ 4-carboxyli ~ eu, isom ~ re ~ y ~, - acidc 3-acCtoxyrll ~ t}) yl 7- ~ 2 ~ (2-alnino thiazol-4-yl) 2 - / (cyano-``: ``

5 '~
methyl) oxyimin ~ acetamid ~ ceph-3-th 4-carbo ~ ylique, isomer syn;
- 3-acetoxymethyl 7- / 2- (2-amino thiazol-4-yl3 2 - / (amino carbonyl) m ~ thyl oxyimin ~ ac ~ tamid ~ ceph-3-th 4-carboxylic, isom ~ re ~ y ~;
- 3-ac acid ~ toxymethyl 7- / 2- (2-amino thiazol-4-yl) 2- ~ (1-carboxy l-methyl ethyl) oxyimin ~ acetamid ~ ceph-3- ~ me 4-carboxylic, syn isomer, as well as their pharmaceutically acceptable salts with alkali, alkaline earth metals, magnesium, or amino organic bases, and more. especially:
- the disodium salt of the acid of the acid 7- ~ 2- (2-amino thiazol-4-yl) 2-hydroxy carbonyl methyl oxyim.ino acetamid ~ 73-acetoxymethyl ceph-3- ~ me 4-carboxylic, syn isomer, - the sodium salt of 3-acetoxym acid ~ thyl 7- / 2- (2-amino thiazol-~ -yl) 2- ~ (cyanomethyl) oxyimin ~ acetamid ~ ceph-3-th 4-carboxy-lique, isomer ~ y ~, - the sodium salt of 3-acetoxymethyl acid 7- ~ 2- (2-amino thiazol-4-yl) 2 - / (amino carbonyl) methyl oxyimino7acétamido7ceph 3-th 4-carboxylic, isomer ~ y ~, and - the disodium salt of 3-acetoxymethyl acid 7- / 2- (2-amino thiazol-~ -yl) 2- ~ (1-carboxy l-methyl ethyl) oxyimin ~ acetamid ~ ceph-3-th 4-carboxylic, isomer s ~ n.
The disodium salt of 7- / 2- (2-amino thiazol-4-yl) 2-hydroxy carbonyl methyl oxyimino acé-tamid ~ 3-acetoxymé-thyl ceph-3-th 4-carboxylic, isomer ~ y ~, is especially endowed with a very good activity on bacteria ~ ram (-).
The compounds of formula (I), pharmaceutically ac-accountants, so they can be used to prepare for compounding pharmaceuticals containing, as active ingredient, one at least of said compounds.
These compositions can be administered by buccal, rectal, parenteral, intramuscular or locally "~ ~ 13; ~ 75 ~ n topical application on the. pe ~ u and mucous membranes They can be solid or liquid and are present under commonly used pharmaceutical for ~ es in human medicine, like, for example, tablets, simple or sugar-coated drinks, capsules, granules, suppositories, injections, ointments, creams, gels; they are prepared according to the usual methods.
The active principle (s) can be incorporated into excipients usually used in these compositions pharmaceuticals, such as talc, gum arabic, lactose, starch, dem.a ~ nesium stearate, butter cocoa, aqueous vehicles or not, original fatty substances animal or vegetable, paraffinic derivatives, glycols 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, understood between 0.250 g and 4 g per day, orally in humans with the product described in example 5, 8, 11 or 14 or even between 0.500 g and 1 g three times a day, per ~ goose intramuscular.
It should be mentioned that the preparation process ration of products of formula (I) makes it possible to obtain a title of new industrial products:
- the products of formula (VIII), isomer ~ y ~

5 ~ 7 ~

NllR2 SN
CO2H (VIII) ~ 3 in which R2 represents an easily removable group by acid hydrolysis or by hydrogenolysis, or a chlorine radical ac ~ tyle - the products of formula (X ~ II), syn isomer:

N ~ IR2 SNI (XVII) N ~ ~ 1 OR4 0 ~ CH2 11 3 C02A ' in which, R2 has the meaning defined above, A 're-has a hydrogen atom or an easily eliminated ester group ~ ble by acid hydrolysis or by hydrogenolysis and R4 re-has a hydrogen atom or a 1 methyl l-methoxy radical ~ thyle and the products of formula (I '), syn-~ I-R2 (I ') S / ~ ~ O

~ R 'NH
~ 0 C-R3 r ~ ~
R "ON ~ Cl-l -0-C, -CH3 CO2 ~
dan ~ which R2, R ', R ", R3 and A' are defined, s comrne previously.

'75 The products of formulas (IV) and (x) are described in French patent application 2. 346 .014.
Products of formula (V) which are not known can be obtained by halogenation according to conventional methods has products of formula-~ ' ~ _ f_ R7 R ' in which I ~ 7 represents either a group C02R ~ in which R8 represents an alkyl radical or a hydrogen atom, ie R7 represents a nitrile radical.
The products of formula (V) in which R3 represents a CONH2 group can be obtained by am ~ difica-tion of corresponding acids.
The following examples illustrate the invention without any times limit it.
Example 1: Acid 7- ~ 2- (2-tritylamino 4 = thiazolyl ~ 2-carbethoxy methyl_oxyimino acetamid ~ 3 ~ acetoxymethyl ceph ~ 3-th 4-carboxylic, syn-isomer.
Stage A: Acid 2- (2 tritylamino 4-thiazolyl) 2-cabethoxy methyl oxyimino acetic, syn isomer:
10.5 cm of a molar solution are introduced under argon of potassium tert-butoxide in tetrahydrofuran and adds in 10 minutes at 20C, a suspension of 2.15 g of acid 2 (2-trityl-amino ~ -thiazolyl) 2-hydroxyimino ac ~ tick, isom ~ re s ~ n, in 35 cm of dry tetrahydrofuran and 2.5 cm3 of a 4M solution of water in tetrahydrofuran. The temperature rises to 27C. We stir for one hour and add drop ~ drop 5 cm3 of an ob- solution held by adding to 1.1 cm3 of ethyl bromoacetate a quantity sufficient t ~ trahydrofuran to complete ~ 10 cm3.
Stir one hour, e ~ t again adds 1 cm of a molar solution of tert ~ potassium butylate in tetra-32i ~
~ 9 ~
hydrofuran, agitates cncore one hour, wring out the slight insolubl ~, rinsing with tetrahydrofuran, flushes out the solvent, resumes with 50 cm3 ethyl acetate, 15 cm3 of normal hydrochloric acid and 15 cm3 of water, agitation, cante, washing with water, re-extracting ~ ethyl acetate, dry, dry concentrated, add 20 cm3 of ethyl acetate, the product crystallizes. Ice, wring out the crystals, rinse with the minimum of ~ ac ~ ethyl tate and emp ~ te with ether, s ~ che and obtien-t 1.3 g of pure product.
~ Concentrate the filtrate, resume with ethyl acetate ~, crumble, ice, wring out the crystals, rinse with ethyl acetate, pastes ~ ether and obtains a second spray of 185 mg of product pure, i.e. a total of 1.485 g of product.
An analytical sample is obtained by bringing to the neighborhood of the reflux 3.1 ~ g of product obtained as indicated ~ ci-above in 30 cm3 of ethyl acetate. Dissolution is by-tielle. Cool in ice water, wring out the crystals, rinse, emp ~ te with ether and dry, and obtains 2.77 g of purified product.
Analysis: C28 H25 5 N3 S-Calculated: C%: 65.23 H%: 4.89 N%: 8.15 S%: 6.22 Found: 65.1 4.9 8.0 6.1 NMR = (CDC13, 90 MHz): 6.76 ppm (pro-ton of the cycle thiazolyque) - 7.28 p ~ pm (trityl group).
Stage B: Acid 7- / 2- (2-tritylamino 4-thiazolyl) 2-carbethoxy methyl oxyimino acetamid ~ 3-ac ~ toxymethyl ceph-3-th 4-carboxylic, isomer ~ y ~:
1.55 g of product obtained are mixed under argon in stage A, and 22 cc of mfithylene chloride, cools in glacc c ~ ajou ~ c unc solutiorl comprcllar) t 345 m9 dc dicyclo-hexylcarbodiimide in 1.5 cm3 of methylene chloride. We shake one hour refreshing in cold water, wringing out the dicyclo-hexylurea formed, rinse with methylene chloride and dry ~
gets 270 Jng).

