CH626370A5 - Process for the preparation of the syn isomer or of a mixture of syn and anti isomers of 7beta-acylamidoceph-3-em-4-carboxylic acids with antibiotic activity - Google Patents

Description

The invention relates to processes for the preparation of the above-mentioned new class of cephalosporin compounds which have valuable antibiotic properties.

The cephalosporin compounds of the present description * are described with reference to "Cepham" (J.

Amer. Chehi. Soc., 1962, 84, 3400) and the term "cephem" refers to the basic structure of cepham with a double bond.

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, for example in the treatment of diseases caused by bacteria against other antibiotics such as penicillin compounds. are resistant, as well as in the treatment of patients sensitive to penicillin. For many applications, it is desirable to use a cephalosporin ^ antibiotic that has activity against both gram-positive and gram-negative microorganisms, and much research has been done on the development of various types of broad-spectrum cephalosporin antibiotics.

At present, there is substantial interest in the development of broad-spectrum cephalosporin antibiotics that are highly active against gram-negative organisms. 65 Existing, commercially available / J-lactam antibiotics tend to have relatively low activity against certain gram-negative organisms, such as Proteus organisms,

40

45

which are an increasing cause of infection in humans and are also generally substantially inactive against Pseudomonas organisms. Certain Pseudomonas organisms are resistant to the majority of existing commercial antibiotic compounds, and the practical therapeutic use of aminoglycoside antibiotics, such as gentamicin, which have pseudo-monas activity, tends to be unlikely due to the high toxicity of these compounds. to be limited or complicated. It is known that the cephalosporin antibiotics normally have low toxicity in humans, so the development of broad-spectrum cephalo-sporin antibiotics, which have a high activity against Gram-negative organisms such as Proteus and Pseudomonas strains, corresponds to a chemotherapeutic need.

Examples of Ra and Rb are, for Ci to G »alkyl, methyl, ethyl, n-propyl, isopropyl or butyl, for C2 to C4 alkenyl, vinyl or allyl, for C3 to C7 cycloalkyl, cyclo- propyl, cyclobutyl, cyclopentyl or cyclohexyl, for C2 to Cs alkoxycarbonyl, ethoxycarbonyl, and of Ra and Rb together with the carbon atom to which they are attached, for a C3 to C7 cycloalkylene or cycloalkenylidene radical which Cyclobutylidene, cyclopentylidene or cyclo-hexylidene radical.

These compounds have broad-spectrum antibiotic activity, which is particularly notable for gram-negative microorganisms, including those which form /? - lactamases, and also have a high stability towards β-lactamases which are produced by some gram-negative organisms. A characteristic feature of the compounds is their high activity in vitro against gram-negative organisms such as Enterobacter cloacea, Serratia marcescens and Klebsiella aerogenes. The compounds have a particularly high activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms, e.g. B. strains of Proteus morganii and Proteus mirabilis.

Compounds in which at least one of Ra and Rb is not hydrogen also have an extraordinarily high activity against Pseudomonas organisms, e.g. B. Pseudomonas aeruginosa strains.

The compounds obtainable according to the invention are in terms of the configuration of the rest

Ra

0. (CHo) .C. (CHj .COOH

JL Ol I 2m XI

, V <b is defined as having the syn-isomeric form with respect to the carboxamido group. In the present description

5 '

626 370

The syn configuration is structurally described as follows:

R.C.CO.NH-

H

N.

R f

0. (CHj .C. (CHj .COOH 2m. 2 n

- "'K

10th

this configuration is mapped based on the work of Ahmad and Spenser (Can. J. Chem., 1961, 39, 1340). As mentioned above, the compounds can be present as mixtures of the syn and anti isomers, with the proviso that such mixtures contain at least 90 ° / o 15 of the syn isomer. However, it is preferred that the compounds are syn isomers that are substantially free of the corresponding anti isomer.

“Non-toxic derivatives” refer to those derivatives that are physiologically compatible in the dosage administered. Such derivatives can include, for example, salts, biologically compatible esters, 1-oxides and solvates (in particular hydrates). Such derivatives, such as salts and esters, can be formed by reactions of either or both of the carboxyl groups contained in the compounds of the formula I.

