SU544376A3 - The method of obtaining derivatives of cephalosporin or their salts in the form of a mixture of diastereoisomers or individual diastereoisomers - Google Patents

Description

(54) METHOD FOR OBTAINING DERIVATIVES OF CEFALOSPORIN OR THEIR SALTS AS A MIXTURE OF DIASGEREOISOMEGES OR THEIR INDIVIDUAL DIASGEREOISOMERS

.

.. E

SOSH

where B, E, C have the indicated meanings, are subjected to interaction with the formula of the general formula

N COW

where A has the specified value 1; W - halogen, azido-p phenoxy-, nitrophenoxy-, di-shiropenoxy group,

in a solvent environment in the presence of a base and at a temperature of from -20 to + 50 ° C, followed by a set of products in free form or as a salt, as a mixture of diastereoisomers or individual isomers.

It is desirable to conduct the process at 0–20 ° C. To these nontoxic / pharmaceutically tolerable salts of soyedinaksh forglyslg GOIOSYA 5SYA salts with acidic carboxyl number of gp / dL, eg sodium, potassium, magic. E. calcium, aluminum and ammonium salts, and nontoxic substituted ammonium salts, such as 5– as dihydric alkaline / preferably (1–4 carbon atoms for each alkyl group), procaine, d benzylamine, N, N - dibenzylethylene diamine, N- b.chzil- / - phenylethylalshi, N-methyl N-ethylmorpholine, 1-phenamine, dehydroabiethyls, M, N-bis-dihydroabiethylethylenediamp, M-lower alkyl piperidine and other amines used in pharmaceutical chemistry such as, for example, are used and for the formation of penicillium salts.

New before; Agents of a conjugate have a markedly stronger antibacterial effect, in particular against bacteria from the Ents robacier oceae family of the PssudoijTsona da ceae family than those known from the level of cephalosporins cefaloglylisch and cephalothin.

The use of the compounds of the general formulas II and III as starting materials is known and can be obtained using known methods or easily obtained by conventional methods. Compounds of general formula III, in which W is azide, are knocked out of the corresponding compounds of general formulg III, in which W is halogen, for example chlorine, by reacting with an alkali metal azide. Compound P1 of general formula III. Which W means unsubstituted or substitutional |) radyl radical or benzylthio radical, is obtained from compounds of the general formula 1 P, from which W stands for halogen, and from the corresponding phenols (whether benzyl mercaptan, or by

the corresponding imidazoles with the corresponding esters of chloroic acid or chloroagonal acid.

As diluents of the proposed reaction of compounds of the general formula P with compounds of the general formula fft, there are mixtures of water with such solvents that can be mixed with water, such as ketones, for example acetone and methyl ethyl ketone, esters, for example tetrahydrofuran and dioxane, lower alkyl nitriles, for example, acetoxystryl, dimethylformamide, alkyl alcohols, for example isopropanol and or dimethylsulfoxide, as well as these organic solvents (alone or in a mixture) without the addition of water. If, due to the presence of water, it is possible to determine the pH during the proposed reaction, the pH value of the reaction mixture can be maintained 6.5 - 7.5 by adding base or by using buffer mixtures. The proposed reaction can also be carried out at pH values, for example, 4.5-9.0 or 2.0-5.5. In addition, it is possible to carry out the reaction in solvents that are incompatible with water, such as halogen {hydrocarbons, for example chloroform or methylene chloride, with added organic gases, preferably triethylloxyl, p ethylamine or N - zlipiperidine. In addition, the mohs reaction is carried out in a mixture of water and a solvent that is not displaceable with water, such as, for example, ethers (diethyl ether), halogenated hydrocarbons; for example, chloroform, methylene chloride, carbon disulfide, water-immiscible ketones, for example isobutyl methyl ketone, esters , e.g., ethyl acetic acid, acetic acid, hydrocarbons, e.g. benzene, and it is advisable to intensively place and maintain a pH value of 4.5–9.0 or 2.0 3, 0 by adding base or applying buffer solutions. The reaction can be carried out in water, i.e. in the absence of organic solvents, in the presence of an organic or inorganic base, or by adding buffering substances. As the organic bases added with the proposed 45 reactive-ffl bases, it is advisable to use tertiary aliphatic or aromatic amines, for example, niridine or trialkylamines, for example triztilamine, or difficultly adylated sterically hindered secondary aliphatic or aromatic amines, e.g. dicyclohexylamine. The number of bases applied is therefore almost unlimited.

