CS204988B2 - Process for preparing cephalosporine antibiotics - Google Patents

Abstract

Preparation of the syn isomer or of a mixture of syn isomer and anti isomer, where the content of the syn isomer is at least 90%, of 7-acylaminoceph-3-em-4-carboxylic acids with antibiotic activity and the formula I <IMAGE> in which B is > S or > S->O; R<1> is furyl, thienyl or phenyl; and R<2> is C1-C4-alkyl, C3-C7-cycloalkyl or phenyl, and of their non-toxic salts, including their solvates, and esters by acylation of the corresponding 7-amino compound, where appropriate with intermediate protection of the 4-carboxyl group and/or of the 3-carbamoyloxymethyl group, and subsequent isomerisation of a ceph-2-em compound which is obtained where appropriate to the ceph-3-em compound. The compounds are distinguished by a broad spectrum of action on pathogenic microorganisms, the ability to resist beta -lactamases and good stability in vivo.

Description

The invention relates to a process for the production of antibiotics of the cephalosporin series.

These compounds are named according to the nomenclature during the application and by the abbreviation "cefam" according to J. Am. Chem.

Soc., 1962, 84, 3400, the term "cefem" refers to a cefam single-bonded cefam structure.

A number of cephalosporin compounds with varying degrees of antibacterial activity are known, which compounds have a double bond at the 3-position and are usually substituted at the 3-position by a methyl group or a substituted methyl group and at the 7β position by an acylamide group. It is well known that the antibiotic properties of certain 3-cephem-4-carboxylic acids are predominantly determined by the nature of the substituents at the 7β and the 3-position. Efforts have been made to find suitable combinations of these groups to give compounds with good antibiotic properties.

Cephalosporin antibiotics are widely used in humans and animals, for example in the treatment of diseases caused by bacteria resistant to other antibiotics, for example penicillin compounds, and in the treatment of penicillin-hypersensitive patients. It is often desirable to use cephalosporin, effective against both gram-positive and gram-negative microorganisms, while it is still necessary to find cephalosporin antibiotics with a broader and wider spectrum.

The practical use of many cephalosporin antibiotics is limited by the relatively high susceptibility to the β-actamases of various bacteria. A desirable property of rock-age antibiotics is therefore that they are substantially. Another disadvantage of cephalosporin antibiotics is that they are subject to degradation in vivo. Many known antibiotics of this type are deactivated in this manner, often very rapidly, mainly by enzymes, e.g. esterases of a human or animal organism.

It has been found that a group of antibiotics with a particular combination of 7/3 acylamino groups and a substituent at the 3-position. has a wide spectrum of efficacy and. At the same time great stability against β-lactamases and good stability in organism. These compounds have 2-aryl-2- (etherified oxyimino group) as a 7β-acylamide group, which is essentially in the form of the syn-isomer, with the carbamoyloxymethyl group in the 3-position.

Thus, the present invention provides a process for the preparation of cephalosporin antibiotics of the general formula. AND

Μ w ïc -CO / VW-j - f °

A, D- ⁿ CHO.CO.NR o * *

COORA (I) where

R ¹ represents furyl, thienyl or phenyl,

R ² represents C 1 -C 6 alkyl, C ² -C 7 -cycloalkyl or, phenyl and

Ra represents hydrogen or an ester-forming group giving physiologically acceptable esters, in the form of a syndsomer or in a mixture of the syn-isomer and the anti-isomer containing at least 90% of the syn-isomer, and their physiologically acceptable salts derived when Ra is hydrogen; the most preferred compounds of formula I are syn-isomers substantially free of the corresponding anti-isomers.

The process according to the invention consists in condensing a compound of the formula II at a temperature of -50 to 4-50 ° C

where

B '' represents = S or S ->O; R ¹¹ represents hydrogen or a carboxyl protecting group, such as d-phenylmethyl or tert-butyl,

R 12 is hydrogen or. . An N-protecting group such as. for example, mono-, di- or trichloroacetyl or chlorosulfonyl and the dashed line (--- -} between positions 2, 3 'and 4 indicates that it may be a 2-cephem or 3-cephem compound, or an acid addition salt of the compound, or an N-strength derivative of the compound, with an acylating agent corresponding to the acid of formula III

..... Ri.C.COÚH

II.

N

AND.-. \

OR2 (III) where

R1 a. R2 is as defined above for the corresponding sulfide, and then the compound of formula I is isolated, optionally after separation of the syn-isomer and the anti-isomer, and optionally after. converting a compound of formula I to its 1-oxide (when Ra is hydrogen in formula I), or physiologically acceptable salts or esters thereof.

The process of the invention can be carried out by isolating a compound of formula I or a physiologically acceptable salt of a compound of formula I wherein Ra is hydrogen or its 1-oxide in the form of a syn-isomer free of anti-isomer.

Another embodiment of the process of the invention may be such that the compound is a general compound. Formula II wherein B, R11, ^R12 and the dotted line is as defined in .bodě 1 is condensed with an acid halide of formula III wherein R1 and R2 have the meaning given therein.

The process may also be carried out by condensation in the presence of an acid binding agent selected from the group consisting of tertiary amines, inorganic bases or oxiranes.

A compound of formula II wherein B, R, R ¹² and the dotted line are defined as in point 1 may be condensed with a free acid of formula III in the presence of a condensing agent selected from the group of a carbodiimide, carbonyldiimidazole or isoxazoliniových salts.

A preferred compound of formula I wherein R ¹ is 2-furyl may be prepared starting from the corresponding compound of formula III, i.e., where R ¹ in formula III is 2-furyl.

The process according to the invention makes it possible to produce the preferred compounds of formula I, wherein R 2 is. methyl, ethyl, tert-butyl, cyclopentyl or phenyl, by using a compound of formula III as the starting compound, wherein R 2 is as defined above.

The compounds of the invention are found in the syn (cis) isomeric form due to the OR2 configuration. ke. carboxamido. Thus, in the description of the present invention, the syn configuration is represented as follows:

Ri.C.CONH—

N

OR ²

The configuration of the son is shown by work,. by Ahmad and Spenser in Can. J. Chem., 1961, 39, 1340.

Salts of the compounds of formula I may be salts with inorganic bases, for example alkali metals such as sodium and potassium, alkaline earth metals such as calcium or calcium. salts with organic bases such as. procaine,. phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-mea are converted into any A ² -isomer to the desired A3-isomer and / or the carboxyl-blocking or N-protecting group is removed and / or cephalosporin sulphoxide 204988 is reduced with thylglutamine. The salts may also be in the form of resins, for example with a polystyrene resin or a copolymer of polystyrene and divinylbenzene with cross bridges and containing amino or quaternary amino groups.

When R ¹ in formula I is furyl, it may be 2-furyl or 3-furyl, and in the case of thienyl it may be 2-thienyl or 3-thienyl. A preferred value of R1 is 2-furyl.

As mentioned above, the substituent R 2 in formula I is alkyl of 1 to 4 carbon atoms, for example methyl, ethyl or tert-butyl, cycloalkyl ^. alkyl of 3 to 7 carbon atoms, for example cyclopentyl, or phenyl.

The compounds according to the invention have valuable properties, namely high activity against a large number of Gram-positive and Gram-negative microorganisms, and at the same time high stability against β-actamases of various gram-negative organisms and good in vivo stability, especially in the case of esterase action.

The compounds of the invention can be advantageously used for the treatment of various diseases in humans and animals caused by bacteria.

An important compound of the invention is (6R, 7R) -3-carbamoyloxymethyl-7- [2- [2-uryl] -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in the form of the syn-isomer, which can be expressed IV

COOH (IV) is usually in the form of an alkali metal salt, especially the sodium salt. This compound is active against a wide variety of gram-negative and gram-positive microorganisms, for example Staphylococcus aureus, Streptococcus pyogenes and Streptococcus vilidans, Diplococcus pneuminiae, Haemophilus influenzae, Neisseria and Clostridia species, Escherichia coli, Klebsiella, Proteus species, Proteus species in vivo. In particular, the compound has a high activity in vitro against Haemopbilus inRuenzae, Neisseria gonorrhoeae and Neisseria meningitidis. The compound is very stable against β-lactamases of a number of gram-negative organisms, as demonstrated, for example, in vitro against enzymes of various strains of Escherichia, Enterobacter and Klebsiella. The compound is resistant to the action of mammalian esterases and thus stable in both human and animal organisms as evidenced by high levels of unchanged compound in the urine. In addition, high levels of these compounds occur in serum after parenteral administration in humans and animals, with little binding to serum.

The use of highly soluble basic salts, for example sodium salts, is advantageous because these salts are spread very rapidly throughout the body after administration.

The sodium salt, (6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-furyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate, in the form of the syn-isomer, has been found to occur in the a wide variety of crystalline forms, including solvates, all of which are within the scope of the invention.

The sodium salt is usually prepared by reacting a solution of a compound of formula IV in a polar solvent such as dimethylacetamide, a mixture of these solvents, such as a mixture of dimethylacetamide and acetone or dimethylamide and formamide, or polar mixtures of water and organic solvents, e.g. a mixture of water and acetone with a small molar excess of sodium 2-ethylhexanoate in the form of a solution in an aqueous organic solvent such as an alkanol such as ethanol, a ketone such as acetone, a chlorinated hydrocarbon such as methylene chloride, an ester such as ethyl acetate or ether; such as dioxane, usually at room temperature, and the precipitated salt is separated after optionally cooling the solution to, for example, 4 ° C.

When substantially anhydrous solvents are used, Form I (6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-

sodium furyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate in the form of a syn-isomer. This material contains about 1.5% water. When the solvent contains more than 2% water, the reaction results in a salt of Form II, which also contains approximately 2% water. If the solvent contains more than 60% dioxane, a salt of Form III is obtained, the material being a dioxane solvate with. containing about 1 mole of dioxane. Form II can also be obtained by using a water-containing solvent at a temperature of 60-80 ° C. Crystallization of the same compound from the lyophilized form in an appropriate anhydrous, water-containing or dioxane-containing solvent can also be obtained in Form I, II or III.