Non-toxic salt derivatives that can be formed from the compounds of general formula I include salts of inorganic bases, such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. 30 calcium salts), salts of organic bases (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglu-cosamine salts) and optionally acid addition salts, e.g. B. with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, to-luol-p-sulfonic acid and methanesulfonic acid. The salts can also be in the form of resinates which, for example, contain a polystyrene resin or crosslinked polystyrene-divinylbenzene copolymer resin which contains amino or quaternary amino groups or optionally sulfonic acid groups,

or optionally with a resin containing carboxyl groups, e.g. B. a polyacrylic acid resin are formed. The use of highly soluble salts of the compounds of the formula I with bases (for example alkali metal salts, such as the sodium salt) is generally advantageous in therapeutic use, since such salts are rapidly distributed in the body when administered. However, if insoluble salts of compounds of formula I are desired for special applications, e.g. B. for use in depot preparations, such salts can be used in a conventional manner, for. B. with suitable organic amines.

Biologically compatible, metabolically labile ester derivatives that can be formed from the compounds of formula I include, for. B. acyloxymethyl ester, e.g. B. low-alkane S5 noyloxymethyl, such as acetoxymethyl or pivaloyloxy methyl ester.

If the radical R in the formulas above is a furyl radical, this can be a fur-2-yI or fur-3-yl radical, and if R represents a thienyl radical, this can be a thien-2-yl or thien-3-yl radical.

If Ra and Rb are different in the above formulas, the carbon atom to which they are attached may include an asymmetry center. Thus compounds according to the invention in which Ra and Rb are different can be diastereoisomeric. The invention encompasses the individual diastereoisomers of such compounds as well as their mixtures.

The 3-hydroxymethyl compounds used as starting material and their non-toxic derivatives can have an antibacterial activity and it should be noted that they can be metabolites of the corresponding 3-acetoxymethyl compounds.

Examples of the alkyl group R 'in formula I include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and sec-butyl.

A particularly interesting class of cephalosporin antibiotics obtainable according to the present invention comprises compounds of the general formula:

H H

R.C.CO.NH-

N

0

\

R

OK COOH

ld

X Y

I (HD COOH

wherein R has the above meaning, Re represents methyl, ethyl, propyl, allyl or phenyl and Rd represents hydrogen, carboxy or preferably a radical as defined for R °; or Rc and Rd together with the carbon atom to which they are attached form a cyclobutylidene, cyclopentylidene or cyclohexylidene radical, and W is selected from carbamoyloxymethyl and N-methyl-carbamoyloxymethyl, and also their non-toxic derivatives.

These compounds have broad-spectrum antibiotic activity (including very high activity against strains of Haemophilus influenzae and Proteus organisms) and high / 5-lactamase stability and are furthermore notable for particularly high activity in vitro against Pseudomonas organisms, such as Strains of Pseudomonas aeruginosa, from.

Particularly preferred compounds of the above type due to their particularly high activity against Proteus and Pseudomonas organisms include the following:

(6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid ( syn-isomer),

(6R, 7R) -3-carbamoyloxymethyl-7- [2- (l-carboxycyclopent-l-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid ( syn-isomer),

(6R, 7R) -3-carbamoyloxymethyl-7- [2- (l-carboxycyclobut-l-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid ( syn-isomer)

and their non-toxic derivatives, e.g. B. alkali metal salts such as the sodium and potassium salts.

Another interesting class of cephalosporin antibiotics obtainable according to the invention comprises compounds of the general formula:

H H \

R.C.CO.NH

N

0. (CH2) p.C00H

626 370, 6

where R and W are as defined above and p is 1 strong organic acid, such as trifluoroacetic acid, relieved or 2, and their non-toxic derivatives. becomes. The action of cyanic acid corresponds to that of a compound

These compounds have a broad-spectrum antibiotic of the formula Re.NCO, in which Re is hydrogen, and overactivity coupled with a high / Î-lactamase stability. One leads therefore 3-hydroxymethylcephalosporin compounds in characteristic feature of the compounds is their high 5 their 3-carbamoyloxymethyl analogues.