As inorganic bases, alkali and alkali hydroxide metals, such as sodium, potassium and calcium hydroxides, are used in particular.

The amount of base used is determined, for example, by the desired maintenance of the desired pH. In that case, if not

Claims (2)

The pH is determined 60, preferably 1 5 (in particular about 2) M equivalent of base is added. As buffer mixtures, for example, phosphate buffers (sodium phosphate / phosphoric acid), acetate buffers (sodium acetate / acetic acid), citrate buffers (catri citrate / citric acid) can be used, and to maintain the desired pH values, the ratio components of the mixture. The reaction can be carried out at normal, reduced or elevated pressures. Mostly work at normal pressure. When carrying out the proposed method, the reagents can be left to react, for example, in equimolar amounts. It may be advisable to use one of the reagents in excess to facilitate purification of the cephalosporin or to obtain it in pure form. Reagents of general formul: tT can, for example, be used in excess of 01-0.3 M equivalents, and thereby achieve a weaker decomposition of the reagents of general formula 111 in a water-containing solvent mixture. Excess reagents of the general formula I, due to the very good solubility in aqueous mineral acids, can be easily removed when separating the reaction mixture. It is advantageous to use the reagents of the general formula TP in excess, for example, 0.1-1.0 M equivalents. Since the compounds of general formula II 3 in excess added to water are rapidly converted into neutral, nitrogen-containing heterocycles, which can easily be removed, the purity of penicillins does not decrease. The separation of the initial reaction mixture to obtain 1X cephalosporins and their salts, as well as the purification of new compounds, are carried out in a known manner. The preparation of free acids of formula I can occur, for example, by acidifying a solution of salts, for example sodium, with an inorganic or organic acid, for example dilute hydrochloric or acetic acid. Free acids of general formula I can be converted to salts with non-toxic bases in the usual way, for example, by adding an appropriate base to the ether solution of acids of formula P. The NMR spectra of cephalosporins are removed in a SOZOO solution, unless indicated otherwise in the examples. The letters in the brackets mean: S-singlet t-multiplet d-doublet AB-system AB t-triplet AX-system AX with -quarte A B-system AZ Bj IR spectra of cephalosporins are removed in suspension of nuzhol. The content of 3-lactam in cephalosporins was determined by extinction of bands (3 lactam caronyl of the IR spectrum and NMR spectrum. Example 1. A suspension of 1.3 parts by weight of cephalogenate dihydrate in 15 parts by volume of 80% aqueous tetrahydrofuran with triethylamine was adjusted to RE at pH 7.5 and portion by portion for 10 in at 10-20 ° C was mixed with 0.5 parts by weight of chloroarbonyl-2-oxoimidazolidine, and the value of H was held at 7-8. mixed with 20 bw of water, distilled tetragastrofuran at room