DE2223375C2 - 7 β- (α-Substitute hydroxyiminoheteroarylacetamido) cephalosporins and processes for their preparation - Google Patents

Description

is (where Y is as defined above) a compound of formula VI

-N. -I-CH ₂ Y ¹

COOR ¹⁰ (where acyl is the group

RC CO- ll

i
0R ^a

or a precursor thereof, B, R \ R ¹⁰ and the dashed line have the above meanings and Y is an exchangeable residue of a nucleophile) is reacted with a corresponding nucleophile, after which, if necessary or desired, one of the following reactions is carried out in each case .:

D) (i) Conversion of a precursor for the group

RC CO-

10

15th 20th

30th

OR ^a

in this group.

(ii) converting a ^ isomer to the desired ^ isomer;
(iii) removal of any carboxy> 1 blocking groups;

35 40

(iv) reduction of a compound wherein Z) is s - O to form the desired compound with Z =) S

(ν) deacylation of a compound in which Y is an acyloxy group to form a 3-hydroxy aa

methyl compound and
(vi) acylation of a compound where Y is hydroxy to form a 3-acyloxymethyl or

3-carbamoyloxymethyl compound and

E) Obtaining the desired compound of the formula I, after separating off the isomers, if necessary.

4. The method according to claim 3, characterized in that the acid of the formula IV is in the syn-isomer form is present.

5. A pharmaceutical composition containing a compound according to any one of claims 1 to 2 together with a pharmaceutical carrier or diluent.

The invention relates to 7 / Ha-SUbStU. HydroxyiminoheteroarylacetamidoJ-cephalosporins
The cephalosporin compounds described herein are generally named with reference to Cepham (J. Amer. Chem. Soc. 1962, 843400). The term "cephem" means the cepham backbone with a double bond.

It is well known that antibiotics of the cephalosporin series 7> acylamido-ceph-3-em-4-carboxylic acids and their various non-toxic derivatives, for example the salts, esters, lactones (if such are formed can), the amides, hydrates or the corresponding sulfoxides. are. These antibiotics can be different Substituents. contained in particular in the 7- and 3-position, as can be seen, for example, from the four half-

60 65

■■ "—- ~

synthetic cephalosporin antibiotics that are already on the market:

50

link 7 position CO NH - 3-position • CO CH ₃ Cefaloiin <^ ~ ^ V-CH, CO- NH- -CH ₂ O Cefaloridin <^ ~ V ~ CHj -CO -NH- - CH ₂ N Cefalexin A K (Dl
<f V-CH - CH ₃ NH ₂ -CO NH- Ceialoglycine <f ^> - CH -CK ₂ O

10 15 20

NH ₂

Other cephalosporin antibiotics which are not commercially available are from GB-PS 12 08 014 and 12 08 015 known. These relate to 7-arylglyoxylamido-cephalosporin compounds, the aryl group being preferred Is phenyl or substituted phenyl, but optionally also a heterocyclic aromatic Group can be. Although both patents are primarily the simple 7-aryIglyoxylamido compounds concern, are possible derivatives thereof, such as the oxime, semicarbazone thiosemicaroazone, isonicotinoylhydrazone, Hydrazone and Methoxirnderivate mentioned. As for the methoxime derivatives are the only ones Examples Example 34 in GB-PS 12 08 014 and Example 35 in GB-PS 12 08 015, and in both cases it is indicated that the product is likely a mixture of syn and anti forms. The repetition of these examples showed that the products consisted of a mixture of syn and anti isomers in an approximate ratio consist of 50:50.

Of the compounds according to GB-PS 12 08 014 and 12 08 015 it is stated that they are orally active and it will provide activity data for some of the compounds against strains of the Gram-positive organism Called Staphylococcus aureus. However, nothing is mentioned about an activity of these compounds against gram-negative organisms or the lactamase stability of these compounds.

Another well-known cephalosporin antibiotic that was not yet on the market in 1971 is the following:

40

Connection 7-position 3-position

N N

Cefamandol -CH CO NH- -CH ₂ S-Ji N

OH V

This connection is described in DE-OS 20 18 600, especially on page 3 and in claim 6 of the Compounds of DE-OS 20 18 600 are stated to have a high activity and also exceptional be stable; in particular it is indicated that the compounds against cephalosporinases, which produced by Gram-negative bacteria are stable.

According to the invention it has surprisingly been found that new Cephalosponn compounds which are characterized in that the acylamido group in 7-Ste) 'ung of the cephalosporin antibiotic (σ-etherified oxyimino) acylamido group and the compounds are syn isomers or mixtures in which the syn-isomeric form predominates, have high antibacterial activity against a number of Gram-posili-60 ven and gram-negative organisms, associated with a particularly high stability for J? -lactamases, the

\ are produced by various gram-negative organisms. In particular, it has been shown that the

§ jS-lactamase-Siability of the new cephalosporin compounds, which by the presence of the mentioned

syn- (a-etherified oxyimino) -acylamido group in the 7-position are characterized, is much higher than the-

Those of cefalotin, cefaloridin, cefalexin, cefaloglycine and cefamandol and other cephalosporin compounds

"'65 fertilize with similar 7-acylamido groups, but without the syn-oxyimino group. It also has

demonstrated that the syn-oxyimino compounds of the present invention had superior antibacterial activity have compared to the corresponding anti-oxyimino compounds. Has the mentioned syn- (a-etherified oxyiminoJ-acylamido group in the compounds according to the invention

the structure

RC -CONH-

OR '

(wherein R and R ^{a are} as defined below), the compounds according to the invention being in the form of the syn isomer or being present as a mixture containing at least 75% of the syn isomer. The isomer mixtures preferably contain at least 90% of the syn isomer and not more than 10% of the anti isomer. The designation of the syn (cis) -isomeric form as

R-C-CO -NH-

OR "
and the anti form as

R-C-CO-NH-

Il

N R'O

25th

is based on the work of Ahmad and Spencer (Can. J. Chem., 1961, 39, 1340).

According to one feature of the invention, 7j5- (e-substit. HydroxyiminoheteroarylacetamidoJ-cephalosporins of the general formula I.

R — C —CO —NH

OR ^a

COOH

O)

30th

35

in which the symbols R, R ^a and P have the following meanings:

R is a 5-membered heteroaromatic group with at least one 0, S or N atom;

R ^{a is} an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 8 carbon atoms, propynyl, a cycloalkyl group with 3 to 7 carbon atoms or a phenyl group or any of these groups substituted by hydroxy, methoxy, ethoxy, bromine, nitro, amino, carboxy or Benzoyl and

P methyl, vinyl or the group -CH ₂ Y, in which Y is

(I) the remainder of a pyridine base,

(II) azido,

(III) the group -SR ⁶ , where R ^{6 is} lower alkyl or a 5- or 6-membered heterocyclic group with at least one O, N or S atom,

(IV) hydroxy;

(V) the group -O · CO · R ^9, wherein R ⁹ is a C, _ ₄ alkyl, vinyl, propenyl, phenyl or C ₃ - ₆ -CydoalkyI radical;

(VI) the group -O · CO · NH (CH ₂ ) _m X, where X is hydrogen, chlorine, bromine or iodine and m is an integer from 1 to 4;

(VII) carbamoyloxy or pyridylcarbamoyloxy,

and the physiologically acceptable salts and sulfoxides thereof, the compounds being the syn isomers or are mixtures of syn and anti isomers that are at least 75% of the syn isomer contain.

Salts which, if they can be used, can be prepared from the compounds according to the invention, include (a) salts of inorganic bases such as of alkali metal, for example sodium and potassium, alkaline earth metal, for example calcium, and organic bases such as procaine, phenylethylbenzylamine and Dibenzylethylenediamine, salts and (b) acid addition salts, for example with hydrochloric acid, hydrobromic acid. Sulfuric acid, nitric acid, phosphoric acid, toluene-p-sulfonic acid and methanesulfonic acid. The salts can also be in the form of resinates, made for example with a polyslyrole resin, that contains amino, quaternary or sulfonic acid groups, or with a resin that contains carboxyl groups,

40

45

50 I [

60 I.

I. i ü

65 I.

for example a polyacrylic acid resin. The resin can be crosslinked if desired, for example it can be a copolymer of styrene and divinylbenzene which contains the appropriate groups. The derivatives can also exist in the form of chelates with heavy metals such as iron or copper. As mentioned above, the compounds of the present invention are characterized by their high antibacterial activity versus a wide range of gram-positive and gram-negative organisms associated with one particularly high stability for ^ -lactamases, which are produced by various Gram-positive organisms, marked.

The stability against ^ -lactamases can be determined by using cefaloridin, the arbitrary Value 1 is assigned to lcanruin with respect to the particular organism being compared. The stability for

10β-lactamases can be determined in a similar manner in comparison with cefamandol.

The compounds according to the invention have been shown to have a higher stability towards / f-lactamases, which generally corresponds to a value of at least 30, compared with both cefaloridin and cefamandol "in tests against the R-plasmid-mediated enzyme TEM as also the chromosomally mediated enzymes Kl and P99. Due to their higher ^ -lactamase stability, the compounds of the invention have a superior activity compared to known compounds, such as cefaloridin and cefamandol, against Gram-negative organisms which produce S-lactamase enzymes, including the void Gram-negative organisms which are producers of R-plasmid-mediated jβ-lactamases.
The superiority of the compounds according to the invention compared to cefamandol over certain organisms which produce ^ -lactamase is shown in Tables A and B below by biological test data.

In the following Table A are the inhibitory concentrations for four compounds according to the invention and given for cefamandol against s-lactamase and non-s-lactamase producing strains. The> lactamase-producing Strains were specially grown in the laboratory by adding plasmids which are responsible for the production of S-lactamase are responsible have been transferred to a non-producing strain. If you have the Activities of the compounds according to the invention and of cefamandol towards the jS-lactamase-producing Strains with their activities towards the non-lactamase-producing original strain compares, so one can see the effect of the particular jJ-lactamases, which by the transferred plasmids to determine the connections. For example, if the aclivity ratio for a connection against a strain of E. coli which produces TEM-1-./5 -lactamase to the activity against the original non-jS-lactamase producing strain is less than 4, it can be said that the compound is stable to TEM-1-jS-lactamase. However, if the ratio is greater than or equal to 4, then will considered the compound sensitive to TEM-1-jJ-lactamase. If a connection for a particular / -lactamase is sensitive, so it is likely that there will be a marked increase in the ratio

35 is present at the higher inoculum levels (10'cfu). Table A, O-Lactamase Stability

Organism Main inhibitory values at 10 ⁵ and 10 'inoculum levels

> Laciamase Cefamandol Example 1 Example 12 Example 25

10 ⁵ 10 ⁷ 10 ⁵ 10 ⁷ 10 ⁵ 10 ⁷ 10 ⁵ Iu ⁷

To show that these results are not a laboratory phenomenon, the four were made according to the invention Compounds and cefamandole with a number of S-lactamase and non-Lactamase-producing Strains of each of the following species Staph. aureus, E. coli and Proteus spp. compared. All tribes of these species were fresh clinical isolates. The ratio of the geometric mean inhibition values for the compounds against J? lactmase producing strains at the geometric mean inhibition values for the same

Compounds against non-lactamase-producing strains at both 10 ^s and 10 ⁷ inoculum levels are given in Table B below. Thus, if the ratio of activity for a compound is less than 3, then the compound can be considered stable to S-lactamase. However, if the ratio is greater than or equal to 3, the compound is considered sensitive to -lactamase. Again, a clear increase in the ratio in the higher (10 ⁷ cfu) inoculum is an indication that

65 that the compound is sensitive to a particular j8-lactamase.

E. coli J53REK TEM-I 8th 250 1 0.5 1 0.5 1 1 E. coli RP4 TEM-2 > 250 > 250 0.5 1 0.5 1 0.5 1 E. coli R1010 SHV-I 8th 62 1 1 1 1 1 2 E. coli R455 OXA-I 2 4th 1 i 2 2 1 2 E. coli R46-T ^{see p} OXA-2 8th 52 i i *
i 1
1 1 1 E. coli R57b OXA-3 4th 4th 1 0.5 1 1 1 1

Table B.