2 ~ 5 The ~ iltrat is cooled in a methanol-ice bath, and a solution of 410 mg of acid 7- is added all at once cephalosporanic amino in 7.5 cm3 dry methylene chloride and 0.42 cm3 of triethylamine. We are dealing with the spon-tanned for 3 hours, add 7.5 cm3 of water and 3.75 cm3 of acid normal hydrochloric acid, agitates, wring out the insolubule, decant the filtrate, re-extracted with methylene chloride, washed with water, dried and center the ~ iltrat. The residue is taken up in 7.5 cm3 of acetate ethyl, stir for an hour in ice water, wring out the crystals, rinses and obtains 600 mg of expected product.
We remove the solvents from the ~ iltrate and obtain 1.3 ~ g of residue. This residue is dissolved in 6 cm3 of ethyl acetate, add 0.15 cm3 of pure diethylamine, diluted pro ~
stirring with 35 cm3 of ether, obtains an insoluble gum which resolves into crystals. We wring, rinse with a 15% solution ethyl acetate in ether, mash with ether and dry. We isolates 983 mg of purified diethylamine salt.
This salt is dissolved in 10 cm3 of methylene chloride, 1.3 cm of normal hydrochloric acid (p ~ l = 2) are added, stirred, decanted, washed with water, re-extracts the aqueous phase with methylene, dry, remove solvents, take up in ether, spin dry insoluble and isolates an additional 818 mg of expected product.
2- (2-tritylamino 4-thiazolyl) 2-hydroxyimino acid acetic, syn isomer used at the start of example 1 was pre-dressed as follows:
A) 2- (2-amino ~ -thiazolyl) 2-hydroxyimino ac ~ tate ~ thyle, i ~ om ~ re syn.
We dissolve 0, ~ gd ~ thiour ~ e in 2, ~ cm3 of ethallol and 4.8 cm of water. The solution of 2 g of 4- is added in 5 minutes chloro 2-hydroxyimino acetyl ac ~ ethyl tate ct agitates a hcurc ~

ambient temperature. We hunt most of the ethanol under partial vacuum and neutralizes to pll 6 by adding acidic carbonate solid sodium. Ice, spin, wash ~ 1 ~ water, dry ~ vacuum at 40c. 1.32 y of expected product are obtained. F = 232C.
Analysis c5 ~ 9 03 N3 S-Calculated: C%: 39.06 H%: 4.21 N%: 19.52 S%: 14, g Found: 38.9 4.4 19.7 14.6 B) 2- (2-tritylamino 4-thiazolyl) 2-hydroxyimino ethyl acetate, isom ~ re ~ y ~.
43.2 g of 2- (2-amino 4-thiazolyl) 2- are introduced.

hydroxyimino acetate ~ of ~ thyle, isom ~ rc sy ~ pr ~ by ~ at stage A ci-above in 120 cm3 of dry dimethyl formamide.
Cool to -35C, in-product 32 cm3 of triethylamine then in 30 minutes by fractions, 60 g of trityl chloride. We let the temperature rise, observe a total dissolution, then heating up to 30C. After an hour, pour on 1.2 1 of ice water containing 40 cm3 of hydrochloric acid 22Bé.
Stir in an ice-water bath, wring, rinse with normal hydrochloric acid, pastes ~ ether.
69.3 g of hydrochloride are obtained.
The free base is obtained by dissolving the product in 5 volumes of methanol supplemented with 120% triethylamine, then by gently precipitating with S ~ olumes of water.
Analysis C26 H23 3 N3S, 1/4 H20.
Calculated: C%: 67.6 H%: 5.1 N%: 9.1 S%: 6.9 Found: 67.5 5.1 8.8 6.8 C) 2- (2-Tritylamino 4-thiazolyl) 2 ~ hydroxyimino acetic acid, isom ~ re syn.
11.5 g of product obtained in stage B are introduced.
pr ~ c ~ dellt in 30 cm3 of dioxane and 25 cm3 of Soudo 2N. 01 ~ wave 1 hour in a 50C water bath. Ice 10 minutes, spin, rinse with dioxane aquQux ~ 50%, with dioxane-ether mixture (1-1) and ether. After drying, 11.05 g of sodium salt are obtained.
The corresponding acid is obtained by taking up the salt in the .

aqueous methanol in the presence of hydrochloric acid.
Example 2: 7- / 2- (2-amino 4-thiazolyl) 2- acid carbethoxy methyl oxyimino acetamid ~ / 3-acetoxy methYl ceph-3-th 4 = carboxylic, isom ~ re syn.
0.818 g of product obtained is suspended in l ~ Example 1 in 4 cm3 of 50% aqueous formic acid. We wear suspension in a 60C water bath for 20 minutes, tri-phenyl carbinol crystallizes. Cool, dilute with 4 cm3 of water, stir for 15 minutes ~, wring out the triphenyl carbinol, rinse it ~
water, dries and gets 305 mg. We concentrate the filtrate dry under vacuum, take up the residue in ethanol then remove the solvent, finally resumes with water, ice for 15 minutes, wring insoluble, rinses with water, dries and obtains 229 mg of product expected.
AnalY3e: Clg H21 g ~ 5 2 Calculated: C%: 43.26 H% o 4.01 Found: 43.3 4.3 NMR: (DMSO, 60 MHz):
= NO-CH2-CO2 CH2-CH3: (a) triplet centered on 1.2 ppm J = 7 Hz (c) (b) (a) (b) quadruplet centered on 4.15 ppm J = 7 Hz (c) ~ ingulet at 4.66 pp ~ m.
proton of the thiazolic cycle: singlet at 6.8 ppm ~
Example 3: 7- ~ 2- (2-trikYlamino 4-thiazolyl) 2-tert-butoxy carbonyl methyl oxyimino acetamid ~ / 3-acetoxymethyl ceph-3-~ me tert-butyl 4-carboxylate, isom ~ re syn.
Stage A: 2-tert-butoxy carbonyl methyl oxyimino acid 2-t2-tritylamino ~ -thiazolyl) ac ~ tick, i30 ~ re 3yn.
~) 80US argon is mixed 8.59 g of 2-hydroxyimino acid 2- (2-tritylamino 4-thiazolyl) acetic in 10 cm3 of dioxane containing 4 moles of water per liter, and 80 cm3 of dioxane, and stirred 15 minutes ~.

~) A solution of 5.13 ~ g of is prepared separately potassiwn tert-butoxide in 40 cm3 of dioxane, stirred ambient temperature under argon for 10 minutes, and obtains a homogeneous suspension. Then introduced at 23C-25C at 15 minutes, the suspension prepared in a) above, cooling slightly and rinsing with 25 cm3 of dioxane.
Stir one hour at 23C-25C. Then we introduce in 15 minutes ~ 28C-29C, a solution of 4.919 g of bromoacetate tert-butyl in 15 cm3 of dioxane. We stir for an hour at 26C-28C, then add at 10 minutes interval 0.471 g of potassium tert-butoxide then a solution of 0.772 g of bromo-tert-butyl acetate in 2 cm3 of dioxane. Shake ~ 5 minutes at 25C under ar ~ on, brings to pH 6 with 0.5 cm3 of acetic acid and then dry distilled, and obtained 19.4 g of a resin.
It is taken up in 100 cm3 of methylene chloride and 100 cm3 of water then acidifies to pH 2-3 with 25 cm3 of chlorine acid normal water. Decanted, washed with distilled water, filtered, methylene chloride extract, dry, rinse with methylene and distills dry under vacuum. 12.3 g of pro-20 picks. It is taken up in 31 cm3 of ethyl acetate, initiates the crystal-read and stir 1 hour at room temperature then 2 hours at 0, + 5C. It is wrung and rinsed at this temperature with acetate ethyl. It is dried under vacuum and 5.04 g of expected product is obtained.
The product is purified as follows:
3.273 g are dissolved in 60 cm3 of methyl ethyl ketone saturated with water at reflux, 0.33 g of activated carbon is added ~ hot, wring and rinse twice with 3 cm3 of methyl ethyl c ~ ton ~ saturated with boiling water. Concentrate the filtrate under vacuum by recovering 36 cm3 of solvent. The product crystallizes.
30 We hit a stroke at 0, + 5C 80U ~ I stir, wring and rinse with m ~ thyl ~ thyl c ~ log saturated with water. We dry under vacuum and holds 2.6 ~ 3 g dc expected product, pure. F = 190C.

`` \
~ 32 ~ t75 Anal ~ Se: C30 H2g 5 3 Calculated: C%: 66.28 H%: 5.38 N%: 7.73 S%: 5.9 Found: 66.5 5.7 7.7 5.6 NMR (CDC13, 60 MHz) 1.46 ppm (proton of tert-butyl) 6.8 ppm (proton of the thiazole cycle).
Stage B: 7- ~ 2- (2-tritylamino 4-thiazolyl) 2 ~ tert-butoxy carbonyl methyl oxyimino acetamid ~ 3-acetoxymethyl ceph-3-~ me tert-butyl 4-carboxylate, isomer ~ y ~.
on In ~ lallgc 2.174 g of 2-tert-butoxy acid c ~ rbonyl methyl oxyimino 2- (2-tritylamino 4-thiazolyl) acetic, isomer syn pr ~ prepared in stage A above, 1.313 g of tert-butyl ester 7-amino cephalosporanic acid and 35 cm3 of chloride methylene. Stirred at 20C for 5 minutes and introduced at 20C-22C in 5 minutes, 8.8 cm3 of dicyclohexylcarbodiimide in solution in methylene chloride at 2.06 g per 20 cm3. We shake under argon for 2 hours. The dicyclohexylurea precipitates. We add 4 drops of acetic acid and shakes for 5 minutes. We wring out the di-cyclohexylurea, rinses with methylene chloride (collected 523 mg). The solution is distilled under vacuum, resumed with ether, wring the dicyclohexylurea again (204 mg is collected), add 30 cm3 of ether to the filtrate, wash with an acid solution aqueous hydrochloric, then with water. The organic solution is then washed with an aqueous solution of sodium carbona-te.
It is collected in the form of insoluble 0.438 g of sodium salt of aide 2-tert-butoxy carbonyl m ~ thoxyimino 2- (2-tritylamino 4-thiazolyl) ac ~ tic. Wash with water until neutralit ~, r ~ ex-trait leq ether wash water, s ~ che organic phase, treats activated charcoal ~, wring, rinse ~ r and distill ~ ~ ec 90U9 empty.
3.16 g of prod ~ bed are obtained.
This product is chromatographed on silica, eluting with an ether-benzene mixture (1-1), and recovers a first ~ re frac-tion majority ~ n product of R ~ = 0.5 (1.15 g) and a second fraction homog ~ ne r ~ f = 0.5 containing 0.937 g of expected product.
Example 4: Acid 7- / 2- ~ 2-amino 4-thi z lyl) 2-hydroxy carbonyl methyl oxyimino ac ~ tamid ~ 3-ac6toxy7n ~ thYl ceph-3-~ me 4-carboxylic, isom ~ re syn.
We m ~ larlge under argon ~ 20 "C-22C, 11.5 cm3 of acid trifluoroacetic and 1.15 g of 7- ~ 2- (2-tritylamino 4-thiazolyl) 2-tert-butoxy carbonyl m ~ thyl oxyimino acetamid ~ 73-acetoxymé-thyl ceph-3-th 4-tert-butyl carboxylate.
Stir 10 minutes at 20C-22C. We distill under empty up to a volume of 3 cm3. We take up with 35 cm3 of ether isopropyl by cooling in an ice bath, a product precipitate. Stirred at room temperature for 10 minutes, spin and rinsed with isopropyl ether. The trifluoroacetate is dried under empty and obtains 0.557 g of product.
0.526 g of trifluoroacetate obtained is placed in 2.5 cm3 ethanol, stirred at room temperature until dissolved (pH 1-2). Then 0.47 cm of a 2M solution of pyridine in ethanol.
We observe a precipitation of free amine, we stir 5 minutes at 20C-25C under argon. We spin at am-biante. Rinsed with an ether-ethanol mixture and then with ether.
Dried and obtained 0.261 g of yellow product.
The mother liquors are concentrated and taken up in ether.
A second jet of 0.084 g of product is obtained. We bring together two fractions and pastes them with ether-ethanol mixtures and then with ether. Dried and obtained 0.316 g of the expected product.
NMR (DMSO, 60 MHz): 4.16 ppm (-O-CH2-CO2H) and