temperature on a rotary evaporator, and one solution was extracted once 20 vol. of acetic ester is added and, with ice-cooling, acidified with 2N HCl to a pH of 2, and the free cephalosporin acid, which is difficult to dissolve in water and acetic ether, precipitates as a crystalline precipitate. It is filtered off with suction and washed with ethyl acetate. The product is dried for a short time in a rotary evaporator 3 and dissolved in 5 parts by volume of dimethylacetamide and mixed with 3 parts by vol., M, solution;. Sodium 2-ethylhexanoate in ether containing a little methanol, Solution, stirring and cooling with ice, is added in 30 vol. including mixtures of ether and methanol (volume ratio 10: 1). Leave to stand, decant the solvent, stir with ether and suck dry. They are dried in a vacuum desiccator over paraffin struxes for 24 hours. Yield of 7-o-c ;-( 2-oxo-imidazolidin-1 yl). Carboxy-1-1-phenylacetamido-3-acetoxymethyl-3-it-4-sodium carboxylate 80%. The IR spectrum bands at 3250, 3060, 1765, 1723, 1652, 1607, 1540, 1274, 1235 and 1032. NMR signals at 55 (5.5H) 4D7 + 4.95 (AH, 1H-IN), 4.5 (S, 1H), 5.2 (S, 2H), 6.05-6.8 (AH , 4P) 6.5 - (- 6.8 (AB, 2H), and 7.9 ppm (S, SH) (in D, O). P p and M e p 2.7-lD-a- 2-Oxoimidazolidine-H-yl-yl) - carbonylamino-phenylacetamido-3-methylceph-3 em-4-carboxylic acid was prepared as in Example 1 of 1.83 ppm, cephaloxin monohydrate and 0.82 ppm. h-chlorocarbonyl-2-oxoimidazolidine in the form of crystalline free cephalosporic acid. Yield 86%. The IR spectrum bands at 3335, 3270, 3040, 1782, 1724.1663, 1530, 1310 and 1240cm. NMR signals at t-0.6 (d, lH), 0.8 (d, lH), 2.3 (s, lH) 2.6 (s, 5H), 4.0-4.4 (m, 2H), 5.0 (q, lH), 5.9-6.9 (t, 6P), and 7.9 h. Namln. (3H), (ii DMCO - dft). The electrophoregram shows only one spot with antibiotic activity. PR and ME 3. 2.2 weight. including cefaloglycine using the required amount of trimethylamine is dissolved in 30 vol. including 80% aqueous tetrahydrofuran. At 20 ° C, stirring, add 0.85 wt. Part 1 - chlorocarbonyl-2-oxo-3-methylimidazolidine. By adding an appropriate amount of Tpn3THJiaNmHa at this m and after that the pH value is maintained at 7.0. Additionally, they are stirred until Shch1 half-globular PI 7.0 is no longer required to be added to triethylamine (for example) within an hour). The mixture is then diluted with the same volume of water, the pH is adjusted to 6.5, the tetrahydrofuran is removed in vacuo. A mixture of simplicity of ether and ethyl acetate is added to the remaining aqueous solution (1: O stirred and cooled slightly, acidified to pH 2, the organic phase is separated, washed with water, dried over magnesium sulfate and using 1 M solution of 2-ethylhexanoate sodium in cephalosporin sodium salt is separated in methanol-containing ether. The sodium salt is obtained in the form of a gel-like precipitate, which, however, can be sucked off. After washing with ether, it is dried in a desiccator. Out of 2.1 parts by weight of sodium salt - {O- a- ((3-methyl-2-oxoimidase Lidin-1-yl) -carbonylamino-phenylacetamido-3-acetoxymethyl-3-em-4-carboxylic