FI56839C - PROCEDURE FOR THE FRAMEWORK OF ANTIBAKTERIELLA PENICILLINDERIVAT - Google Patents

Description

ΓβΊ advertisement publication ΓΛβ ^ α flSg lBJ UTLÄOGNINCSSKRIFT 56839 C (45) Patent granted 10 Q4 1930 '' ^ (51) Kv.tk.vint.ci. * C 07 D 4-99 / 64 FINLAND —FINLAND (21) Pttvnttibtk'mn -HfntMnAknini 2897/72 (22) HtkamllpOvt - An «6knlnpdt | 19.10.72 ^ ^ (23) Alkuptlvt — Glttigh «t * d» g 19 * 10.72 * (41) Tullut lulktMkal - Bttvtt offMtUg 2k. OU .73

National Board of Patents and Registration ^ Nlhttvlk »lptn« »1. kuaUuik» * »

Patent · ocfl ragltteratyralten Alaska utlagd och udjkrHIw published 31 * 12 * 79 (32) (33) (31) Pyydetty «cuoiktus — Begird prtoritet 23 * 10.71

Federal Republic of Germany Förbundsrepubliken Tyskland (DE) P 2152967.9 (71) Bayer Aktiengesellschaft ;, Leverkusen, Federal Republic of Germany Förbunds-republiken Qtyskland (DE) (72) Hans-Bodo König, Wuppertal-Elberfeld, Wilfried Schrö Karl Georg Metzger, Wuppertal-Elberfeld, Germany Federal Republic of Germany (DE) (71 *) Oy Kolster Ab (5 ^) Method for the preparation of new penicillin derivatives for use as antibacterial agents - Förfarande för framställning av nya anti-bak , with penicillin derivatives

The invention relates to a process for the preparation of penicillin derivatives of the formula

* S CH

A-CO-NH-CH-CONH-I-S T

; Π p

o ^> - N ^ C00H

where A is 0 I! B-x-rSr- *

V

56839 wherein R represents hydrogen when X = CO, alkyl having 1 to 1 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, alkoxy containing 1 to 1 carbon atoms when X = CO, cyclohexyloxy when X = CO, phenyl, phenoxy, when X = CO, amino, mono- or dialkylamino having 1 to 1 carbon atoms per alkyl group, phenylamino, tetra- or pentamethyleneimino, ethoxycarbonylamino, methylsulfonylamino, optionally halogen-substituted furyl, thienyl, iso-thiol, isoxazolyl or pyridyl, X is CO or SOg, Q1 is an optionally methyl-substituted group - (CH2) 2- or - (CH8) 2-, and B is phenyl, hydroxy-phenyl or cyclohexa-1,1'-dien-1- yl, which penicillin derivatives due to the C * center of chirality may be in the R or S configurations and mixtures of the resulting diastereomers, or for the preparation of salts of these compounds.

The process according to the invention is characterized in that the compound of the formula T-NH-CH-CO-NH-jS 5 "X. CH 3 COOT1 in which B denotes the same as above, and T and T1 each independently denote a hydrogen atom or a group having formula

A

-Sir?

V

U 5. 6. .. .......

wherein R, R and R each independently represent an alkyl group having 1 to 6 carbon atoms are reacted with a compound of formula

A-CO-W III

wherein V is halogen, and A is as defined above, in a solvent and optionally in the presence of a base at a temperature in the range of -50 ° C to 50 ° C, after which the compound obtained is optionally converted into a salt.

The new synthetic compounds are valuable in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, and in particular intestinal bacteria and Pseudomonas bacteria, in poultry and mammalian and human drugs. They can be used in both oral and parenteral dosages.

3,06833

Bactericidal agents such as ampicillin (U.S. Patent 29,956,6) have been shown to be very effective in treating infections caused by gram-positive and gram-negative bacteria. However, they cannot prevent infections caused by, for example, bacteria of the Klebsiella-Aerobacter group or indole-positive strains of Proteus.

Carbenicillin (U.S. Pat. Nos. 3,1 ^ 2,673 and 3,282,926) is effective in humans against infections caused by bacteria of the Klebsiella-Aerobacter group only if it is administered continuously in high doses, which can only be administered by injection.

U.S. Pat. 3 1 + 83 188 and DE-A-1 959 920 disclose 6- (o <-bureido) -acetamido-penicillanic acids, but none of the 6 - («(- biureido) -acetamido-penicillanic acids described in these patents has a biureido residue 5 at the nitrogen atom in the position of the acyl residue.

The salts of the compounds of formula I are preferably non-toxic, pharmaceutically acceptable carboxyl group salts such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts, and non-toxic substituted ammonium salts of amines such as di- and tri-minialkylamines, procainine, procaine. , Ν, Ν'-dibenzylethylenediamine, N-benzyl-N-phenylethylamine, N-methyl and N-ethylmorpholine, 1-efenamine, dehydroabietylamine, Ν, Ν'-bis-dehydroabiethylethylenediamine, N-small alkyl salts of amines. If silylated compounds of general formula II are used as starting materials in the synthesis and reacted with compounds of formula III, the reaction must be carried out in solvents free of water and hydroxyl groups, e.g. methylene chloride, chloroform, benzene, tetrahydrofuran, acetone or dimethylformamide. In this case, it is not necessary to add bases, but in some cases the yield and purity of the products can be improved by adding them. However, the opposite effect may also be possible. The bases which may be added must be either tertiary amines, such as pyridine or triethylamine, or secondary amines which are difficult to acylate due to the ether barrier, such as dicyclohexylamine. The number of useful bases is hardly limited by this.

As with most chemical reactions, temperatures higher or lower than those indicated in the examples can be used for these reactions. However, if values significantly higher than those indicated are used, an increasing number of side reactions will occur which will reduce the yield or adversely affect the purity of the products. On the other hand, excessive lowering of the reaction temperatures lowers the reaction rate so much that the yield may decrease. Therefore, the preferred temperatures are in the range of -20 to + 50 ° C, with a temperature of about 0 to + 20 ° C being particularly preferred.

11 56833

The reactants may be allowed to react with each other in equivalent molar amounts. However, it may be appropriate to use the other reactant in excess to facilitate purification or preparation of the desired penicillin in pure form and to increase the yield.

The amount of base used in the reaction depends on the amount required to maintain the desired pH. When pH measurement and adjustment do not take place or the dilution does not contain enough water to allow it to be measured, 2 molar equivalents of base are preferably added. The reaction batches are further processed according to known methods commonly used in the preparation of penicillins.