In the case that the Form I is exposed to water vapor, for example at a relative humidity of 75 ° / o absorbs salt further quantity of water and its crystalline form changes to Form IV, which comprises about 4 ^1% water, i.e. about 1 mole, and it is therefore probably a hydrate. This form is reversible so that form IV can be converted back to form I, for example by drying under vacuum with phosphorus pentoxide. Form II does not absorb additional water, but can be converted to Form I by heating a suspension of Form II in boiling methanol.

Form III can be precipitated in the form of a gel, which can then be dried under vacuum to give a solid having a very high density, very little crystalline or amorphous. However, crystalline form III can also be obtained by treating the aqueous sodium salt solution with a large excess (e.g. 8 volumes) of dioxane, optionally in the presence of a small amount of ethanol, and then separating the resulting white needle crystals after cooling to 4 ° C. washing the product with dioxane and the crystals are dried, for example, under vacuum at 20 ° C.

Form III is hygroscopic and, when exposed to water vapor at e.g. 75 ° / o humidity, this form loses dloxane and becomes form IV, which can then be dried, for example phosphorus pentoxide to form I. In the case of crystalline treatment Form III, the crystalline form does not change. Form III can be converted to Form I by heating in hot methanol, then the crystalline form is lost when Form III has been used in the crystalline form.

The four forms of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-furyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate (sine-isomer) sodium salt as was described above, were characterized in X-ray powder form (d-distance and intensity) and in the infrared spectrum:

X-ray values of powder samples

Camera: Debye-Scherrer, radius 114.6 mm radiation: copper K _o = 1.5418 10 “ ¹⁰ m intensity (I) visually compared to calibrated standard

Form I d AND d AND 8.33 80 3.05 4 7.44 4 2.93 14 (wide) 6.85 45 2.72 8 (poorly separated) 6.38 5 2.69 10 (poorly separated) 5.86 4 2.57 9 5.36 4 2.47 6 4.82 100 ALIGN! 2.40 10 4,56 35 2.35 10 4.36 6 2.26 4 4.19 40 2.20 3 3.95 26 2.11 8 (wide) 3.82 24 2.04 3 3.62 28 1.94 4 3.47 28 1.89 5 3.32 10 1.82 6 (wide) 3.19 10 1.77 2 Form II d AND d AND 8.7 » 60 3.49 14 7.81 9 3.07 6 (wide) 6.65 25 2.91 8 4.68 100 (wide) 2.77 6 4.45 10 2.32 3 (wide) 4.20 10 2.19 2 3.76 20 (wide) 2.08 2 Form III d AND d AND 14.98 60 4.29 20 May 12.95 40 4.16 100 ALIGN! 10.16 20 May 3.81 25 (wide) 8.23 45 3.60 20 May 7.52 5 3.47 5 6.61 65 3.32 10 6.08 3 3.26 30 5,57 20 May 3.13 17 (wide) 4.98 40 2.43 10 4.73 60 2.15 15 Dec

Form IV

d AND d AND 8.85 70 3.75 35 7.80 6 3.10 1 7.15 25 2.93 4 6.01 20 May 2.76 12 5.06 18 2.62 1 4.65 100 ALIGN! 2.41 2 4.30 25 2.30 3 4.01 25 IR spectrum 4000—650 cnr ¹ spectra recorded jolového mule (bars for nu jol were Spectrometer - Perkin-Elmer 521, area Prices) Form I 3520 w +1590 s 1262 m 1004 m 3460 m 1556 m 1248 m 978 m 3370 m 1534 s 1170 m 918 w 3265 s 1480 m 1152 m 882 s 1770 sh 1410 s 1134 w 878 sh 1752 s 1400 s 1112 m 838 w 1706 s 1338 s 1076 m 814 w 1660 s 1328 s 1054 sh 790 w 1620 s 1284 m +1042 s 778 w 754 m Form II 3526 m 1544 m 1152 m 920 m 3492 w 1478 m 1142 m 882 m +3364 m 1412 S 1112 m 878 w 3250 m 1398 s 1080 m 840 w 1758 s 1332 s 1058 m 818 w 1695 s 1284 m +1045 m 792 w 1665 s 1268 m 1005 m 752 m 1642 sh 1240 m 980 m 1624 s 1172 m 954 w Form III 3465 m 1532 s 1155 m 820 w 3415 m 1482 m +1124 s 800 w 3345 m 1412 s 1078 m 790 w 3275 m 1395 s +1058 s 768 m 3200 m 1326 s 1048 s 748 m 1780 s 1285 m 1014 m 1702 s 1260 m 985 m 1660 s 1230 m 938 w 1632 m 1225 m 888 m 1618 s 1196 w 878 s 1552 m 1180 m 836 w

Form IV

3585 w 1594 s 1264 m 1008 m 788 w 3520 w 1555 m 1240 m 980 m ..... 752 · · m 3370 m 1540 m 1172 w 956 w +3260 s 1478 m 1152 m 920 w 1758 s 1410 s 1114 w 882 m 1712 s 1400 d 1078 m 878 · w 1664 s 1330 s 1058 m 838 w 1620 s 1285 m '1042 m 818 'w ¹ · · · · ···

Explanations s = strong sh ^! =? 'hťb m = medium w = weak 4 - bands, characteristic of a certain crystalline form

When Compound (I) is to be present as an insoluble salt for some uses, the salt can be prepared in a conventional manner, for example by reaction with an appropriate amine. .

In the above compound of formula II

R11 represents a hydrogen atom or a carboxyl-protecting group, such as the ester of an aliphatic or araliphatic alcohol forming an ester, phenol, silanol or stannanol or a symmetrical or mixed anhydride group derived from the corresponding acid, while

R 12 represents a hydrogen atom or an N-protecting group, for example acyl, especially a lower alkanoyl such as acetyl or a halogen substituted lower alkanoyl such as monochloroacetyl, dichloroacetyl, trichloroacetyl or chlorosulfonyl.

The compound of formula II may optionally be used in the form of a derivative thereof, for example an addition salt and an inorganic acid such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid or with an organic acid such as methanesulfonic or p-toluenesulfonic acid or N-silyl derivative .

The aforementioned physiologically acceptable carboxylic acid derivatives of formula (I), i.e. when R ^a is hydrogen, can be prepared by any known method. Salts with bases can be formed, for example, by reaction of cephalosporic acid with sodium or potassium 2-ethylhexanoate. Biologically acceptable esters can be obtained using conventional esterifying agents. The 1-odides may be obtained by treating the corresponding sulfides with an oxidizing agent, for example, a peracid such as meta-periodic acid, peracetic acid, monoperphthalic acid or n-chloroperbenzoic acid, a target, butylhypochloride, for example in the presence of a weak base such as pyridine.

Compounds of formula (I) may be prepared by condensation of a compound of formula (II) with an acid halide-containing acylating agent such as chloride or bromide, and the acylation is carried out at a temperature of -50 to +50 ° C. Celsius, preferably -20 to + 30 ° C.ve. aqueous or non-aqueous environment. ,

The acid halide acylation may be carried out in the presence of an acid-binding agent, for example a tertiary acid-binding agent, for example a tertiary amine such as triethylamine or dimethylamine, in the presence of an inorganic base such as calcium carbonate or sodium bicarbonate or in the presence of an oxirane, preferably a lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide, which binds the hydrogen halide that is released upon acylation.

The free acid of formula III can also be used as an acylating agent. Acylation of this type is usually carried out in the presence of carbodiimide; such as N, N'-diethylcarbodiimide, N, N'-dipropylcarbodiimide or diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-dimethylaminopropylcarbodiimide, in the presence of a carbonyl compound such as carbonyldiimidazole, or in the presence of an isoxazole; as N-ethyl-5-phenylisoxazolinium-3'-sulfonate or N-tert-butyl-5-methylisoxazolinium perchlorate. The condensation is usually carried out in an anhydrous reaction medium such as methylene chloride, dimethylformamide or acetonitrile.

The acylation may also be carried out with other acid derivatives of the formula (III) which form amides, for example with symmetrical or mixed anhydride, for example with paleic anhydride or with a haloformate, for example a lower alkyl haloformate. Mixed or symmetrical anhydrides are usually prepared directly in the reaction mixture. For example, a mixed anhydride can be prepared using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed from phosphoric acids, for example phosphoric or phosphorous, with sulfuric acid or aliphatic or aromatic sulfono

14 acids such as p-toluenesulfonic acid.

The protecting group substituting the 4-carboxyl group of the compounds of formula II is suitably a group which is readily cleavable after acylation, which is preferably from 1 to 20 carbon atoms. Suitable protecting groups are well known; they are for example. cited in the Belgian patent cited above. Preferred groups are, for example, lower arylalkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl. diphenylmethoxycarbonyl, lower alkoxycarbonyl groups such as tert-butoxycarbonyl, and lower haloalkoxycarbonyl groups such as 2,2,24-trifluoromethoxycarbonyl. This group can then be removed in a known manner, for example by acid, base or enzymatically catalyzed hydrolysis.

If the sulfoxide of the compound of formula (I) is obtained at the end of the reaction, the reaction can be carried out. to the corresponding sulfide, for example, by reducing the corresponding acyloxysulfonium salt, or. an alkyloxysulfonium salt prepared directly in the reaction mixture by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt, which reduction is carried out, for example, with sodium dithionide or an iodide ion, for example with potassium iodide , dimethylformamide or dimethylacetamide. The reaction is carried out at a temperature of -20 to - | -50 ° C.

When the reaction product is a 2-cephem-4-carboxylic acid ester, the desired 3-cephem compound can be obtained by treatment with a base.

The antibiotic compounds obtained according to the invention can be formulated into pharmaceutical preparations intended for suitable routes of administration similar to other antibiotics; from the compound produced according to the invention may in particular be treated with a compound of formula I or their physiologically acceptable salts (in cases where R ^R 'in formula I represents hydrogen] or 1-oxides modified for use in human or veterinary medicine. To feed them - use with the aid of conventional pharmaceutical carriers or excipients.

Antibiotics of the invention may be for injection in ampoules or larger containers with preservative. These may be suspensions, solutions or emulsions in oil or in an aqueous medium, optionally with the use of agents which facilitate the formation of a suspension, stabilizers and / or dispersing agents. The active substance may also be in the form of a powder, which dissolves just before administration, for example, in sterile, pyrogen-free water.