^ -Lactamase stability:

Effectiveness of geometric MiUel inhibition value results

08-lactamase-producing: non-jS-laciamase-producing)

species Cefamandol 10 ⁷ example 1 10 ⁷ Example 12 10 ⁷ Example 25 10 ⁷ 10 ⁵ 3.4 1O ⁵ 1.3 10 ⁵ 1.1 10 ⁵ 1.4 Staph. spp. 1.4 13.5 1.2 1.3 0.8 1.1 1.2 1 E. coli 3.9 18.7 1.1 1.7 1 1.2 0.9 0.9 Proteus 5.3 1 1.1 1 (Indole negative)

A ratio of> 3 is significant.

The properties of the compounds of the invention make them useful in the treatment of a wide variety diseases caused by pathogenic bacteria in humans and animals are useful.

The group R ¹ in the above formula I can be, for example: a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl group; a vinyl, allyl, isopropenyl or dimethylallyl group; a propynyl group such as propargyl; a cyclopropyl, cyclopentyl or cyclohexyl group; or a phenyl group.

In general, R 'can be unsubstituted or carry a substituent, such as hydroxy; Methoxy or Ethoxy, such as in methoxymethyl or 1-ethoxyethyl; Bromine, such as in 2-bromoethyl; Amino, such as in 2-aminoethyl; Nitro; Carboxy; or benzoyl.

The group R in the general formula above may be selected from the following list which does not exhaustive is:

Thien-2-yl, thien-3-yl, furyl, such as fur-2-yl, pyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or 4-isoxazolyl, and benzothienyl such as benzothien-3-yl, benzofuryl and indolyl.

The substituent P in the 3-position of the above compounds of the formula I can be one of those as defined above be organic groups, the characteristic feature of the invention being the presence of the syn-oxyimino group is in the 7-substituent. For example, P can be methyl or vinyl; or a group the formula

-CH ₂ Y

wherein Y is the residue of a nucleophile which is defined in more detail in claim 1. Examples of nucleophiles include:

Nitrogen nucleophiles

Examples of nitrogen nucleophiles are pyridine bases such as pyridine, carbamoyl pyridine and alkyl pyridines. Other examples are azides, e.g. B. such as sodium azide.

Sulfur nucleophiles

Examples of sulfur nucleophiles are compounds of the general formula R ⁶ SH, in which R ^{6 is} lower alky !, 2. B. methyl, ethy! or n-Propy! is; or a 5- or 5-membered heterocyclic group with at least one O, N and S atom, e.g. B. thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, benzimidazolyl, benzoxazolyl, triazolopyridyl or purinyl.

Oxygen nucleophiles

Examples of oxygen nucleophiles include water, the compounds of the invention then being 3-hydroxymethyl-cephalosporin compounds are. Such compounds have the formula II

R-C-CONH

OR

CH ₂ OH

OD

COOH

60

65

wherein R and R ^{a have} the meanings defined above. Compounds of the formula Π can be acylated to form derivatives which are characterized by being the group 3-CH ₂ · O · CO · R ⁹ or 3-CH ₂ - O · CO · NH (CH ₃ ) _m X possess, wherein R ^{9 is} C ₁ _ ₄ alkyl, z. B. methyl, ethyl, propyl, isopropyl, n-butyl,

20th

25th

30th

35 i

40

45

50

55

- Phenyl or C ₃ - ₅ cycloalkyl, ζ. B. cyclohexyl, cyclopentyl f

_scl5lull ^^ omorjodiundmistemenumberoflbi ^ .Other examples for |

gen der'Formel II are the 3-CarbamQyloxymethyl- and 3-Pyndylcarbamoyloxyme- j

thyl-cephalosporins. |

Manufacture |

created which includes either | (A) condensing a compound of formula III
B.

* - * I ti 11UJ i

COOR ¹⁰

20th

tel advantageous to the syn isomer, corresponding to the acid iv
RC-COOH

! 1 5

N *

( 1

OR ^a \

(in which R and R 'have the meanings given above) or with an acylating agent corresponding to an acid which is a precursor for acid IV; or
B) Reaction of a compound of the formula V

O = C = NJ (\ (γ) j

<f T ^]

COOR ¹⁰ \

(wherein the dotted line, B, P, and R "have the meanings given above ha _b ^ _{of Ausnahrn} e.
that R ^{10 is} not hydrogen) with an acid or precursor thereof, of the formula IV, or,

C) if P is the group

-CH ₂ Y i

(wherein Y is as defined above), reaction of a compound of VI;

Acyl NH-

-N Λ — CH ₂ Y ¹ ι

^ "

COOR ¹⁰

(woirin acyl the group
60

R c coll

N
1

OR '

agile or desired, one of the following reactions is carried out in each case:
D) (i) Conversion of a precursor for the group
RC-CO—

0R ^a

in this group;

(ii) converting a ^ -isomer to the desired ^ -isomer;
(iii) removal of any carboxyl blocking groups;

(iv) reducing a compound wherein Z is / S-O to form the desired compound with

Z =

10

15th

(V)

R-C-COOH

Ii

(vn)

0R ^a

wherein R and R 'have the meanings given above, with an amino compound of the formula III

H ₂ N

(HD

20th

Deacylating a compound where Y is an acyloxy group to form a 3-hydroxymethyl compound and

(vi) acylation of a compound wherein Y is hydroxy to form a 3-acyloxymethyl or 3-caruäüiüyiüxyrneihylveibinduiig and

E) Obtaining the desired compound of the formula I, after separating off the isomers, if necessary.

The salts of the compounds according to the invention can be formed in a manner known per se. For example Salts with bases can be formed by reaction of cephalosporic acid with sodium or Potassium 2-ethylhexanoate.

In practice it is advisable to use an acylating agent corresponding to acid VII

30th

35

40

[wherein the dashed line, P and B have the meanings defined above and R ^{10 is} hydrogen or a carboxyl blocking group, e.g. B. the residue of an ester-forming alcohol (aliphatic or araliphatic), phenol, silanol, stannanol or acid] is condensed, the condensation being carried out, if desired, in the presence of a condensing agent; then, if necessary, the group R ^{10 can be} removed. One can also use a derivative of the amino compounds, such as a salt, e.g. B. a tosylate, use.

The compounds of the formula I can be prepared using an acid halide, in particular an acid chloride or bromide, as the acylating agent. The acylation can 5O ⁰ C at temperatures from -50 to +, are preferably -20 to +30 ⁰ C is performed. The acylating agent can be prepared by reacting the acid VII or a salt thereof with a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride. The use of oxalyl chloride together with the sodium or potassium salt of acid (VII) is preferred since isomerization is minimal under these conditions; the acylation can be carried out in aqueous or non-aqueous medium, and suitable media include an aqueous ketone such as aqueous acetone, an ester such as ethyl acetate, or an amide such as dimethylacetamide, or a nitrile such as acetonitrile or mixtures thereof.

Acylation with an acid halide can be carried out in the presence of an acid binding agent, for example a tertiary amine (e.g. triethylamine or dimethylaniline), an inorganic base (e.g. Calcium carbonate or sodium bicarbonate) or an oxirane, which is used in the acylation reaction released hydrogen halide binds, be carried out. The oxirane is preferably a low-1,2-alkylene oxide, for example ethylene oxide or propylene oxide.

If the free acid form of a compound of formula (VII) is used, suitable condensing agents include for the preparation of the compounds according to the invention carbodiimides, for example N, N'-diethyl, Dipropyl- or diisopropylcarbodiimide, Ν, Ν'-dicyclohexylcarbodiimide or N ^ ethyl-N '- ^ dimethyl-

aminopropylcarbodiimide, a suitable carbonyl compound, for example carbonyldiimidazole, or a Isoxazolinium salt, for example N-ethyl-5-phenylisoxazolinium-3'-sulfonate and N-tert-butyl-5-methylisoxazolinium perchlorate. The condensation reaction is preferably carried out in an anhydrous reaction medium, for example in methylene chloride, dimethylformamide or acetonitrile, since the reaction is then

5 control parameters such as temperature better and more precisely.

Alternatively, the acylation can be carried out with other amide-forming derivatives of the free acid such as, for example a symmetrical anhydride or mixed anhydride, for example with pivalic acid, or with a Haloformate, for example a lower alkyl haloformate, take place. The mixed or symmetrical Anhydrides can be formed in situ. For example, you can form a mixed anhydride,

ίο by using N-ethoxycarbonyl-l-ethoxy-l ^ -dihydroquinoline. Mixed anhydrides can be used also with phosphoric acids (for example with phosphoric acids or phosphorous acids), sulfuric acid or aliphatic or aromatic sulfonic acids (for example p-toluenesulfonic acid). Another a useful acylating agent is an activated ester, for example a compound of formula VIII

■ 5 R-C-CO-L (VIE) i

Il

N OR ^a

where L is, for example, an azide, oxysuccinimide, oxybenztriazole, pentachlorophenoxy or p-nitrophene

means oxy group. I.

Alternatively, the compounds according to the invention can be prepared from a compound of the formula V f

are prepared (where the dashed line, B, P and R ^{10 have} the definitions given above, with the exception that R ^{10 is} not hydrogen), by reaction with an acid or the precursor, of the formula VI and subsequent removal of the Group R ¹⁰ (see, for example, Belgian patent specification 7 60 494). The reaction of the compound of the formula (III) or (V) can be carried out towards the end of the preparative sequence or the step reaction, the only additional reactions being the reactions in which the protective groups are removed and the purification processes. If desired, you can first use a compound of the formula IX §

⁴⁰ R-CO-CO-NH-

COOR ¹ " _K

(in which the dashed line, R, R ¹⁰ , B and P have the meanings given above) and then one can react the compound of formula (IX) with R "O · KH ₂ (in which R" has the definition given above ) and then remove ^{group R 10 if necessary.} The reaction product can be separated off, the desired syn isomer being obtained before or after the removal of the R ¹⁰ group.
A useful preliminary to the desired

R-C-CO group

55 Il

OR "is the corresponding 2-hydroxyiminoacyl group

R-C CO- I

Il »

^N H

⁶⁵ OH

since this can easily be converted into the desired group by etherification. You can have such a connection of the formula (I) obtained by adding a compound of the formula X

10

R-C CO-NH

OH

wherein all dashed lines, R, R ¹⁰ , B and P have the definitions given above, are reacted with an etherifying agent which serves to introduce the group R ^s and then, if desired and necessary, any of reactions D (ii) - (vi), which have been described above, carry out and, if necessary, isolate the desired compound according to the invention after separation of the isomers.

The etherifying agent can be, for example, an organic halide or sulfate or a sulfonate such as a tosylate. Other acidifying agents include diazoalkanes such as diazomethane or diazoethane, alkyl fluorosulfonates such as methyl fluorosulfonate, and alkyloxonium tetrafluoroborates such as trialkyloxonium tetrafluoroborate such as triethyloxonium tetrafluoroborate and diphenyliodonium bromide. _{It may be necessary to add auxiliaries, for example a Lewis acid such as BF 3} , in etherification reactions in which a diazo compound, a fluorosulfonate or a tetrafluoroborate is used.

If desired, one P group can be replaced by another preferred P group, after the acylation of the 7-amino or 7-isocyanato compound has been carried out »" Especially if P the group

-CH ₂ Y

where Y is as defined above, the group Y can according to any one in the literature procedures described are introduced. You can thus compounds in which Y is a thioether group, as described in Belgian patents 7 34 532 and 7 34 533. Links, wherein Y is the residue of a nucleophile can be prepared by adding a 3-acetoxymethylcephalosporin compound with a Nucleophii, for example a pyridine base, as it is in the British Patent 9 12 541 is described; a sulfur-bound or nitrogen-bound nucleophile, as described in British Patent 10 12 943; a sulfur-bound nucleophile, as described in British Patents 10 59 562, 11 01 423 and 12 06 305, or one Nitrogen-containing nucleophiles as described in British Patents 10 30 630, 10 82 943 and 10 82 962 is described.

Compounds according to the invention in which Y denotes the radical of a nucleophile can also be carried out by Reaction of a 3-halomethylcephalosporin with any of those described in the above references Nucleophiles are produced, for example according to a method as described in Belgian Patent 7 19 711 is described. If Y is a hydroxy compound, the compound can according to Processes as described in British patent specification 1121,308 can be obtained.

Compounds containing a vinyl group as a 3-substituent can be prepared according to the method as described in Belgian patent 7 61 89 ".