The compound of formula II used as a starting material in the process according to the invention may, due to its configuration, due to the center of asymmetry in the side chain (: C +), exist in the D- = R form or in the L- = S form. They are described in DE Patent Publication No. 1,156,078, U.S. Patent Publication Nos. 3 3 * + 2,677, 3,157 61 + 0, 2,985 61 + 8, 3 1 * + 0 282, and ZA Patent Publication No. o 68 / P290 and (anhydrous form) U.S. Patent No. 3 1 * + * + 1 + 1 + 5. All crystalline forms and configurations of the compounds of general formula II are suitable for use as starting materials in the reaction of the invention. In the compound of general formula II, the configuration of the asymmetric centers of the 6-amino-penicillanic acid core must be identical to the corresponding centers of asymmetry of the 6-aminopenicillanic acid obtained, for example, from penicillin-G by a fermentation process.

The preparation of the compounds of formula II used as starting materials is described in NL Patent Publication No. 68/18057. · The preparation of the compound of formula III used as starting material in this invention is described in more detail in the examples.

The efficacy of the new penicillins as chemotherapeutic agents was studied in in vivo and in vitro experiments. In the following tables, the in vitro inhibition values (MHK =. X.

The inhibition strength is expressed in units of E / ml) of medium. The assay was performed in liquid medium as a tube serial dilution assay, with reading occurring after 2 * + hours of incubation at 37 ° C. The MHK value is determined from the turbidity-free tube of the dilution series. A substance having the following composition was used as the growth medium:

Lab Lemco (0X0ID) 10 g

Peptone (DIFCO) 10 g

NaCl 3 g D (+) Dextrose (MERCK) 10 g

Buffer, pH 7 »** 1000 ml x) The value of 8 * 1 moles of penicillin is known to be 5.951 * + x 10 E.

5 66839 The numbers reported herein for penicillins correspond to the numbers in the examples describing the preparation of each penicillin.

The spectrum of action includes both gram-negative and gram-positive bacteria. A particular advantage of the penicillins according to the invention is that they are active both in vitro and in animal experiments against ampicillin and carbenicillin-resistant bacteria of the Klebsiella-Aerobacter group, ampicillin- and carbenicillin-resistant indole-positive Proteus and Providencia bacteria and ampidillin. carbenicillin-resistant Escherichia coli strains and ampicillin- and carbenicillin-resistant Pseudomonas aeruginosa and Serratia marcescens.

Concentrations required for killing are reached when administered parenterally. The results obtained in animal experiments for some penicillins prepared according to the invention are summarized in Table 3.

In general, an excellent effect is achieved both once and in several batches. The new penicillins are stable to gastric acids. Some of the new penicillins are very well tolerated, as evidenced in particular by the high dose that the mouse tolerates when administered intravenously to the tail without complications (Table k).

Table 1 shows the set of minimum inhibitory concentrations of penicillin No. 1 + (see Example Ua) compared to the corresponding values for carbenicillin.

6 56839

Table 1:

Minimum inhibitory concentrations E / ml Ρβηίβίΐΐΐίήί Earbeni- _____- Nr. 4

bacterial Species

Pseudomonas Bonn 16 - 32 200 aeruginosa Walter 8 100 * F 41 25 100 E 27 500 12,5 100 V 10 818 25 100 V 10 797 12,5 50 V 10 887 12,5 100 V 10 900 12,5 50 A 12 , 5 25

«ΗΜΜΜΜΜΜΗ ··· OTMNMaMMMMtMII

Klebsiella- 60 <0.8 100

Aerobacter 62 1.6 100 63 4- 16 400 69 1.6> 400 70 3 400 1852> 400> 400 K 10 4-? 6> 400 1871 6 400 75 6> 400 aerogenes 418 3 400

Escherichia 14 <1 1.6 inches A 261 32 - 64 400 C 165 1-4 1?, 5 183/58 1-4 12.5 B <0.8 B 94 <0.8 1.6 55 B 5 < 0.8 ----- _ - _ * - - -------- J --- • - 7

Jatl “*: G6839

Minimum inhibitory concentrations E / ml 'I *

Penicillin Carbene- - Nr. 4 herring

bacterial Species

Escherichia T 7) 400) 400 in. T 20/2> 400> 400 1465) 400> 400 26/6 <0,8 3 N 1,6 6 5 32 400

Serratla 2 1.6 12.5 marcescens 3 12.5 400 4 1.6 12.5 6 1.6 12.5 7 1.6 100 9 <0.8 6 13 <0.8 6 K <0.8 6

Provldencla 930 <0.8 6 933 12.5 3 945 <0.8 3

Bacillus Proteus rettgerl Sp. 0.8 1.6 * 1,050 ►400) 400 824) 400> 400 mlrabills Sp. 1.6 1.6 G. <0.4 1.6 605 3,400 1,235 1.6 3 morganll Sp. 3 3 932 6 6 1 102 200> 800 vulgaris 1 017 1,6 3 _ 3 400_ 6_ SO 1 8 56839

Continued f

Minimum inhibitory concentration E / ml

Penicillia Karbeniaillii-No. 4 ni

bacterial Species

Haemophilus 2,689 0.25 1 »6

Influenzae.> 2,718 0.1 0.8 2,786 0.06 1.6 2,788 0.5 <0.4 2,684 0.1 -

Strepto- 8 709 12.5 200 coccus 8 711 3 50 faecalls 8 698 1.6 100

Staphvlo- BRL 1 756 200 200 coccus 133 1 1 aureus P 209 <0,8 <0; 8 SG 511 <0,8 <0,8

Table 2 shows the minimum inhibitory concentrations (MHC values) of some penicillins prepared in accordance with this invention in units of E / ml against different bacterial species.

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Tables 1 and 2 show the superiority of the in vitro effect of the new penicillins over the effect of commercial ampicillin and carbenicillin.

Table 3 indicates the effective doses (ED 2 values) in mice infected with intraperitoneally reported bacteria. This demonstrates the superiority of the penicillins prepared according to the invention over carbenicillin in an animal experiment using gram-negative bacteria. Furthermore, Table 3 also shows their good effect against gram-positive bacteria.

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13 56839

Table U shows the excellent tolerability of some of the penicillins prepared according to the invention.