In veterinary medicine, these may be preparations for administration to the mammary gland.

The formulations usually contain at least 0.1%, for example 0.1 to 99%, preferably 10 to 60%, of the active ingredient depending on the route of administration. A single dose is usually 50 to 1500 mg of active ingredient. In adults, 500 to 4000 mg per day are administered depending on the route and frequency of administration.

The compounds of the invention may also be administered in combination with other compatible antibiotics, for example penicillins, tetracyclines or other cephalosporins.

The invention is illustrated by the following examples. All temperatures are in degrees Celsius. temperatures - melting - were determined at Kofler. block.

A) Preparation of starting materials

Preparation 1 a] Diphenylmethyl (6R, 7R) -7- (thien-2-ylacetamido) -3-trichloroacetylcarbamoyloxymethyl-4-cephem-a-carboxylate

13.2 g (70 mmol) of trichlotacetyl isocyanate are added to a stirred suspension of diphenylmethyl (6R, 7R) -3-hydroxymethyl-7- (thien-2-ylacetamido) -3-cephem-4-carboxylate (26.0 g). 50 mmol] in 600 ml of anhydrous acetone at 20 DEG C. The solid was soon dissolved and the mixture which was stirred at 20 DEG C. for 1 hour was cooled for one hour and the resulting precipitate was filtered off and washed with ether to give 33. 1 g (93%) of the title compound, m.p. 183-184 ° C.

[α] D 21 + 24 ° (c 0.95 in DMSO),

Λ ^Et P ^H 295 nm ^- (ε 3120).

inf.

and '1' λ Ef 264 nm (ε 17 400 _к

The data obtained by IR spectroscopy, NMR spectroscopy and microanalysis confirm the structure of the resultant compound.

b) Salt of p-toluensuHonové d.ifenylmethyl- acid (6R, 7R] ^{-7-allΊinilЗ-tгichlи'acetylkarbamoy:} loxyiuethylcef-3-em-4 - carboxylate '

Anhydrous pyridine (31.0 ml) (0.384 mol) was added to a solution of phosphorus pentachloride (20.0 g, 96 mmol) in 300 ml of anhydrous dichloromethane at 3 DEG C. The suspension was stirred at 3 DEG C. for 10 min. with 22.5 g (32 mim) diphenylmethyl (6R, 7R) -7- (thien-2-ylacetamido) -3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylate.

The reaction proceeds with stirring at about 2 ° C for an hour. The dark solution was slowly poured into a cold anhydrous mixture of 80.0 mL of methanol

200.0 ml of dichloromethane, the temperature of which is kept below 5 ° C. The temperature of the solution is then

The 1S is allowed to rise to 23 ° C and after stirring the solution at this temperature for one hour, 200.0 ml of water are added. The organic layer was separated and washed with 2 N sulfuric acid, water, sodium bicarbonate solution and water, dried with magnesium sulfate and evaporated in vacuo. The resulting oil was dissolved in ethyl acetate and treated with a solution of p-toluenesulfonic acid in ethyl acetate. About 350 ml of the mixed solutions were poured into about 1 liter of diethyl ether and the resulting solid was filtered off and dried in vacuo to give 17.2 g (72%) of the title compound having a boiling point of 150-153 ° C.

[α] D ²⁰ + 7.5 ° (c 0.82 in DMSO),

EtOH λ max 278 nm (ε 16 650).

and λ \ ^{0 0} 259 nm (ε 20 000),

Data obtained by infrared spectroscopy, NMR spectroscopy and microanalysis confirm that the structure is consistent with the resultant compound.

Evaporation of the filtrate and trituration of the residue with ethanol gave 3.2 g (14.2%) of the unchanged starting material.

c) p-Toluenesulfonic acid salt with diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate

17.2 g (22.7 mmol) of p-toluenesulfonic acid salt of diphenylmethyl (6R, 7R) -7-amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylate are dissolved in a mixture of 900.0 ml of anhydrous methanol and 45.0 ml of acetyl chloride and allowed to stand at 20 ° C for 5 hours. Removal of the solvent under reduced pressure gave an oil which was dissolved in dichloromethane. This solution was shaken with an aqueous solution of sodium bicarbonate and then washed with water. 4.3 g (22.7 mmol) of p-toluenesulfonic acid monohydrate were added and the solvent was evaporated in vacuo. The residue is dissolved in about 150 ml of hot isopropanol and the solution is poured into about 600.0 ml of diisopropyl ether. The precipitate was filtered off and dried in vacuo to give 8.9 g (64%) of the title compound, m.p. 110-112 ° C. Celsius.

[Α] 21 D -14 ° (c, 1.0 - in CHCl 3),

EtOH max.

259 nm (ε 6120)

EtOH λ 295 nm (ε 3700).

Data obtained by infrared spectroscopy, NMR spectroscopy and microanalysis confirm that the structure is consistent with the resultant compound.

Preparation 2

P-Toluenesulfonic acid salt with diphenylmethyl- (6R, 7R) -7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate

The stirred suspension of 156.0 g (0.75 mmol) of phosphorus pentachloride in 1.5 liters of anhydrous dichloromethane is cooled. in an ice bath and treated with pyridine (60.5 ml, 0.75 mol) at such a rate that the temperature of the mixture remains at about 20-25 ° C. The mixture is shaken and cooled to 8 ° C and 354.5 g (0.5 mol) of diphenylmethyl (6R, 7R) -7- (thien-2-yl) acetamido-3-trichloroacetylcarbamoyloxymethyl-3-cefems4-carboxylate are added in portions. within 10 minutes. The mixture was stirred at 8 ° C for one and three quarters and then; is added for 10 minutes to a stirred mixture of 225 ml (2.5 mmol) of 1,3-butanediol and - 500 ml of dichloromethane pre-cooled to -20 ° C so that the temperature of the mixture is in the range of -15 to -20 ° C. The cooling bath was removed and the mixture was stirred at about -10 ° C for 20 minutes. 1 liter of water was added and the biphasic mixture was stirred for 30 minutes. The aqueous phase is extracted twice with 500 ml of dichloromethane and the organic phase is washed successively with 1 liter of 2 N hydrochloric acid, mixed and evaporated to a brown gum. This was dissolved in 3.6 L of methanol, stirred and treated with 1.2 L of saturated aqueous bicarbonate for 10 minutes.

The mixture was shaken at about 20 ° C for 1.5 hours, a small amount of brown precipitate was removed by filtration. Concentrate the yellow filtrate in vacuo (bath temperature not higher than 40 ° C) to about 1.5 liters and add 1.5 liters of water. The resulting suspension is frozen for 1 hour and the yellow precipitate is filtered off, washed well with water, sucked off as dry as possible and dried under vacuum at 40 ° C for 24 hours. The oily precipitate thus obtained, followed by p-toluenesulfonic acid monohydrate (81 g, 0.425 mol) was added to 2 liters of stirred chloroform. After a few minutes, the p-toluenesulfonic acid salt began to crystallize. Stirring is continued for a further 30 minutes after which the water is removed azeotropically under vacuum with a continuous replacement of chloroform to maintain a volume of 2 liters. The suspension was then frozen overnight and the resulting product was filtered off, the slurry was washed twice with 250 ml of chloroform, filtered again, washed with an overlay of chloroform and dried under vacuum at 40 ° C to give the title compound as 237.8 g (71.1%). ) of white crystalline solid.

Λ max (EtOH) 262 nm (ε 7250).

NMR Spectrum (DMSO-d 6) - indicates the presence of 0.25 mol of chloroform.

Preparation 3

(6R, 7R) -7-Amino-3-carbamoyl-. oxymethyl-3-C6-form-4-carboxylic acid

300.0 g (0.44 mol) of p-toluenesulfonic acid salt with diphenylmethyl- (6R _, 7R) -7-amino-3-carbanioyloxymethyl-3-cephem-4-carboxylate dissolved in about - 0.6 mol - chloroform 300 ml of trifluoroacetic acid and 300 ml of anisole immersed in a 20 ° C water bath are added to the stirred mixture over 30 minutes. The temperature of the mixture rises from 23 to 28 ° C after the first 20 minutes, but returns to 26 ° C at the end of the addition. The gold-yellow solution was stirred for 1 hour, the temperature dropped to -21 ° C, then added to the stirred mixture -1.5 liters. ethyl acetate and 1.5 liters of water immersed in an ice bath. ?

The pH of the stirred mixture was adjusted to 3.8 after 10 minutes with the solution. - ammonia (specific gravity 0,880), allow the temperature to rise to 38 ° C. The suspension was stirred and cooled to 10 ° C for 1.25 hours, and then filtered. The creamy precipitate is washed with - 750 ml of water - and four times with 200 ml of ethyl acetate and dried under vacuum. The title compound was obtained (115.6 g, 96.2%) _.alpha . (PH 6 phosphate) 265 nm (ε 7750), purity by liquid chromatography at high pressure 99.7%.

Microanalysis data confirmed that the spectrum was consistent with the resultant compound.

Preparation 4

(a) (6R, 7R) -7- (R-Benzoylamino-5-carboxypentanamido) -3-hydroxymethyl-O-cephem-4-carboxylic acid

A stirred solution of 62.0 g (about 100 mmol) of (6R, 7R) -7- (R-5-amino-5-amino-5-carboxypentanamidopO-hydroxymethylce-α-ω-carboxylic acid monopotassium salt (about 67% pure) in 300 ml of water The reaction mixture was cooled to -5 ° C and treated with a solution of benzoyl chloride (17.4 mL, 150 mmol) in acetone (200 mL) for 25 minutes.

8.2-8.5 by controlled addition of 30% (w / v) aqueous potassium orthophosphate solution. The mixture is stirred for an additional 10 minutes and is then overlaid with 140 ml of ethyl acetate and the pH is lowered to 5.6 with orthophosphoric acid. The layers were separated and the aqueous portion was washed with an excess of twice 400 mL of ethyl acetate. The aqueous portion was diluted with 2 L of water in an overlay with 2 L of ethyl acetate and adjusted to pH 2.0 with orthophosphoric acid in the pH of the stirred mixture. The layers were separated and the aqueous layer was extracted with an additional three times 1500 mL of ethyl acetate.