Activity *: against strains of Haemophilus influenzae, 3-hydroxymethylcephalosporins, which can be used in the pairs above with their particularly high activity against strains from the carbamoylation reactions, Escherichia coli and Proteus organisms. can e.g. according to the GB.ps 1 m 3Q8 and the BE_

A particularly preferred compound of the above described pSen 783 449 and g41 937 herge-type methods due to their particularly high activity against ash-10 stejjt richia coir and Proteus organisms is the (6R, 7R) -3-carba- If a compound of the formula I as a mixture of the moyloxymethyl-7- [2-carboXymethoxyimino-2- (far-2-yl) acet isomers, the syn isomer z. B. by amido] -ceph-3-em-4-carboxylic acid (syn-isomer) and their usual methods> such as crystallization or chromatography,

non-toxic derivatives, e.g. B. Alkali metal salts, how the Na- are obtained. The syn_ and anti.Isomers can by trium or potassium salts. ... 15 suitable techniques, e.g. B. by their ultraviolet spectra,

With respect to the prior art, here too, by thin-layer or paper chromatography or by

BE-PS 783 449 and GB-PS 1 241 656, 1 241 657.1 277 415 whose NMR spectra are distinguished from one another. So and 1 279 402 pointed out. shows z. B. the NMR spectrum of DMSO-de solutions

According to the invention, the compounds of the formula I, syn compounds of the formula I, the doublet for the amide are prepared by the process defined in claim 1. 20 NH at a lower field than similar solutions of the non-toxic derivatives of Compounds I can on corresponding anti-isomers. These factors can be built up in any conventional manner, e.g. B. according to the known monitoring or control of reactions used valued methods. So z. B. salts of bases by reed action of cephalosporinic acid with sodium 2-ethylhexanoate barboxyl blocking groups R \ which are produced by the manufacturer or potassium 2-ethylhexanoate. Biologically, the compounds of the formula I or the esters compatible with the manufacturer can be obtained using standard VQn starting materials necessary for esterification agents. 1-Oxides can be, by desires, desirably those groups that easily deal with the corresponding cephalosporin sulfides with other substances in a suitable stage of the reaction sequence, advantageously suitable oxidizing agents, e.g. B. with a peracid, as is usually the last stage, can be split off. Metaperiodic acid, peracetic acid, monoperphthalic acid or, in some cases, it can be advantageous, biologically an-m-chloroperbenzoic acid, or with metabolically labile carboxyl-blocking group which is acceptable with tert-butyl hypochlorite, the latter reagent usually being incorporated into pen> such as acyloxymethyl groups (e.g. pivaloyloxymethyl), the presence of a weak base such as pyridine, and to retain it in the final product to become- "a biologically acceptable ester derivative of a compound

In the process of making the 3J compounds to obtain the pormei j.

Formula I, in which Ra or Rb mean carboxy, it may be necessary in suitable carboxyl-blocking groups, in many cases, the carboxy group, e.g. B. familiar by a specialist, a list of representative

Substitution with a carboxyl blocking group, e.g. B. blocked carboxyl groups in BE-PS 783 449-

the rest of an ester-forming aliphatic or araliphatic is held. Preferred blocked or protected carboxyl

alcohol or an ester-forming phenol, silanol groups include aryl-lower alkoxycarbonyl groups, such as or stannanol (the alcohol, the phenol, silanol, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl or Stanna.nol preferably containing 1 to 20 carbon atoms Djpbenylmethoxycarbonyl; lower alkoxycarbonyl

holds) or a symmetrical or mixed anhydride group groups, such as tert-butoxycarbonyl; and low halogen

pe, which is derived from a suitable acid. alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl.

The carbamoylation of 3-hydroxymethyl compounds and the carboxyl blocking or protective group can

gene can be done by usual methods. So z. B. including after any suitable one described in the literature

3-Hydroxymethylcephalosporin be removed with an isocyanate of the prescribed method, such. B. by acid

mel Re.NCO (in which Re is a labile substituent or or base-catalyzed hydrolysis or by enzymatically an alkyl group) can be converted to catalyzed hydrolysis.