Table k:

Penicillin DL 2 value in mice when injected intravenously into the tail in units of mg / kg 2> 3,000 1 »> 3,000

Tables 5, 6 and 7 show the minimum inhibitory concentrations of some known penicillins and penicillins prepared according to the invention with respect to different microorganisms. Table 5 shows the following general formulas for known penicillins and penicillins prepared according to the invention

CH

R-N-CO-NH-CH-CO-NH -] - 3 i X I ^ ch3 Cl ^ cooKa (known) f / CH3

R-N N-CO-NH-CH-CO-NH-T-f 'S> N <C

Table 6 shows the general formula S / CH3 for penicillins

R-C0-NH-CH-C0-NH-✓ ö \ / J

A J— A—

Γ M ^ COOH

Table 7 shows the general formula 0 C S CH_ for penicillins

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Minimum inhibitory concentration, E / ml E.coli Prot. Psdm. Klebs.

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The doses of the new penicillins when administered orally or parenterally are about 25,000 to 1 million. E / kg / day. For topical use, new penicillins can be formulated as ointments or powders and used as such.

The following examples are intended to illustrate the invention.

The OC-aminobenzylpenicillin used in the examples contained about 10% water, but anhydrous O (-aminobenzylpenicillin can also be used as well (cf. U.S. Patent 3 IUU5).

Unless explicitly stated otherwise, ampicillin means cf-amino-benzylpenicillin having the D (-) - = R configuration in the side chain.

The β-lactam content was determined iodometrically. All of the penicillins described herein had an IR spectrum corresponding to their structure, the IMR spectra of the penicillins were taken in CD 2 OD solution, the signals reported in the examples correspond to the structure in question; the locations of the signals are expressed as ^ values.

The water content has been taken into account when calculating the analytical values.

When reporting "efficacy in an animal experiment", "A" means that the penicillin in question, when administered subcutaneously to mice against Pseudomonas aeruginosa F1 strain, is more effective than Carbenicillin, "B", that it is more effective against Klebsiella 63 than Carbenicillin, "C" it is more effective against Klebsiella 63 strain than Cephalotin and "D" that it is more effective against Klebsiella 63 strain than Cefalexin.

The numbers reported as efficacies against specific bacteria (E / ml) are the mini-male concentrations obtained in a tube serial dilution assay after 2U of incubation.

Example 1 A) Sodium D-c - [(3-acetylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin:

x Q

CH -co-N N-CO-NH-CH-CONH- / CH 3 w (R) COONa 17.5 parts by weight of ampicillin were suspended in 80% aqueous tetrahydrofuran (1 x 0 parts by volume) and added dropwise at 20 ° C. stirring just enough triethylamine (about 6.3 parts by volume) to give a clear solution and a pH between 7.5 and 8.2 (glass electrode). After cooling to 0 [deg.] C., 7.6 parts by weight of 3-acetylimidazolidin-2-one-1-carbonyl chloride were gradually added portionwise with stirring over a period of 30 minutes, the pH being kept between J and 8 by the simultaneous addition of triethylamine. . Stirring was continued for 10 minutes at 0 ° C and then at room temperature until no more triethylamine had to be added to maintain the pH between 7-8. 150 volumes of water were then added and most of the tetrahydrofuran was removed on a rotary evaporator at room temperature. The remaining aqueous solution was shaken once with> 23,568,339 ethyl acetate, then 250 volumes of fresh ethyl acetate were poured on and the pH was adjusted to 1.5-2.0 with ice-cold dilute hydrochloric acid. The organic phase was separated, washed twice with 50 volumes of water, and dried for 1 hour in a refrigerator with anhydrous MgSO 4. After filtration, about 45 parts by volume of a 1 molar ethereal solution of sodium 2-ethylhexanoate in methanol was added to the penicillin solution. The mixture was then evaporated to an oil on a rotary evaporator, dissolved vigorously by shaking with a sufficient amount of methanol, and rapidly added dropwise to vigorously stirred 500 volumes of ether containing 10% methanol. After allowing to settle for 30 minutes, the solution was decanted from the precipitate, which was slurried once more in ether, filtered and washed with anhydrous ether. After drying in a vacuum desiccator over P 2 O 2, the sodium salt of penicillin was obtained as a white solid.

Yield: 95% γ-lactam content: 8U JC calculated: C 48.3 H 1, 9 N 12.8 S 5.8 'obtained: C 48.6 H (6.2) N 11.7 S 5.6 NMR signals 2.3-2.7 (5H), 4.3 (1H), 4.5 (2H), 5.8 (1H), 6.15 (4L), 7.5 (3H), 8.4 (3H) and 8.45 ppm (3H).

The electropherogram of the product had only one spot with antibiotic activity.

Efficacy in an animal experiment: B and C Efficacy against E. coli l83 / 58 ~ strain: 3 Efficacy Prot.morg. Against 932 strain: 6 Efficacy against Psdm.aerug.Bonn strain: 25 Efficacy against Klebsiella 63 strain: 25.

B) 3-Acetyl-imidazolidin-2-one-1-carbonyl chloride: O-3-co-h-yi-coci

20 parts by weight of N-acetylimidazolidone-2, 25 parts by weight of triethylamine and 150 parts by volume of dry benzene were first added to the reaction vessel, and 27 parts by weight of trimethylchlorosilane in 40 parts by volume of benzene were added dropwise over 30 minutes at room temperature. Protect from moisture and then reflux for 18 hours, after cooling it was filtered off from the separated triethylamine hydrochloride (22 parts by weight 3 100%), which was washed thoroughly with dry benzene. To the benzene solution thus obtained was added at 5 ° C a solution of 17 parts by weight of phosgene in 30 volumes of benzene and the mixture was allowed to stand overnight at 3 ° C. The solvent was then sucked off in vacuo and the residue was dried using an oil pump. Recrystallized from acetone / pentane.

Yield: 81% M.p. 10l * ° C

calculated: C 37.7 H 3.7 Cl 18.6 N 11 +, 7 found: C 39.3 H 1 *, 3 Cl 17.7 N 11, 7 IR peaks at 1798, 17 ^ 0, 1690 and I660 cm "1.

NMR signals * T = 5.65 - 6.3 (1 * H) and 7.1 * 5 ppm (3 H).

Based on the NMR spectrum, the product still contained 5-10% of N-acetylimidazolone, which, however, did not interfere with the reaction with empiicin (Example 1 A).

C) N-acetylimidazolidone-20 0

CH- CO-N NH

3 w

To a suspension of 25.8 parts by weight of imidazolidone-2 in 350 volumes of dry tetrahydrofuran was added dropwise over 60 minutes at 0 ° C 23.6 parts by weight of acetyl chloride dissolved in 100 volumes of tetrahydrofuran. After stirring for 3 hours at room temperature, dry air was blown through the solution for some time, then the solvent was removed in vacuo and the residue was recrystallized from boiling nitromethane.