The combined extracts are washed with 800 ml of saturated brine, dried and concentrated in vacuo at a volume of 300 vol. -400 ml. The resulting precipitate is stirred with 2 liters of ether for 20 minutes and then filtered. The collected precipitate was washed twice with 250 ml of ether and dried in vacuo. The resulting compound was 54.95 g (88.6%) as a white powder. [α] ²⁰ + 74 ° (c 1.00, dioxian), + iax (pH buffer) 231 nm • 1% (E, _x cm 275), 266 nm - (inflexion, ^{e 1} cm ¹⁴⁵ ) · NMiR-? Ethanol (DMSO-d6) showed contamination of the 20% lactone in about 0.4 moles of ethyl acetate.

(b) Sodium salt of (6R, 7R) -7- (R-5-benzoylamino-5-carboxypanatamido) -3-chloroacetylcarbamoyloxymethylcef-3em-4-carboxylic acid

N in 25.46 g of the compound described in (v) is treated with a solution of 9.00 g (75 mmol) of chloroacetyl isocyanate in 92 ml of anhydrous acetone. The resulting solution was stirred at 20 ° C for 25 minutes, cooled to 5 ° C for 5 minutes and treated with a solution of 8.47 g - (51 mmol) of sodium 2-ethylhexaacetate in 51 ml of acetone. The crystalline suspension is stirred for 5 minutes at 5 ° C. the precipitate was collected by filtration, washed with 80 mL of acetone in 50250 mL of ether, then dried under vacuum (133 Pv, to give the title compound (27.23 g, 107.0 wt%).

mp ²⁰ 4-72.0 ° (c 1.00, 3% aqueous NH 4 CO 3),

Amax (pH buffer) - 227 nm (E ^j 249) ^{, 2} 61 nm (mf16x10 ^{, E 1} % ¹⁰⁵ ).

The NME-1 was found to have an impurity of 35% lactone in about 1.0 mol of chloroacetamide.

(c) (6R, 7R) -7-Amino-3-chloroacetylcarbamoyloxymethyl-3-C6-methyl-4-carboxylic acid

A suspension of 24.77 g of the compound obtained in b) in 320 ml of dry methyl chloride is cooled to 10 ° C with stirring under nitrogen. Pyridine (17.6 ml, 218.0 mmol) was added, followed by dichloromethylsilane (16.8 ml, 139.2 mmol) and the pale brown slurry was stirred at 20 ° C for 20 minutes and then cooled. nv —17 st. Celsius. Phosphorus pentachloride (10.84 g, 52.0 mmol) was added and the mixture was stirred at -17 to -23 ° C for 2 hours. 6.48 ml (80 mmol) of pyridine is added in the mixture and added to me204988 thanol (104 ml + 20 ml wash, precooled to -35 ° C) at such a rate that the temperature of the stirred solution does not exceed -10 ° C. The stirred solution is allowed to reach 4-2 ° C over 25 minutes, then 88 ml of water are added and the pH of the mixture is adjusted to from 0.6 to 3.8 with aqueous ammonia solution (specific gravity 0.880).

The resulting biphasic mixture containing the precipitated precipitate was frozen for 1 hour and then filtered. The precipitate was washed sequentially with 100 mL of 50% (v / v) water / methanol, 80 mL of methanol and 40 mL of methylene chloride, then dried under vacuum (1 mm Hg) to give the title compound 6.86 g (27.7 wt%). ) in the form of a cream powder, [α] ¹⁹ D 4-48 ° (c 1.04, Me 2 SO),

Amax (pH 6 buffer)

237.5 nm ₁ % (E 1 cm 149), 261.5 nm (E%

cm

145).

B) Examples

Example 1

a) Diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate (syn-isomer)

Method (i)

The p-toluenesulfonic acid diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate salt obtained from the corresponding 3-trichloroacetylcarbamoyloxymethyl compound (25.0 g, 0.33 mol) was dissolved in a mixture of ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with water, dehydrated with magnesium sulfate and evaporated on a rotary evaporator to give 11.5 g (0.262 mol, 77%) of diphenylmethyl- (6R, 7R) -7-amino-3-carbamoyloxymethyl-3. -cephem-4-carboxylate in the form of a foam.

The syn-isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid (5.32 g, 0.312 mol) in anhydrous dichloromethane (100 mL) was added to a solution of this amine in dichloromethane (50.0 mL). cooled to 3 ° C, 10 minutes later, followed by the addition of a solution of DL-β-cyclohexylcarbodiimide (6.5 g, 0.312 mol) in 30 mL of dichloromethane. The reaction mixture is stirred in an ice bath for 45 minutes during which time a precipitate (especially N, N‘-dicyclohexylurea) crystallizes. This was filtered off and discarded, and the filtrate was washed with aqueous sodium bicarbonate solution and water, freed from water, magnesium sulfate and evaporated to dryness. The residue was triturated with ethanol to give the crude product (10.6 g) which was purified by chromatography on silica gel (1 kg). Elution with 10% acetone in dichloromethane removes non-polar contaminants and the fractions eluted with 20% acetone in dichloromethane give the title compound (4.8 g, 31%), mp 199-202 ° C, [α] 21 D + 14 ° (c, 1) , 0 in DMSO), λ (235 nm (ε 14 500) and

λ ( ^OH, 256 nm, 8820).

Infrared and NMR spectroscopy and microanalytical data confirm the structure of the resulting compound.

Method (ii)

1.86 g (18.4 mmol) of trimethylamine was added to a solution of 3.1 g (18.4 mmol) of 2- (fur-2-yl) -2-methoxy-aminoacetic acid (syn-isomer) in 35 ml of dichloromethane. After cooling the solution for 5 minutes in an ice bath, 1.57 ml (18.4 mmol) of oxalyl chloride and a drop of N, N-dimethylformamide are added. After half an hour, the solvent was removed under reduced pressure and the dry residue was dried in vacuo for 1 hour. 150 ml of anhydrous ether was added to dissolve the previously formed acid chloride and insoluble triethylamine hydrochloride (2.5 g). The ether was evaporated on a rotary evaporator and the oily residue was redissolved in dichloromethane.

8.9 g (14.7 mmol) of p-toluenesulfonic acid salt of diphenylmethyl- (6R, 7R-7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate) are dissolved in anhydrous dichloromethane. The solution was shaken with an aqueous solution of sodium bicarbonate, washed with water and freed from water with magnesium sulfate. To this free amine solution was added a dichloromethane solution of the syn-isomer, 2- (fur-2-yl) -2-methoxyiminoacetyl chloride, and 5%. After 10 minutes, 1.1 g of a crystalline precipitate was filtered off, which was immediately identified as the hydrochloride salt of diphenylmethyl (6R, 7R) -7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylate. The reaction mixture was washed with 2 N sulfuric acid, water, aqueous sodium bicarbonate solution and water, freed from water with magnesium sulfate and evaporated to dryness to give 2.5 g (30.5 why) of the title compound of similar physical properties as the above product. methods (i).

b) Sodium (6R, 7R-3-carbamoyloxymethyl-7- [2-fur-2-yl) -2-methoxyimino-, acetamido] -3-cephem-4-carboxylate syn-isomer

20.0 ml of trifluoroacetic acid is slowly added to a mixture of 5 ml of anisole and 4.7 g (8 mmol) of the syn-isomer diphenylmethyl- (6R, 7R) -3-carbamoyloxymethyl) -7- [2- (fur-2- yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate, which is cooled in an ice bath. The flask is then occasionally shaken for the next 10 minutes to ensure complete dissolution of the precipitate. It is then removed from the ice bath and the excess trichloric acid is removed on a rotary evaporator. Trituration of the residue with 5 mL of ethyl acetate afforded 3.3 g (94%) of the 6R, 7R) -3-carbamoyloxymethyl-7- (2- (fur-2-yl) -2-methoxyiminoacetamido) -3- Cephem-4-carboxylic acid as a solid which is filtered off and washed with diethyl ether.

The free acid was dissolved in acetone and added in a slight excess of 2-ethylhexa. sodium acetate in acetone (8.0 ml molar solution). After stirring the reaction mixture at 0 ° C for 2 h, 2.3 g (73%) of the resulting salt was filtered off. This was combined with another batch of the resultant salt (0.8 g) and purified by washing the aqueous solution (250 mL) with ether (2X100 mL, 1X50 mL) to lyophilize to give 2.66 g of the syn-isomer (6R). 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate.

(a] ² and + 73.5 ° (c 1.06, DMSO), _X λ ⁶²⁶³ nm (ε 7600)

Vmax (nujol) 3450, 3330, 3250, (NH, NH 2 and H 2 O),

1752 (azetidin-2-one) and 1652 and 1600 cm ^-1 (carboxylate), τ (Me2SO-α6) 0.24 (d, J8Hz, CONH),

2.12 (d, J 2 Hz, furyl, C 5 -H],

3.25 and 3.30 (m, furyl, C3-H and Cu-H),

3.44 (broad s, CONH2),

4.34 (dd, J 5 and 7Hz, C7-H),

4.92 (d, 3.5 Hz, Ce-H),

5.15 (q, J 13 Hz, C 3 -CH 2), δ 6.07 (s, NOCH 3) and

6.58 (q, J 18 Hz, C2-H2).

Analysis for. CteHisNíNaOeS. O. 5 H2O (455.37] calculated:

C, 42.2; H, 3.5; N, 12.3; S, 7.0%.

H, 3.8; N, 12.1; S, 7.2%

Example 2 ________________

(6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid syn-isomer

A stirred mixture of 75 ml of N, N-dimethylacetamide with 75 ml of acetic acid, 42 ml (0.3 mol) of triethylamine and (6R, 7R) -7-amino-3-carbamoyloxymethyl-3-carboxylic acid. tert-4-carboxylic acid (16.40 g, 0.06 mol) was immersed in an ice bath and 10 mL of water was added and the mixture was stirred at 0-2 ° C for 45 minutes, slowly dissolving the solid to give a yellow solution. .