The 3-halomethyl-Ceph-3-em compounds used as starting material can be obtained by halogenation of a T ^ acylamidoO-methylcephO-ern ^ -carbic acid ester-L / I-oxide, followed by reduction of the ljff-Oxyd-Gruppe can be prepared later in the sequence as described in Belgian patent 7 55 256 is described.

The corresponding Ceph-2-em compounds can according to the published Dutch patent application 69 02 013 described method can be obtained, wherein one Ceph ^ -emO-methyl compounds reacted with N-bromosuccinimide and the Ceph-2-em-3-bromomethyl compound is obtained.

Cephalosporin compounds which contain an acyloxymethyl group as a substituent in the 3-position can be prepared by well-known processes. For example, they can be prepared from cephalosporin _{compounds which contain a 3-CH 2} Y ¹ group, where Y ¹ = OH or the remainder of an acid HY ¹ , which has a pKa value of not greater than 4.0 and preferably not more than 3.5 (determined in water at 25 ° C).

The group Y 'can have a chlorine, a bromine or an iodine atom, a formyloxy or an acetoxy group at least one electron withdrawing substituent on the ^ carbon atom or a Kürnsubslituierten Benzoyloxy group, with the core substituent belonging to the group that withdraws electrons, as in the British Patent 12 41657 described, and the nucleophüe substitution reaction in which the desired substituent is introduced at the 3-position can be carried out as in the aforementioned British Patent 12 41 657 by the same applicant.

Alternatively, when Y is a hydroxy group, the desired S-acyloxymethylcephalosporin can be used be obtained by acylating in a manner analogous to that described in British patent specification 11 41 293, wherein in this patent a process for the preparation of. ^ - cephalosporin with a 3-acyloxymethyl substituent from the corresponding 3-hydroxymethyl analog, which consists in that the 4-carboxy group is aralkylated, the 3-hydroxymethyl group of the protected compound is acylated and then removed the aralkyl group.

The acylation can be carried out by any known method using, for example, a Acid chloride, acid anhydride or a mixed acid anhydride as acylating agent, preferably in Presence of an acid-binding agent, for example an organic base such as pyridine or a lower one Alkyleroxide, such as ethylene oxide or propylene oxide, are carried out, the reaction being carried out in

Solution in an inert, anhydrous solvent, for example methylene chloride, carried out. Alternatively the acylation can be carried out in aqueous acetone / sodium bicarbonate solution. The preferred one The acylating agent is the acid chloride.

The acylation reaction should be carried out as quickly as possible, since under the acylation conditions Rearrangements of the ^ 'derivatives can occur.

Compounds of formula III can be used as esters. Compounds of formula V are esters.

One can also use the free amino acid or an acid addition salt of the free amino acid or the ester use of it. Salts that can be used include acid addition salts, for example with Hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, toluene-p-sulfone-

10 acid and methanesulfonic acid.

The esters can be mixed with an alcohol, phenol, silanol or Stannano! formed with up to 20 carbon atoms and which can easily be split off at a later stage in the overall implementation.

Any esterifying group which substitutes the 4-carboxyl group of the compound of formula (III), (V) or (IX), is preferably with an alcohol (aliphatic or araliphatic), phenol, silanol, stannanol or an acid is formed which can easily be split off at a later stage of the reaction. Suitable Esters thus include compounds which contain ester groups selected from the following list that is not exhaustive.

(i) -GOOCR ^f R * R ^h , in which at least one of the radicals R ^r , R »and R ^{h is} an electron donor, for example p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxy or fur-2-yl. The remaining R ^f -,

R ^g and R ^h groups can be hydrogen or organic substituent groups. Suitable ester groups of this type include p-metnuxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.

(ii) -COOCR ¹¹ R ¹ R ¹¹ , in which at least one of the radicals R ^f , R »and R ^{h is} an electron attractive group, |

for example benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl. Iodomethyl, cyano- |

methyl, ethoxycarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitrophenyl or |

Cyano. The remaining R ^f , R ¹ and R ^h groups can be hydrogen or organic substituent groups |

be. Suitable esters of this type include BenzoyLo.ethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyri-I

dylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromoethoxycarbonyl. |

(iii) -COOCR ^f R ^g R \ in which at least two of the groups R ^f , R ¹ and R ^{h are} hydrocarbon radicals such as alkyl, |

for example methyl or ethyl, or aryl, for example phenyl, and the remaining R ^r -, R'- and j

R ^h groups, if any. Mean hydrogen. Suitable esters of this type include tert-butyloxy- |

carbonyl, tert-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl. I.

(iv) -COOR ¹ , where R 'is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl or tetrahy- J

means dropyran-2-yl. |

(v) Silyloxycarbonyl groups, which can be obtained by reacting a carboxyl group with a derivative of a SiIa- $,

nols receives. The derivative of a silanol is conveniently a halosilane or a silazane of the formula |

Rj ¹ SiD; Rj ¹ SiD ₂ ; Rj ¹ Si ■ NRj ¹ ; Rj ¹ Si · NH · SiRj ¹ ; Rj ¹ Si · NH · COR "; 1

Rj ¹ Si NH CO-NH-SiRj ¹ ; R ¹¹ NH CO-NR ¹¹ -SiRj ¹ ; or R ¹¹ C (OSiRj ¹ ): NSiRj ¹ I

I.

wherein D is a halogen atom and the various groups R ", which can be the same or different, *

Hydrogen atoms or alkyl, for example methyl, ethyl, n-propyl, isopropyl, aryl, for example J

Denote phenyl, or aralkyl, for example benzyl groups. Preferred derivatives of silanols are |

Silyl chlorides such as trimethylchlorosilane and dimethyldichlorosilane. 1

1

The carboxyl group can be regenerated from an ester by any of the conventional methods, for example Hydrolysis catalyzed by acids and bases is easy to carry out, as is enzymatic catalyzed hydrolysis. However, aqueous mixtures can be poor solvents for these compounds and this can cause isomerizations, rearrangements, side reactions and general degradation, so special procedures may be desirable.

Five suitable saponification methods or ester cleavage reactions are |

(1) Reaction with Lewis acids. j Suitable Lewis acids for reaction with the esters include trifluoroacetic acid, formic acid, | Hydrochloric acid in acetic acid, zinc bromide in benzene and aqueous solutions or suspensions of | Mercury OIJ compounds. The reaction with the Lewis acid can be carried out by adding a nucleophile how anisole can be relieved.

(2) reduction.

Suitable systems to carry out the reduction are zinc / acetic acid, zinc / formic acid, zinc / low-alcohol, zinc / pyridine, palladium-on-charcoal and hydrogen and sodium and liquid

Ammonia.

(3) attack by nucleophiles.

Suitable nucleophiles are those which contain a nucleophilic oxygen or sulfur atom, for example Alcohols, mercaptans and water.

(4) Oxidative processes such as those using hydrogen peroxide and acetic acid. (5) irradiation.

Where towards the end of a preparative production sequence compounds are obtained in which B / S - * O represents-

I I I I

represents, the conversion into the sulfide can be done, for example, by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salt, which is prepared in situ by reaction with, for example, acetyl chloride in the case of an acetoxyjulfonium salt, the reduction, for example, with nairium dithionite or by iodide ion in the form of a / solution of Potassium iodide in a water-miscible solvent, for example acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide, takes place. The reaction can be carried out at a temperature of -20 to +50 ⁰ C.

Alternatively, the reduction of the 1-sulfinyl group with phosphorus trichloride or tribromide 5O ⁰ C durchEftführt in a solvent such as methylene chloride, dimethylformamide or tetrahydrofuran preferably at a temperature of -20 ⁰ C to + can.

If the resulting compound is a Ceph-2-em-4-ester, the desired Ceph-3-em compound can be can be obtained by treating the first with a base.

The acid IV, which corresponds to the acylation agent, can be obtained by reacting a glyoxylic acid of the formula

R-CO-COOH

wherein R has the definition given above, or of an ester therefrom with R ¹ O · NH ₂ are obtained (R 'has the definition given above).

The resulting acid or ester can then be separated into the syn and anti isomers, for example by crystallization, chromatography or distillation, and then you can optionally, hydrolyze the ester if necessary.

In particular in the case of esters of acids of the formula (IV) in which R "is an alkyl group, the Separation of the syn and anti isomers takes place by selective hydrolysis of the esters, since this is less steric hindered anti-isomer tends to saponify faster and it can therefore be removed as free acid, and the purified syn ester remains. The separated syn isomer can then, as desired, in the corresponding Acyliemngsmittel be transferred.

The acid (IV) can also be produced by undergoing some kind of O-alkylation or O-arylation reaction on a compound of the formula

RC COOH Il

OH

performs, ie a 2-hydroxyimino acid or, more preferably, on an ester of such a 2-hydroxyimino acid. The desired reaction can be carried out with an organic halide, sulfate or sulfonate, for example a compound of the formula R ¹ J, in which R ^{a has} the definition given above and J denotes a halogen, sulfate or sulfonate such as a tosylate. Alternatively, the 2-hydroxyimino acid or an ester thereof can be reacted with a diazoalkane, for example diazomethane, an alkyl fluorosulfonate, for example methyl fluorosulfonate, or an alkyloxonium tetrafluoroborate, for example a trialkyloxonium tetrafluoroborate, such as trimethyloxonium tetrafluoroborate, or an ester thereof (VII), or an ester thereof (VII), oxoxy, is obtained, the desired ester of which is obtained. or with a diphenyliodonium bromide, the corresponding phenoxyimino acid (VII) being formed. It may be necessary to add auxiliaries, for example a Lewis acid such as BF ₃ , in these reactions with a diazo compound, a fluorosulfonate or a tetrafluoroborate.

When the acid (IV) is converted into the corresponding acylating agent, it should be noted that it is desirable is that amino groups present in R or R "should be protected as much as possible in order to avoid undesired i Avoid side reactions. Similar protection of amino groups is also desirable if the acylating agent is then reacted with a compound of the formula (III) or (V).

The syn and inu isomers can be distinguished by suitable methods, for example by their ultraviolet spectra, by thin-layer or paper chromatography or by their NMR spectra. For example, DMSO-oV solutions of compounds of the formula I show the doublet for the amide-NH lower field for the syn isomers than for the anti isomers. These factors can be used if you want to follow the implementation.

The antibacterial compounds of the present invention can be administered in any suitable manner Formulated in an analogous manner to other antibiotics and the subject of the invention are therefore pharmaceutical Compositions containing an antibacterial compound according to claims 1 or 2 and which are suitable for use in human or veterinary medicine.

Such compositions can be used in the usual manner with the help of the necessary pharmaceutical Carriers or diluents are produced.

The antibacterial compositions of the invention can be formulated for injection and they can be in unit dose forms, in ampoules, or in multi-dose containers with added preservatives to be available. The compositions can also be in the form of suspensions, solutions, Emulsions are present in oily or aqueous vehicles, and they can contain formulating agents such as suspension, Contain stabilizers and / or dispersants. Alternatively, the active ingredient can be used in powder form Reconstitution with a suitable carrier, for example with sterile, pyrogen-free: =. M water before the Use.

The compositions can be in a form suitable for absorption in the gastro-

10 15th 20th 25th 30th

40

50 55 60 65

13th

intestinal tract. Tablets and capsules for oral administration can be in unit dose presentation forms are present, and they can be suitable diluents such as binders, for example syrup, Gum arabic, gelatin, sorbitol, tragacanth or polyvinyl pyrrolidone, filler, for example lactose, Sugar, corn starch, calcium phosphate, sorbitol or glycine, lubricants or glidants, for example Magnesium stearate, talc, polyethylene glycol, silicon dioxide, disintegrants such as potato starch, or suitable crosslinking agents such as sodium lauryl sulfate. The tablets can according to known processes are coated. Oral liquid preparations can be in the form of aqueous or oily Suspensions, solutions, emulsions, syrups or elixirs or they can be in the form of a dry product present, which is reconstructed with water or other suitable carrier material before use ίο will. Such liquid preparations can contain known additives such as suspending agents, for example sorbitol syrup, Methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, fj aluminum stearate gel or hydrogenated edible fats, emulsifiers, for example lecithin, sorbitol mono-

■ ι __ oleate or gum arabic, non-aqueous carriers, edible oils, such as almond oil, fractionated

^ `` tes coconut oil, oily esters, propylene glycol or ethyl alcohol, preservatives, for example methyl

or propyl p-hydroxybenzoates or sorbic acid. Suppositories can contain common suppository raw materials, for example cocoa butter or other glycerides.