acid. Content) 3-lactam is about 75%. IR spectrum spectra of J 780, 1720, 1650, 1610 and 1540 cm carbon dioxide ( ). NMR signals at C, 4-2.8 / 5H /, 4.15-4.35 / 1H /, 4.9-5.2 (4H), 6.2-6.8 (6H) - 7 , 2 (3N) and 7.95 parts per million (3N). The 1-chlorocarbonyl-2-oxo-3-methyl midazolidine used as the starting compound is obtained from 1-methyl-2-oxoimidazolidine and phosgene. T. pl.94-95 ° C. PRI me R 4. Cephalosporin sodium salt was prepared as in Example 3 out of 2.2 wt. including cefaloglycine and 0.8 wt. including 1-chlorocarbonyl-2-oxo3-methylimidazolidine. Output 1.9 weight.h. sodium salt of (3-ztil-2-oxoimidazolidin-1-yl) -carbonylamino-phenylacetamido-3-acetoxymethyl ceph-3-e-4-carboxylic acid. The content of (3-lactam is approximately 82%. The IR spectrum bands for carbonyl are 1780, 1720, 1675, 1610 and 1540 cm. The sodium cephalosporin salt contains approximately 2 moles of Species and is contaminated with approximately 0.5 moles of sodium 2-ethylhexanoate. This taken into account when analyzing the results of the analysis. Calculated,%; C 49.0; And 5.5; N 10.2; 54.7 Found,%: 48.7; H5.5; N 10.4; 54.9 EXAMPLE 5 Cephaloslorin sodium salt was prepared as described in Example 3, out of 2.1 parts by weight of cephalexin and 1.0 part by weight of 1-chlorocarbonyl-3-oxo-3-ethylimidazolidine and isolated as a free acid. Cephalosporic acid drops on acidification. in the form of a mucous, insoluble in the phase of simple and acetic esters of the precipitate. Yield 3.1 parts by weight - ({3 - ethyl-2-oxoimidazolidin-b) -carbonylamino-phenylacetamido} 3-methylceph-3-e-4-carbon acids. Content (3-lactam is approximately 81%. NMR signals with tr -2.4-2.8 (5H) 4.1-4.4 (2H), 4.9-5.1 (W), 6, 1-6.9 (ZN), 7.8-8.0 (ZN) and 8.7-9.0 ppm (ZN). The MK-spectrum bands in carbonyl 1770, 1710.1650 and 1530 P EXAMPLE 6 - a, (2-Oxo-3-mesylimide zolidin-1-yl) -carbonylamino-1-chloroacetates to-3-ad-methoxymethyl-3-em-4-carboxylate nati are obtained in an octanized-in the manner from 1 , 3 weight.h. cefaloglycine dihydrate and 0.77 parts by weight. 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine in 71% yield. The IR spectrum bands at 3230, 1760, 1727, 1654, 1598, 1518, 1250, 1230, 1157, 11 20, and 973 cm. NMR signals pr, 1 T -2.3-2.7 (t, 5H) ,, 4.25 + 4.95 (AH, 1H + W), 4.4 (5Sh), 5.1 (d, 2H ), 6.05 (S (4H), 6.6 (), and 7.9 ppm / 3N /. Elec: trophoregramm shows only one spot with antibiotic activity. Example 7 2-Oxo-3-phenylsulfonylimidazolidin-1-yl) -carbonylamino-phenylacetalShDO} -3-acetoxymethyl-3-em-4-carboxylate, sodium is prepared as described in Example 1 p 1.3 times from 1.3 parts by weight defaloglitsin dihydrate and 1.0 weight.h. 1-chlorocarbonyl-2-oxo-3-f- /. nilsulfonylimidazolidine with a yield of 64%. The IR spectra bands at 3250, 1760, 1728, 1670, 1604, 1515, 1240, 1170, and 1118 cm. NMR signals at t 0.5 / d, lH /, 1.25 / d, lH /, 1.7-2.0 (), 2.0-2.3 (, 2.3-2.8), 4.1M, 5 (), 4.85.1 (), 6.05 / wide 8DN), 6.6 (gth2H) and 7.9 ppm (S, 3H) (in DM CO-dg ). The content of (3-lactam by NMR spectrum and IR spectrum of 80-90%. Example V. Cephalosporin is prepared as described in Example 1 from 1.5 parts by weight of defapolitinate dihydrate and 0.95 parts by weight of 1-chlorocarbonyl -2-oxo-3-megilaglinosulfonylimidazolidine. 