Meanwhile, a stirred suspension of phosphorus pentachloride (14.99 g, 0.0072 mol) in anhydrous dichloromethane (150 ml) was cooled to 0 ° C and N, N-dimethylacetamide (27.5 ml) was added. The resulting solution was cooled to -10 ° C and 12.17 g (0.072 mol) of the syn-isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid was added. The mixture was stirred at -10 ° C for 15 minutes, and 35 g of crushed ice was added. The mixture was stirred for 10 minutes at 0 ° C, then the lower dichloromethane phase was added over 10 minutes to the cephalosporin solution prepared as above. Cool at -10 ° C. Celsius, so that the temperature of the reaction mixture continuously reached 0 ° C.

The mixture was stirred at 0-2 ° C for 1 hour, then the cooling bath was removed and the temperature of the reaction mixture was allowed to rise to · 20 ° C over an hour. The reaction mixture was then added slowly to 2 N hydrochloric acid (100 mL) diluted with cold water (1.15 L) at 5 ° C. The pH of the biphasic mixture was adjusted under 2 N hydrochloric acid (10 mL) and the mixture was stirred and recooled to 5.5 ° C. The precipitate that precipitated was washed with dichloromethane (100 mL) and water (250 mL), and dried under vacuum overnight at 40 ° C to give the title compound (22.04 g, 86.6 percent), (α D 2 °). + 58 ° (c 1.08, DMSO), Amax (pH 6 phosphate buffer) 274 nm (ε 17,500),

Amax (nujol) 3480, 3440, 3367, 3255, and 3133 (NH and · NH2), .....

2725 and 2590 (CO2H), 1760 (azf ^ eii ^ ii ^ - ^ 1-one),

1728, 1712 and 1698 (OCONH2 and CO2H), 1655 and 1530 cm (CONH), τ (Me2SO-d6)

0.25 · (d, J8Hz, CONH)

2.18 (s, furyl Cs-H),

3.28 and 3.4 (m, furyl C1-H and C3-H),

3.42 (s, CONH 2),

4.19 (dd, J 7 and 5 Hz, G 1 -JH),

4.80 (d, J 5 Hz, C 6 H),

5.06 and 5.39 (q, J 13 Hz, C-CH),

6.09 (s, NOCH),

6.44 (positioning ABq, C2H2) and 7.99 [0.03 mol of CH3CON4].

Example 3

(a) (6R, 7R) -7- (R-5-Benzoylamino-4-carboxypentanamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid, monoquinoline salt monohydrate

A stirred solution of monopotassium salt of 204988 (6R, 7R) -7- (R-5-amino-5-carboxypentanamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid (18.45 g, 30 mmol) in 93 mL The water was cooled in an ice bath to 0-5 ° C and treated with a 5.19 mL (45 mmol) solution of benzyl chloride in 63 mL of acetone for 25 minutes. The pH of the reaction mixture is maintained at pH

8.5 0.1 by controlled addition of 30% (w / v) aqueous solution. potassium orthophosphate (about 100 ml). The mixture was stirred for an additional 5 minutes, overlaid with ethyl acetate (150 mL), and stirred overnight. The pH is then lowered to 5.6 with orthophosphoric acid. The layers were separated and the aqueous portion was washed with additional ethyl acetate (2.times.300 mL).

The combined washings were extracted with water (200 mL). Mixed water. portion and washes were diluted with 600 mL of water, overlaid with 600 mL of ethyl acetate, and the pH of the stirred mixture was maintained at 2.0 with orthophosphoric acid. The organic layer was separated and 10.64 mL (45 mmol) was added. of quinoline in ethyl acetate (25 mL) with stirring to form a white precipitate. The aqueous portion is extracted with. additional ethyl acetate (3X300 mL) and added to the quinoline containing slurry. The mixture was stirred at 18 ° C for 1 hour and then concentrated in vacuo to about 500 ml. 900 ml of ether are added with stirring and after 30 minutes the precipitate is collected by filtration, washed with 2X 200 ml of ether and dried in vacuo. vacuum (133 Pa). The resulting compound was obtained as a white powder (19.20 g, 104.1% by weight), ¹⁸ ] ¹⁸ + 78 ° (c 1.00, dioxane), λmax (pH 6 buffer) 258 nm (inflection,

Infrared and NMR spectroscopy data confirm the structure of the title compound and a content of about 15% lactone contamination and trace amounts of ether and ethyl acetate.

(b) (6R, 7R) - (R-5-Biphenyl-6-carboxypentanamido) -3-trichloroacetylcarbamoyloxymethyl-S-cephem-4-carboxylic acid monoclimino acid salt

4.24 g (equivalent to 7 mmol) of the product obtained above were treated with anhydrous dioxane (100 mL) and partially dissolved. To the stirred mixture was added trichloroacetyl isocyanate - (2.90 mL, 24.5 mmol). The resulting solution was stirred for 30 minutes and then clarified by filtration and evaporated in vacuo to give a yellow foam. This was dissolved in acetone (about 10 mL) and poured into 100 mL of stirred isopropyl ether. The resulting white precipitate was collected by filtration and dried in vacuo (1 mm Hg) to give the title compound as 6.26 g (147.8 wt%) of a white powder. NMR spectroscopy data confirm the structure of the title compound and also show the presence of lactone (about 22%), isopropyl ether (0.75 mol), dioxane (0.2 mol) and a small amount of acetone.

c) [6R, 7R) -7-Amino-3-trichloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid

A solution of 4.77 g (equivalent to 6 mmol) of the above product in anhydrous methylene chloride (40 mL) was cooled to about 10 ° C under nitrogen with stirring. It will be added

2.20 ml (27.3 mincO) pyridine then. Dichlorodimethylene silane (2.10 mL, 17.4 mmol) was added and the brown solution was stirred at rt for 20 min. about 17 ° C and then cooled to -17 ° C. 1.355 g (6.5 mmol) of phosphorus pentachloride was added and the mixture was stirred at about -16 ° C for two hours. Pyridine (0.81 mL, 10 mmol) was added and the mixture was added to methanol (13 mL + 2.5 mL per wash) precooled to -35 ° C at a rate such that the temperature of the stirred solution did not exceed -10 ° C. . The stirred solution is allowed to reach -9 ° C over time. 25 minutes, then add. 11. ml of water and the pH of the mixture are maintained at 0.3 to 3.8 with an ammonia solution (specific gravity 0.880).

The resulting biphasic mixture. containing the precipitated solid again to. Freeze for 1 hour and then filter. The precipitate is washed successively with a 50% (v / v) mixture of water and methanol. (12 mL), methanol (10 mL), and methylene chloride. (5 ml), then. is dried under vacuum (1 mm Hg). It is obtained. final compound as a cream powder (1.22 g, 25.6% (w / w)), [α] _D + -44 ° (c 1.02, MezSO), Amax (pH 6 buffer) 240 nm (E!% ^u _m 133), 263 nm (E%)

cm

140).

Odd NMR analysis confirmed the structure of the title compound.

d) Synth isomer of (R) -4- (34: 8) bamoyloxy methyl 1-7- (2- (fur-2-yl) -2-methoxyiminoacetamido) -ceph-3-em-4-carboxylic acid

4.5 g (21.5 mmol) of phosphorus pentachloride was dissolved in anhydrous nethylene chloride (90 ml) and cooled to -15 ° C with stirring. N, N-dimethylacetamide (9 ml) was added slowly, keeping the temperature below -10 ° C and stirred for 10 minutes. 3.66 g (21.5 mmol) of the syn-isomer of 2- (fur-2-yl) -2-methoxyiminoacetic acid are added and the mixture is stirred at. -15 ° C for 15 minutes, add 18 g of crushed ice carefully so that the temperature of the mixture does not exceed -7 ° C. The mixture was stirred for 10 minutes and the organic portion was separated and added dropwise to a solution of (6R, 7R) -7-amino-3-trichloroacetylcarbamoyloxy-ethyl-3-cephem-4-carboxylic acid (7.52 g, 18 mmol) in anhydrous methylene chloride (90 mL) and at 1010 ° C. Celsius pre-cooled triethylamine (5.5 mL, 40 mmol).

The acid chloride solution was added over 20 minutes while maintaining the temperature of the reaction mixture at -10 to -8 ° C. The mixture was then stirred for 80 minutes during which the temperature was allowed to rise to +3 ° C and 6 ml of methanol were added. After stirring for an additional 5 minutes, the solution was extracted with 3% (w / v) sodium bicarbonate (2X200 mL) and water (150 mL).

The combined extracts were allowed to stand at about 20 ° C for 3.5 hours and then washed with ethyl acetate (100 mL) and acidified to pH 1.5 with concentrated hydrochloric acid. The resulting settled oil was extracted into ethyl acetate (2X300 mL). The combined organic portions were washed with water (2 x 100 mL), dehydrated with magnesium sulfate and evaporated in vacuo to give a yellow precipitate (7.1 g) which was stirred in 150 mL of ether, filtered and evaporated in vacuo (133 Pa). gives the title compound as a pale yellow solid (5.20 g, 68.2% of theoretical), λmax (pH 6 buffer) 275 nm ( ^E margin ³⁸⁵ ) ·

Infrared and NMR spectroscopy data confirm that the structure is. coincides with the resulting substance and pollution with ether traces.

Example 4

(6R, 7R) -3-Carbamoyloxymethyl-7- [2-methoxyimino-2- (thien-2-yl) acetamido] -3-cephem-4-carboxylic acid syn-isomer

Following the procedure of Example 2, the title compound (888 mg, 50%) was prepared from (6R, 7R) -7-amino-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid (1.09 g, 4 mmol) and syn- isomer of sodium 2-methoxyimino-2- (thien-2-yl) acetate (923 mg, 4.8 mmol). It has the following properties: mp 157-163 ° C, [α] _D 2 -7-57.3 ° (c 1.0 in dioxane), Rp _At; 0.8 (see note after Table 1). Solvent system A (see note after Table 1), Amax (pH 6 buffer) 262.5 nm (ε 15 550), and inflection at 235 nm (ε 10 350), τ (DMSO-ds) 0.20 ( d, J8Hz, NH)

2.29 (dd, J2 and 5Hz, thienyl OH),

2.7 to 2.9 (m, thienyl C3-H and C1-H),

3.40 (s, CONH 2),

4.13 (dd, J5 and 7Hz, C7-H)

4.75 (d, J 5 Hz, C 6 H),

5.01 and 5.34 (AB-q, J13Hz,

C3-CH2),

6.08 (s, NOCHs) and 6.42 (collapsed AB-q, C2-H2), Amax (nujol) 3700 to 2100 (CO2H), 3480, 3440, 3365 and 3255 (NH and NH2), 1760 (azetidine) -2-one), 1722 (CO 2 H), 1709 (OCONH 2), and 162 and 1530 cm -1 (amide).