The composition may also be in forms suitable for absorption by the mucous membranes of the nose and throat or through the bronchial tissues and these can be expedient in the form of powders or liquid sprays or ingredients, lozenges or middle! to pin out of the throat. For the medication of the eyes and ears, the P preparations can be used as individual Capsules, in liquid or semi-liquid form, or they can be used as drops. Topical Applications can be in hydrophobic or hydrophilic base materials as ointments, creams, lotions, agents for brushing or powdering.

For veterinary medicine, for example, the compositions can be used as intramammary preparations be formulated in basic substances that either work for a long time or release the active ingredient quickly.

The compositions can contain from 0.1% upwards, preferably from 10 to 60% of the active material, depending on the method of administration. When the compositions contain dosage units, so each unit dose will preferably contain 50 to 500 mg of active ingredient. The dose that is for the Adult human treatment is preferably in the range of 100 to 3000 mg / day, for example 1500 mg / day, depending on the route and frequency of administration.

The compounds according to the invention can be used together with other therapeutic agents such as antibiotics, for example with other cephalosporins, penicillins or tetracyclines ^ are administered. The following examples illustrate the invention.

Manufacturing process 1

2-methoxyimino (thien-2-yl) acetic acid (syn isomers)

-to A solution of methoxyamine hydrochloride (5.85 g) in dry methanol (60 ml) was mixed with a solution from sodium methylate in methanol (from sodium, 2.5 g, and dry methanol, 50 m. "> neutralized to phenolphthalein. The precipitated sodium chloride was removed by filtration and the filtrate was removed added to a solution of thien-2-ylglyoxylic acid (10 g) in dry methanol (60 ml). The emerging Solution was refluxed for 1 hour, cooled and evaporated to give an oil. ether

(100 ml) was added, the mixture was filtered and the filtrate was evaporated to an oil (13.06 g).

The oil (12.5 g) was dissolved in ether (50 ml) and an ether solution of diazomethane was added until the permanent yellow color remained. The excess diazomethane was destroyed by adding the solution Left in sunlight for 1 hour. Evaporation of this solution gave 13.2 g of oil.

The oil (10.33 g) was _{purified by preparative layer chromatography (silica gel PF 254 + 366} ), eluting three times with 75% petroleum ether (b.p. 60 to 80 °) in benzene, and a) methyl-2- methoxyimino-2- (thien-2-yl) acetate (syn-isomer) (3.44 g, 27%), x _max (EtOH) 290 nm (ε 11 250), X _inl 271 nm (c 5400), v _{mo <} (CHBr ₃ ) 1738 and 1230 cm " ¹ (CO ₂ Me). r values (CDCl ₃ ) include 6.06 (s, CO ₂ CH ₃ ), 5.78 (s, OCH ₃ ). 2n Sodium hydroxide (8.27 ml) was added to a solution of methyl 2-methoxyimino-2- (thienyl-2-yl) aceiate (syn-Isomeres) (3.28 g) in methanol (50 ml) and the solution was stirred at room temperature for 18 hours, water (20 ml) was added and the solution was evaporated to remove the methanol and then washed with ethyl acetate The pH of the solution was changed to 2 with 2N hydrochloric acid under ethyl acetate (50 ml) Layers were separated and the aqueous phase was extracted with ethyl acetate and the organic extracts were taken combined, dried and evaporated to give a colorless solid (2.58 g). This was crystallized from cyclohexane to give (syn isomer) (2.23 g, 73%) of the title compound, mp. 105.5 ° / l _"al (EtOH) 289 nm (c 10 \ OQ), X , _nJ 262 and 271 nm (c7750 and 8150), ι (CDC1 ₃ ) values include 0.32 (OH) and 5.92 (OCH ₃ ).

Production process 2 syn-tert-butoxyiminothien-2-ylacetic acid

A solution of thien-2-γ-glyoxylic acid (6.2 g) and sodium bicarbonate (3.36 g) in water (100 ml) was made dropwise to a stirred solution of tert-butoxyamine hydrochloride (5.65 g) and sodium bicarbonate

(3.78 g) in water (100 ml) at 0-5 ° and the mixture was stirred at room temperature for 18 hours. The mixture was acidified to pH 2.0 with 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dried and concentrated to give a solid (9.75 g). Recrystallization from pelrolether (boiling point 60 to S ( ⁰ ° C.) provided the title compound (4.0 g, 44%), melting point 106 ° to 107 °, X _max (EtOH) 290 nm (r 11,600), r (CDClj ) Values include 2.46, 2.66, 2.98 (d doublets, thienyl protons), 8.60 [C (CH ₃ ) ₃ ].

Manufacturing process 3 to 15

2-alkoxyiminoarylacetic acids

General procedures

A mixture of the substituted glyoxylic acid and an excess (10 to 15%) alkoxyamine hydrochloride were suspended in water or aqueous ethanol, stirred and the pH of the mixture was between 4 and 5 adjusted with sodium hydroxide solution (n to 1On). By adding more sodium hydroxide solution and ethanol as needed became a clear at pH 4 to 5 during dcf reaction Maintain solution. The reaction mixture was kept at room temperature until all of the Keto acid was consumed (it may be necessary to use a higher proportion of the more volatile alkoxyamines to add). The progression of the reaction was determined by acidifying an aliquot, extracting with ethyl acetate and thin layer chromatography of the extract on silica gel plates (developed with a mixture of Chloroform: methanol: acetic acid 18: 2: 1). The alkoxyiminoacetic acids were less polar than the ketonic acids used as the starting material. The reaction times ranged from 2 hours to 2 days.

After completion of the reaction, the pH of the mixture was adjusted between 7 and 8 and the Ethanol (if present) was removed by evaporation. The aqueous mixture was extracted with ether, the extract was discarded and the aqueous phase was brought to pH <2 acidified with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, the extract was dried and evaporated to give a crude product which can be purified by one of the following methods became.

(a) crystallization and recrystallization (if necessary) from a suitable solvent;

(b) The crude product, dissolved in ether, was with a small excess of a solution of diazomethane in Ether treated. The excess reagent was destroyed with acetic acid and the solution was made with Sodium bicarbonate solution washed and evaporated, leaving the crude. Received methyl ester. the Esters were determined by preparative thin layer chromatography or column chromatography on silica gel separated and then hydrolyzed with alkali in a known manner, whereby n; an obtained the pure syti-acid.

(c) The mixture of esters was prepared as in (b) and the isomers were crystallized out separated by a suitable solvent and hydrolyzed accordingly.

These procedures were used to prepare the intermediates (syn-isomers) shown in Table I.

eh | ft oriät

15th

X.

.-t

earth jnal

Table I.

R CO ₂ H

OR ¹

Mr

recruitment procedure No.

Q-

R *

CH ₃

C ₂ H ₅

Cleaning Fp. '

r-words (solvent) R.

(a)

108-

(a) 89.5-91.5

2.61-2.91
(CDCI ₃ )

2,29,2,76,2,86
(DMSO-d *)

5.92

"» WA

nm (EtOH)

Yield,% (before purification)

289 10 700 91

5.79 (CH ₂ ) 289.5 12 500 87

8.72 (CH,)

CH ₂ CH ₂ Br (b) 92.6

2.23.2.71.2.83 5.54.6.28 289 12 200 77

.; «* ■ <e" ~ ii «/«. Mi ίί

Table I (F'orlseUung)

Mr

recruitment procedure No.

Cleaning Fp. '

r-values
R.

CH ₃

C (CHj),

CHj

C (CHj),

CH,

-C ₂ H ₃ -C ₂ H ₅

-C ₂ H ₅

(a)

(a)

(C)

(a)

(a)

(a)

85-87

129-130

175-176

143-144 (Zcrs.)

91-92 74.0

125.5-126

2.10, 3.18, 3.33, 6.06

110.5-111.5 2.12.3.24.3.35 8.70

1,40,1,83,1,95,2,44 5,92

1.88.2.03.2.3-2.7 8.6

2.00, 2.36, 2.55, 6.00

2,10,3,19,3,33
2.2-2.4.2.65

2.1-2.8.2.75

5.79, 8.25
5.81.8.75

5,69,8,71

A-max

nm (EtOH)

275
275.5

233
284
296.5
306.5

234
284.5
297
307.5

231

252.5

296.5

274.5
258.5

2'28 inf,
290
297
307

22 900

10900

10 500

9 270

21 900

11200

10 800

9 400

5,400

7,300

23 600

15 800 13 800

7 200 22 940 24 600 22 500

Yield,% (before purification)

21 500

16 040

99

93

98

92 96

84

tjss

ra ^

Table II

Production method

Cleaning h>

(Solvent) , Values (DMSO-d _(l ) R

R "

"trie *

nm
(EiOH)

(b) (cyclohexane)

124.5-125.5 2.1-2.45

- C (CH ₃ ), (a) 2.45-2.85

(Cyclohexane) 2.7 δ

8.66

10 900

2.30.2.7-3.0 5.25.7.9-8.6 291.5

232.5 6700 296 25400 307.5 23 500

Production process 16 (a) methyl-2- {I-ethoxy) -ethoxyim! No-2- (thien-2-yI) -acetate (syn-isomer)

To a stirred mixture of MethyI-2-hydroxyimino-2- (thien-2-yl) acetate-syn isomer (3.98 g) and Ethyl vinyl ether (2.5 ml) in ethyl acetate (25 ml) was added phosphorus oxychloride (2 drops). After 20 minutes at 50 ° the ethyl acetate was washed with saturated sodium bicarbonate solution over sodium sulfate dried and evaporated to give an oil containing 2- (l-ethoxy) ethoxyimino-2- (thien-2-yl) acetate (syn isomer) revealed.

(5.7 g, 100%), A _max (EtOH) 289 nm (ε 11 700), τ (CDCl ₃ ; 60 MHz) 2.61 (multiplex, thienyl H ₅ ), 2.82 to 2.97, (Multiple, thienyl H ₃ and H ₄ ),

4.64 / quartet, J5 Hz; —O - CH -

I CH ₃

6.06 (Süiglett, -COOCH ₃ ), 6.24 (quartet. J 7 Hz, OCH,), g., 56 (doublet, J 5 Hz, CH- £ H3), 8.7? (Triplet, J 7Hz. Q-CH ₁ CHA

(b) 2- (l-ethoxy) -ethoxyimino-2- (thien-2-yl) -acetic acid sodium salt (syn-isomer)

15th 20th

Adding sodium hydroxide (1 eq.) And enough methanol to form a homogeneous system turned to Methy! -2- (l-ethoxy) ethoxyimino-2- (thien-2-yl) acetate (syn isomer) (5.7 g) was added. After 4 hours at 50 ° the methanol was evaporated and the residue was azeotroped with benzene / methanol, whereby one colorless solid, 2- (l-ethoxy) -ethoxyimino-2- (thien-2-yl) -acetic acid-sodium salt-syn-isomeres was obtained.

(4.6 g, 78.5%), 4 "(pH 6 buffer) 287.5 nm (r 10 650), r (D ₂ O) values include 2.42 (multiplet; thienyl H ₅ ), 2 .68 to 2.84 (multiplet; thienyl H ₃ and R ₁ ),

4.63 / quartet, J 5 Hz; —CH.— '

I CH ₃

6.21 (quartet, J 7 Hz; -CH ₂ -CH ₃ ) 8.57 / doublet. J 5 Hz; -CH-

V QlL

8.82 (triplet, J 7 Hz, -CH ₂ -CHj).

30th 35

40

Manufacturing process 17 (a) (I-tert.-Butoxycarboxarr.idoJ-ethoxyimino-thiene ^ -ylacetic acid (syn-isomer)

N-Carbo-tert-butoxy ^ -bromoethylamine (1.12 g) was added to a solution of the sodium salt of methyl-synhydroxyimino-thien-2-ylacetate (1.035 g) in benzene: dimethylformamide (2: 1 V / V, 30 ml) and the mixture was stirred for 16 hours. Ethyl acetate (50 ml) was added and the mixture was washed several times with water, dried and evaporated to dryness ^r to give methyl-syn- (2-iert.-buloxycarboxamidoäthoxyj-imino-thien ^ -ylacetat (1.21 g, 75%), r (CDC ^ values include 2.62, 2.86, 299 (thienyl protons), 5.10 (NH). 6.06 (s * CH ₃ ) 8.58 (s, C (CH ₃ ) ₃ ).