Yield: 52% Sp. = 188 ° C

calculated: C 1 * 6.9 H 6.9 N 21.9 found: C 1 * 7.0 H 6.2 H 22.5 IR peaks at 3230, 1730 and 16U0 cm-1.

NMR signals T * 6.2 (2 H), 6.5 (2 H) and 7.6 ppm (3 H).

Example 2 A) Sodium D - [(3- (3-methylaminocarbonylimidazolidin-2-on-1-yl) carbonylamino] -benzylpenicillin: 0A </>> (CH3-HH-CO-). H-COSH-CH-COMH, _ / \ / w δ rf "COONa 25 56839 This penicillin was prepared as described in Example 1A from 6.5 parts by weight of 3- (N-methyl-N-trimethylsilylaminocarbonyl) imidazole- din-2-one-1-carbonyl chloride and 10 parts by weight of ampicillin.

Yield: 27% β-lactam content: 83%, calculated: C U6.5 HU, 9 N li *, 8 S 5.6 obtained: C 1 * 6.0 H 5.6 N 11 *, 0 S 5 , 2.

IR peaks at 330, 1765, 1722, 1672 and 1266 cm-1.

NMR signals δ = 2.3-2.8 (5 H), 1 », U (1H), U, 55 (2 H), 5.85 (1H), 6.25 H), 15 (3 H), 8.1 * 5 (3 H) and 8.5 ppm (3 H).

Efficacy in animal experiments: B, C and D.

Efficacy against E.coli strain 183/58: 1.6 Efficacy Prot.morg. Against 932 strain: 1.6 Efficacy against Psdm.aerug.Valter strain: 25 Efficacy against Klebsiella'63 strain: 12.

B) 3- (N-Methyl-N-trimethylsilylaminocarbonyl) imidazolidin-2-one-1-carbonyl chloride: 0

X

CH -N-CO-N 2 -N-CO 2 Ί vy.

Si (CH 3) 3

To a suspension of 7.1 parts by weight of N-methylaminocarbonyliminidazolidone-2 in 150 volumes of benzene and 12 parts by weight of triethylamine were added dropwise over 30 minutes with stirring and protection from moisture at room temperature 13 parts by weight of trimethylchlorosilane and then the mixture was boiled. 2l * hours. It was then cooled, filtered off from triethylamine hydrochloride, washed with benzene and 5 parts by weight of phosgene in 20 parts by volume of benzene were added. The mixture was allowed to stand in the refrigerator overnight, the solvent was sucked off in vacuo and the residue was dried using an oil pump. The residue was slurried in a 1: 1 mixture of benzene and pentane and filtered, the filtrate was evaporated to dryness, reslurried in dry ether and filtered again. The filtrate thus obtained was cooled on ice for about an hour, the separated precipitate was filtered off again and the resulting solution was evaporated to dryness. The semi-solid mass was dried using an oil pump.

Based on the NMt spectrum, the material thus obtained was a mixture of 26: 56839 3: 1 1-methylaminocarbonylimidazolidone-2 (NMR signals at 6.1, 6.5 and 7.15) and 3 - (N- methyl N-trimethylsilylaminocarbonyl) iridazolidin-2-one-1-carbonyl chloride (NMR signals at 6.0, 7.0 and 9.7 ppm) reacting with ampicillin to give the corresponding penicillin (Example 2 A) .

C) N-Methylaminocarbonyl) -imidazolidin-2-one: 0

X

CH_NH-CO-N NH

3 vy

To a solution of 20 volumes of 50% aqueous methylamine in 50 volumes of tetrahydrofuran adjusted to pH 8.5 with concentrated hydrochloric acid were added portionwise under ice-cooling 10 parts by weight of N-chlorocarbonylimidazolidone-2 and pH was then maintained at 8.5 with the simultaneous addition of triethylamine. It was then stirred until the pH remained unchanged for 15 minutes without the addition of triethylamine. The pH was adjusted to 6.5 by the addition of HCl and the tetrahydrofuran was sucked off in vacuo. Filtered, washed with a small amount of ice water and recrystallized from methanol.

Yield: 72% Sp. = 198 ° C, calculated: C Ui, 9 H 6.3 N 29, U found: C Ui, 7 H 6.5 N 30.2.

IR peaks at 3220, 1728 and I6U5 cm-1.

NMR signals λ = 2.0 (1H), 2.5 (1H), 6.2 (2H), 6.6 (2H) and 7.2 ppm (3H).

Example 3 A) N at ri um-D-ot- β. 3-Methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylamino} -benzyl lipenisoline:, X (r) /

CH-O-CO-N N-CO-NH-CH-CONH-r X \ CH

- φ P ^ ·.

COONa This penicillin was prepared as described in Example 1 from 7.8 parts by weight of 3-methoxycarbanylimidazolidin-2-one-1-carbonyl chloride and 17.5 parts by weight of ampicillin.

27 S 6 8 3 9

Yield: 97% γ-lactam content: 87% calculated: C 48.8 H 4.4 N 12.9 S 5.9 obtained: C 48.6 H (6.7) N 11.0 S 5.5 IR peaks at 3300, 1775, 1740, 1667, 1605 and 1262 cm-1.

NMR signals T "· 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.15 (3H), 6.0-6.3 (4 H), 8.4 (3 H), and 8.5 ppm (3 H) The electropherogram of the product had only one antibiotically active spot.

Efficacy in an animal experiment: B and C.

Efficacy against E.coli l83 / 5ö “position: 4 Efficacy Prot.morg. Against 932 strain: 8 Efficacy against Psdm.aerug.Walter strain: 16 Efficacy against Klebsiella K 10 strain: 16 B) 3-methoxycarbonylimidazolidin-2-one-1-carbonyl chloride: 0 CH_0-C0-N N- COCl 3 w This carbamic acid chloride was prepared as described in Example 1B from 8 parts by weight of N-methoxycarbonylimidazolidone-2, 9.7 parts by weight of trimethylchlorosilane, 9 parts by weight of triethylamine and 6.2 parts by weight of phosgene. Yield: 72% Sp. = 129 ° C, calculated: C 34.8 H 3.4 Cl 17.2 N 13.6 Found: C 34.8 H 3.4 Cl 17.1 N 13.6.

IR peaks at 1820, 1737, 1690 and 1260 cm-1.