Example 5

(6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid syn-isomer

1.5 ml of Ν, Ν-dimethylacetamide is added to a phosphorus pentachloride solution (750.0 mg,

3.6 mmol) in anhydrous dichloromethane (15 mL) cooled to -10 ° C. After 10 minutes, the 2- (fur-2-yl) -2-methoxyiminoacetic acid syn-isomer (612 mg, 3.6 mmol) was added to the resulting suspension, which soon became a clear solution and stirred at -10 °. C 15 minutes. 3 g of ice are added and after 10 minutes the layers are separated in a separating funnel. The organic phase slowly (over 5 minutes). to a cooled solution of 1.05 g (3 mmol) of (6R, 7R) -7-amino-3-chloroacetylcarbamoyloxymethyl-3-cephem-4-carboxylic acid. in 15 ml of dichloromethane containing 0.9 ml (6.5 mmol) of triethylamine. After 40 minutes, 1 ml of methanol was added and 5 minutes later, the reaction mixture was extracted twice with 3% (w / v) aqueous. sodium bicarbonate solution (150 mL). The aqueous extract was washed with ethyl acetate (25 mL) and left at 20 ° C for 4 hours. The solution was washed twice with ethyl acetate, acidified with 2N hydrochloric acid and extracted three times with ethyl acetate. The combined organic layers were dehydrated with magnesium sulfate, decolorized with charcoal and evaporated in vacuo to give a pale yellow solid (1.15 g, 87%). This was washed with diethyl ether and filtered to give the title compound (0.91 g, 71 percent),

T TT TT λ £ 274 nm (ε 17 300).

The IR and NMR spectra of the product agree with the spectra of the authentic sample.

Example 6

Sodium (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylate syn-isomer form

Method (i)

Per 100.0 g · syn-isomer of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamide] -3-cephem-4-carboxylic acid of a mixture of N, N-dimethylacetamide (400 ml) with 1 liter of acetone is treated with 40 g of sodium 2-ethylhexanoate in 200 ml of acetone. The mixture was shaken at ambient temperature for 1.25 hours. The product was filtered off, washed with acetone (500 ml) and finally precipitated with ether to give the title compound (101.4 g, 92.5%) containing 0.65 mol equivalents of water after equilibration.

The product has [α] _D + 61 ° (c 0.5 pH 4.5 phosphate buffer) and λ _max 273 nm%

_EI ^{/ O} _m 412 (H2O).

Infrared and NMR spectroscopy data confirm the structure of the resulting compound, and the infrared spectrum shows that the compound is a salt of Form I.

Method (ii)

The method of method (i) is repeated except that cephalosporic acid is initially dissolved in a mixture of N, N'-dimethylaceamide with ethanol denatured with methanol instead of a mixture of N, N-dimethylacetamide with acetone to give the title compound (80%) with properties a similar product obtained according to method (i). The infrared spectrum shows that the compound is a salt of Form I.

Method (iii)

Dissolve 4.24 g (10 mmol) of the (8R, 7R) -3-carbamoyloxymethyl-7- [2-fluoro-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid syn-isomer in N, N-dimethylacetamide (20 mL), which was dried with molecular sieve (Linde 4A) for 24 hours. To this was added a solution of sodium 2-ethyl hexanoate (2.0 g, 12 mmol, recrystallized from dioxane and dried over phosphorus pentoxide) in ethyl acetate (80 mL), which had been dehydrated by molecular sieving (Linde 4A) for 24 hours. The solution was stirred in a sealed vessel for about 15 minutes until crystallization began and then cooled at 4 ° C for one hour. The product was filtered off, washed with anhydrous ethyl acetate (about 100 mL) and, while still wet with solvents, transferred to an oven and dried at 20 ° C under vacuum over phosphorus pentoxide overnight to give the title compound (3.89 g, 87%). ).

The IR and NMR spectra of the product agree with the spectra of the authentic sample.

Example 7

Sodium (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxy-aminoacetamido] -3-cephem-4-carboxylate syn-isomer Form II

Method (i)

0.2 g of activated carbon is added to the solution of the (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -c-3-em-4 acid syn-isomer. -carboxylic acid (4.00 g, 9.42 mmol) in a mixture of 132 mL of acetone and 1.33 mL of water, stirred for 30 minutes and filtered through a pad of diatomaceous earth, the filter pad washed with 10 mL of acetone. Sodium (1.66 g, 10 mmol) in acetone (20.0 mL) was added to the stirred filtrate after one hour and the resulting suspension was stirred for an additional 10 minutes and the white precipitate was filtered off, washed with acetone (2X 25 mL) and dried in vacuo. The resulting compound (4.06 g, 93.0%) [α] _D ² ® + 60 ° (c 0.91, H 2 O), λ _max (H 2 O) 274 nm (ε 17 400), [found% :

C: 41.0, 41.2, H: 3.45, 3.6, N: 12.3, 12.4, Na: 5.2, S: 6.6, 6.85, H2O: 2, 7, 2.7,

C16H15N4NaO8S. 0.7 H O (459.0) requires%:

C: 41.8, H: 3.6, N: 12.2, Na: 5.0, S: 7.0, H2O: 2.7], HPLC purity 99.4%.

The NMR spectrum of the resulting compound corresponded to an authentic sample, and the infrared spectrum indicated that the product was an antibiotic salt form II.

Method [ii]

(6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid syn-isomer (16.98 g, 40 mmol) was added to a stirred mixture of acetone (333 mL) and water (8.5 mL), treated with activated carbon and filtered to slowly add sodium 2-ethylhexanoate (7.32 g, 44 mol) in acetone (85 mL) over an hour. The mixture was stirred for 15 minutes, filtered and the product washed with acetone (2 X 65 mL) and dried in vacuo at 20 ° C overnight. This gave the title compound (17.95 g, 98.5%) containing 0.5 mol H2O. The NMR spectrum of the product is identical to that of an authentic sample, the infrared spectrum indicates that the product is a salt of the form

II.

Example 8

Sodium (6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate syn-isomer form

4.0 g of sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate syn isomer was dissolved in 20.0 ml of water. 20 ml of industrial methanol and 160 ml of dioxane are added. The solution is filtered and then left to crystallize at 4 ° C. The very white, needle-like crystals are filtered off, washed with 100 ml of dioxane and, while still dioxane wet, transferred to an oven and dried at 20 ° C under vacuum overnight. The title compound was obtained (3.96 g, 78.5%). IR and ^NMR: spectrum of the product correspond to the spectrum of the authentic sample.

Example 9

Form IV syn-isomer of sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate

Samples of Form I and Form III of the sodium 3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate syn-isomer prepared according to the method (iii) of Example 6 and 8 were allowed to wet (75% RH) to give the title compound. The infrared and NMR-spectra of the products matched the authentic sample. The Karl Fischer water determination gives 4.0 and 3.85%, respectively (1 mol H2O is equivalent to 3.9%).

Example 10

a) Syn-isomer of tert-butyl (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate

A suspension of 4.4 g of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid syn-isomer in 200 mL of anhydrous methylene chloride is treated with 6.6 ml of O-tert-butyl-N, N'-dicyclohexylisourea to form a pale yellow solution. . After 24 hours at 23 ° C, the starting material remains and 3.3 ml of isourea are added. After 48 hours, the mixture was filtered and the filtrate was evaporated under reduced pressure. The resulting material was stirred with a mixture of ether and ethyl acetate to remove the remaining dicyclohexylurea. The filtrate was washed with saturated aqueous sodium bicarbonate solution and water, then dried and evaporated to give a foam (5.2 g). Purification by silica gel chromatography with toluene: ethyl acetate 2: 1 as solvent gave the title compound (3.9 g) as a pale yellow foam, λmax (ethanol) 275.5 nm (ε 18,400).

b) Syn-isomer of tert-butyl (1R, 6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl)] -2-methoxyiminoacetamide] -3-cephem-4-carboxylate -l-oxide

0.3. ml of tert-butyl hypochlorite is added to a vigorously stirred solution of 0.98 g of tert-butyl- (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem Of 4-carboxylate in 25 mL of pyridine and 1 mL of water at -45 ° C. After stirring for 2 minutes, 1 ml of 2 N sulfuric acid is added and the mixture is immediately poured into 100 ml of 20% (w / v) orthophosphoric acid. The solution was extracted with ethyl acetate (2X 100 mL) and the combined organic extracts were washed with sodium bicarbonate solution (100 mL) and water (100 mL), dried with magnesium sulfate and concentrated in vacuo. The crude product is. Chromatography on silica gel preparative plates using ethyl acetate as eluent, a minor proportion of the S-oxide is ahead of the R-oxide. Extraction of the slower component with ethyl acetate gave the title compound (0.27 g, 27%).

Infrared and NMR spectroscopy data confirm the structure of the title compound.

c) 11R, RP, 7R-3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-carboxylic acid 4-carboxylic acid 1-oxide

0.42 g of tert-butyl-4H-R (R) -3-carboamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate-1-syn-isomer of the oxide are dissolved in 5 ml of acid. trifluoroacetic acid and stirred at room temperature for 8 minutes. The solution was evaporated in vacuo to a red oil, dissolved in 5 mL of ethyl acetate / acetone (1: 1) and added dropwise to 50 mL of petroleum ether (60-80 ° C) with stirring. The deposited solid was collected and dried in a desiccator. The crude product is stirred with ethyl acetate and the liquid phase is separated and added dropwise to 50 ml of petroleum ether (60-80 ° C). . The title compound was obtained as a colorless solid (150 mg, 40%),

Amax (0.25 N NaHCOs) 263.5 (ε 15,000) and 281 nm (ε 13,700), vmax (nujol) · 1799 (β-actam), 1725 and 1716 (COOH and OCONH2), 1684 and 1538 (CONH) and 1060 and 1050 cm ⁴ (S-O), τ (DMSO-ds) values include 0.02 (d, J8Hz, CONH), 4.17 (dd, -J4 and 8Hz, 7-H), 4.99 (d, J 4 Hz, 6-H) and 6.09 (s, N-OCH 3).