The crude ester (1.1 g) in methanol (20 ml) was treated with 2N sodium hydroxide solution (3.4 ml) and stored for 16 hours. The methanol was distilled off and the aqueous residue, after washing with ether, was acidified to a pH of 2.0 and extracted with allyl acetate. The extracts were washed (water, saturated saline), dried and evaporated to dryness. Recrystallization of the residue from cyclohexane gave the partial compound (951 mg, 90%), melting point 112.8 to 114.4 °, X _max (EtOH) 290.5 nm (c 11 600), r (DMSO-d ₆ ) - Values include 2.19, 2.6 to 2.9 (thienyl protons), 3.14 (NH), 8.52 (s, C (CH.,).,).

The alkylating agent used in the above preparation was prepared as follows:

(b) N-Carbo-tert-butoxy-2-bromoethylamine

A mixture of tert-butyl azidoformate (15.81 g) and triethylamine (30 ml) was added dropwise to one stirred suspension of 2-bromoethylamine hydrobromide (20.5 g) in methylene chloride (100 ml). the The mixture was stirred for 3 hours and then filtered. The filtrate was concentrated to a small volume

45

50

55

60

65

and the residue was partitioned between ether and water. The ether layer was dried and then was distilled under reduced pressure, collecting the fraction boiling at 92 to 94 ° / 0.9 mm became. It was N-carbo-tert-butoxy ^ -bromoethylamine (1.756 g).

Manufacturing process 18

n-Buioxyimino-thien-2-ylacetic acid (syn-isomeres)

ίο 1-bromobutane (0.6 ml) was added to a solution of methyl-syn-hydroxyimino-thien-2-ylacetate sodium salt (produced by treating methyl-syn-hydroxyimino-thien-2-ylacetate with 1 eq. sodium ethoxide) (1.0 g) in benzene: dimethylformamide (2: 1.15 ml) and the mixture was left at room temperature for 17 hours stirred and then poured into water. The aqueous solution was extracted with ethyl acetate, with Washed water and dried and evaporated to give syn methyl ester (0.88 g) as a pale yellow oil

15 received.

2N sodium hydroxide (4.0 ml) was added to ^e: given ner solution of the syn-Methylesters (0.85 g) in methanol (10 ml) and the mixture was kept for 18 hours at room temperature. The methanol was removed by evaporation, the aqueous residue was diluted with water, washed with ether and acidified to pH 2.0 with 2N hydrochloric acid. The mixture was extracted with ethyl acetate, the combined extracts were washed with water, dried and evaporated to give the title compound (0.74 g, 81%) as a pale yellow oil, r (DMSO-d * (- values include 2 , 30.2.7 to 3.0 (thien-2-yl protons), 5.84 (OCH ₂ ), 9.10 (CH ₃ ).

25 Manufacturing process 19

2-methoxymethoxyimino- (thien-?> I) -acetic acid (syn-isomeres)

A solution of sodium methylate in methanol (approximately 0.2M) became methyl 2-hydroxyimino-2- (thien-2-yl) acetate (syn-Isomeres) (0.5 g) and the resulting solution was evaporated to give a yellow Obtained oil, which was distilled azeotropically with petroleum ether (boiling point 40 to 60 °), the sodium salt of Methyl 2-hydroxyimino-2- (thien-2-yl) acetate (syn-isomeres) (0.49 g, 88%). To a stirred solution of the sodium salt (0.49 g) in benzene / DMF (5 ml, 2: 1) was added chlorodimethyl ether (0.22 ml). After 10 minutes the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with benzene.

The combined extracts were washed with water, dried over sodium sulfate and evaporated,

using a yellow oil, Mslh> 1-2'meihoxymethQxyirnino- (thien-2-yl) acetate (syn-isomeres) (0.62 g, 100%)

obtained, X _max (EtOH) 288 nm (r 10 300), v "" (CHBr ₃ ) 1730 (COOCHj), 1660 cm " ¹ (-C = N-), r (CDCIj) -wene include 2.61 to 2.83 (multiplet, thien-2-yl), 4.83 (singlet, CH ₂ ), 6.06 (CO ₂ CH ₃ ) 6.56 (singlet, CH ₂ OCJi ₃ ).

A solution of sodium hydroxide (4 ml, 2N) and methanol was added to the methyl ester (0.4 g), j

After 30 minutes the mixture was poured into water, washed with ethyl acetate. The aqueous layer | was acidified to pH 1 using 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was dried and evaporated to give a colorless oil that was mil Petroleum ether (b.p. 40 to 60 °) was distilled azeotropically, giving a colorless solid, syn-2-methoxyme- % thoxyimmo- (thien-2-yl) acetic acid (0.21 g, 55%), melting point. 61.2 °, X _max (EtOH) 286 nm (r 10 400), v _muj> (Nujol) J.

1732, 2600 cm "(CH ₂ H). r (DMSO-cL> values include 2.26 (Mullipleti; thienyl H ₅ ), 2.7 to 2.9 (multiplet, s thienyl H ₃ and H ₄ ) 4.88 (singlet, 0-CH ₂ -), 6, 6 (singlet, OCH ₃ ) j

Manufacturing process 20 |

I.

2-tert-Butoxyiminobenzo [b] -thien-2'-ylacetic acid (syn-isomeres) |

Benzo (b] -thien-2-ylglyoxylic acid (3.09 g) and tert-butoxyamino hydrochloride (1.98 g) were dissolved in 50% aqueous ethanol (100 ml) and the solution was brought to pH value of 4.5 \ adjusted and stored for 4 hours at room temperature the thin layer chromatography showed only;... an incomplete reaction of tert-Butoxyaminohydrochlorid (500 mg) was added and the solution \ was stored at room temperature overnight the alcohol was removed by evaporation removed and the aqueous phase was adjusted to pH 8 and washed with ether. the aqueous phase was' then adjusted ether at a pH value of 1.5. the ether solution was washed with water and dried. evaporation gave an Cream colored solid (4.05 g). Fractional crystallization from cyclo-J hexane gave the anti-isomer of the title compound (1.6 g). The mother liquors were combined and evaporated to give an cream colored solid (2.1 1 g), which was received in ether with excess Diazome- ^ä than in ether treated at 0 to 5 °. The excess reagent was destroyed by acetic acid and the ι ether solution was washed with sodium bicarbonate, water and dried. Evaporation provided an oil j (1.75 g). This was dissolved in methanol (70 ml) and treated with sodium hydroxide solution (n; 7 ml) at room temperature for 3 hours. Hydrochloric acid (2N, 3.5 ml) was added and the methanol was removed by evaporation. The aqueous residue was partitioned between ether and sodium bicarbonate solution. The ether layer was washed with water and dried. Evaporation gave an oil (0.92 g) which in =

20;

Methanol (20 ml) was dissolved and washed with sodium hydroxide (n, 7 ml) at reflux temperature for 3 hours was treated. Sodium hydroxide (n, 5 ml) was added and the solution was refluxed for 6 hours warmed up. The methanol was removed by evaporation and the residue was partitioned between ether and water distributed. The aqueous phase was acidified under ether (pH 1.5) and the ether layer was washed with water washed, dried and evaporated to give a pale orange crystalline solid (760 mg, 18%).

Crystallization from benzene containing cyclohexane gave syn-tert-butoxyiminobenzo [b] -thien-2-ylacetic acid (430 mg), m.p. 108 to 109, A _mav (EtOH) 231, 253, 297 nm (f 17,000 , 7240, 24 500).

Production method 21 Benzo [b] -thien-2-ylglyoxylic acid and Benzo [b] -thien-3-yl-glyoxylic acid

A mixture of 2- and 3-acetylbenzo [b] thiophene (approx. 1: 1) (11.0 g) in pyridine (80 ml) was heated to 60 ° C. with vigorous stirring and selenium dioxide (9.92 g) were added in portions. The mixture was heated to 11O ⁰ C and an exothermic reaction occurred. The temperature rose to 120 °. The reaction mixture was stirred at 90 ° for 45 minutes and then allowed to cool. Water (80 m!) Was added and the mixture was filtered through a bed of kieselguhr. The pyridine was removed by evaporation and the aqueous residue filtered again. The filtrate was acidified to pH 2 with 40% o-phosphoric acid (40 ml) under ether.

The aqueous phase was extracted with ether and the ether fractions were combined, washed with water and dried. Evaporation gave an orange-colored crystalline solid (11.0 g, 86%). Crystallization from benzene (100 ml gave pale yellow crystals of benzo [b] -thien-2-ylelyoxyls, acid (2.3 g, 18%), m.p. 175.9 °,; "", (EtOH) 233.247, X _1n ,, 308 nm (c 11 400,7200,14 600), r (DMSO - ") values include 1.83 (C-4 and C-7 protons), 1.42 (C-3 protons), 2, 40 (C-5 and C-6 protons).

The mother liquors were concentrated to give an orange oil which crystallized on standing (8 g). Recrystallization from benzene (20 ml) gave pale yellow needles from benzo [b] -thien-3-y! Glyoxylic acid (1.6 g, 12.5%), melting point 92 to 93 °, r (DMSO-d ") - Values include 0.83 (C-2 proton), 1.32 (C-4 proton) 1.79 (C-7 proton), 2.40 (C-5 and C-6 protons), X _max (EtOH) 235, 310.5 nm (c 11,200 and 7,400).

Preparation process 22 syn-propoxyiminothien-2-ylacetic acid

A mixture of thien-2-ylgiyoxylic acid (3.12 g), n-propoxyamine hydrochloride (2.8 g), ethanol (75 ml) and water (75 ml) was brought to pH 4 with sodium hydroxide solution (2N) , 5 to 5 set and stirred at room temperature. Additional base or ethanol was added as required in order to maintain a clear solution at a pH of 4.5 to 5. After 4 hours an additional portion of n-propoxyamine hydrochloride (1.4 g) was added and the mixture was stirred for an additional 3 hours (keeping the pH at 4.5-5) and then stored overnight. The ethanol was evaporated and the remaining solution was diluted with water, acidified and extracted with ethyl acetate. Evaporation of the dried (MgSO ₄ ) ethyl acetate solution gave a mixture of the syn and anti forms of the title acid as an oil (4.8 g).

The mixture of acids was esterified in the usual way with diazomethane, a mixture of the syn- and anti-methyl ester (3.17'5 g) obtained.

The mixture of esters in methanol (50 ml) was treated with sodium hydroxide solution (2N, 14 ml) for 10 minutes at room temperature. The methanol was quickly removed by evaporation and the residue was extracted into water with ethyl acetate. Evaporation of the dried (MgSO ₄ ) ethyl acetate solution gave the syn methyl ester (0.416 g). The ester was treated with sodium hydroxide solution (2N, 1.7 ml) in methanol (10 ml) and kept at room temperature for 26 hours. Isolation in known manner of the acidic material provided the title compound as an oil <Ό, 235 g), τ (DMSO-cy values include 2.28.2.7 to 2.9 (thienyl), 5.90 (Q- CH-,).

Manufacturing process 23

General procedure to convert 2-alkoxyiminoarylacetic acid into the acid chloride without converting isomerization

A solution of the pure syn-2-alkoxyiminoarylacetic acid (1 eq.) In methanol (approx. 2 to 4 ml / mmol) was treated with sodium methylate (1 eq.) in methanol at 0-25 ° and the mixture was evaporated, whereby the sodium salt was obtained, which by azeotropic distillation with some proportions of benzene and / or drying phosphorus pentoxide was dried in vacuo.