NMR signals δ 5.7-6.3 (4 H) and 6.1 ppm (3 H).

C) N-Methoxycarbonylimidazolidone-2:

X

CH 2 O-CO-N 2 NH

3 v.y. 14.9 parts by weight of N-chlorocarbonylimidazolidone-2 were placed in 70 parts by volume of ice-cold methanol and stirred at room temperature and then at 40-50 ° C. After excess methanol was sucked off, the product was recrystallized from acetone.

28 56839

Yield: 55% Sp. = 185 ° C calculated: C Ui, 6 H 5 * 5 N 19 »U obtained: C Ui, 8 H U, 8 N 19 * 2.

IR peaks at 3320, 17U5 and 1670 cm 1.

Example U

A) Sodium Ώ-ι & τβ3-methylsulfonylimidazolidin-2-on-1-yl) carbonylamino-4-benzylpenicillin O (R), i.e. CH3-SO2-N N-CONH-CH-CONH- \ / 1 w 6 CO ON a This penicillin was prepared as described in Example 1A from 5.1 parts by weight of 3-methylsulfonylimidazolidin-2-one-1-carbonyl chloride and 9.3 parts by weight of ampleillin.

Yield: 90% β-lact Aarn content: 8% calculated: C U2.7 H U, 6 N 11.8 S 10.8 obtained: C U2.7 H 5, U N 11.6 S 11, U.

IR peaks at 3305, 1760, 1728, 1670, 1605, 1360 and 117U cm -1. NMt signals 'T'> 2.3-2.7 (5 H), U, 35 (1H), U, Δ (2 H), 5.8 (1H), 5.8-6.2 (1H), 6.65 (3 H), 8, U (3 H) and 8.5 ppm (3 H). Efficacy in an animal experiment: A, B, C and D Efficacy against E.coli A 261 strain: 32-6U Efficacy against E.coli st83 / 5Ö strain: 1-U Efficacy against Proteus 1017 strain: 1.6

Efficacy against Psdm.aerug.Walter strain: U-16 Efficacy against Klebsiella K 10 strain: U-16 B) 1-chlorocarbonyl-3-methylsulfonylimidazolidone (2): 0

/ X

CH_SO 0 -N N-COCl 2 w 29 S6839

A mixture of 16 parts by weight of 1-methylsulfyl imidazolidone (2) in dioxane and 27 parts by weight of trimethylchlorine and 20 parts by weight of triethylamine was boiled for 3 days. The precipitated triethylamine hydrochloride was filtered off, 11 parts by weight of phosgene were added and allowed to stand overnight at room temperature. It was then evaporated to dryness and the product was recrystallized from boiling acetone. Yield: 70%. Sp. = 178 °.

calculated: C 26.5 H 3.1 Cl 15.7 M 12.1 »s lU, l found: C 27.2 H 3.1» Cl 15.3 M 12.0 S ll », l.

NMR signals 5.6-6.2 (U H) and 6.6 ppm (3 H).

IR peaks at 3010, 1807 »1721, 1360, 1165, 98H and 7 *» 2 cm -1.

The same product can also be prepared well from 1-methylsulfonylimid solidone (2) and excess phosgene in methylene chloride.

C) N-methylsulfonylimidazolidone-2: 0 Λ

CH -SO -N NH

3 2W

Help 1

To a suspension of 1 to 3 parts by weight of imidazolidone-2 in 1 to 3 parts by volume of dry tetrahydrofuran at room temperature was added dropwise 63 parts by weight of methanesulfochloride, stirred for 1 hour at 30 to 1 ° C and then heated to reflux for one hour. time under the reflux condenser. The solvent was then distilled off in vacuo and kept at 60 ° C for one hour using an oil pump. The residue was recrystallized from warm acetone.

Yield: 25% Sp. 193 ° C.

calculated: C 29.3 H 1, 9 N 17.1 S 19.5 found: C 29.0 H 5.0 N 17.2 S 19.6.

IR peaks at 3250, 3115, 1715, 1350 and 1160 cm-1.

ΝΜΪ signals Γ = 2.1 »(1H), 6.2 (2H), 6.5 (2H) and 6.8 ppm (3H).

Help 2

A suspension of 1 to 3 parts by weight of imidazolidone-2 in 300 volumes of dry tetrahydrofuran was added dropwise over 30 minutes with stirring to 80 parts by weight of methanesulfochloride and then to 56 parts by weight of triethylamine while maintaining the internal temperature at 35 ° C to 0 ° C. . After stirring for 2 hours at U5 ° C, the solvent was removed in vacuo, the remaining residue was extracted twice with 150 volumes of chloroform, and the remaining crystals were recrystallized from methanol.

30 56839

Yield: k9% · The product corresponds to N-methylsulphonylimidazolidone-2 described above on the basis of melting point and IR spectrum.

Example 5 A) Sodium D- (N- (3-aminocarbonylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin: 0. (*) A JM 3 w 6 J = 9 ^ - COONa

A mixture of 16 parts by weight of ampicillin in 170 parts by volume of methylene chloride and 10 parts by weight of triethylamine and 20 parts by weight of anhydrous sodium sulfate was stirred for 90 minutes at room temperature. It was then filtered, and a suspension of 11 parts by weight of 3-aminocarbonylimidazolidin-2-one-1-carbonyl chloride in 30 parts by volume of methylene chloride was added to the solution thus obtained at 0 ° C. After stirring for 1 hour at 0 ° C and for one hour at room temperature, the mixture was poured into 200 volumes of water, the pH was adjusted to 7 and the methylene chloride was filtered off with suction. The aqueous solution thus obtained was extracted once with 100 volumes of ethyl acetate, 300 volumes of fresh ethyl acetate were poured on top, and the pH was adjusted to 1.3-2.0 under ice-cooling with dilute hydrochloric acid. The precipitated precipitate, which was relatively poorly soluble in ethyl acetate, consisting of slightly impure free penicillinic acid, was filtered off and washed with water. The organic phase was then separated from water, washed once with water, dried over MgSO 4 and the penicillin was recovered as described in Example IA after the addition of sodium 2-ethylhexanoate as its sodium salt.

Yield: 23% β-lactam content: 76% calculated: C 1 * 5.5 H M N 15.2 S 5.8 obtained: C U 5.6 H 6.0 N 13.7 S 5.6.

IR peaks at 3300, 1760, 1725, 1670 and 1275 cm-1.

NM1 signals λ = 2.3-2.8 (5H), (1H), U.5 (2H), 5.8 (1H), 6.2 (UH), 8, H (3 H) and 8.5 ppm (3 H).