6.84 ppm ~ proton of cyclc thiazoliquo) ~
~ xample 5: Disodium salt _e acid_7- / 2- (2-a! nino 4-thiazolyl) 2-hydroxy carbonyl methyl oxyimino ac ~ tamld ~ 73-acetoxy-methyl ceph-3-th 4-carboxy ~ lique, isom ~ 3rd syn.
0.224 y of acid prepared at Example 4 in 1 cm3 of m ~ thanolic solution of acetate molar sodium and 2 cm of methanol. We spin and rinse with thanol. Concentrate under vacuum to about 1 cm3 and add 5 cm of ethanol. The sodium salt precipitates, the mixture is stirred for 10 minutes at room temperature, spin and rinse with ethanol and ~ ther.
It is dried and 200 mg of product is obtained.

An ~ ys_: C17 Hls g N5 S2 2 Na:% calculated: 8.46 found: 8.54 Rf = 0.3 (acetone ~ 10% water).
Example 6: 3-acetox ~ methyl 7- ~ - (2-tritylamino thiazol 4-yl) 2-/ (cyanomethyl) oxyimin tert-butyl, isom ~ re syn.
Stage A: 2- ~ (c ~ ano methyl) oxyimin ~ 2- (2 ~ tritylamino _______ __ _ ________ _____ ____ _________ ______ thlazol 4-yl) cyano methyl acetate, syn isomer.
12.9 g of 2- acid are mixed under an inert atmosphere.
/ (hydroxy) imin ~ / 2- (2-tri-tylamino thiazol 4-yl) acetic isomer syn, 9.12 g of neutral potassium carbonate, 60 cn ~ of dimethyl dry formamide and 7.6 cm of chloroacetonitrileO Stirred. After 2 ~ solidification, 65 hours are left in a closed atmosphere. We pour on a mixture of 750 cm3 of water, 130 cm3 of hydrochloric acid normal, 150 cm3 of ethyl acetate, agitate, wring out the insoluble matter, rinsed with ethyl acetate and with water and cante. We wash with 100 cm3 of water, extracted with three times 100 cm3 of ethyl acetate, dry the organic phase, spin, rinse concentrated ~ scc and obtain a residue which is chromatographed on a silica column, eluting with ether. The ether is removed and 8.69 g of product is obtained.
stretched as oil.
NMR: CDC13 60 M ~ lz Thiazole proton: 6.8 ppm, trityl proton: 7.37 ppm Stage B- acid 2- ~ (cyanomethyl) _oxy_min ~ / 2 - (__ trltyl 5 ~
amino thiazol 4-yl ~ aceti ~ eu, syn isomer.
________________ _______ _____________ _ 8.69 g of product obtained in stage A are placed in 52 cm of dioxane ~ Cooled in an ice bath ~ and added twenty-one minute drop ~ 17.1 cm3 soda normal soda. We abandon gives spontaneous warming and adds 10.5 cm3 of chlorine acid 2N lyrical, flushes out dioxane and almost all of the water.
We add 20 cm3 of water and 30 cm3 of ether, stir for 15 minutes, wring out the crystals, rinse with water and ~ ether, dried and obtained 4.32 g of the expected product. F: with decomposition about 180C ~
NMR: CDC13 60 MHz 4.7 ppm: OCH2 CN
6.7 ppm: thiazole proton

7.34 ppm: trityl proton.
Stage C: 3-acetoxymethyl 7- ~ - (2-tritylamino thia ~ ol 4-yl ~ 2-~ ______ ________ ____ ___ ________ _____________ ~ ____ _____ / (cyanomethyl) oxyimin ~ acetamid ~ ce ~ h-3-th 4-tert-carboxylate _______ _____ ____ _______ __ ________________ _____________ butyl, isomer s ~ n.
___ _____________ _ 1.875 g of 2- acid are mixed under an inert atmosphere ~ (cyano methyl3 oxyimin ~ 2- (2-tritylamino thiazol 4-yl) acetic syn isomer prepared in stage B and 1.312 g of tert-butyl ester 7-amino cephalosporanic acid in 12 cm3 of chloride methyl ~ not dry.
Stirred and added a solution of 960 mg of dicyclo-hexyl carbodiimide in 12 cm3 of dry methylene chloride. We shakes, leaves at room temperature for an hour and 45 minutes, sore the dicyclohexylurea formed and isolates ~ 57 mg.
Concentrate the filtrate to dryness and obtain a residue that we chrolllatography ~ ur silica by ~ glowing ~ u chlorurc de methylene then ~ etherO
We collect the rich fractions, drive out the ether then resume with ether. We start the crystallization, the product slowly crystallizes into ice. On cs ~ ore, rinse ~ ther à

7 ~
0C by pasting and drying. 776 mg of expected product are isolated.
F = 180C with decomposition.
NMR: 60 ~ 1z CDC13 4 r 9 p ~ pn m: 0-CH2 - CN
6.8 ppm: proton of the thiazole cycle 7.31 ppm: trityl proton.
Example 7: 3-acetoxymethyl 7- / 2 (2-amino_thiazol 4-yl ~ 2-~ (cyanomethyl) o ~ yimin ~ ceph-3- ~ me 4-carboxyli ~ eu, iso-m ~ re synl under ~ trifluoroacetate elm.
Introducing 779 mg of product obtained ~ ex ~ mple 6 in 4 cm3 of trifluoroacetic acid. We act until dissolved.
tion, leave in contact for 17 minutes then pour into 40 cm3 of ether isopropyli ~ ue. Shake, spin, dry and isolate 523 mg of product expected.
Example 8: Sodium salt of 3-acetoxymethyl acid 7- ~ 2 ~
aminothiazol 4-yl) 2 - / (cyanomethyl) ox ~ imin ~ acetamid ~ ceph-3-th 4-carboxylic, syn-isomer.
We di ~ sout 523 mg of trifluoroacetate obtained at Example 7 in 2 cm of normal methanolic acetate solution soda.
Diluted with 6.6 cm3 of ethanol, stirred 10 minutes, wring out the insoluble material, rinse with ethanol, dry and obtain 226 mg of expected sodium salt. F = 200C approximately with decomposition.
~ MN: CDC13 60 ~ 1z 4.98 ppm: 0-CH2- CN

=

6.86 ppm: proton of the thiazole cycle.

Analysis: CHONS Na Calculated: C% 40.64 H% 3.01 Na% 4.57 Found 40.2 3.3 4.5 Example 9 ~ 3-acetoxymethyl 7- ~ 2- (2-trityl amino thiazol 4-yl ~ _2-~ (amino ca ~ bonyl) methyl oxyimin ~ acetamid ~ ceph-3-th 4-carboxylate of tert-butyl isom ~ re syn ~

~ 34-3 ~; 3 ~

Stage A: 2 - (2- trltylamino 4-thlazolyl) 2 - ~ ethyl carboxy) methyl oxyimin ~ Ethyl Jacetate, syn isomer.
____ ____ ____ _____________ ____.___ ____ _ Place sou ~ argon 9.88 g of hydrochloride 2- (2-tri-tylamino 4-thiazolyl) 2- (hydroxy imino) ethyl acetate in 25 cm of dry dimethylformamide and add 8.28 g of potassium carbonate-pure sium. The medium is stirred for 15 minutes and then cooled during for 10 minutes in a methanol-ice bath then add drop to drop in S minutes 11.2 cn ~ of ethyl bromacetate and abandon to spontaneous reheating with stirring and under an inert atmosphere.
Then poured into a mixture of 400 cm3 of water e ~ 80 cm3 of acetate ethyl tate, stir, decant, wash with twice 80 cm3 of water, re ~ extracted with 80 cm3 and 50 cm3 of ethyl acetate. We dry 1a organic phase, wring, rinse and concentrate ~ dry.
The residue is taken up in ether and the expected product is stirred to crystallize.
It is filtered, rinsed with ether, dried and isolated 7.54 g of product at stretched F = 154C.
- NMR, CDCl3; 60 MHz 4.75 ppm: 0-CI12-CO ~
6.55 ppm: proton of the thiazole cycle Analysis: C ~ l ONS