The anhydrous sodium salt (1 aqu.) Is in dry benzene (approx. 5 ml / mmol), the few drops in dry Contains dimethylformamide, suspended and treated with freshly distilled oxalyl chloride (1 to 2.5 eq.). The mixture is stirred at room temperature for 1 hour and then evaporated to remove the benzene. The resulting acid chlorides were not characterized, but rather dissolved in acetone or methylene chloride

and used immediately to acylate the corresponding cephalosporin nucleus. The following acids were converted into their acid chlorides in this way:

syn-2-methoxyimino (thien-2-yl) acetic acid, 5 syn-2-ethoxyimino (thien-2-yl) acetic acid,

syn-2-n-butoxyimino- (thien-2-yl) -acetic acid, fyn-2-tert-butoxyimino- (thien-2-yl) -acetic acid, syn-2- (2-bromoethoxy) -imino- (thien-2-yl) -acetic acid,

syn ^ -Ctert.-ButoxycarbonylaminoäthoxyJ-imino-Cthien ^ -ylJ-acetic acid, 10 syn-2- (l-ethoxy) -ethoxyimino- (thien-2-yl) -acetic acid,

syn-2-methoxyiminobenzo [b] -thien-3'-ylacetic acid, syn-2-tert.-butoxyiminobenzo [b] -thien-3'-ylacetic acid, syn-2-methoxyiminobenzo [b] -thien-2'-ylacetic acid,

syn-2-tert-butoxyiminobenzo [b] -thien-2'-ylessi2. acid, 15 syn-2-methoxyimino (fur-2-yl) acetic acid,

syn-2-tert-butoxyimino- (fur-2-yl) -acetic acid, syn-2-ethoxyimino- (fur-2-yl) -acetic acid, syn-2-propoxyimino (thien-2-yl) acetic acid and

syn'i2-ethoxyimino (thien-3-yl) acetic acid. 20th

Manufacturing process 24 syn-phenoxyiminofur-2-yl-acetic acid

39 ml (43 mmol) of 1.12 M methanolic sodium methylate solution and then 8.0 g (22 mmol) of diphenyliodonium bromide were added to a solution of 3.1 g (20 mmol) of syn-hydroxyiminofur-2-yl-acetic acid in 40 ml of methanol . The mixture was stirred under nitrogen for 4 hours at which time thin layer chromatogram (chloroform-methanol-acetic acid; 18: 2: 1) indicated the absence of starting material. A small amount of the solid was filtered off and the filtrate was evaporated to dryness. The residue was diluted with water, the pH was adjusted to 7.0 and the mixture was washed with ether. The aqueous layer was acidified to pH 1.8 under ether. The layers were separated and the aqueous layer was extracted with more ether. The combined ether layers were washed, dried and concentrated and gave a dark red crystalline solid. This was triturated with 2 ml of cold nitromethane, filtered off and washed with a small amount of cold nitromethane to give 1.63 g (35%) of the title compound F = 100.6 ⁰ C, X _max (ethanol 270.5, 292.5 nm) (c 14 300, 15 700). In a similar manner were made.

Manufacturing process 25

2-Phenox ^u imino-2- (thien-2-yl) acetic acid (syn isomer) (52%), mp. 98.3 to 99.5 °, λ,. ,, (ethanol 267.5 303 nm (r 9,900; 12,000).

45 Manufacturing process 26

(a) (Z) -2-Isothiazol-3-yl-2-methoxyiminoacetonitrile

74 mg of sodium were dissolved in 11.5 ml of methanol under nitrogen and 360 mg of isothiazol-3-ylacetonitrile (described by R. Raap et al in US Pat. No. 3,268,523 (1966), page 6) were added with stirring. 0.36 mi undistilled isopropyl lnitrit was added and the solution was stirred for 2 hours at 21 ⁼ C. The solution was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed with brine and dried with magnesium sulfate. Evaporation gave 340 mg of solid. This solid (330 mg) was dissolved in 3 ml of DMF and 400 mg of potassium carbonate followed by 0.16 ml of methyl iodide were added with stirring under nitrogen. After one hour the mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed twice with brine. After drying with magnesium sulfate, the solution was concentrated and chromatographed on 50 g of Sorbsil * U 30 in ethyl acetate (10 to 40%) in petroleum ether (b.p. 40-60 ° C.) and gave 210 mg of the title compound as an oil which solidified, F . = 57 to 63 ° C, τ (CDCl ₃ ) U5 (d, J 5 Hz; 5'-H), 2.31 (d, J 5 Hz; 4'-H) and 5.78 (Me).

(b) (Z) -2- (Isothiazol-3-yl) -2-melhoxyiminoacetic acid

500 mg of (Z) -2- (isothiazol-3-yl) -2-methoxyiminoacetonitrile was treated with 10 ml of 10 N sodium hydroxide solution and; 10 ml of ethanol were heated to reflux under nitrogen for 2 hours. The mixture was cooled and \ between ethylacetate and water, containing concentrated hydrochloric acid (13 ml), distributed. The aqueous layer was extracted with more ethyl acetate and the combined organic solutions were washed with brine

22nd

iitrile

urde xtra- ■ ülfat DMF fabric | The earthen | and 'Krgab 12,31

■ gund it and thicht solution

washed, dried with magnesium sulfate and evaporated to give 440 mg of the title compound.

ν "(Nujol) 3700 to 2100 (OH), 1730 (acid) and 1598 cm ' ¹ (C = C and C = N); r (d ₆ DMSO) 0.78 (d, J 5Hz; 5'-H). 2.28 (d, J 5Hz; 4'-H) and 6, CO (Me).

Manufacturing process 27 2-Cyclopentyloxyimino-2- (fur-2-yl) acetic acid (syn-isomer)

F ^r ur-2-yl glyoxylic acid (2.80 g) and Cyclopentyloxaminhydrochlorid (3.3 g) were added (ml 100) in a mixture of water and ethanol (50 ml) and the pH of the solution was adjusted to 5 , 0 set. The solution was stirred for 19 hours. The alcohol was evaporated and the solution was acidified to pH 1.5 under ethyl acetate. The acidic mixture was extracted into ethyl acetate and the combined extracts were washed, dried and evaporated to give the crude acid (4.38 g). This acid was treated with charcoal in benzene for 15 minutes, filtered and the filtrate evaporated to give a solid which was recrystallized twice from cyclohexane to give the titic acid (2.28 g, 51%), m.p. , 6 to 97.7 ", X _max (Äihanoi) 277.5 nrn (t 15 6 (X)).

Manufacturing process 28 Cyclopentyloxamine-byrochloride

A mixture of bromocyclopentane (14.9 g), N-hydroxyphthalimide (16.3 g), triethylamine (15 ml) and dimethylformamide (30 ml) was stirred for 16 hours and then poured into water (500 ml). The oily mixture was extracted with ethyl acetate and the combined extracts after washing (water), drying and removal gave? of the solvent a colorless solid. This solid was recrystallized from ethanol to give N-cyclopentyloxyphthalimide (11.37 g, 49%), mp 81.2 ° to 82.5 °; v _m0X (CHBr ₃ ) include 1780, 1720 cm ' ¹ (CO-N-CO), 970 cm' ¹

(> -o-c6)

/ Values (DMSO-d ₀ ) 2.08 (4 Ar-H), 5.12 (cyclopentyl 1-H), 8.18 (4-Ch ₃ ). ii

A mixture of N-Cyclopentyloxyphthalimid (11 g), LQ0 ⁰ 4igem hydrazine hydrate (2.6 g) and ethanol (30 ml) was heated at reflux for 5 minutes. Concentrated hydrochloric acid (6 ml) was added to the mixture which was then refluxed for an additional 5 minutes. Water (20 ml) was added to the mixture, which was cooled to room temperature and filtered. The filtrate was evaporated to dryness. Ethanol (50 ml) was added to the residue and a small portion of the insoluble material was filtered off. The filtrate was evaporated to dryness and the residue was recrystallized from ethanol / ether, giving cyclopentyloxamine hydrochloride (6.28 g, 96%), melting point 156.9 °.

Preparation process 29 2-Phenoxyimino-2- (fur-3-yl) acetic acid (syn isomer), cyclohexylamine salt

The title compound was obtained in 30% yield using the method of Preparation 24. The product had a melting point of 120 to 121 ^° C. and a _ax (ethanol) 260 nm if 14 500).

Manufacturing process 30 2-Phenoxyimino-2- (thien-3-yl) -acetic acid (syn-isomer)

The title compound was prepared in 31% yield. The N.M.R. spectrum of the product included Signals at r 2.0 to 3.0 (multiple, phenyl and thien-3-yl-protoneni.

Manufacturing process 31 2-Cyc! Opentyloxyäm! No-2- {thien-3-y!) - acetic acid (syn-isomeres)

The title compound was prepared using Preparation Methods 14 and 15, generally described above. After purification by method b and crystallization from cyclohexane, the product had a melting point of 90 ° C .; ;. "" (PH 6 buffer) 261 nm (r 13 500); and r values (DMSO-Ci ₆ )

50 55

65

containing 2.29, 2.35 and 2.67 (thien-3-yl protons) and 5.25 and 8.0 to 8.6 (cyclophonyl protons).

Manufacturing process 32

2-p-nitrophenoxyiminothien-2-ylacetic acid (syn-isomer)

A solution of methyl hydroxyiminothien-2-ylacetate (syn-isomeres) (1.85 g) in dry methanol (10 ml) was neutralized with 1.12 M methanolic sodium methoxide solution (9 ml). The solvent

ίο was removed under reduced pressure and the residue after drying overnight in vacuo over phosphorus monoxide, dissolved in benzene / N, N-dimethylformamide (2: 1, V / V, 30 ml) and with p-nitrofluorobenzene (1.41 g) The resulting solution was stirred for 24 hours and then poured into 150 ml of water. the The mixture was extracted with ether (3 × 30 ml) and the combined extracts with water and saturated saline solution washed, dried and evaporated to a white solid which recrystallizes from cyclohexane and 23 g of 2-p-Nitrophenoxyiminothien-2-ylessigsäuΓemethylester (syn-Isomeres) (75%) in colorless

Needles F = 118.9 ^C C (Mettler) gave. ). _max (ethanol) 321.5 nm (ε 24 500), ), "". 285 nm (r 11400). |

4.1 g of the above ester were suspended in 150 ml of methanol and 13.4 ml of 2N sodium hydroxide solution. |

Most of the solid dissolved on heating. The mixture was left at room temperature for 48 hours Stirred temperature, thin layer chromatography showed the absence of starting material. The J

Methanol was evaporated and the residue was diluted with water. After washing with ether, the aqueous phase was acidified to pH 2 under Aihet and then extracted with more ether. The combined extracts were washed Ätherex-%, dried and evaporated to dryness. By crystallization of the residue from | Nitromethane there was obtained 1.65 g of 2-p-Nitrophenoxyiminothien-2-ylacetic acid (syn-lsomeres) (42%), from the 1 F = 137.9 ⁰ C (Mettler) X _max (ethanol) 264, 322.5 nm ( c 9 400; 18 500). 6th

The acids described in preparation processes 29 to 32 above were converted into their acid chlorides I , the general method described above for converting a 2-substituted, oxyimino-2-arylacetic acid into its acid chloride, without isomerization, being used. |

Examples I.

General processes for the preparation of 7j5- (2-alkoxyimino-2-subst..acetamido) -3- (subsi.) Methylceph- | 3-em-4-carboxylic acids using dicylohexylcarbodiimide 6

(i) Production of intermediate 4-carboxylic acid esters *

Procedure A §

To a solution of tert-butyl or diphenylmethyl esters of 7j! KArnino-3- (sub5t.) Methylceph-3-ner- |

4-carboxylic acid (1 eq.) And dicyclohexylcarbodiimide (1 to 1.2 eq.) In dry methylene chloride (as f

Cosolvents were used, for example, dimethylformamide or dioxane) was added at 0 to 20 ° |

a solution of syn-2-alkoxyimino-substituted acetic acid (1 eq.) in dry methylene chloride. After the rest g

Ren for 45 minutes to 3 hours at room temperature, the mixture was filtered, the filtrate became |

successively with 2 η hydrochloric acid, saturated sodium hydrogen carbonate solution, water and salt!

weschen solution The organic phase was dried and evaporated to give the desired ester

received as oil or foam. ί

(u) Cleavage of the protective groups in the intermediate esters 50 Procedure B

The tert-butyl or diphenyl ester was dissolved in trifluoroacetic acid (5 to 10 ml / g ester) and treated with room |

temperature for 5 to 10 minutes and then evaporated under reduced pressure. The |

Crude product was taken up in ether or ethyl acetate, in aqueous sodium hydrogen carbonate solution f

extracted and washed with ethyl acetate. The aqueous layer was acidified with 2η hydrochloric acid

and extracted into ethyl acetate. The organic layer was washed, dried and evaporated, whereby *

the desired syn-7> (2-alkoxyimino-2-subst.aceiarnido) -3- (subsi.) methylceph-3-cm-4-carboxylic acid |

received. I.