Free penicillinic acid obtained in 37 # yields contained 65% β-lactam and 66839

Based on the analysis and spectra, its structure was correct.

Efficacy in an animal experiment: B, C and D.

Efficacy against E. coli strain 18/58: U

Efficacy against Proteus 1017 ~ strain: H

Efficiency against the Psdm.aerug.Walter strain: 32

Efficacy against Klebsiella 83 strain: 16 B) 3-Aminocarbonylimidazolidin-2-one-1-carbonyl chloride: 0

A

H_N-C0-Ii N-C0C1 2 \ _ /

In a mixture of 7 * 7 parts by weight of N-aminocarbonylimidazolidone-2, 16.3 parts by weight of trimethylchlorosilane, 15 parts by weight of triethylamine and 100 parts by volume of benzene, a silyl compound was first formed as described in Example 2B, and the compound was then converted, using 6 parts by weight of phosgene, to carbamic acid chloride.

Catch: 11.6 parts by weight.

IR peaks at 3 00, 3300, 2950, 2895, 1795 and 1600 cm-1.

C) N-aminocarbonylimidazolidone-2H-N-CO-1 ·? ΙίΗ

2 VJ

29.7 parts by weight of N-chlorocarbonylimidazolidone-2 was reacted at pH 8.5 with 20 parts by volume of 5 5N aqueous ammonia in 80% aqueous tetrahydrofuran at room temperature. After the tetrahydrofuran was sucked off in vacuo, the precipitated product was filtered off and washed with a small amount of water. After drying in a desiccator above P 2 O 2, the yield was 62%, m.p. = 200 ° C.

calculated: C 37.2 H 5, U N 32.6 found: C 37.7 H 5.3 N 33.2.

IR peaks at 33 ^ 5, 3260, 3200, 17 ^ 0, 1677 and 1590 cm-1.

After boiling to dryness after main precipitation, a further 12% of product was obtained after boiling with several portions of acetone (m.p. 8,199 ° C, IR lines as in the main portion).

32 56839

Example 6 A) Sodium D, N - ((3-dimethylaminocarbonylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin: CH 3 N, N / CO-N N-CONH- CH-CONH ___ / ·, '\ _j * COONa This penicillin was prepared as described in Example 1A from 7.1 parts by weight of 3-dimethylaminocarbonylimidazolidin-2-one-1-carbonyl chloride and 13 parts by weight of amplsillin.

Yield: 76 β-lactam content: 93% calculated: C 1 (7.9 H 5.1 N 11, 6 S 5.5 obtained: CW, 1H 5.7 H 1, 0.0 S 6.1 IR peaks at 3290, 1760, 1722, 1662, 1600 and 1260 rear ”1.

NMR signals λ = 2. ^ - 2.75 (5 H), U, U (1H), U, 53 (2 H), 5.8 (1H), 6.2 (k H), δ .0 (6H), 8, H3 (3H) and 8.5 ppm (3H).

Efficacy in an animal experiment: B, C and D.

Efficacy against E. coli 1883/5 strain: U

Efficacy against Proteus 1017 ~ strain: 16

Efficacy against Psdm.aerug.Walter strain: 32 Efficacy against Klebsiella K 10 strain: 16.

B) 3-Dimethylaminocarbonylimidazolidin-one-1-carbonyl chloride: “n Λ N-CO-N N-COCl

ch3 ^ VJ

This carbamic acid chloride was prepared as described in Example 1B from 6 parts by weight of N-dimethylaminocarbonylimidazolidone-2. Crystalline substance.

56839 33

Yield: 93% Calculated: C 38.3 HU, 6 Cl 16.2 N 19.1 Found: C 38.8 H 5 »O Cl 16, h N (17.3) IR peaks at 2930, 1800, 1758 , 1720 and 1675 cm -1.

C) N-Dimethylaminocarbonylimidazolidone-2: Λ

N-CO-N NH

CHj / \ - /

A mixture of 50 parts by volume of 50 .mu.l of an aqueous solution of dimethylamine and 70 parts by volume of tetrahydrofuran was adjusted to pH 8 with 5N hydrochloric acid. and the pH was maintained by the simultaneous addition of dimethylamine solution. Stirred until the pH remained constant, then the tetrahydrofuran was sucked off, saturated with brine and extracted several times with ethyl acetate. The organic solution was washed with brine, dried over MgSO 4, filtered and the solvent was evaporated. The residue was recrystallized from acetone and dried in a vacuum desiccator over PgO 2.

Yield: 36% tsp. = 135 ° C. calculated: C 15 H 19 N 6 O 26.8 found: C 1 5.9 H 6.8 H 27.1.

IR peaks at 3280, 17 ^ 0, 1715 and 1660 cm-1.

Example 7

Sodium D- (trans-3-propyloxycarbonylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin: CH3 3, 4,56839 This penicillin was prepared as described in Example 1A from 6.3 parts by weight of 3- (i-propyloxycarbonyl) imidazolidin-2-one-1-carbonyl chloride and 10.9 parts by weight of ampleillin.

Yield: 62% β-lactam content: 85% calculated: C 1 * 9.1 H 5.1 N 11.9 S 5.5 obtained: C 1 * 9.2 H 6.2 N 11.6 S 5.6.

IR peaks at 3300, 1765, 1665, 1600 and 1260 cm-1.

NMR signals δ = 2.3-2.8 (5 H), U, 3 (1H), 1 *, 5 (2 H), 1 * .5 * 5.1 UH), 5.8 (1 H), 6.1 (1 * H), 8, U (6 H) and 8.6 ppm (6 H). Efficacy in an animal experiment: B, C and D.

Efficacy against E. coli strain 18/58: 1

Efficacy Proteus morg. Against strain 932: k

Efficacy against the Psdm.aerug.Walter strain: 8

Efficacy against Klebsiella K 10 strain: U.

B) 3- (i-Propyloxycarbonyl) -imidazolidin-2-one-1-carbonyl chloride: CH 2 O-CO-N N-COCl CH 2 This carbamic acid chloride was prepared as described in Example 1B from 11 parts by weight of Ni -propyloxycarbonylimidazolidone-2, 13.5 parts by weight of trimethylchlorosilane and 7 parts by weight of phosgene. Recrystallization from acetone / pentane.

Catch: 6.8 parts by weight. Sp. = 98 ° 102 ° C.

Based on the NMR spectrum and analysis, the material contained 65% of the final product and 35% of the starting material, which, however, did not interfere with the reaction with penicillin.