Calculated: C% 66.28 H% 5.38 N% 7.73 S% 5.90 Found: 66.1 S, 4 7.5 5.9.
Stage B: Acid 2- (2-tritylamino 4-thiazolyl) acetate ________ _____ ~ _________ _ ~ ____________._ __________ ethyl 2-iminoxy aceti ~ eu, lsomer syn ~
One mixes under inert sphere and in a water bath 4.077 g of product obtained in stage A in 11.3 cm3 of dio-xanne. After cooling, we introduce in 20 minu ~ es 8.25 cm3 of a normal soda solution. We leave the middle to the oid one hour, flushes dioxane to 25 pui ~ adds 9.75 cm3 of a solution tion of normal hydrochloric acid. 40 cn ~ of ethyl acetate are added, the mixture is stirred, washed and treated with ~ line ~ ethyl acetate. We dry the organic phase on magnesium 3ulfate, wring, cha ~ se le9 3 ~

solvents, resumes ~ e-ther, initiates crystallization, agitates a half an hour the crystals formed, wring, rinse with ether, dry and 3.462 g of expected product is obtained. F = 200C.
The pure product for analysis is obtained as follows:
400 mg of product obtained are dissolved in 1 tc of dio-xanne, diluted with 10 cm3 of isopropyl ether, stirred, leaves to coat in an ice-water bath, wring, rinse with a solution tion of isopropyl ether containing 10% dioxane, ends up blocking isopropyl ether and isolates 320 mg of purified product.
NMR: 60 MHz CDC13 4.71 ppm -0-C ~ 2-CO2 6! 46 p ~ pm: proton of the thiazole cycle.
Stage C: 2- (2-tritylamino 4-thiazolyl) 2- ~ (arninocarbonyl) methyl ______ _________ ________________ ____ ___________ _______ _ oxyimin ~ acé ~ ethyl tate, syn isomer.
__ ___ _____________ _____________ _ Is introduced under an inert atmosphere and into a bath methanolcarboglace, a mixture of 3.609 g of 2- (2-tritylamino acid 4-thiazolyl) ethyl acetate 2-iminooxy acetic prepared at the stage B in 28 cm3 of dry tetrahydrofuran, 21 cm3 of chloride dry methylene and 0.77 c ~ of pure N-methyl morpholine.
A dissolution is observed, the medium is cooled in a bath at -20C and a drop-by-drop 0.91 cm3 of chloroformate isobutyl.
Stir 3 minutes at this temperature then cool to -3SC and adds excess gaseous ammonia. Shake 15 minutes -30C then an hour at ambient temp ~ rature. We know ~
dry, resume with ethanol, stir for 20 minutes, wring out the crystals form ~ s rinses ~ thanol and d ~ che.
We o ~ holds 3.33 g of product a ~ tcndu. L; ' = 1 ~ 0 "C.
- RMN CDC13 60 ~ Iz 4.76 ppm: 0-C ~ I2- CO2 6.53 ppm: proton of the thiazole cycle.
AnalySe: C28H26 04N4 :

Calculated: c% 65.35 H% 5.09 s% 6.23 Found: 65.5 5.1 6.3.
Stage D- Acid 2- (2 ~ tritylamino 4-thia ~ olyl) 2- ~ (amino ca ~ bonyl) _______ ____ ~ __________ ________________ ____ ___ ___ ____ _ methyl oxylmln ~ _cetl ~ ue lsomère syn.

3.5 g of product pr ~ prepared in stage C are introduced into 24 cm3 of dioxane and 6.8 cm3 of 2N sodium hydroxide ~ Stirred ~ temp ~ rature ambient observes the dissolution then the crystallization of the salt of sodium after 45 minutes of contact. We give up with agitation in a closed atmosphere for three hours 15 minutes. We wring the sodium salt, rinse with a dioxane-water mixture (70-30) then with ether, dry and isolate 1.81 g of sodium salt. We dissolve this salt in 5.3 cm of dimethyl sulfoxide adds 5 cm of a solution normal hydrochloric acid observes precipitation then a crystallization. Diluted with 70 cm3 of water, stirred for 20 minutes, wring, rinses with water, dries and obtains 1.3 g of the expected product.
F = 200C.
RMN CDC13 60 MHz 4.58 ppm: -O-CII2-CO

===
6.66 ppm: proton of the thiazole cycle.
Stage E: 3-acetoxymethyl 7- / 2 - / (amino carbonyl) methyl oxyimin ~ 2-~ 2_tritylamino thlazol 4-yl) acetamldo / ceeh-3-th 4-carboxylate tert-butyl_, syn isomer.
488 mg of product obtained are mixed under an inert atmosphere.
held at stage D and 328 mg of tert-butyl ester of the acid ~ -amino c ~ phalosporanic in 3 cm of dry methylene chloride.
A solution is then added at room temperature comprising 240 mg dicyclohexylcarbodiimide in 3 cm chloride m ~ thyl ~ ne s ~ c. After the solution, we observe the appearance of cry ~ rate, stir for two hours, wring out the dicyclohexylur ~ e, formed the rinses with methylene chloride, s ~ che and obtains 130 mg.
Concentrate to dryness and chromatography on a silica column eluting with an ethyl acetate-ethanol-e melanye ~ at ~ 70-2U-10) f ~ 5 '~

and collects the fractions containing the expected product. We flushes the solvents, takes up with 1 cm3 of ethanol then dilutes with

8 cm3 of isopropyl ether the product precipitates. We loreore, rinses with a solution of isopropyl ether - ~ thanol (89-11), pastes with isopropyl ether, dries and obtains 324 mg of product expected.
R ~ N CDC13 60 MHz 6.68 ppm: proton of thiazole.
Exelllple 10: ~ cidc 3-ac ~ ox ~ neCthyl 7- ~ 2- ~ (alnino carbonyl) m ~ thyl oxYimino / 2- (2-amino thiazol 4-yl) acé-tamid ~ / ceph-3-eme 4-carboxyli-that, syn isomer, in the form of trifluoroacetate.
357 mg of product obtained ~ Example 9 are dissolved in 1.1 cm of trifluoroacetic acid. We leave 2 ~ minutes to rest in a closed atmosphere and precipitates by adding 11 cm3 of ether isopropyl, spin dry, rinse with dry isopropyl ether and holds 275 mg of trifluoroacetate of the sought product.
Example 11: Sodium salt of 3-acetoxy acid meth ~ 2-~ (aminocarbonyl ~ methyl ox ~ imino / 2- ~ 2-amino thiazol 4-yl) aceta ~
ceph-3-th 4-carboxylic, syn-isomer.
275 mg of trifluoroacetate obtained in the example are dissolved 10 in 1.2 cm3 of molar solution of sodium acetate in the methanol. Diluted with 4 cm3 of ethanol. The product precipitates, drained, rinsed with ethanol, dried and finally obtained 153 mg expected sodium salt. F with decomposition: around 200C.
NMR DMSO 90 ~ lz:
4.4 pp ~ m: = NO-CI-12-CO
===
6.8 ppm: proton of the thiazole cycle.

~ xelllple 12: -ac ~ tox ~ n ~ hyl? - ~ 2- [2-tritylalllino tlliazol 4-yl) 2-/ (l-tertbutoxy carbonYl l-methyl ~ thyl ~ oxyimin ~ ac ~ ta ~ nido_ceph-3-eme tert-butyl 4-carboxylate, syn-isomer.

Stage A- 2- (2-tritylarn1no thiazol 4-yl) 2- ~ tertbutoxy carbonyl l-methyl ethyl) oxyimin ~ ethyl acetate, syn isomer.
_ ~ ____ _______ ~ _____ _____ ____ ______ ~ ______ _____ ______ _ 9.88 g of 2- (2-tritylamino hydrochloride) are mixed thiazol 4-yl) 2 ~ / (hydroxy) imin ~ ethyl acetate and 8.28 g of car-neutral potassium bonate in 25 cm3 of dimethylformamide se. We cools for 10 minutes in a bath at -10C and adds in 3 minutes lg cm3 of crude tert-butyl 2-brorno 2-methyl propionate.
Allow to warm and stir for 16 hours. We observe a solidified. Poured onto a mixture of 400 cm3 of distilled water and 200 cm3 of ethyl acetate. We stir, decant, and wash with water, extracted with twice 100 cm3 of ethyl acetate, s ~ che, wring, concentrate, collect an oil to which you add 240 cm3 petroleum ether, cools, initiates crystallization, wring after half an hour and obtains 10 ~ 8 g of the expected product.
F = 134C.
NMR ~ 0 MHz, CDC13 6.71 ppm: thiazole proton, 7.28 ppm: trityl proton.
AnalySe: C34H37O5N3 Calculated: C% 68.09 H% 6.22 N% 7.01 S% 5.35 Found: 68.3 6.3 6.9 5.3.
Stage B: Acid 2- (2-tritylamino thiaæol 4- ~ 1) 2- ~ (1-tert butoxycarbonyl l-methyl ethyl) oxyimin ~ aceti ~ eu, _isomer syn.
1.2 g of product obtained in stage A are mixed in 2 cm 3 lN methanolic po-cup solution and 4 cm3 of methanol. We carries two hours at reflux, cools, observes crystallization of the starting protuit from which 390 mg is recovered. So we saponified 810 mg of product. The filtrate is concentrated to dryness, added 1 cm3 dimethylformamide and 2 cm3 of a normal solution of chlor-water (pH = 2). Stirred, add 10 cm3 of water, chloride methylene, stir, decant, wash ~ water, r ~ chloride extract methylene, dries the organic phase, spins, concentrates the filtrate until an oil is obtained. 4 cm 3 of chloroform are added and diluted with 30 cm3 of ether. We begin crystallization, wring the crystals after half an hour of agitation, rinse with ether, dries and isolates 472 mg of expected product. F = 190C.
DMSO NMR, 60 MHz 6.76 ppm: thiazole proton, 7.33 ppm: trityl proton.
Stage C: 3-acetoxym ~ thyl 7- ~ 2- (2-tritylamino thiazol 4-____ __ ________ ____ ____ _______ __________________ yl) 2- ~ tertbutoxycarbonyl l-methyl ethyl) oxylmin ~ / acetamid ce ~ h-3-th 4-tert-butyl carboxylate, syn-isomer.
__ ________________ ________________ _____________ _ We mix ~ 1, ^ / 15 g of product prepared in stage B and 984 mg of tert-butyl ester of 7-amino cephalosporanic acid in 26 cm3 of methylene chloride ~ We heat to dissolve, re ~
cools to room temperature and adds 678 mg of dicyclohexyl-carbodiimide in 6.6 cm3 of dry methylene chloride. We shake at room temperature for two hours. We observe the crystal-dicyclohexylurea, wring it out and collects 268 mg.
Concentrate the filtrate to dryness, take up in ether, add a little acetic acid (up to pH 4). We stir for twenty minutes, wring insoluble, rinses ~ ether and obtains 79 mg of dicyclohexylurea (a total of 347 mg).
The ethereal phase is concentrated to dryness and chromatographs the residue on a silica column, eluting with ether. We collect first a mixture, then 463 mg of pure expected product.
R = 0.7 (eluan-t ether).
Example 13: ~ cide 3-ac ~ toxym ~ thyl 7- ~ -~ carbo_y l-methyl ethyl) oxyimin ~ acetamid ~ ceph-3- ~ me 4-carboxylic, syn-isomer, in the form of trifluoroacetate.
43Z g of product obtained in Example 12 are introduced into 4.3 cm3 of pure trifluoroacetic acid ~ t kept at rest 15 minutes after dissolution. Diluted with stirring with 43 cm3 of ether isopropyl, wring out the insoluble matter, flushes out the solvent, dilutes new with 50 cm3 of isopropyl ether, wringing out the insoluble matter formed, rinses with isopropyl ether and finally obtains 173 mg of 3 ~ 5'7 ~