to obtain bond which contains in the 3-position a substituent of the antibiotic verbin formula -CTbO.CONHR6 obtainable according to the invention, in which Re fertilize the above, e.g. B. compounds of formula I and their non-meaning. If Re is an unstable substituent, toxic derivatives can be used for administration in any purpose, this substituent can then, if desired, be formulated in a moderate manner, analogously to other z. B. by hydrolysis, are split off to form a 3-car antibiotic, and the invention therefore comprises in bamoyloxymethyl group to form. Unstable residues Re, which in the context of pharmaceutical compositions which are easily split off during the subsequent treatment, are adapted to the antibiotic compound according to the invention and include chlorosulfonyl and bromosulfonyl; halogenated for use in human or veterinary medicine, low alkanoyl groups such as DicMoracetyl and Tnchlor- contain. Such compositions can be used for application acetyl; and halogenated lower alkoxycarbonyl groups, in the usual way with the aid of any necessary such as 2,2,2-trichloroethoxycarbonyl. These labile groups of pharmaceutical carriers or excipients can generally be produced by acid- or base-catalyzed ^ Qn

Hydrolysis (e.g. by base-catalyzed hydrolysis under The antibiotic compounds can be used for injection

Using sodium bicarbonate). can be formulated and can be

Another useful carbamoylating agent for the pullen or in multidose containers with added carbamoylating of 3-hydroxymethylcephalosporins is 6J th preservative. The together

Cyanic acid, which advantageously in situ from z. B. an Al settlements can be produced in forms such as suspensions, solutions of potassium cyanate such as sodium cyanate, or emulsions in oily or aqueous vehicles, the reaction by the presence of an acid, for. B. one and can formulating agents such as suspending agents, sta-

7

626370

Contain bilisier and / or dispersant. Alternatively, the active ingredient may be in the form of a powder for remanufacturing with a suitable vehicle, e.g. B. sterile pyrogen-free water, before use.

The antibiotic compounds can also be in a suitable form for absorption by the gastrointestinal tract. Tablets and capsules for oral administration can be in unit dosage form and conventional excipients such as binders, e.g. B. syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; 10 fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Lubricants such as magnesium stearate, talc, polyethylene glycol or silicon dioxide; Disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets 15 can be coated according to the known methods. Oral liquid preparations can be in the form of e.g. B. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or as a dry product for remanufacturing with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as. B. suspending agents, e.g. B. sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifiers, e.g. B. lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles, which may include edible oils, e.g. As almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, and preservatives, such as. B. methyl or propyl p-30 hydroxybenzoate or sorbic acid. The antibiotic compounds can also be formulated as suppositories, e.g. B. conventional suppository bases, such as cocoa butter or other glycerides.

In veterinary medicine, the compositions 3J z. B. formulated as intramammary preparations either in long-acting or quick-release bases.

In general, the compositions can range from 0.1%, e.g. B. 0.1 to 99%, preferably from 10 to 4Q 60 0/0, of the active material, depending on the method of administration. If the compositions comprise dosage units, each unit preferably contains 50 to 1500 mg of the active ingredient. The dosage used to treat adult humans is preferably in the range of 500 to 5000 mg per day, depending on the route and frequency of administration, although higher daily doses may be necessary in the treatment of Pseudomonas infections.

The antibiotic compounds can be used in combination with other therapeutic agents such as antibiotics, e.g. B. penicillins, tetracyclines or other cephalosporins.

The following examples illustrate the invention.

All temperatures are given in ° C. The structure of the 5J compounds was confirmed by NMR spectroscopy and IR spectroscopy.

example 1

(6R, 7R) -3-carbamoyloxymethyl-7- [2- (l-carboxycyclobut-l-yloxyimino) -2- (fur-2-yl) -acetamido] ceph-3-em-4-carboxylic acid 60 (syn- Isomeres) a) (6R, 7R) -3-hydroxymethyl-7- [2- (lt-butoxycarbonyl-cyclobut-l-yloxyimino) -2- (fur-2-yl) -acetamido] ceph-3-em-4 -carboxylic acid (syn isomer)

216.3 g (6R, 7R) -3-acetoxymethyl-7- [2- (1-6-butoxycarbonylcyclobut-l-oxyimino) -2- (fur-2-yl) acetamido] ceph-3-em -4-carboxylic acid (syn isomer), which in Example 11 of the