Calculated as the product containing 65% of the final product and 35% of the starting material: C U3.7 H 5.5 Cl 9.9 M 13.5 obtained: CM *, 3 H 5.5 Cl 10.1 N 1¾, 5 IR peaks at 3220, 1820, 1760, 17l * 0, 1695 and 1685 cm -1.

NMR signals 7 * U, 85, 6.1 and 8.6 ppm (final product) and 1 *, 9, 6, U and 8.7 ppm (starting material).

56839 35 C) N-i-propyloxycarbonyl) -imidazolidone-2: v x

CH-O-CO-N NH

ch3 ^ \ _ /

A mixture of 14.9 parts by weight of N-chlorocarbonylimidazolidone-2 in 100 parts by volume of i-propanol and 100 parts by volume of dioxane was heated at 50 ° C for 3 hours. After sipping the solvent, recrystallization from acetone was performed.

Yield: 67% Sp. = 86 ° C

IR peaks at 3320, 1764 and 1670 cm-1.

NMR signals δ = 5.05 (1H), 5.7-6.75 (5H) and 8.75 ppm (6H).

Example 8 A) Sodium D-β- [3-pyrrolidyl-N-carbonylimidazolidin-2-on-1-yl) carbonylamino] -benzoylpenicillin: N, N-CO-NH-CH- CONH ____ / CH3 w COONa This penicillin was prepared as described in Example 1A from 8 parts by weight of 3-pyrrolidyl-N-carbonylimidazolidin-2-one-1-carbonyl chloride and 13.2 parts by weight of ampleillin.

Yield: 82% β-β-lactam content: 95% calculated: C 49.2 H 5.3 N 13.8 obtained: C 49.3 H (7.1) N 13.4 IR peaks at 3290, 1760, 1720, 1655, 1600 and 1250, cm ”1. IMR signals Τ '= 2.4-2.8 (5 H), 4.4 (1H), 4.55 (2 H), 5.8 (1H), 6.2 (4 H), 6.3-6.6 (4H), 7.9-8.3 (4h), 8.45 (3H) and 8.5 ppm (3H).

36 $ 6839

Efficacy in an animal experiment: A, B and C

Efficacy against E.coli l83 / 5ö ~ strain: l *

Efficacy against Proteus 1017 ~ strain: 32

Efficiency Psdm. against the position of aerug.Walter: 32

Efficacy against Klebsiella K 10 strain: Θ.

B) 3- (Pyrrolidyl-N-carbonyl) -imidazolidin-2-one-1-carbonyl chloride:

^ V_J

This carbamic acid chloride was prepared as described in Example IB from 9.2 parts by weight of N- (pyrrolidyl-H-carbonyl) imidazolidone-2, 13.6 parts by weight of trimethylchlorosilane and 5.6 parts by weight of phosgene. Recrystallization from acetone / ether.

Yield: 1st fraction with m.p. = 125 ° C: 71% Fraction 2, m.p. = 120-122 ° C: 25% Fraction 1: calculated: C UU.OHU, 9 Cl 1U, 5 H 17.1 found: C UU, 1 H 5.3 Cl 15.0 μl 16.8 IR peaks at 1795, 1755, 1725 and 1660 cm-1.

C) N- (pyrrolidyl-N-carbonyl) -imidazolidone-2: 0

r ^ \ A

^ \ _J

This material was prepared as described in Example 6C from N-chlorocarbonylimidazolidone-2 and pyrrolidine.

Yield: 56% Sp. = 155 ° C calculated: C 52.3 H 7.1 N 22.9 found: C 51.5 H 7.0 N 22.6 IR peaks at 32 ^ 0, 1720, 1698, 16 ^ 7 and 1620 cm "1.

NMR signals 6.0-6.8 (8 H) and 8.0-8.3 (* ♦ H).

Example 9 A) Sodium D- (N-3-piperidyl-N-carbonylimidazolidin-2-on-1-yl) carbonylamino-7-benzylpenicillin: 37 S6839 K3 COONa This penicillin was prepared as described in Example 1A from 5.0 parts by weight of 3- (piperidyl-N-carbonyl) -imidazolidin-2-one-1-carbonyl chloride and 7.6 parts by weight of ampicillin.

Yield: 92% β-lactam content: 9% calculated: C 51.0 H 5, N 13.7 S 5.2 obtained: C 50.7 H (6.8) H 13.5 S 5.7 IR- peaks at 3295, 3050, 1865, 1725, 1667, 1608 and 1265 cm-1. NMR signals T »2.3-2.7 (5 H), U, 3 (1H), U, 65 (2 H), 5.8 (1H), 6.2 (¾ II), δ , 3-6.6 (¾H) and 8.1-8.5 ppra (12H),

Efficacy in an animal experiment: B and C

Efficiency E.coli l83 / 5Ö “against position: 1»

Efficacy against Proteus 1071 strain: 32

Efficacy against the Psdin.aerug.Walter strain: 32

Efficacy against Klebsiella K 10 strain: U.

B) 3- (Piperidyl-N-carbonyl) -imidazolidin-2-one-1-carbonyl chloride O-Si-co-iryl-coci [1] This carbamic acid chloride was prepared as described in Example 1B in a weight of 15.7% by weight. part of N- (piperidyl-N-carbonyl) -imidazolidone-2, 21.7 parts by weight of trimethylchlorosilane and 8.5% by weight of phosgene. Recrystallization from road / ether.

Yield: 1st fraction with m.p. = 117 ° C: 27.5% Fraction 2, m.p. »112 ° C: ¾9% * 1st fraction: calculated: C ¾6.3 H 5, ¾ Cl 13.7 N 16.2 found: C ¾6.3 H 5.8 Cl 1 ^ 6 N 15.8 IR- peaks at 3θ6θ, 1793– 1710, 1659, and 123¾ cm λ.

38 56839 C) N- (piperidyl-N-carbonyl) -imidazolidone-2: 0

ΓΝ A

^ V_J

This material was prepared as described in Example 6C from N-chlorocarbonylimidazolidone-2 and piperidine.

Recrystallization from nitromethane.

Yield: 85% M.p. = 187 ° C

calculated: C 5 M H 7.6 N 21.3 found: C 55.2 H 7.8 N 20.3 IR peaks at 32 U0, 1710, 1675 and 16U0 cm-1.

NMR signals 6.0-7.0 (8 H) and 8.0-8.6 ppm (6 H).