trifluoroacetate of the expected product. Rf = 0.5 (eluent acetone a 10% water).
Example 14 Disodium Salt of 3-Acetoxymethyl Acid 7- ~ 2- ~ 2_ aminothiazol 4-yl ~ 2- ~ (1-carboxy l-methyl ethyl) oxYimln ~ ac ~ tamid ceph-3- ~ me 4-carboxYlique, isom ~ re syn.
173 mg of trifluoroacetate obtained in the example are mixed 13 and 0.95 cm3 of a 1 M solution of sodium acetate in methanol.
After slight heating, the traces of insoluble material are filtered, rinsed, concentrated ~ small volume, diluted with 2.5 cm3 of ethanol. We ob-~ erve the precipitation of the expected product, stir, spin, rinse ethanol then with ether, dry and obtain 77 m ~ of product at-tense.
R ~ N DMSO 60 MHz: 6.75 ppm: thiazole proton.

Calculated: C% 39.93 H% 3.35 Found: 39.5 3.6.
Example 15: 3-acetoxymeth ~ l 7- ~ 2- (2-trityl amino thiazol 4-yl) 2-~ (tertbutoxycarbonyl meth ~ l) oxyimin ~ / acetamid ~ ceph-3-th 4-diphenylmethyl carboxylate, syn isomer.
Stage A: Acid 2- (2-trltylamino thlazol 4-yl) 2- (1-methyl l-methoxy ethoxy imino) acé-ti ~ eu, syn isomer.
____ __________ ______ _____________ ____________ _ Stirred 20 minutes at room temperature 12.9 g of acid 2 - ((hydroxy ~ imino ~ 2- (2-trityl amino thiazol 4-yl) acetic isomer ~ y ~ in 120 cm3 of methylene chloride and 12 cm of 2-m ~ thoxy prop ~ ne. Concentrate to dryness and stir again for 30 minutes in 60 cm3 of methylene chloride and 12 cm3 of methoxy propene. We concentrated to dryness under reduced pressure.
We obtain the expected product which we use in this state.
Stage B: 3-acetox ~ ethyl acid dlethylamlne salt 7- / 2- (2-tritylamino thiazol 4-yl) 2 - / (1-m ~ thyl lm ~ thoxy) ~ thoxy __ ________ ____ ____________ ___ imin ~ acetamid ~ ceeh ~ 3-th 4-carboxyli ~ eu, syn isomer.
____ ________ __ _______________ 7 ~

Dissolve the acid 2- ~ 2-tritylamino thiazol 4-yl) 2- (1-methyl l-methoxy ethoxy imino) acetic syn isomer obtained according to the process described in stage A from ~ 7.25 g of 2- (2-tritylamino tl) iazol 4-yl) 2-hydroxyimino ac ~ tic in 230 cm3 of methylene chloride. 12.5 g of dicyclohexyl carbodi- are added.
imide and stir for one hour at room temperature. We wring the dicyclohexylurea formed which is rinsed with a little chloride of methylene (9.82 g are obtained). The solution is added to the filtrate.
13.6 g of 7-amino cephalosporanic acid in 70 cm3 of methylene chloride and 14 cm3 of triethylamine. We shake two hours at room temperature. Wash in ampoule with 350 cm3 hydrochloric acid N, decanted, washed with water, dried and concentrated dried up. The residue is dissolved in 100 cm3 of ethyl acetate and initiates crystallization. Leave to crystallize for 30 minutes, sore and collects 5.5 g of starting material. The filtrate is centered ~ dry and the residue is stirred for 30 minutes with 200 cm3 of ether isopropyl. After wringing and drying, 37.35 g of raw condensate. To purify it we proceed as follows:
the product is dissolved in 148 cm3 of ethyl acetate.
5.5 cm3 of diethylamine are added and precipitated with vigorous stirring per 650 cm3 of ether. It is wrung, washed with ether, dried and obtained 26.35 g of expected product. Then concentrated to dry the ~ iltrate, taken up in 50 cm3 of ether and obtained a second jet of 2.8 g identical to the pre ~ jet in TLC The diethylamine salt is used read ~ so, then:
RMN CDC13 60 Mllz Ci ~ 3 (a) ta) = 1.54 ppm O - ~ Cll3 (a) (b) = 3.27 ppm, OCH3 (b) 30 proton of the thiazole cycle: 6.78 ppm Stage C: 3-acetox ~ methyl 7- / 2- (2-tritylamlnothiazoi 4-yl) 2 ~ methyl l ~ methoxy) ethoxx imin ~ acetamid ~ cc ~ h ~ 3 ~ th 4 ~

~~ ~ ____ ~ ~ _ ~ _ ~ _ ~~ _ _ ~~ _ ~~~ _ ~ ___ ___ ~~ __ ~ ~~ _ ~ _ ~ _ ~~ ___ - \

di ~ hényl methyl carboxylate, syn isomer.
______ __________ ___ ______ _______ ___ ~ _ _ 4.15 g of diethylamine salt obtained are introduced.
stage B in 40 cm3 of methyl chloride ~ ne and 55 cm3 of acid hydrochloric 0.1 lN.
We ac ~ it ~ ~ 0 minute3 ~ temp ~ rature ambianto, d ~ can ~, lav ~
the organic phase with twice 25 cm3 of water. This phase is then dried ~ e, wring ~ e, and rinsed with methyl chloride ~ ne.
15 cm 3 of diazodi ~ h ~ nyl methane at 8% in benzene. We act you 15 minutes at room temperature then evaporates the solvents under pressure reduced to 30. We resume ~ isopropyl ether, disintegrates and - evaporates the solvent under reduced pressure. After another re-taken with isopropyl ether, it is wrung and rinsed. After drying, 4.41 g of expected product are obtained.

RMN CDC13 60 MHz (e) 03 C - NH

SN ¦ ~

(d) ~ C ~ l3 ~ a) ~ ~ ~
~ CH3 (a) N ~ CH2OCCH3 (b) CI13 ~ c) CO2CH 02 (~) = 1.53 ppm, (e) tb) = 2.01 ppm, (c) = 3.26 p.pOm, (d ~ = 6.78 ppm, (e) = 7.33 ppm Stage D: 3-acetoxymethyl 7- ~ 2- (2-tritylamino thiazol 4-yl) 2- (hydroxy imino) acetamid ~ cee ~ -3-eme 4-ca_boxylate dl ~ enyl ____ ____ ________________ _ methyl, syn-isomer.
____ _____________ _ 2.755 g of product obtained in stage C are placed.
in 14 cm of ac ~ tone and 4.5 cm3 of hydrochloric acid N ~ Shake . ~ 32 ~ 7 ~ ii two hours at room temperature and flushes the tone under pressure reduced sion.
We added 20 cm of ethyl acetate, stirred and then decanted.
The organic phase is washed with 4 times 10 cm of slightly salted water.
The lava ~ es are extracted with 5 cm3 of ethyl acetate.
The organic fractions are combined and dried. We wring, rinses ~ ethyl acetate then evaporates the solvent under pressure scaled down. The residue is taken up in ether and crystallized. We disintegrate, ~ ssore and rinse ~ ether. After drying, 1.88 g of expected product.
RMN CDC13 60 ~ z 6.88 ppm: proton of the thiazolic cycle 7.33 ppm: proton of phenyl nuclei.
Rf = 0.5 (eluent = ether containing 20% acetone ~.
Stage E: 3-acetoxymethyl 7- ~ 2- (2-tritylamino thiazol 4-yl) 2- (tertbutoxy carbonylmethyl oxy imino) acetamid ~ / ce ~ -3-th 4 di ~ hényl methyl carboxylate, syn isomer.
______ __________ ___ ____ ~ _ _ ___________ _ 0.85 g of product obtained in Stage D is introduced into 4 cm3 of dimethylformamide and 0.3 cm3 of tert-bromoacetate butyl.
After stirring for 5 minutes in an ice bath, 1.7 g of silver oxide are added.
Stir one hour after removing the bath. We wring and rinse with ethyl acetate. To the filtrate, 80 cm 3 of water are added, decanted, extract the aqueous phase with twice 20 cm3 of acetate ethyl. The organic phases are washed twice with 50 cm3 salt water. The organic phases are dried in the presence of 80 mg of activated carbon. It is filtered and rinsed with ethyl acetate.
The solvent is removed under reduced pressure, the residue is taken up with isopropyl ether. We disintegrate, spin and rinse with iso- ether propyl. After drying, 0.724 g of expected product is obtained.
Rf = 0.34 ~ methylene chloride 5% ether).