60 Procedure C

The ester was dissolved in anisole (1 to 5 ml / g ester) and treated with trifluoroacetic acid (4 to 10 ml / g ester) at room temperature for 5 to 10 minutes and then worked up as described in method B. f |

Example 1 §

F (a) tert-Butyl-3-acetoxymethyl-7> [2-methoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylate (tyn- |

Isomer) I

24 ί

S 20 °

ia merit The solution is acidic

iiZimir is working.

ι (syn-

was obtained as a solid (85%), X _max (EtOH) 262 to 263 nm, (c 14 900), )., “ _f . 280 nm (c 13 280), v _{mo (} (CHBr ₃ ) 3400 (NH); 1780 08-lactam), 1738.1120 (CO ₂ R) and 1684.1514 cm " ¹ (CONH) τ (CDCl ₃ ) 2 , 5 to 2.7,2.95 (thienyl protons), 5.97 (OMe), 7.93 (OAc), and 8.48 (tert-butyl) according to method A. The cleavage of the protective groups according to method B provided the free acid:

(b) 3-Aceloxymethyl-7jH [2-methoxyimino-2- (thienyl-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-Iso s meres)

(56%), [c} £ + 60 ° (c. 0.8 in dioxane), ). _m , _x 262 nm (c 15 700), ?. _max 290 nm (c 10 700), v _mex 3275 (NH), 1768 08-lactam), 1728 (OAc), 1700.2600 (CO ₁ H) and 1648.1520 cm " ¹ (CONH), T (DMSO- O ₆ ) 2.2 to 2.9 (thienyl), 6.08 OMe), 0.13 (NH), 4.12, 4.76 OS-lactam), 6.28, 6.52 (J 18Hz), CH ₂ in the ring), 4.94, 5.27 (J 13Hz CJl ₂ OAc) and 7.94 (OAc).

Example 2

(a) tert -Butyl-3-acetoxymethyl-7β- [2-methoxymethoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-eiL1-carboxylate (syn isomer)

A "" (EtOH) 260 nm (c 12 940), v _m "(CHBr ₃ ) 1778 08-Uctam), 1688 and 1510 cm" ¹ (CONH), 7 (CDCl ₃ ) 2.74 (doublet, NH) , 4.76 (-OCJLOCHj), 6.49 (QCH ₇ OCHq 7.91 (OCOCH ₂ ), 8.44 (Bu ¹ ) was prepared according to Method A and then treated with trifluoroacetic acid according to Method B, whereby

(b) 3-Acetoxymethyl-7 _J Ä- [2-methoxymethoxyimino-2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomeres) '

obtained, [a] _D + 51 ° (0.8. DMSO), An «(pH 6 phosphate buffer) 262.5 nm (r 16 400), v _m » (Nujol) 1778 (β-lactam), 1670.1530 cm " ¹ (CONH), 7 (DMSO-U ₆ ) 0.11 (doublet, NH), 4.89 (OCH ₂ OCH ₃ ), 6.62 (OCH ₂ OCU ₃ ), 7.96 (OCOCH ₃ ) .

Example 3

3-acetoxymethyl-7jS- (2-tert-butoxyiminothien-2'-ylacetamido) -ceph-3-em-4-carboxylic acid (syn-isomer)

Methanolic sodium methylate (0.53N, 7.5 ml) was added dropwise to a stirred solution of syn-tert-butoxyiminothien-2-ylacetic acid (0.9 g) in dry methanol (10 ml) at 0-5 °. The mixture was evaporated to remove the methanol and dried by azeotropic distillation with dry benzene. Oxalyl chloride (0.63 ml, 0.95 g) was added to the stirred suspension of the sodium salt and dimethylformamide (3 drops) in dry benzene (40 ml). The mixture was stirred at room temperature for 1 hour and evaporated to remove the benzene. The acid chloride in acetone (10 ml) was added dropwise to a stirred solution of 7JS-AmInOCePHaIoSpOrBnSaUrC (1.09 g) and sodium bicarbonate (0.672 g) in acetone (20 ml) and water (20 ml) at 0-5 ° and the The mixture was stirred at room temperature for 2 hours. The resulting solution was evaporated to remove the acetone and washed with ethyl acetate. The aqueous solution was acidified to pH 1.5 with 2N hydrochloric acid in the presence of ve \ thylacetate and extracted with ethyl acetate. The combined extracts were washed with water, dried and evaporated to give the title compound (1.15 g, 61%) as a pale yellow foam, [a] ^: _D ^J + 61 ° (r, 1.0, dioxane), X _max (pH 6 phosphate buffer) 260 nm (ε 12 500), v _ma3C (Nujol) 1780 Oß-Lactam) 1666 and 1520 cm " ¹ (CONH). r values (DMSO-d ₆ ) include 0.28 (doublet, J 8Hz, NH), 2.36 (IH) and 2.84 (2H) (dien-2-yl protons), 7.98 (OAc), 8.68 (Bu ').

Example 4

3-acetoxymethyl-7jS- (2-tert-butoxyiminobenzo [b] -thien-3'-ylacetamido) -

ceph-3-em-4-carboxylic acid (syn-isomeres)

syn-tert-Butoxyiminobenzo [b] -thien-3-ylacetic acid (0.976 g) was treated with sodium methylate solution (0.445 m, 6.1 ml) treated at room temperature. Evaporation provided the sodium salt as a colorless powder (1.05 g). This was dried over phosphorus pentoxide overnight.

The sodium salt (0.5 g). suspended in dry benzene (10 ml) containing dimethylformamide (1 drop) was treated with oxalyl chloride (0.4 ml) for 1 hour at room temperature. The solvent was removed by evaporation and the residue in acetone (20 ml) was added dropwise to a solution of 7 ^ -arninocephalosporic acid (0.49 g) and sodium bicarbonate (0.378 g) in water (30 ml) at 0-5 ° . The resulting pale yellow suspension was stirred at room temperature for 2 '/ ₂ hours. The acetone was removed by evaporation and the aqueous phase was acidified to pH 2 under ether. The ether fraction was washed with water and dried. Evaporation gave a cream colored foam which was dissolved in methylene chloride and evaporated again to give the title compound after drying (0.85 g, 95%), [a] _D + 61 ° (c, 1 dioxane), k _max (pH 6 buffers), 230,297,304 inf. nm (ε27 600, 11 500, ΙΟ 630). r (DMSO-d ,,) values include 0.29 (doublet, NH), 4.04 (double doublet, 7 proton), 4.73 (doublet, 6 proton), 8.59 (Bu ') .

Example 5

3-acetoxymethyl-7, / H2-tert-butoxyiniinofur-2'-ylacetamido) -ceph-3-em-4-carboxylic acid (syn isomer)

syn-tert-Buioxyiminofur-2-ylacetic acid (2.11g) was treated with sodium methylate (0.525m, 19.1ml) at room temperature. The methanol was removed by evaporation and the resulting chamois-colored powder was dried over phosphorus pentoxide overnight. The sodium salt (933 mg) in dry benzene (10 ml) containing dimethylformamide (1 drop) was treated with oxalychloride (0.8 ml) at room temperature for 1 hour. The solvent was removed by evaporation and the residue in acetone (30 ml) was added dropwise to a solution of 7β-aminocephalosporanic acid (1.09 g) and sodium bicarbonate (672 mg) in water (50 ml) at 0-5 °. The resulting solution was stirred at room temperature for IV ₂ hours. The acetone was removed by evaporation and the aqueous phase was adjusted to pH 8 and washed with a little ether. The aqueous layer was acidified to pH 2.0 under ether and the organic layer was washed with water, dried and evaporated to give a pale yellow foam. This was dried over silica gel and potassium hydroxide pellets to give the title compound as weak -yellow foam received (1.6 g, 86%), [a] _D + 62 ° (c, 1 dioxane), X _max (pH 6 phosphate powder) 272 nm (c 18 600), v _m "(CHBr ₃ ) 1780 (^ -lactam) 1674 and 1510 cm "'(CONH), τ (DMSO-cy values include 0.34 (doublet, NH), 2.17 and 3.34 (fur-2-yl, protons), 8.71 (Bu ¹ ).

20 ·

Examples 6 to 2i

General process for the preparation of 25 3-substituted-methyl-7 _J ß- (2-subsL-oxyimino-2-arylacetamido) -ceph-3-em-4-carboxylic acids

Procedure A

A solution of the appropriate syn-2-substituted-oxyimino-2-arylacetyl chloride (prepared from 1 eq. Of the corresponding Sodium salt with oxalyl chloride) was dissolved in acetone and the solution was added dropwise to a stirred ice-cold (0 to 5 °) solution of 7 ^ -aminocephalosporanic acid (1 eq.) in water, the sodium bicarbonate (2 to 2.5 eq.) Was given. The mixture was stirred for 30 minutes to 2.5 hours, whereby let the temperature rise to 7.imme?. "temperature. Acetone was obtained by evaporation under reduced pressure removed, the pH was adjusted to 1.5 to 2.0 and the product was dissolved in ethyl acetate (or occasionally Ether) extracted. The extra !. "e were washed with water or saturated saline, dried and evaporated, whereby a foam or a solid was obtained.

Procedure B

As in Method A, but the product was purified by soaking it in aqueous sodium bicarbonate solution dissolved and precipitated again by acidification.

Procedure C

A solution of the appropriate acid chloride (1 eq.) Was in dry methylene chloride (approx. 5 ml / mmol) dissolved and the solution was added to a suspension or a solution of 7jS-aminocephalosporanic acid (1 eq.) and triethylamine (3 eq.) in methylene chloride at 0 to 5 °. After stirring at room temperature during For 1 to 1.5 hours the solution was evaporated to dryness, dissolved in water, washed with ethyl acetate and the aqueous layer acidified to pH 1.5 under ethyl acetate. The ethyl acetate extract was washed with water and with saturated saline solution and evaporated, leaving a foam or received a solid.

26th

Table ul

ι «)
R CONH

OR ¹ O

CH ₂ OAc

CO _: H

Example R

R "

CHj

C ₂ H ₅ n-C4i "Ü9

CHOC ₂ H ₅

CH ₃

CH ₂ CH ₂ Br

CH ₃ CH,

+ 51.5 °

+

Method Ia) ₀ pH

(Dioxane) -Wv

+ 60 ° 262 + 88 ° 262.5 + 55 ° 262.5 + 64 °
(DMSO) 260.5

226
298.5

273

./f-Laclam

cm " ¹ (solvent)

r values for DMSOd ₆ at 100 MHz

χ R " y

200

(Nujol)
1780 (CHBr ₃ )

600 1768 (Nujol)

500 1762 (Nujol)

300 1788 (CHBr,)
800

0.13 6.08

0.19 5.82 (CH ₂ )
8.75 (CH ₃ )

0.18 5.86.8.2-8.8
and
9.06 (CHj) ₃ CHj

300 1776 (Nujol) 0.16

+ 53 ° 262.5 15 500 1778CNuJoI) 0.14

8.6 (CH ₃ )

8.84 (CH ₂ CiJ ₃ )

4.66 (CHCHj)

5.59 (OCH ₂ )
6.30 (CH ₂ Br)

yield

0.2 5.97

100 1784 (CKBr ₃ ) 0.16 6.07

4.12 76

4.12 77

4.11 87

4.10 S4

4.10 93

4.11 77 4.13 50

Table III (Continuation)

r-Werle for DMSO-d «at 100 MHi

Carried out Mo pH ⁶

(Dioxnn)

C ₁ H ₅

CHj

C (CH ₃ ),

+ 59.5 ° 274

+ 58

+ 44.5

19 300 1790 (CHBr,)

20 800 1790 (CHBr ₅ ) 18 450 20 800

20 900 1780 (CHBTj) 15 200 22 200

0.21 5.79.8.72 4.11

-01.04 5.97

0.12 8.61

4.00

4.00

/
co £ Z O = z O
U N. SZ U
I. O ai υ
\ —Z 3 7th > WJ .O \ _ 'S
.e

<J »

J »SS

O rf

On

Os O

in

r-

S. υ οο U vo_ O CS oo *** OO OO VO

Sd.

O. O

O 00

r-

cn

'5 " Z,

ο r— r—

VO

in

it

'5 ¹ Z,

ο co r—

ο ο ο ο rs ■ * es cn

ts η CS οο VO νο VO OO CS CS CS

CS

VO

approx

'Ξ.