7-Do yield: - (2-oxo-3-methylaminosulfonylimidazolidine -1-yl) -carbonylamino-phenylacetamido-3-acetoxymethyl-de-3-4-carbonoxy-Ylata sodium 52% -. IR-sp-e bands; tra at 3220, 1760, 1T18, 1665, 1600, 1518 1252, 1230 and 1175 cm. NMR signals of dri t -2.4-2.9 (m, 5H), 4.35 +5.05 (AH, 1H + 1H), 4.45 (S, IH), 5.1 (d, 2H, 6.15 (S, 4H), 6.6 (AB, 2H) and 8.0 hours per million (ZN). Contents | 3-lactam. IR spectrum y and an NMR spectrum of 85-90%. - Example 9: 2.2 parts by weight of defaloglitsin dihydrate are suspended in 30 parts by volume of methylene chloride, mixed with 1.3 parts by weight of triztilamine, cooled to -20 ° C, then add a solution of 1.0 weight, including 1-chlorocarbonyl-3-cyaiemethylcarbonylimidazolidinone- (2) in 6 parts by volume of methylene chloride. Stir for 30 minutes at -10 ° C and for 30 minutes at 20 ° C and then methylene chloride is distilled off. The processing in (2-oxo-3-dianacetyl-imidazolidine-bil) -carbonylamino-phenylendetamide-3-acetoxymethyl-de-3-em-4-sodium carboxylate is carried out in a manner similar to Example 1. A lactam content of 70-75%. The characteristic bands of the IR spectrum: 2210,1760,1679,1610cm. Example 10 .. 2.2 weight. including dihydrate cefaloglycine as described in example 9 is mixed with 1.1 weight.h. 1-chlorocarbonyl-3-cyanopropionylimidazolidinone (2). Get 3.2 weight.h. reaction product (71%) with m. 203 ° C / 3-lactam content 90%. (2-Oxo-3-D-cyanopropionylimidazolycin-1-yl) carbonylamido-phenylacetamido 3-acetoxymethyl cef-3-eme-4-sodium carboxylate. Calculate y,% C 50, 32; H 4.06; N 13.54; 55.17 Found;% с49,6; H4.2; N 13.6; 55.2. Typical IR spectrum bands: 2250 ,. 1765, 1735.1675.16 cm. Example 1. The reaction of 2.2 parts by weight cefaloglycine dihydrate as described in Example 9 with 1.3 parts by weight. 1-chlorocarbonyl-Z- tsianimetilsulfonilimidazolidinona- (2) is prepared 7- Da- carbonylamino (whether Dinc yl-2-oxo-Z- tsianome tilsul fo nilimidazo) - phenylacetamido - 3- atsetoksimetiltsef-3- em-4-carboxylate ( content of 3-lactam from the IR spectrum 70-75%). The characteristic bands of the IR spectrum: 2210, 1760, 1735, 1675.1610 cm. Example 12. 7- {p-a- (-Oxo-3-methoxycarbonylimidazolidin-1-yl) -carbonylamino-phenylacetamido-3-acetoxymethyl-S-4-carboxylate sodium in the manner described in example 1 is obtained from 1.55 weight . h. 1-chlorocarbonyl-2- oxo-3-letoxycarbonylimidazolidine and 3.0 parts by weight cef loglicin with a yield of 23%. The IR spectrum bands at 3270, 1760, 1750, 1670, 1610, and 1525 cm (in the nuke). NMR signals at t 2.3-2.9 / 5H /, 4.25 (1H), 4.43 (W), 4.95 (W), 5.3 (2H) 5.9-6.4 ( 7G) 6.6 (2H) and 7.8 ppm (3N), (in DjO). EXAMPLE 13.7- {o-a- (2-Oxo-3-benzoylimidazolidin-1-yl) -carbosh1-amino-phenylacetamido | -3-acetoxymethyldef-3-em-4-sodium carboxylate is prepared in the manner described in example 1 from 1.9 weight.h. 1-chlorocarbonyl-2-oxo-3-benzoyl-imidazolidine and 3.0 parts by weight cefaloglitsin. Yield 67.5%. The IR spectrum bands at 3300, 1750, 1730, 1665,1615 and 1505 cm (in the nuke). NMR signals with t 2.2-2.9 (10H1,4.25 (1H), 4.4 (1H), 5.0 (1H), 5.3 (2H), 5.8-6.3 ( 4H), 6.5 (1H), 6.9 (1H) and 7.8 ppm of (3N), (in DjO). Example 14. 