`~ ~ ~
2 ~
Example 16: Acid 3-acetoxymeth ~ 7- ~ 2- (2-amino thiazol 4-yl ~ 2-(carboxyl_methyl oxy imino? acetamid ~ ceph-3-th 4-carboxyli ~ eu isom ~ re syn in the form of trifluoroacetate.
Cooled by a methanol-ice bath 5 cm3 of acid trifluoroacetic. 0.4a2 g of product obtained is added ~ the excmple 15 and stir 15 minutes after removing ~ the bath. We observe a dissolution after 5 minutes. The acid is removed ~ under re pressure pick and add 20 cm3 of isopropyl ether. Shake 5 minutes and rinse with isopropyl ether. After drying, we get 0.277 g of expected trifluoroacetate, identical to the product obtained in example 4.
Example 17: Disodium salt of 3-acetoxymethY1 acid 7- / 2- (2-amino thiazol 4-yl) 2- (carboxyl methyl oxy imino) acetamid ~ ceph-3-core 4-carboxylic, syn-isomer.
The salt obtained in Example 16 is dissolved in 0.5 cm3 of methanol and slowly adding 1.5 cm3 of a molar solution sodium acetate in m ~ thanol. We disintegrate and add slowly-5 cm3 of ethanol. We spin, rinse twice with ethanol and then with ether. After drying, 0.178 g of disodium salt is obtained expected. Ie product is identical to that obtained in Example 5.
Example 18: 3-acetoxymethyl 7- / 2- (2-tritylamino thiazol 4-yl) 2-(tèrtbutoxycarbonyl methyl oxy imino ~ acetamid ~ ceph-3- ~ me 4-tert-butyl carboxylate, syn isomer.
Stage A- 3-acetoxymethyl 7- / 2- ~ 2-tritylamino thiazol 4-yl) 2-_______ ________ ____ ___ _ ______ _________________ _____ ~ (l-methyl l-methoxy) ethoxy lmln ~ acetamld ~ / ce ~ h-3-th 4-tert-butyl carboxylate, syn isomer.
______ ________________ ______ ___.__ _ The acid is dissolved in 120 cm3 of methylene chloride 2- (2-tritylaminothiazol 4-yl) 2- (1-methyl l-methoxy ~ thoxyimino) acetic isomer ~ y ~ obtained in stage A of example 15. We add

9.84 g of tert-butyl ester 7-amino cephalosporanic acid.

Cool to ~ 10C and add 6.6 g of dicyclohexylcarbodiimide.

Remove the cooling bath and leave for three hours 50US agitation S ~ 7 ~

at room temperature. The dicyclohexylurea obtained is drained ~ 4g) concentrated to dryness and dissolves the residue in 25 c ~ of acetate ethyl. 100 cm3 of ether are added and washed with 100 cm3 of acid 0.2N hydrochloric acid and 100 cm3 of water and 20 cm3 of molar solution sodium bicarbonate. The sodium salt is thus precipitated of the starting product which is wrung, dried and recovered ~ re 3.9 g.
Washed with water, dried, wrung, concentrated to dryness.
We take up in 50 cm3 of ether, initiate and complete the crystallization by adding 50 cm of isopropyl ether. We spin, wash and dry, 10.8 g of expected product are obtained.
F = 160C ~
RMN CDC13 60 MHz N ~ CH3 (a) (a) 1.53 ppm ~ C -CH3 (a) (b) 3.26 ppm 0-CH3 ~ b) thiazole proton: 6.76 ppm Stage B: 3-acetoxymethyl 7- / 2- (2-tritylamino thiazol 4-yl) 2-_______ ________ ____ ____ ________ _ ~ __________ ____ _____ (hydroxyimino) acetamid ~ ce ~ h-3-th 4-tert-butyl carboxylate, __ ____ _______________ __ ________________ ________________ _ syn isomer.
_________ _ The mixture is heated for three hours at ambient temperature.

the solution of 0.812 g of product obtained in stage A in 4 cm3 of ac ~ tone and 1 cm3 of normal hydrochloric acid. We add 1 cm3 of molar solution of aqueous sodium hydrogen carbonate,

10 cm3 of water and 5 cm3 of ethyl acetate. 0.551 g of expected product. F - 200C.
Analysis: C38H377N5S2 Calculated: C% 61.69 H% 5.04 N% 9.47 S% 8.66 Found: 61.5 5.0 9.1 8.4.

NMR: CDC13 60 ~ - ~ z 1.55 ppm: tert-butyl, 6.88 pp ~ m: proton of thiazole.
Stage C: 3-acetox ~ methyl 7- ~ - (2-tri-tylamino thiazol 4- ~ 1) 2-_______ ________ ____ ___ ________ _________________ _____ (tertbutoxycarbonyl methyl oxy imino) acetamid ~ ce ~ h-3-eme 4-__________ ______ ______ ____ _______ ________ __ __________ -4 ~ -s syn-isomer tert-butylel carboxylate ______ ________________ __ __________ _ We mix ~ 0.074 g of product obtained in stage B, 0.7 c ~
of dimethylformamide and 0.5 cm of tert-butyl bromoacetate ~ A
20, 0.5 g of silver oxide are introduced. Shake 30 minutes spin dry, rinse with ethyl acetate. 10 cm3 of water are added, cante, extracted with 5 c ~ of ethyl acetate then wash the phases organic combined, per 5 cm3 of salt water. We dry on sulfate of magn ~ sium, wring, rinse with ethyl acetate, chase them solvents and take up the residue in isopropyl ether. We untie you, spin and rinse with isopropyl ether:
After drying, 0.02 g is obtained of product. RF = 0.34 (methylene chloride 5% ether ethyl).
The product is identical to that obtained in Example 3.
EXAMPLE 19 Diethylamine salt of 3-ac acid toxymethY1 7-~ 2- (2-tritylamino thiazol 4-yl) 2- (tertbutoxy carbonyl methyl oxy imino) acetamid ~ eph-3-th 4-carboxylic, syn-isomer.
Stage A: Diethylamine salt of 3-acetoxy methyl acid _______ ____________ _____________________ ____ _____ _ 7- / 2- (2-tritylamino thlazol 4-yl) 2- (hydroxy imino) acetamid ~
ce ~ -3-th 4-carboxyll ~ eu, isom ~ re syn.
7.6 g of diethylamine salt of 3- acid are dissolved.
acetoxymethyl 7- / 2- (2-tritylamino thiazol 4-yl) 2 - / (1-methyl 1-methoxy ~ thoxy imin ~ acetamid ~ ceph-3- ~ me ~ -carboxylic, isomer syn, pr ~ prepared in stage B of Example 15 in 30 cm3 of acetone and 10 cm ~ 2N hydrochloric acid ~ Stir 40 minutes at temperature ambient ture ~ aioute 20 cc of water, flushes acetone at 30 ~ C, under reduced pressure; 25 cm3 of ethyl acetate, decanted, are added, reextract, wash with water, dry and spin, add to the filtrate 1 cm3 of diethylamine, clean, ice and wring out the diethyl salt amine formed, the ~ re to ether and obtains 6 g of pure product.
AnalySe: C38H407 6 2 Calculated: C% 60.30 H% 5.33 N% 11.10 S% 8.47 ~ 47-3 ~

Found: 60.5 5.7 10.9 8.2.
RMN CDC13 60 MHz 6.63 ppm: thiazole proton, 7.33 ppm: trityl proton.
Stage B: Di ~ thylamine salt of aclde 3 ~ ac ~ toxym ~ thyl 7- ~ -(2-tritylamino thiazol 4-yl) 2- (tertbutoxycaxbonyl methyl oxy imino) acetamid ~ ce ~ h-3-th 4-carboxyli ~ eu, syn isomer.
________ __ ________________ __ ______ ______ _ 10.25 g of 3-acetoxymethyl acid 7- ~ 2- (2-tritylamino thiazol 4-yl) 2- (hydroxy imino) acetamid ~ / ceph-3-th 4-carboxylic from the corresponding diethylamine salt pre-trimmed according to stage A above by treating the diethyl salt amine by aqueous hydrochloric acid after dissolution in the methylene chloride and taking up with isopropyl ether liquefy the dry residue.
The 10.25 g of acid is dissolved in 225 cm3 of chloride methylene. 150 cm3 of distilled water are added. We introduce under vigorous stirring 21 cm3 of triethylamine. We get an emul-if we. Then introduced 13.2 cm3 of tert-bromoacetate butyl. Shake three and a half hours at 20 ~ 25. We acidify at 15-20 per 90 cm3 of 2N hydrochloric acid. We stir and decant, we wash ~ distilled water, extract the waters of ~ age with chloro-form. Dry, spin, rinse with methylene chloride, concentrate dry and obtains 14.85 g of a brown resin.
This resin is taken up in 30 cm3 of ethyl acetate and slowly add 1.65 cm3 of diethylamine. The solution is introduced in ten minutes into a flask containing 60 cm3 of ether isopropyl with stirring. Shake 30 minutes at 20-25 then wring and rinses with two ~ ais 5 cm3 of a mixture ac ~ tate of ~ ethyl-isopropyl ether (1-2) then with isopropyl ether. We dries under reduced pressure and obtains 11.14 g of the expected product.
The salt is taken up in 30 cm3 of ethyl acetate. To this solution tion 30 cm3 of ethyl acetate ~ 10% isopropyl ether are added.