29

sra «^

■ <f. $ "■■■: ■ /

Table HI (continued)

<Jf) Ο ')

R CONH H H

^Ν ο

OR 'O

Example R

CO _Z H

CHiOAc

QC ₃ H ₇

C ₂ H

₂ H ₅

C ₂ H ₅

Method [a] _D pH 6

(Dioxin) X _mmx

nm

+ 56 ° (dioxane)

+ 53 ° (dioxane)

+ 55.5 ° (dioxane)

262.5 289 inf.

_0-lactam

cm " ¹ (solvent)

r values for DMSO-d ₆ at 100 MHz

16 000 1778 (Nujol)
11200

12 900 1785 (CHBr ₃ ) '0.03 5.71.8.68

15 500
23 600

yield

0.17 5.9.8.32.9.06 4.09 82

261.5 20 300 1786 (Nujol) 0.28 5.81.8.75 4.1 95

4.09 77

(j example 22

I 3-acetoxymethyl-7 ^ - [2-aminoethoxyimino- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid,

Jj trifluoroacetate salt (syn isomer)

|| A solution of syn- (2-tert-butoxycarboxamido) -ethoxyiminothien-2-ylacetyIch! Orid (from the acid

I 314 mg), dissolved in acetone (10 ml) was added dropwise to an ice-cold, stirred solution of 7 / ^ amino-

f cephalosporanic acid (272 mg) in water (20 ml) containing sodium bicarbonate (168 mg) was added. The solution

was stirred for 2 hours, then the acetone was distilled off. The aqueous mixture was acidified to pH 2.0 under ethyl acetate and extracted with ethyl acetate. The combined extracts were washed (water, brine), dried and evaporated to dryness, giving 3-acetoxymethyl-7jS- [2-tert-butoxycarboxamidoethoxyimino- (thien-2-yl) -acetamido] -ceph-3-em- 4-carboxylic acid (540 mg, 95%) obtained, τ (DMSO-d ₆ ) values include 0.27 (d, NH), 7.96 (s, OCOCH ₃ ), 8.62 (s, C (CH ₃ ),).

This crude acid (500 mg) was dissolved in trifluoroacetic acid (5 ml) and the solution was at room temperature Stored for 5 minutes and then evaporated to dryness at room temperature. Dry benzene (25 ml) was added to the residue and the mixture was evaporated to dryness again. Of the ι * 'Oily residue was triturated with ether, whereby the title compound was obtained (346 mg, 64%) as colorless

I solid [a] _D + 39 ° (c, 0.97 dioxane), X _n ^ (pH 6 phosphate buffer) 283 nm (c 16 500), v _max (Nujol) 1780 cm " ¹ , τ

1 (DMSO-dJ values include 0.31 (doublet, J 8Hz, NH), 1.98 (NH ₃ ), 4.08 (C-7 proton), 5.66 (-OCH ₂ ), 6.8 _2Q

f (-CH ₂ -NO, ^7-96 (OCOCH _3).

I "Examples 23-30

$ - ^2S

? General Methods of Making

ΐ ^: 3-acetoxymethyl-7X2-substituted-oxyimino-2-arylacetarnido) -ceph-3-em-4-carboxylic acids

k procedure A

t ..

j- A solution of the corresponding syn-2-substituted-oxyimino-2-ar% 'lacetyl chloride (prepared from 1 equiv. des

I * corresponding sodium salt with oxychloride) was dissolved in acetone and the solution was added dropwise

- ■■ to a stirred cold (0 to 5 °) solution of 7.5? - Aminocephalosporanic acid (1 equiv.) In water containing sodium bicarbonate (2 to 2.5 equiv.) Added. The mixture was stirred for 0.5 to 2.5 hours, then the temperature was allowed to rise to room temperature. Acetone was removed by evaporation under reduced l <pressure, ethyl acetate was added, the pH was adjusted to 1.5 to 2.0, and the product

i; was extracted into ethyl acetate. The extracts were washed with water and saturated saline,

t dried and evaporated to a foam or solid.

', j, method B

■ < As in method A, but the 'product was extracted into ether.

The cephalosporin derivatives so prepared are listed in Table IV.

31

mim

Table IV

R CONH

OR *

Example R

-N J-CHT ₂ OAc

COjH

R "

Ph

Ph

procedure

(Dioxane)

+ 72 °
+ 68 °
+ 69 °
• 5-59 °

-C (CH ₃ ), B

pH 6 nm

270.5
296

263.5
305

275

262.5 294

+ 52.5 ° 235.5
273
301.5

14 750 13 300

16 200 10 700

16 800

15 700 12 300

13 100 17 000 24 300

/ (- lactam

cm (Solvent)

1780 (Nujol) 1770 (Nujol) 1782 (Nujol) 1782 (Nujol)

, Values HIr DMSO-d ₆ be! 100 MHz

-0.14 2.4-2.8

-0.14 2.4-2.8

1780 (CHBr ₃ ) 0.20 8.62

yield

4.04 98

4.01 96

0.33 5.28.8.0-8.6 4.16 98 0.26 5.25.8.0-8.6 4.10 95

4.04 93

Γ "! Τι-ι

example
No. R. R " Mon
(Solvent) pH 6
nm C. jj-luctam
cm"'
(Solvent) r-toilets for
X DMSO- (Ii at 100 MHz
R " y the end
bump
% to
to 28 Ph + 106 ° (DMSO) 262
266 20 400
20 400 1760 (Nujol) 0.03 2.3-3.0 4.21 71 OJ 29 Ph + 114 ° (DMSO) 264 17 800 1750 (Nujol) 0.04 1.93-2.1.3.08 4.24 65 30th ΙΓΊΓ + 96 ° (DMSO) 265 21 200 1754 (NuJoI) 0.4; » 5.23 and 8.0-8.5 4.30 83

The constants apply to the sodium salts of the compounds.

i ^ fgs ^^

Examples 31 to 35

General Methods of Making

7jS- (2-subsL-oxyimino-2-arylacetamido) -3- <subst.) - ceph-3-em ^ l-carboxylic acids 5 using dicyclohexylcarbodiimide

(i) To a solution of diphenylmethyl ester of T ^ -amino-S-CsubstO-ceph-S-em ^ -carboxylic acid {1 equiv.} and dicyclohexylcarbodiimide (1 to 1.2 equiv.) in dry methylene chloride was added at 0 to 20 °

ίο Solution of syn-2-alkoxy- or 2-aryloxyimino-2-aryl-acetic acid (1 equiv.) in dry methylene chloride. After stirring for 45 minutes to 3 hours at room temperature, the The mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate successively washed with sodium bicarbonate solution, water and brine. The organic phase was dried and evaporated to a foam or solids. The arising ·; Ester became through crystallization or chromatography on silica gel and purified by PMR and thin layer chromatography cha

characterizes.

(H) The intermediate esters thus obtained were deprotected by treating them in a Mixture of trifluoroacetic acid (3 to IG ml / 1 g ester) and anisole (1 to 5 ml / 1 g ester) dissolved and kept at room temperature kept for 5 to 10 minutes. Then the solvents were evaporated

removed under reduced pressure. The crude acid was extracted with ether or ethyl acetate and an excess shaken on aqueous sodium bicarbonate and the aqueous layer was washed with ethyl acetate. The aqueous phase was separated, covered with ethyl acetate and brought to pH 1-2 mil 2N hydrochloric acid, acidified. The organic layer was washed, dried and evaporated, whereby the desired syn-7jS- (2-alkoxy- or 2-aryloxy-2-arylacetamido) -3- (subst.) - ceph-3-

25 enM-carboxylic acid was obtained. The compounds thus obtained are listed in Table V.

The table below shows the yields as total yields for the coupling reaction and the Deprotection reactions given [steps (i) and (ii) as above].

34

Table V

R CONH

\ •

0R ^a

CO ₂ H

Example R No.

R ^J

C (CH ₃ ),

C (CH ₃ ),

C (CH ₃ ),

C (CHj) ₁

Iff b (acetone)

jO-Lactiim ^ mox

^ Solvents)

r-valuec for DMSO-d <, at 100 MHz

χ R " Y

yield

CH = CH ₂ -47 ° 292
(EtOH) CH = CH ₂ -49 ° 232
287.5
297
(EtOH) CH ₂ OCOCh = CHCH ₃ + 44 °
(DMSO) 260

17 200 1764 (CHBr ₃ )

0.29 8.66 2.75 4.68 4.9

54

24 900 1764 (CHBr ₃ ) 0.32 8.57 2.75

19 800 4.69

18,900 4.93

CH ₂ OCOCH = CHCHj + 37.5 ° 231.5 (DMSO) (EtOH) 15,000 1788 (NuJoI)

27 200 179OfMuJoI)

0.32 8.70 3.04.4.07 8.14

0.28 8.56 3.0.4.05 8.12

-NO ₂ CH ₃ OCOCHj

+ 69 ° (DMSO) 1770 (NuJoI) <0.0 1.63 4.01

2.53

The following example illustrates the formulation of pharmaceutical preparations.

Example A. Dry mix for an oral syrup

Sodium 3-acetoxymethyl-7X2-methoxyimino-2- 5.00 g thien-2'-ylacetamido) -ceph-3-em-4-carboxylate

10 (syn isomer)

Sodium saccharin 0.10 g

Sodium citrate (anhydrous) UOOg

Citric acid (anhydrous) 0.10 g

15 amaranth, 0.01 g

spray-dried raspberry flavor ■ 1.00 g

Sucrose Wf 75.00 g

The product is intended for reconstitution with adequately purified water, adding a final volume of 100 ml and the drug is to be administered within a few days, with Each 5 ml dose of syrup containing 250 mg of cephalosporin derivative should be given.

To make the mixture, the amaranth is mixed well with some of the sodium citrate and ground The sodium saccharin and citric acid are then mixed together. You'll be fine with that Mix the color mixture and then with the rest of the sodium citrate, the taste and the antibiotic powder in the order given. The mixture was ground, mixed with the sucrose, and then 75 g are each filled into a row of 150 ml bottles and these are made moisture-proof with screw caps locked.

Claims (3)

Patent claims:
1.7 / Har substit. HydroxyiminoheteroarylacetamidoJ-cephalosporins of the general formula in which the symbols R. R ^a and P have the following meanings: R is a 5-membered heteroaromatic group with at least one O, S or N atom; R ^{E is} an alkyl group with 1 to 4 carbon atoms, an alkenyl group with 2 to 8 carbon atoms, PTopinyl, a cycloalkyl group with 3 to 7 carbon atoms or a phenyl group substituted by hydroxy, methoxy, ethoxy, bromine, nitro, amino, carboxy or any of these groups Benzoyl and P is methyl, vinyl or the group -CH ₂ Y, in which. Y means (I) the remainder of a pyridine base, (H) azido, (III) the group -SR ⁶ , where R ^{6 is} lower alkyl or a 5- or 6-membered heterocyclic group with at least one 0, N or S atom, (IV) hydroxy; (V) the group -O · CO - R ⁹ , where R ^{9 is} a C _{1 -C 4} alkyl, vinyl, propenyl, phenyl or C _{3 -C 6} cycloalkyl radical; (VI) the group -O · CO -NH (CHj) _n , X. where X is hydrogen, chlorine, bromine or iodine and m is an integer from 1 to 4; (ViI) carbamoyloxy or pyridylcarbamoyloxy, and the physiologically acceptable salts and sulfoxides thereof, the compounds the are syn isomers or mixtures of syn and anti isomers which are at least 75% of the contain syn isomers. 2. A compound according to claim 1, in the form of a mixture which contains at least 90% of the syn isomer. 3. A method for producing a compound according to any one of claims 1 to 2, characterized in that that one in a known manner A) a compound of the formula III B COOR ¹⁰ wherein P is as defined above, B / S or / S - O is, R ^{10 is} water skiing or a carboxyl blocking group, and the dashed line connecting the 2-, 3- and 4-positions indicates that the compound is a Ceph-2-em or Ceph-3-em compound, with an acylating agent corresponding to acid IV RC COOH I 0R ^a or condensed a precursor thereof; or that one
(B) a compound of formula V COOR ¹⁰ Acyl NH (wherein the dashed line, B, P and R ^{10 have} the meanings given above, with the exception that R is not hydrogen) reacts with an acid or a precursor of the formula IV; or that one C) if P is the group - CH ₂ Y