Example 11

(1R, 6R, 7R) -3-Carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid syn-isomer

To a stirred solution of sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate syn-isomer (2.59 g) in water (25 mL) was added 1.93 g of sodium metaperyodate. The solution was stirred for 30 minutes at ambient temperature and then acidified with 2 N hydrochloric acid added dropwise. The resulting precipitate was collected, washed successively with water, ethanol and ether and dried in vacuo to give the title compound as a white powder (1.63 g) [α] _D ²⁰ + 113 ° (c 0.86, Me 2 SO),

Amax (pH 6 buffer) 264.5 (ε 17,200) and 279 nm (ε 15,600), Kmax (nujol) 1770 (β-lactam), 1740 and 1716 (CO2H), 1688, 1654, 1589 and 1530 ( CONH and OCONH2) and 1030 cm ^-1 (S - O), τ (DM SO-de) 0.60 (d, J8Hz, NH), 211, 319, 3.31 (multiplet, furyl protons), 4.08 (c, J5 & 8Hz, C-7H)

4.87 and 5.45 (ABq, J 1, J 2, Z 2, CH 2 OCONH 2), 4.96 (d, J 5 Hz, C-6H), 6.08 (s, OCH 3),

6.10 and 64.2 (ABq, J 18 Hz, C-2 CH 2).

Example 12

(1R, 6R, 7R) -a (1S, 6R, 7R) -3-Carbamoyloxymethyl-methyl- [2- (fur-2-yl) -1,2-trimethyl-acetamido] -phenyl-4-carboxylic acid syn-isomer

Solution. Sodium periodate (1.93 g) in water (10 ml) was added to a stirred solution of (6R, 7R) -1,3-carbamoyloxymethyl [2- (fur-2-yl) 1,2-methoxyiminoacetamido] -3-cephem-4-carboxylate (2). 59 g) in water (25 ml). Stirring was continued for 30 minutes at room temperature, and the solution was then acidified with 2 N hydrochloric acid (2 mL). The deposited 1S-oxide was filtered off, washed with ethanol (5 ml) and ether (20 ml) and dried in a desiccator. Yield 1.55 g of a colorless solid, [ _.alpha. ] _D @ + -110 DEG (c 1, DMSO), corresponding to the product described in Example 11.

Mother liquor is. saturated with sodium chloride and filtered. The filtrate was extracted with ethyl acetate (2X 100 mL). The organic extracts were combined, dried with magnesium sulfate and concentrated in vacuo to give a yellow solid. Raw. The product was washed with acetone and the insoluble material was removed by filtration. The filtrate is evaporated to dryness and the acetone wash is repeated. 380 mg of IR-oxide are obtained. [α] D -88 ° (c 1, DM 50), τ (DMSO-d 6) with similar data to those given in Example 10.

Example 13

(a) Syn-isomer of diphenylmethyl- (6R, 7R) -3-carbamoyloxymethyl-7i [2- (fur-4-yl) -2-phenoxyiminoacetamido] -3-cephem-4-carboxylate

A solution of 7.75 g (0.382 mol) of DL-dicyclohexylcarbodiimide in 50 ml of anhydrous dichloromethane is added over a period of 10 minutes to a solution of 13.7 g (0.312 mol) of diphenylmethyl- (6R, 7R) -7-imino-3-carbamoyloxymethyl-3-cephem. -4-carboxylate and 8.8 g (0.382 mol) of the 2- (fur-2-yl) -2-phenoxyiminoacetic acid syn-isomer in anhydrous dichloromethane (200 mL) at 0 ° C. After 45 minutes, the precipitate consisting predominantly of N, N-dicyclohexylurea was filtered off and the filtrate was washed with aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is chromatographed on a silica gel (1 kg) column. The less polar impurities than the desired product were eluted with dichloromethane (1 liter), acetone-dichloromethane 2-: 98 (1 liter), acetone dichloromethane-5:95 (4 liters). The fractions eluted with acetone-dichloromethane 10:90 and acetone dichloromethane 19: 85 were evaporated to a rubber consistency (11 g) which was triturated with diethyl ether to give a solid (8.35 g, 41%). This was filtered off and further purified by crystallization from aqueous ethanol to give the title compound (7.6 g), mp 143-146 ° C, [α] _D + 48 ° (c 1.0, DMSO),

FtDH λ r _and 273 nm (ε 18 700), λ P-, 271 nm (ε 17 600) and λ 254 nm (ε 16 500).

Infrared and NMR spectroscopy and microanalytical data confirm that the structure is consistent with the resultant compound.

b) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- (2- (fur-2-yl) -2-phenoxyiminoacetamido] 1,3-iodine-4-carboxylate ml of trifluoroacetic acid is added over 10 minutes to 8 ml of anisole and 7.4 g (11.4 mol) of the syn-isomer-diphenyl-methyl-6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2] -phenoxyiminoacetamide-3-cephem-4-carboxylate. After an additional 5 minutes at 0 ° C, the dark solution was carefully poured into a mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous solution was separated and treated with activated charcoal. The ethyl acetate layer was washed with water and the aqueous washings were combined with sodium bicarbonate extract and acidified with concentrated hydrochloric acid. This acidic solution was extracted with a mixture of ethyl acetate and diethyl ether, which was then washed with 5X water, dried with magnesium sulfate and evaporated in vacuo. The residue was washed with diethyl ether and diisopropyl ether to give cephalosporinic acid (4.5 g, 82%) as a precipitate.

This one. the acid was dissolved in ethyl acetate (150 mL), a solution of sodium 2-ethylhexanoate in ethyl acetate (10 mL containing 10 mmol) was added. The solution was cooled in an ice bath and shaken for 2.84 hours during which time 2.84 g of product crystallized and unreacted acid [1.1 g again - then precipitated in petroleum ether - (boiling point 60-80 ° C)] remained in the solution. solution. The precipitate was filtered to give the title compound.

The physical constants of the resulting compound are shown in Table 1 following Example 18.

Example 14

a) Syn-isomer of diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- (2-methoxyimino-2-phenylacetamido) -3-cephem-4-carboxylate

1.83 g (3 mmol) of p-toluenesulfonic acid salt of diphenylmethyl- (6R, 7R) -7-amino-3-carbamoyioxymethyl-3-cephem-4-carboxylate was added to a mixture of saturated aqueous sodium bicarbonate solution (50 ml) and dichloromethane [100 mL). Shake the mixture to dissolve the solid and separate the organic layer, wash twice with water, dry with magnesium sulfate and concentrate under reduced pressure to about 15 mL. This solution was cooled to 0 ° C and solutions of D, L-dicyclohexylcarbodiimide (824 mg, 4 mmol) in anhydrous dichloromethane (10 mL) and 2-methoxyimino-2-phenylacetic acid syn-isomer (716 g, 4 mmol) were added. in anhydrous dichloromethane (10 mL). The reaction mixture was stirred at 0 ° C for 70 minutes, then filtered, washed with 2 N sulfuric acid, water, saturated sodium bicarbonate, water, brine, dried over sodium sulfate and evaporated to give a yellow solid (2.05 g). ). This was dissolved in hot ethyl acetate (25 mL), which was cooled and the dicyclohexylurea was filtered off. Addition of diisopropyl ether to the filtrate gave a precipitate which was filtered, mixed and washed with diisopropyl ether, filtered and finally washed with diethyl ether to give the title compound (1.10 g, 61.5%), mp 173-182 ° C, [a] _D + 22.5 ° (c 1, CHCl 3),

FtOH λ δ 258,4 nm [ε 17 500],

FtQH λ - λ 227 nm (ε 15 800).

Infrared and NMR spectroscopy and microanalysis data confirm the structure of the resulting compound.

b) (6R, 7R) -3-Carbamoyloxymethyl-7- (2-methoxyimino-2-) acid isomer

(phenylacetamido) -3-cephem-4-carboxylic acid

Treatment of the product obtained under the method of Example 1b) afforded the title compound (75%), the compound was purified by trituration of the crude product with ethyl acetate (10 mL), followed by washing twice with diethyl ether (25 mL and 10 mL). The physical constants of the resulting compound are shown in Table 1 below.

Example 15

a) Syn-isomer of diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- (2-phenoxyimino-2-phenylacetamido) -3-cephem-4-carboxylate

The procedure of Example 14a was repeated except that the 2-phenoxyimino-2-phenylacetic acid syn-isomer was used in place of the 2-methoxyimino-2-phenylacetic acid syn-isomer to produce a red solid foam. This crude product was crystallized from a mixture of water and acetone to give 1.3 g of a red solid which was washed twice with stirring with diethyl ether to give the title compound (675 mg, 34%) as a white solid, m.p. 140 ° C, [α] _D 4-44.5 ° (c 1, CHCl 3), λ 277 nm (ε 18,600),

EtOH ^λ inf.

268 and 281 nm (ε 16 850 and 14 000).

The residue obtained after evaporation of the mother liquors. The reaction was crystallized from ethanol to give the next title compound (431 mg, 17%) in two batches, which were washed with diethyl ether with stirring. Infrared and NMR spectroscopy and microanalysis data confirm the structure of the resulting compound.

b) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- (2-phenoxyimino-2-phenylacetamido) -3-cephem-4-carboxylate syn-isomer

The product obtained as described in a) above is treated according to the method of Example 1b) to give crude cephalosporinic acid which is shaken with ethyl acetate and saturated aqueous sodium bicarbonate. The resulting precipitate was filtered off and washed with acetone and ether to give the title compound (66%) having physical constants as shown in Table 1 below.

Example 16

a] Syn-isomer of diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2-cyclopentyloxyimino-2- (fur-2-yl) acetamido] -3-cephem-a-carboxylate

The process of Example 14a) was repeated except that the syn-isomer of 2-cyclopentyloxyimino-2- (fur-2-yl) acetic acid was used instead of the syn-isomer of 2-methoxyimino-2-phenylacetic acid to produce a foam (1). 77 g), which was triturated with ethyl acetate to give the title compound (1.90 g, 67%) as a pale yellow solid, mp 102-108 ° C, (+) d + 12.5 ° (cl) , CHCls),

EtOH

Λ * _and 270 nm (ε 17,900).

b) (6R, 7R) -3-Carboyloxymethyl-7- [2-cyclopentyloxy-imino-2- (fur-2-yl) -acetamido] -3-cephem-4-carboxylic acid syn-isomer

Treatment of the product obtained according to the above process a) by the method of Example 1b) affords crude cephalosporinic acid, which precipitates from ethyl acetate with dlisopropyl ether to give the title compound (55%) having physical constants as shown in Table 1 below.