-4 ~ -7 ~
. ~

lique. A precipitate appears ~ Stir 5 minutes and spin. We dry concentrate until a brown residue is obtained. We take back with 50 cm of isopropyl ether. Stir for one hour at temperature ambient, wring and rinse with isopropyl ether. We obtain 10.75 g of expected product.
Analysis: C44HS09N6S2 Calculated: C% 60.67 H% 5.78N% 9.65 S% 7.36 Found: 61.1 5.8 9.67.1.
NMR CDC13 90 MHz 10 1.43 ppm: tert-butyl, 6.8 ppm: proton of the thiazole cycle.
Example 2n: Acid 3-acetoxymethyl 7- ~ 2- (2-amino_thiazol 4-yl) 2-(carboxymethyl oxy imino) acetamid ~ ceph-3-èrne 4-carboxylic, isom ~ re syn, sou ~ form of trifluoroac ~ tate.
In 36 cm3 of trifluoroacetic acid, one adds in a minute at 20-25 under an inert atmosphere, 9 g of diethylamine obtained in Example 19. The mixture is stirred under an inert atmosphere for 15 minutes.
Cooled by an ice-water bath and quickly introduced 360 cm3 isopropyl ether. Shake for 15 minutes, spin and rinse with isopropyl ether then ethyl ether. We dry and ob-holds 5.08 g of crude product. We perform a purification on different lots, ie 8.28 g of gross product in all. We mash 15 minutes in 33 cm3 of acetone at 1% water. We dilute by 330 cm of sulfuric ether, stir for 15 minutes, spin and rinse with ether sulfuric.
Dried and obtained 7.03 g of the expected product.
The product is identical to that obtained in Example 16.
Example 21: A preparation for injection of form was carried out mule:

- Acid 7- ~ - (2-amino 4-thiazolyl) 2- (carbethoxy methyl oxyimino) acetamid ~ J3-acetoxymethyl ceph-3-th 4-carboxylic acid, syn isomer .................... O ........ I ................. 500 mg - ~ r ~

~ x sterile aqueous container qs ............................ .5 cm3 Exenlplc 22: We ar ~ alis ~ a preparation for in jcction dc formula:
- Disodium salt of acid 7- ~ 2- (2-amino 4-thiazolyl) 2-(hydroxy carbonyl methyl oxyimino) acetamid ~ 3-acetoxymethyl ceph-3rd 4-carboxylic, isomer ~ y ~ ................................ 500 mg - Sterile aqueous excipient qs .............. ~ ............ 5 cm3 Example 23: We ar ~ realized q ~ lules r ~ corresponding to the ~ formulates:
- Disodium salt of 7- / 2- (2-amino 4-thiazolyl) 2 acid (hydroxy carbonyl methyl oxyimino) acetamid ~ / 3-acetoxymethyl ceph-3- ~ me 4-carboxylic, syn isomer ................................. 250 mg - Excipient qs for a capsule terminated at .................... 400 mg Example 24: A preparation was carried out for inl ction of formula:
- Sodium salt of 3-acetoxymethyl acid 7- / 2- (2-amino thiazol 4-yl) 2 - / (cyanomethyl) oxyimin ~ / acetamid ~ / ceph-3-th 4-carboxylic, syn-isomer ...... O ......... O ............ O ......... 500 mg ~ Exciplent aqueous qsO ......... O .... OO .... oo .......... ~ 5 cm3.
Example 25: A preparation was carried out ~ our in ~ tion of formula:
- Salt of ~ odium of 3-acetoxymethyl acid 7- ~ 2- (2-amino thiazol 4-yl) 2- ~ (amino carbonyl) methyl oxyimin ~ / acetamid ~
ceph-3- ~ me 4-carboxylic, isomer ~ y ~ .. ~ ......................... 500 mg - Aqueous excipient qs ....................... O ... .... 5 cm.
Example 26: We made qélules corresponding to the formula:
- Sodium salt of 3-ac acid ~ toxym ~ hyl 7 ~ / 2- (2-amino thiazol 4-yl) 2 - / (cyanomethyl) oxyimin ~ acetamid ~ / ceph-3-th 4-carboxylic, isomer ~ y ~ ................................ 250 mg - Excipient qs for a capsule finished at ...... 400 mg.

Pharmacological study of the products of the invention.
In vitro activity:
Method of dilution_ in liquid medium:
We prepare a series of tubes in which we distribute the same amount of sterile nutrient medium. We distribute in each tube of increasing quantities of the product to be studied, then each tube is seeded with a bacterial strain.
After twenty-four or forty-eight hour incubation at the oven at 37C, the inhibition of growth is appreciated by transillumination which makes it possible to determine the concentrations minimum inhibitors (MIC) expressed in ~ g / cm3.
The following results were obtained:

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11 ~ a) ~) rlh O ~ `a) rl ~ (~ 1 (d ~ rJ rl f ~ ~ rl P ~
rl rl rl r ~ ~ ~ r ~ (.) U
(JO ~ 1 rl U rl rl) 1 ~ (11 rl ~ a) o. rlUl 0 O .4 a) rl h ~. 1 rl E3 -JJCO rd - ~ 1 ~ ~ ~ ~ ~ ~ ~ O ~ rl 11 ~
. ~ h ~ ~ q ~) ~ .1- ~ 1 a) ~ h t) 5 ~. O s: OO rJ ~ O h Ul O r ~ r ~ ~ J ~ 1 1-1 ~ IJ ~ ~ 1 ~ E ~ ~ ~, ~ ~ ~ ~ I ~ ~ ~ u ~
. __ : ~ 325 ~ 75 Product of excm ~ le ~
_ ~ _______________ ____ . ~
CMI CONCERNS eu ~ / ml 24 ~ ~ 8 H __ _ ~ _________________________________________ ______.____ ~
Staphylococcus aureus ATCC 6 538 Pen-Sensitive 2 __2_____ ___________________________________________ ___________ __ Staphylococcus aureus UC 1 128 Pen-Resistant 2 3 ________________ ~ __________________________ ___ _______ __________ Staphylococcus aureus exp. n 5 ~ 146 2 3 ___________________________________________ ___________ I ----------------___ Streptococcus pyogens A 561 0.05 0.05 __________________________________________ ____________ __________ Streptococcus faecalis 5 432 3 20 ______________________________________ ~ ___ ____________ __________ Streptococcus faecalis 99 F 74 10 ~ 40 __ ~ ________________.______________________ ~ ___________ __________ ~ acillus subtilis ~ TBI 6,633 0.5 ____________.____________ _____________ ___ ____________ __________ Escherichia Coli Sensitive Tetracycline ATCC 9,637 0.5 0.5 _______ ___________________________________ ____________ __________ Escherichia Coli Resistant Tetracycline ATCC 11,303 0.05 0.05 ___________________________________________ ___________ __________ Escherichia Coli Exp. TO26B6 0.2 0.2 _______ ___________________________________ ____ ______ __________ Escherichia Coli Resistant Gentamicin, Tobramycin R 55 123 D 0.2 0.2 ___________________________________________ ___________ __________ Klebsiella pneumoniae Exp. 52 145 0.05 0.05 ___________________________________________ ___________ __________ Klebsiella pneumoniae 2,536 Resistant Gentamycin 1 ________ ~ __________________________________ ___________ _____, ____ Proteus mirabilis (indol -IA 235 0.05 0.05 ___________________________________________ ___________ __________ Salmonella typhimurium 420 0.5 0.5 ___________________________________________ ___________ __________ Enterobacter cloacae 681 3 5 ________________________.__________________ ___________ _________ _5 ~ _ s Produl t_de_l 'exem ~ le_ B_ (su1te) _ ~. CMI in, 7uq ~ ml STRAINS _________ __ _ ____ ____________________________________________ 24 H ____ ~ 8_H ____ Providencia Du 48 5 5 ____________________________________________ _________ _____________ Serratia Resistant Gentamicin 2 ~ 32 2 2 _.