65

Swiss patent 617 703 is described, were dissolved in a phosphate buffer solution of pH 7.6. After the solution had been freed from the gases, 100 g of a cell suspension of Rhodosporidium toruloides CBS 349, which had been prepared by the method described in German Offenlegungsschrift 25 50110 ", were added and the mixture was stirred at room temperature for 23 hours. The mixture The mixture was filtered and the filtrate was acidified to pH 2.5 in the presence of methyl isobutyl ketone After separating the organic phase and extracting the aqueous phase again with methyl isobutyl ketone, the organic extracts were combined, washed with brine and dried, obtained by adding an organic base to this solution the salt of the compound mentioned in the title in an amount corresponding to 173 g of the acid.r values (d6-DMSO) 5.72, 5.94, (2d, 12Hz, CH2OH), 8.58 (s, C (CH3 ) 33).

b) (6R, 7R) -3-carbamyoloxymethyl-7- [2- (l-carboxycyclobut-l-yloxyimino) -2- (fur-2-yl) acetamido] ceph-3-em-4-car -bonic acid (syn isomer)

25.4 g (6R, 7R) -3-hydroxymethyl-7- [2- (l-butyloxycarbonyl-eyelobut-l-oxyimino) -2- (fur-2-yl) acetamido] ceph-3-em -4-carboxylic acid (syn isomer) in the form of the salt with an organic base was added in portions over a period of 20 minutes with stirring to a mixture of 290 ml of methyl isobutyl ketone and 89 ml of chlorosulfonyl isocyanate at a temperature of from -10 to -5 ° C. The resulting solution was stirred at -5 ° C for 20 minutes. 50 ml of water were then added and stirring was continued for 15 minutes while warming to 20 ° C. The layers were separated and the organic phase was washed with 50 ml of water and dried over magnesium sulfate. By adding an organic base to this solution, the salt of (6R, 7R) -3-carbamoyloxymethyl-7 - [2- (1-t-butoxycarbonylcyclobut-1-oxyimino) -2- (fur-2-yl ) -aeetamido] ceph-3-em-4-carboxylic acid (syn-Isome-res) in an amount corresponding to the acid. r values (de-DMSO) 3.44 (s, CONH2), 5.06, 5.27 (2d, J 13 Hz, CH2O), 8.55 (s, C (CH3) 3).

The tert-butyl ester was treated by treatment with tri-fluoroacetic acid containing anisole for at least 5 minutes at room temperature. The reaction mixture was evaporated in vacuo and the product was isolated by trituration or by partitioning between ethyl acetate (or ether) and an aqueous sodium hydrogen carbonate solution, separating off the aqueous extracts, acidifying these extracts with ethyl acetate and isolating the title dicarboxylic acid in a conventional manner.

[a] D = + 26 ° C (DMSO), / W 277.5 nm (buffer, pH 6), s 15.100, »-max 1788 cm-1 (Nujol; / 3-lactami); r values for the free dicarboxylic acid in dö-DMSO at 100 MHz:

for the hydrogen of the amide bond: 0.34 for the hydrogen in the 7a position: 4.12 for the cyelobutyl group: 7.57; 8.10

Example 2

(6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer) a) (6R, 7R) - 3-acetoxymethyl-7- [2-tert-butoxycarbonyl-methoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

0.45 ml of oxalyl chloride were added at 5 ° C. to a stirred solution of 1.35 g of 2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn isomer) in 50 ml of dry me-

626 370

8th

ethylene chloride, which contained 0.7 ml of triethylamine and 1 drop of dimethylformamide. The solution was stirred at 5? C stirred and then evaporated to dryness at 5 ° C. The residue was suspended in 50 ml of acetone and within 30 minutes to a stirred ice-cooled solution. 1.yone 1.36 g (6R, 7R) -3-acetoxymethyI-7-amino-ceph-3-em-.4- carboxylic acid in 100 ml of water and 50 ml of acetone, which contained 1.0 g of sodium bicarbonate, added. The reaction mixture was stirred for 1 hour after which the acetone was removed under reduced pressure. The residue 10 was acidified to a pH of 1.8 and this mixture was extracted with ether. The combined extracts were washed (water, saturated saline), dried and evaporated to give 2.52 g (96 ° / o) of the title compound as a pale yellow foam, 15 [a] o + 28.5 ° C (c 0, 96, DMSO); Amax (pH 6, phosphate buffer) 276.5 nm (e = 17.900).

b) (6R, 7R) -7- [2-t-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -3-hydroxymethyl-ceph-3-em-4-carboxylic acid 20 (syn isomer)