Example 17

a) Syn-isomer diphenylmethyl- (6R, 7R) -3-carbamoyloxymethyl-7- (2-ethoxyimino-2-phenylacetamido) -3-cephem-4-

-carboxylate

The process of Example 14a) was repeated except that the 2-ethoxyimino-2-phenylacetic acid syn-isomer was used instead of the 2-methoxyimino-2-phenylacetic acid syn-isomer. Crystallization of the crude product from methanol gave the title compound (1.30 g, 53%), in three portions, mp 199-202 ° C, [α] D 4θ> 7 ° (ci dioxane), λ Z, ax 274 nm (ε 16 500),

A _'f and 267 nm (ε 7350).

b) (6R, 7R) -3-Carbamoyloxymethyl-7- (2-ethoxyimino-2-phenylacetamido) -3-carboxylic acid 4-

-carboxylic

Treatment of the product obtained according to the above process a) by the method of example 1b) yields crude cephalosporinic acid, which is triturated with ethyl acetate (3 ml), filtered and washed with shaking with ethyl acetate (5 ml) and then with diethyl ether (2X 10 ml). ) to give the title compound as a white solid (413 mg, 64%). An additional amount (180 mg, 27%) crystallized from the filtrates, filtered and washed with diethyl ether. The physical constants of the resulting compound are shown in Table 1 below.

Example 1 a d 18

a) Syn-isomer of diphenylmethyl (6R, 7R) -3-carbamoyloxymethyl-7- [2-tert-butoxyimino-2- (thien-2-yl) acetamido] -3-cephem-4-carboxylate

The process of Example 14a) was repeated except that the syn-isomer of 2-tert-butoxyimino-2- (thien-2-yl) acetic acid was used instead of the syn-isomer of 2-methoxyimino-2-phenylacetic acid. The crude product was purified by shaking the slurry in diisopropyl ether (2 X 25 mL) to give the title compound as a pale pink solid (1.90 g, 73%), mp 148-152 ° C, [α] _D +8.5 ° (c 1, CHCl 3),

EtOH ^λ 262 * 8 282 nm U 500 and ε 13 200).

b) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2-tert-butoxyimino-2- (thien-2-yl) acetamido] -3-cephem-4-carboxylate syn-isomer

The product obtained by the above method a) is treated according to the method of example 1b) to give cephalosporinic acid as a pellet consistency which turns to a solid when triturated with diisopropyl ether to give the crude product (1.20 g, 94%) . Part of this acid (811 mg,

Sodium 2-ethylhexanoate (282 mg, 1.68 mmol) was stirred in n-butanol (5 mL) at 20 ° C for 10 minutes and at 0 ° C for 20 minutes. The resulting yellow precipitate was filtered off and washed with cold n-butanol (3 mL) and diisopropyl ether (7 mL) to give the title compound (495 mg, 56%), having the physical constants listed in Table 1 below.

ř o o o

Physical properties of the products of Examples 13b through 18b

Example [a] _D Rpac (1) pH 6 (2) _max ^(cm-1) Nu Jolu number (rozpouš- (dissolution Am _x (ε) NH2 NH-lactam Д COOH, CONH

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4

38

Table 1 - continued (in DMSO-de) C3-CH2 ABq J 13 Hz Side string Example number NH d 8 Hz NHz C7-H dd J 5.7 Hz Ce-H d J 5 Hz aromatic (m) aliphatic 13b) -0.10 3.43 4.23 4.85 5.00 1.98 5.27 2,35— 3.02 3.22 14b) 0.23 3.4 4,11 4.74 5,07 2,1- 6.04 5.34 2.7 (with) 15b) (3) 4.53 1,9- 1.72 - 3.82 4,61 (dark- 4.87 2.9 No) 16b) 0.29 3.4 4.14 4.77 5.02 2.12 5.28 5.32 3.3 7,9- 3.4 8.7 (m) 17b) 0.22 3.4 4.08 4.73 5.09 2,0— 5.76 5.33 3.0 (q J 7Hz) 8.70 (t, J3 Hz) 18b) 0.41 3.48 4.34 4.94 5.16 2.42 8.68 2.92 (with)

Table 1 - continued

Example number Microanalysis (%) found / calculated Empirical formula (solvent present) C H N WITH 13b) 48.2 3.8 10.5 5.9 C21H17N4SO8 48.2 3.6 10.7 6.1 (1 mol H2O) 14b) 50.1 4.3 12.4 7.2 C18H181N1SO7 49.8 4.2 12.9 7.4 15b) 49.5 3.65 9.6 5.8 C25H19N4SO7Na 49.9 4.15 10.0 5.8 (2 mol H2O) 16b) 50.6 5.4 10.5 C20H212NSO8 51.8 5.2 10.8 [0.4 mol (i-Pr) 20J 17b) 52.6 4.3 11.9 7.1 C19H20N4SO7 52.2 4.3 11.9 6.8 (0.2 mol anisole) 18b) C19H21N4SaO7Na Comment:

__________ (R _f compound) _______ (f (6R, 7R) -3-acetoxymethyl-7-phenylacetamido-3-cephem-4-carboxylic acid)

The solvent system (A) is. n-butanol:: ethanol: water (4: 1: 5)

The solvent system (B) is:

: water (7: 3) (2) inf. (3) Trifluoroacetic acid spectrum

C) Examples of pharmaceutical preparations

Example A

Dry powder for solution for injection

Sterile syn-isomer of (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxy204988

Sodium acetate is filled into glass vials, labeled as 500 mg or 1.0 g cephalosporin compound. The filling is performed aseptically under a nitrogen layer. The vials are closed using rubber discs or plugs which are held in place by aluminum sealing rings to prevent gas exchange or micro-organisms. The product is intended to be dissolved in water for injection or other suitable sterile vehicle just prior to administration.

Example В

Intramammary injection (for cattle)

% Composition (wt.

° / o) Sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- (fur-2-yl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate syn-isomer 8.33 vehicle ad 100,00 vehicle composition:

Tween 603,00 white beeswax6,00 peanut oil91,00

The last three components were heated together at 150 ° C for one hour and then cooled to room temperature with stirring. A sterile antibiotic, finely powdered, is added aseptically to this vehicle and the product is finely dispersed on a high speed mixer. The preparation is filled aseptically into sterile aluminum tubes with a fill weight of 3.0 g, each tube containing 250 mg of cephalosporin compound. The product is intended for application to the mammary gland through the mouth of the duct.

Claims (8)

A process for the preparation of cephalosporin antibiotics of the general formula I H И CH 2 O.CO.NH 2 a where R ¹ zůamená furyl, thienyl or phenyl, R ² znarilená Ci to C alkyl, Cs-C7 -cycloalkyl or phenyl, and R® is hydrogen or an ester-forming group giving physiologically acceptable esters, in the form of the syn-isomer or a mixture of the syn-isomer and the anti-isomer containing at least 90% of the syn-isomer, and their physiologically acceptable salts derived when R® is hydrogen, characterized in that a compound of formula (I) is condensed at a temperature of from -50 to -50 ^° C COOR _(u) wherein В means = S or = S-O, Rh is hydrogen or a carboxyl protecting group such as d-phenylmethyl or tert-butyl, R ¹² represents hydrogen or an N-protecting group such as mono-, di- or trichloroacetyl or chlorosulfonyl and the dotted line (-) between positions 2, 3 and 4 means that it may be a 2-cephem or 3-cephem compound, or an acid addition salt thereof, or an N-silyl derivative thereof, and an acylating agent corresponding to the acid of formula III Ri.C.COOH II N \ OR ² (III), where R ¹ and R ² are as defined above, and any A ² -isomer is converted to the desired A ³ -isomer and / or the carboxyl-blocking or N-protecting group is removed and / or the cephalosporin sulfoxide is reduced to the corresponding sulfide, and thereafter The compound of formula (I) is isolated, optionally after separation of the syn-isomer and the anti-isomer, and optionally after conversion of the compound of formula (I) to its 1-oxide, when R @ 6 is hydrogen or physiologically acceptable salts or esters thereof. 2. A process according to claim 1, wherein the compound of formula I or the physiologically acceptable salt of a compound of formula I wherein R6 is hydrogen or its 1-oxide is isolated in the form of a syn-isomer free of anti-isomer. 3. The method according to claim 1 or 2, characterized in that a compound of formula II wherein B, R ¹¹ and R ¹² and the broken line has the meaning indicated in point 1 ⁴¹ is condensed with an acid halide of formula III where R ¹ and R ^z have almost given meaning. 4. The process of claim 3, wherein the condensation is carried out in the presence of an acid binding agent selected from the group consisting of tertiary amines, inorganic bases or oxiranes. 5. A method according to claim 1 or 2, characterized in that a compound of formula II wherein B, R ^11, R ¹² and the dotted line are defined as in point 1, is condensed with a free acid of formula III wherein R ¹ and R ² have the same meaning as given herein, in the presence of a condensing agent from the group of carbodilmide, carbonyldiimidazole or isoxazolinium salts. 6. A process according to any one of claims 1 to 5 for the preparation of a compound of formula I wherein R ¹ is fur-2-yl, wherein the starting compound is a compound of formula III wherein R ¹ is 2-furyl and R ² is as defined above. 7. Process according to claims 1-6 к preparing compounds of formula I wherein R ² is methyl, ethyl, t-butyl, cyclopentyl or phenyl, characterized in that the starting compound used is a compound of formula III where R ² has and R ¹ has the meaning given in point 1. 8. Process according to claims 1-7 к slouj manufacture of compounds of general formula I wherein R ¹ is 2-furyl, R ^a is methyl and R ^and represent hydrogen, characterized in that the starting compounds used are compounds of the formula III, wherein R ¹ is 2-furyl and R ² is methyl.