3 ~ daily Product of Example 11 _________________ _____ . ~. _ STRAINS CM I. in ~ q ~ ml 24 H 48 ~
_______________, _____________________________ __________ ________ Staphylococcus aureus ATCC 6 538 Pen-Sensitive 2 3 ___ ~ ___________ ~ _______ ~ __.___________________ __________ ____ ___ Staphylococcus aureus UC 1 128 Pen-Resistant 5 5 ___________________________________ _________ _________ ________ Staphylococcus aureus exp. n 54 146 3 5 ____ _________________________________________ _________. ________ Streptococcus pyogenes A 561 0.1 0.1 ______________________________________________ ______ ~ ___ ________ Streptococcus faec ~ lis 5 432 __________ ________ Streptococcus ~ aecalis 99 F 74 20> 40 ______________________________________________ __________ ________ Bacillus subtilis ATCC 6,633 0.5 ______________________________________________ __________ _________ Escherichia Coli Sensitive Tetracycline ATCC ~ 637 0.2 0.5 _____________________________________________ _______ ~ __ _________ Escherichia Coli Resistant Tetracycline ATCC 11,303 0.05 0.05 _____________________________ ~ _______________ __________ _________ Escherichia Coli Exp. TO26B6 0 ~ 1 0.1 ______________________________________________ __________ _________ Escherichia Coli Resistant Gentamicin, Tobramycin R 55 123 D 0.1 0.1 _____________________________________________ __________ _________.
Klebsiella pneumoniae Exp. 52 145 0.05 0.05 _ ~ ________________ __________________________ __________ I ------______ Klebsiella pneumoniae 2,536 Resis-tant Genta-mycin 0.5 0.5 _____________________________________________ _______.__ I --________ Proteus mirabilis (indol-) A 235 0.1 0.1 _ ___ ___ ____ ___ _ __ __ _ _ _ _ __ __ __ _ __ _ _ _ _. _ _ __ _ _, _ _. ____ __ I --__ __ _ ___ Proteus vulgaris (indol ~) ~ 232 5 ~ 0 _____________________________________________ ________. _______ Product of example 11 (following) _________________ _______.____ CONCERNED ~ ES CM I. in ~ / mI
. 24 Tl ~ 8 Tl ___________________ ~ ___________________ ____ ________ ____________ Salmonella typhimurium 420 0.2 0.2 _____________________.______________________ ____ ~ ___ ____________ Enterobacter cloacae 681 2 10 ________________ ~ ___________________________ ________ _____.______ Providencia Du 48 5 5 ___________________________ _ ______________ ________ ____________ Serratia Resistant Gentamicin 2,532 Pro ~ him ~ x ~ m ~
_________________ _____ _ _ _ CM I in ~ ml CONCERNED
_________________________________________ __24_H______ 48 H ___ Staphyl.ococcus aurcus ~ TCC 6 533 Pcn-Sensitive 20 20 _________________________________________ ____________ __________ Staphylococcus aureus ~ C 1 128 Pen-Resistant 20 40 I ____ ___ _____ _ __ __ _ ______ _____ __ __ _______ _____. __ _ Staphylococcus aureus exp. n 5 ~ 146 20 ~ 40 ___________________________________ _____ ____________ ___________ Streptococcus pyo ~ nes A 561 1 __________________ ~ __________________ _ ____________ ___________ Streptococcus faecalis 5 432>40> 40 ________________________________________ ___________ ___ _ _____ Streptococcus faecalis 99 F 74 ~ 40> 40 __.___________________ ~ _________________ ____________ ___________ Bacillus subtilis ATCC 6 633 10 ~ 40.
________________________________________ ____________ ___ _______ Escherichia Coli Sensitive Tetracycline ATCC 9,637 0.5 0.5 ________________________________________ ____________ ___________ Escherichia Coli Resistant Tetracycline ATCC 11,303 0.2 0.2 _____________ ~ __________ _.__ __________ ____________ _ _________ Escherichia Coli Exp. TO26B6 0.5 0.5 ________________________________ ~ ________ ____________ __ ________ Escherichia Coli Resistant Gentamicin, Tobramycin R 55 123 D 0.5 0.5 _________________________________________ ____________. ___________ Klebsiella pneumoniae Exp. 52 145 1 _________________________________________ ___________ ___________ Klebsiella pneumoniae 2,536 Resistant Gentamycin 1 _________________________________________ ___________ ___________ Proteus mirabilis (indol-) A 235 0.05 0.05 _________________________________________ ___ _______ ____, .___ __ Proteus vulgaris (indol +) A 232 0.1 3 ________________________________________ ___________ __________ ~ ~ `\
~ 3 ~

Product of 1 example 1 ~ (follow ~
____________ ~ ____ __________ _ STRAINS CM _I in uq ~ ml . 24 H 48 ~ 1 _________ _______________________________ ____ ~ ______. ~ ____________ Salmonella typhimurium 420 1 ___ ~ _________________ _____ _ ____________ ___________ .__________ Enterobacter cloacae 681 40 ~ 40 _________ ________________________________ ___________ .___ ________.
~ rovidencia Du 48 2 3 ________________ ______________ __________ __________ .______.___ __ Serratia Resistant Gentamicin 2,532 1

Claims (8)

The embodiments of the invention, about which an exclusive right of property or privilege is claimed, are defined as follows: 1. Process for the preparation of the acids of formula general:

(III) in which R2 represents an easily removable group by acid hydrolysis or by hydrogenolysis or a chloro- radical acetyl, R3 represents either a CO2R "1 group in which R "1 represents an alkyl radical having from 1 to 3 atoms of carbon, or an ester group easily removable by acid hydrolysis or by hydrogenolysis, a radical nitrile, ie a carbamoyl radical - CONH2, R 'and R ", identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms, the group lying in the syn position, characterized in that:
a) we act in the presence of a strong base on a product of formula (IV):
(IV) in which R2 represents an easily removable group by acid hydrolysis or by hydrogenolysis or a chloro- radical acetyl, and the OH group is in the syn position, a product of formula (V):

(V) in which Hal represents a halogen atom, R 'and R "
identical or different represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms and R3 represents either a CO2R "1 group in which R" 1 represents has an alkyl radical having from 1 to 3 carbon atoms or an easily removable group by acid hydrolysis or by hydrogenolysis, either a nitrile radical or a radical carbamoyl -CONH2, to obtain the product of formula (III) expected; or b) act in the presence of a base on a product of formula (X):
(X) in which alk represents an alkyl radical having from 1 to 4 carbon atoms, a product of formula (V):

(V) in which Hal, R ', R "and R3 have the indicated meaning above, to obtain a product of formula (XVI):

(XVI) product of formula (XVI) which is treated with a base then with an acid to obtain the product of formula (III) expected; or c) processes in the presence of a base a product of formula (X), syn isomer:
(X) in which alk has the meaning indicated above, by a product of formula (V '):

(V ') in which Hal, R 'and R "have the indicated meaning above and alk1 represents an alkyl radical having from 1 to 4 carbon atoms, to obtain a product of formula (XI):
(XI) product that is treated with a base, then with an acid to obtain a product of formula (XII):
(XII) product of formula (XII) from which a derivative is first formed reactive, then treated with ammonia, to obtain a product of formula (XIII):
(XIII) product of formula (XIII) which is treated with a base, then with an acid to obtain a product of formula (III ′), syn isomer:

(III ') in which R2, R 'and R "have the abovementioned meaning, and corresponding to a product of formula (III) in which R3 represents a carbamoyl radical -CONH2; or d) processes in the presence of a base a product of formula (IV), syn isomer:

(IV) in which R2 has the meaning indicated above, by two equivalents of products of formula (XIV):

(XIV) in which Hal, R 'and R "have the indicated meaning above, to obtain a product of formula (XV):

(XV) product of formula (XV) which is treated with a base, then with an acid to obtain a product of formula (III "), syn isomer:

(III ") in which R2, R 'and R "have the abovementioned meaning and corresponding to a product of formula (III) in which R3 represents a nitrile radical. 2. Method according to claim 1, characterized in that one operates starting from a product of formula (Y) in which R3 represents a carbamoyl radical CONH2. 3. Method according to claim 1, characterized in that we treat in the presence of a base a product of formula (X), syn isomer.

(X) in which alk has the abovementioned meaning by a product of formula (V '):

(V ') in which Hal, R 'and R "have the above meaning and alk1 represents an alkyl radical having from 1 to 4 atoms of carbon, to obtain a product of formula (XI):

(XI) product that is treated with a base, then with an acid to obtain a product of formula (XII):

(XII) product of formula (XII) from which a derivative is first formed reactive, then treated with ammonia, to obtain a product of formula (XIII):

(XIII) product of formula (XIII) which is treated with a base, then by an acid to obtain a product of formula (III '), isomer (III ') in which R2, R 'and R "have the abovementioned meaning, and corresponding to a product of formula (III) in which R3 represents a carbamoyl radical CONH2. 4. Method according to claim 1, characterized in that one operates starting from a product of formula (V) in which R3 represents a nitrile radical.

5. Method according to claim 1, characterized in that we treat in the presence of a base a product of formula (IV), syn isomer:

(IV) in which R2 has the abovementioned meaning, by two equivalents of products of formula (XIV):

(XIV) in which Hal, R 'and R "have the abovementioned meaning, to obtain a product of formula (XV):

(XV) product of formula (XV) which is treated with a base, then with an acid to obtain a product of formula (III "), syn isomer:

(III ") in which R2, R 'and R "have the abovementioned meaning, and corresponding to a product of formula (III) in which R3 represents a nitrile radical. 5. The acids of general formula:

(III) in which R2 represents an easily removable group by acid hydrolysis or by hydrogenolysis or a chloro- radical acetyl, R3 represents either a CO2R "1 group in which R "1 represents an alkyl radical having from 1 to 3 atoms of carbon, or an ester group easily removable by acid hydrolysis or by hydrogenolysis, either a radical nitrile, ie a carbamoyl radical -CONH2, R 'and R ", identical or different, represent a hydrogen atom or an alkyl radical having from 1 to 3 carbon atoms, the group being in the syn position, each once they are obtained by a process according to claim 1 or its obvious chemical equivalents. 7. The acids according to claim 6, characterized in that R3 represents a carbamoyl radical -CONH2, each once they are obtained by a process according to the claims 2 or 3, or their obvious chemical equivalents. 8 The acids according to claim 6, characterized in that R3 represents a nitrile radical, whenever they are obtained by a process according to claims 4 or 5, or their obvious chemical equivalents.