Using the same method as in Example 1, the compound mentioned in the title was obtained by enzymatic hydrolysis of the 3-acetoxymethyl compound prepared in accordance with section a). 25th

c) 7.23 g (6R, 7R) -3-carbamoyloxymethyl-7- [2-t-butoxy-carbonylmethoxyimino-2- (fur-2-yl) -acetamido] -3-em-4-car-bonic acid ( syn-isomer)

7.23 g of the hydroxymethyl compound in the form of salt 30 with an organic base was added while stirring a solution of 2.61 ml of chlorosulfonyl isocyanate in 45 ml of ethyl acetate, initially kept at -25 ° C. After 45

Minutes at -15 ° C, 25 ml of water are added at 0 ° C and the mixture was stirred at room temperature for 1 hour. A solution of sodium hydrogen carbonate was added and the two phases were separated from one another at pH 7.5. The ethyl acetate extract was washed with brine and the combined aqueous extracts were acidified to pH 2 in the presence of ethyl acetate. The ethyl acetate phase was washed with brine, dried and evaporated. The residue was dissolved in 75 ml of methyl isobutyl ketone and an organic base was added. The solid was filtered off and dried; a salt of the compound mentioned in the title was obtained in a quantity corresponding to 5.96 g of the acid. r values (de-DMSO) 3.48 (s, NH2), 5.06 and 5.29 (2d, J 13 Hz, CH2O).

d) (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxy-imino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

The acid obtained was treated with 4 ml of anisole and 4 ml of trifluoroacetic acid for 30 minutes at 20 ° C., and the reaction mixture was partitioned between ethyl acetate and an aqueous sodium bicarbonate solution. The aqueous layer was washed with ethyl acetate and acidified to pH 2 with 2N hydrochloric acid under ethyl acetate. Evaporation of the ethyl acetate layer gave a solid which was purified by precipitation from ethyl acetate with isopropyl ether and filtering to give 620 mg (44 ° / o) of the title dicarboxylic acid from F = 159 to 161 ° C; [a] o21 + 35 ° (c 1.0, DMSA); / max (pH 6 phosphate buffer) 275 nm (= 15,400); vmax (Nujol) 1778 cm-1, the (d6-DMSO) values include 0.20 (d, NH), 4.15 (dd, 7-H), 5.32 [3, C (CH3) 2] .

M

Claims (14)