7 - DQ: - (-Oxo-3 acetylimidazolidin-1-yl | ) -Carbamide Lamino-1-phenylacetamido-3-acetoxymethyl cef: -3. We eat sodium 4-carboxylate in the manner described in Primea 1 from 1.43 parts by weight of 1-chloro-carbonyl-2-cc about -Gycetylamideazidine and 3.0 weight. Cefaloglycine h. Yield 65%. IR spectrum bands at 3260, 1750, 1735, 1680, 1615, 1520, 1315,1260,1240-12154И 750 cm (in the nucle). NMR signals at t "0.35 (W) 0.9 (1H), 2.3-2.8 (5H), 4.1-4.55 (2H) 5.03 (3N), 6.2 (4H), 6.65 (2H), 7 , 5 (ZN) and 7.9 ppm (ZN). (In dimethylformamide - d7) Calculated%: C 49.5; H4.1; N 12 , 0; 55.5 Found%; C 48.7; H5.3; N11.4; 35.6 Example 15. (2-Oxo-3 furoyl- (2) -imidazolidin-1 yl) - carbonylamino-phenylacetamido - 3-acetoxymethyl-3-em-4-carboxy-; sodium lat is prepared in the manner described in example 1 from 1.82 weights, including 1-chlorocarbonyl-2 oxo-3-furoyl- (2) -im azolidine and 3.0 weights C. cefaloglycine. The yield is 78.6%. IR spectrum bands at 3310, 3250, 1775, 1750, 1730, 1660.1520.1325, I 260-1220, and 753-738 cm (in Nuujol), NMR signals at t C-0.55 (H) IO (IH) , 1.93 (1P), 2.4-2.75 (6H), 3.2 (1H), 4L-45 (2H), 5.05 (ZN), 6.1 (4H), 6.7 (2H) and 7.98 ppm (3N). dimethylformamide - d), EXAMPLE 16. 7- 0-o; - (2-Oxo-3 benzoylimidazolidin-1-yl) -carbonylamino-phenyl cetamido-3-methylceph-3-e-4- sodium carboxylate is prepared as described in Example 1 from 2.3 parts by weight. 1-chlorocarbonyl-2-oxo-3-benzoylimidaholidine and 3.0 parts by weight, cephalexin. Yield 79%. The IR spectrum bands at 3300, 1740, 1660, 1600, 1500, 1320, 1250 and 1230 (in the nuclean). NMR signals at t 0.6 (1H), 1.0 (1H), 2.1-2.88 (YUN), 4.05-4.6 (2H), 5.07 (W), 6.0 (4H). 6.85 (2H) and 7.95 H — per million (MN). Example 17. (2-Oxo-3 -sulfamylimidazolidine -1-yl) carbonylamino-phenyztanetamido 3-acetoxymethyl ceph-3-em-4-sodium carboxylate is prepared in the manner described in example 3 of 2.2 parts by weight tsefaloglisch1 dihydrate and 2.2 weight.h. 1-chlorocarbonyl-2-oxo-3-sulfamylimidazolidine (which is added in dissolved in 5 parts by weight of acetonitrile) with a yield of 0.5 parts by weight At the same time receive the free acid of the same cephalosporin with the release of 2.4 weight.h. If this free acid is dissolved in 7 vol. dimethylformamide and this solution is added to a mixture of 4.8 ob.h. 1 M solution of sodium 2-ethylhexanoate in methanol containing ether, 120 parts by volume ether and 12 ob.h. ethanol, then get another 1.8 weight.h. cephalosporin sodium salt. The IR spectrum bands (with carbonyl) at 1755, 1720, 1655.1600 and 1520 cm (in the nuclean). NMR signals with t 2.3-2.75 (5H), 4.1 - 4.45 (2H), 4.9 - 5.2 (ZN), 5.9 - 6.2 (4H), 6, 5-6.65 (2H), and 7.9 ppm (G), (SOZOO). From the NMR spectrum it