626370 2nd .. PATENT CLAIM 90%> of the syn isomer contains antibiotic compounds 1. Process for the preparation of the syn isomer or a fertilizer of the formula: Mixture of the syn and anti isomer, which at least r.c.co.nh (I) ch2oconhr ' COOH "" 0. (ch) .c. (ch0) .cooh 2m «, zìi R in which R is thienyl or furyl and R 'is hydrogen or Ci to C4-alkyl, Ra and Rb, which are the same or different, are each hydrogen, Ci to Ci alkyl, C2 to Gi alkenyl, C3 to C7-cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, Cz- to Cs-alkoxycarbonyl or cyano or Ra and Rb together with the carbon atom to which they are attached are a C3- to C7-cycloalkyli- 25 form the or cycloalkenylidene radical and m and n each represent the numbers 0 or 1 such that the sum of m and n is 0 or 1, and their non-toxic salts, characterized in that the syn isomer or a mixture of the syn and anti isomer, which contains at least 90 0/0 of the syn isomer, a 3-hydroxymethyl compound of the formula: ch2oh (II) 0. (ch) .c. (Ch ") .coor1 2 m k in which R, Ra, Rb, m and n have the meanings given above and each R1, independently of the other, represents hydrogen or a carboxyl protective group, with a carbamoyloxy group, a carbamoyloxy group which has a labile substituent on the nitrogen atom or an N- (Ci - Gt-alkyl) carbamoyloxy group to form capable reagent and cleaves existing carboxyl protecting groups or a labile substituent of the nitrogen atom. 2. The method according to claim 1, characterized in that the carbamoylation reagent from an isocyanate of r.c.co.nh 45 50 2 m Formula Re-NCO, in which Re represents an unstable substituent. 3. The method according to claim 2, characterized in that the carbamoylation reagent consists of chlorosulfonyl isocyanate. 4. The method according to claim 1, characterized in that the carbamoylation reagent consists of cyanic acid. 5. The method according to claim 1 for the preparation of the syn isomer or a mixture of the syn and anti isomer, which contains at least 90% of the syn isomer, of compounds of the formula: n \ R o.k.cooh ld ch2oconh2 mt) cooh in which R has the meaning given in Claim 1, R'1 is hydrogen, carboxy or a radical as it is methyl, ethyl, propyl, allyl or phenyl for Rc de-R1 ', or Rc and R' 1 together with the 3rd 626 370 Carbon atom to which they are attached form a cyclo-butylidene, cyclopentylidene or cyclohexylidene radical, and their non-toxic salts, characterized in that that the syn isomer or a mixture of the syn and anti isomer which contains at least 90% of the syn isomer, a compound of the formula: h h r.c CO. NE \ R CH2OH (II ') o.Lcoor3 id coor1 in which R, Rc and Ra have the meanings given above and R1 has the meaning given in claim 1, reacted with the corresponding reagent and cleaved off carboxyl protecting groups or a labile substituent on the 2o nitrogen atom. 6. The method according to claim 5 for the preparation of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (l-carboxycyclobut-1-yl-oxyimino) -2- (fur-2-yl) -acetamido] -ceph -3-em-4-carboxylic acid, syn isomer, characterized in that the 25th uses syn-isomers of a compound of formula II 'in which R represents a fur-2-yl radical and Rc and Rd together with the carbon atom to which they are attached form a cyclobutylidene radical. 7. The method according to claim 1 for the preparation of the syn isomer or a mixture of the syn and anti isomer which contains at least 90% of the syn isomer, of compounds of the formula: 0. (CH2) p.C00H (iv) CH2OCONH2 cooh in which R see the meaning given in Claim 1, salts, characterized in that a compound and p represents the number 1 or 2, and their non-toxicity of the formula: R.C .CO.NH II N CH2OH (II ") coor ^ 0. (CH2) p.C0ÖR1 in which R and p have the meanings given above and R1 has the meaning given in claim 1, reacted with the corresponding reagent and cleaved off carboxyl protecting groups or a labile substituent on the nitrogen atom. 8. The method according to claim 7 for the preparation of (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid, syn -Isomer, characterized in that the syn isomer of a 60 compound of the formula II "is used, in which R represents a fur-2-yl radical and p represents the number 1. 9. A process for the preparation of non-toxic esters of the carboxylic acids of the formula 1 given in claim 1 with the steric configuration given in claim 1, characterized in that a compound of the formula I mentioned is prepared by the process according to claim 1 and then with esterified with an agent corresponding to a non-toxic ester. 10. The method according to claim 9, characterized in that one produces metabolically labile esters, preferably acyl oxymethyl esters, in particular lower alkanoyloxymethyl esters, such as the acetoxymethyl and pivaloyloxymethyl esters. 626 370 4th Cephalosporin antibiotics of the formula: R.C.CO.NH (I) CH-OCONHR1 COOH v0. (CHo) .C. (CH-) .COOH 2 m. , 2 n R 20th 25th in which R. thienyl or furyl and R 'represent hydrogen or Ci to C <t-alkyl, Ra and Rb each selected from the group consisting of hydrogen, Ci to C4 alkyl, C2- to Gi-Alkeriyl, C3- to C7-cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, C2- to Cs-alkoxycarbonyl and cyano, or Ra and Rb together with the carbon atom to which they are attached, a C3- to C7-cycloalkylene or -cycloalkenylidene radical and m and n each represent the number 0 or 1 such that the sum of m and n is 0 or 1, have a broad-spectrum antibiotic activity, which is characterized by a particularly high activity against gram-negative microorganisms including those who form yy-lactamases. The compounds »which are syn isomers or are present as mixtures of syn and anti isomers which contain at least 90 ° / o of 30 syn isomers have a particularly high activity in vitro against strains of Escherichia coli, Haemophilus influenzae , and Proteus organisms or species. Compounds in which at least one of Ra and Rb is not hydrogen "also have unusually high activity 35 against Pseudomonas organisms. Important compounds of the above type include those in which the 7/5 acylamido group is a syn-2-carboxymethoxy- 2- (fur-2-yl) acetamido, syn-2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido or syn-2- (l-carboxycyclopent-l -yloxyimino) -2- (fur-2-yl) acetamido group.