can be seen that the substance contains approximately 3.7 mol of HjO and 0.7 mol of dimethylformamide. Calculated,%: C 39.5; H 4.2; N 12.8; 58.7 Found: C 40.0; H4.2; N 12.3; 58.2. EXAMPLE 18 (2-Oxo-3-phenylimidazol din-1-yl) -carbonylamino-phenylacetamido-3-acetoxymethyl-3-em-4-sodium carboxylate is prepared in Example 3 from 2.2. weight, h, dihydrate cefalogue and 1.0 weight, h. 1-chlorocarbonyl-2-oxo-3-phenylimidazolidine and acidification to pH 2 get free acid (3.5 parts by weight) as an insoluble precipitate. It is dissolved in 3.5 vol. Dimethylpetamide from the insoluble portion is filtered through to to achieve transparency, a calculated amount of a 1 M solution of sodium 2-ethylhexanoate in methanol-containing ether is added to the filtrate and this mixture is stirred at 100 parts by volume. simple ether. The sodium salt which has been injected is filtered off with suction, washed with a mixture of 50 vol.h. ether and 10 ob.ch. methanol and dried. Output 1.6 weight.h. This substance is crystallized by adding 1.5 moles. Calculated,%: C, 52.4; H4.5; N 10.9; S 5.0 Found: C 52.4; H5.5; N 10.9; 35.0 IR spectrum bands (with carbonyl): 1760, 1715.1655, 1600 and 1525 cm1 (in vuzhol). NMR signals with t a2.1-2.9 (W. 4.1-4.5 (2H), 4.9-5.15 (ZN), 5.9-6.1 (4H), 6.5 -6.7 (2H) and 7.95 h per L1da (3N), in dimethylformamide-d,), (CDj OD). Pr and p including cefalexin hydrate and 1.54 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenylimidazolidine, first as free acid and then as sodium salt with a yield of 3.5 weight parts. IR spectrum (for carbonyl ) at 1755, 1720, 1670, 1595 and 1530 cm (in the nucchol). The substance is crystalline and is in the form of a hydrate. Calculated,%: C 52.6; H4.7; N11.8; 55.4 Found,% : C, 52.6; And 4.7; N, 12.0; 35.4. Claim 1. The method of producing the water cephalosporins of the general formula O N-CONHCHGONH-TH, in which A denotes hydrogen, alkyl with a carbon atom number of from 1 to 4, phenyl or the group R, -X in which X represents gr. C.-CO. or Rj is an alkyl unsubstituted or substituted by amino or cyano group with 1 to 4 carbon atoms (phenyl, 1l-alkoxy with the number of atoms in the range from 1 to 4, if X means group - CO, B - phenyl, hydroxyphenyl and E - hydrogen or acetoxy, An asymmetric center, or their salts, in the form of a mixture of diastereoisomers or individual diastereoisomers, characterized by the fact that The general formula, NCHCONH I TtJOr in which B, E and C have the indicated meanings, is reacted with a compound of the general formula AN N-COW in which A has the indicated value, W denotes halogen, azido,: phenoxy, nitrophenoxy or dinitrophenoxy, in solvent in the presence of a base and at a temperature of from -20 to + 50 ° C, followed by separation of the target product in free form as a salt, as a mixture of diastereoisomers or individual diastereoisomers. 2. The method according to claim 1, wherein the reaction is carried out at 0-20 ° C. Sources of information taken into account during the examination: 1. England patent number 1337000, cl. C2A dated 11/14/73.