Example 10 A) Sodium D - ((3-phenylaminocarbonylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin: O / 7 (R) /, CK3

'V-NH-CO-N N-CONH-CH-CONH -, _ / \ X J

w 6 COONa This penicillin was prepared as described in Example 1A from 2.1 * parts by weight of 3- (phenylaminocarbonyl) imidazolidin-2-one-1-carbonyl chloride and 1 *, parts by weight of ampicillin.

Yield: 5% / β-lactam content: 86% Calculated: C 50.9 H 1 *, 9 N 13.2 S 5.0 Found: C 51.3 H 5.5 N 12.2 S 5 , 2,56839 39 IR peaks at 3390, 3290, 1782, 1720, 1678 and 1598 cm-1.

NMR signals 2.3-3.0 (10 H), U, U (1H), U, 5 (2 H), 5.8 (1H), 6.1 (HH), 8. U ( 3 H) and 8.5 ppm (3 H).

Efficacy in animal experiments: B and C.

Efficacy against E. coli strain 183/58: U

Efficacy Proteus morg. Against strain 932: U

Efficacy against Klebsiella K 10 strain: 8 B) 3- (Phenylaminocarbonyl) -imidazolidin-2-one-1-carbonyl chloride (NH-CO-N N-COCl 3 = A / - / This carbamic acid chloride was prepared as described in Example 1B .0 parts by weight of N-phenylaminocarbonylimidazolidone-2, 15.8 parts by weight of trimethylchlorosilane and 7.2 parts by weight of phosgene.

Recrystallization from acetone / pentane.

Yield: 12% Sp. = 198-200 ° C.

The post-doped precipitate, 8.3 parts by weight, was significantly impure.

IR peaks at 32U0, 1785, 1715, 1690 and 1598 cm-1.

C) N-Phenylaminocarbonylimidazolidone-2: 0-NH-CO-H hh

\ = / \ _J

The reaction vessel was first charged with 10.2 parts by weight of aniline in 120 parts by volume of 80%. an aqueous solution of tetrahydrofuran having a pH of 8 and 10 parts by weight of N-chlorocarbonylimidazolidone-2 were added portionwise with stirring at room temperature, while maintaining the pH at 7-8 by adding triethylamine. Stirring was continued until the pH remained constant, 80 volumes of water were added, the tetrahydrofuran was sucked off in vacuo, the pH was adjusted to 2.5 and the product which had settled after being kept in an ice bath for 1 hour was filtered off. Washed with ice water and dried over P 2 O 2 in a vacuum desiccator.

Yield: 91% Sp. = 161 + ° C.

Recrystallization from acetone gave 78 n of product, which also melted at 16-0.888.

calculated: C 58.5 H 5.1 * N 20.5 obtained: C 59.0 H 5.1 * N 20.7 4ο 56839 IR peaks at 3275, 3090, 1735 * 1715, 1653, 1616 and 1600 cm-1 -1.

Example 11 A) Sodium D-ε-ε (3-phenoxycarbonylimidazolidin-2-on-1-yl) carbonyl-amino-4-benzylpenicillin: O / Tv (R

\ _ / JL! _N CH

O »7 Y

COONa This penicillin was prepared as described in Example 1A from 5 parts by weight of 3-phenoxycarbonylimidazolidin-2-one-1-carbonyl chloride and 8.1 parts by weight of ampleillin.

Yield: 42% β-lactam content: 88% (determined by analytical Craig distribution chromatogram), calculated: C 53.7 H 4.3 N 11.6 S 5.3 obtained: C 53.5 H ( 5.8) N 11.1 S 5.4 IR peaks at 3300, 3050, 1775, 1740 (shoulder), 1670, 1600 and 1198 cm-1. NMR signals T = 2.3 * 2.9 (10 H), 4.3 (1H), 4.5 (2 H), 5.8 (1H), 6.05 (4 H), δ .4 (3H) and 8.5 ppm (3H).

Efficacy in an animal experiment: B and C.

Efficacy against E. coli strain 183/58: ^ 1

Efficiency Prot.morg. Against position 932: 8

Efficacy against the Psdm.aerug.Walter strain: 16

Efficacy against Klebsiella K 10 strain: 4 B) 3-Phenoxycarbonylimidazolidin-2-one-1-carbonyl chloride: Λ vVoCO-N7 N-COCl This carbamic acid chloride was prepared as described in Example 1B from 11 parts by weight of N-phenoxazolidinyl -2, 11.7 parts by weight of trimethylchlorosilane and 5.3 parts by weight of phosgene.

1 + 1 56839

Recrystallization from acetone / pentane.

Yield: 21% Sp. about 130 ° C.

IR peaks at 1780, 1758, 1682 and 1591 * cm-1.

C) N-Phenoxycarbonylimidazolidone-2: 0-oco-ir hh w v_y 12.7 parts by weight of sodium phenolate were dissolved in 120 parts by volume of 80% & tetrahydrofuran solution and the pH of the solution was adjusted to 8. Then, 10 parts by weight of 1U were added. N-chlorocarbonylimidazolidone-2, the pH being maintained at the same time by the addition of triethylamine to a constant value of 8. Stirring was continued until the pH remained constant without the addition of triethylamine. Then 100 volumes of water were added, the tetrahydrofuran was sucked off in vacuo, the pH was adjusted to 10 with sodium hydroxide solution and the solution was extracted with ethyl acetate. The organic solution was washed with water, dried over MgSO 4, evaporated to dryness, dried using an oil pump for 1 hour at 60 ° C and the residue was recrystallized from acetone.

Yield: 56% Sp. = 182 ° C.

calculated: C 58.3 H U, 9 N 13.6 found: C 58.5 H 5.1 N 13.6 IR peaks at 3260, 3110, 3050, 1780-1760, 1695, l68fc, 1597 and 1182 cm

Example 12 A) Sodium D-O- (N- (3-benzoylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin: O

(f ') —CO-N N-CONH-CH-CONH - _ / \ / J

w 6 COONa This penicillin was prepared as described in Example 1A from 5.5 parts by weight of 3'-benzoylimidazolidin-2-one-1-carbonyl chloride and 10.1 parts by weight of ampicillin.

1.2 56839

Yield: 92% β-lactam content: 89% calculated: C 1 * 9.2 H 5.2 N 10.8 SU, 9 obtained: C 1 * 9.2 H 5.3 N 10.8 S 5, 2.

IR peaks at 3220, 3050, 1755, 1725 and 1667 cm-1.

NMR signals δ '> 2.2-2.8 (10 H), k9k (1H),, 55 (2 H), 5.85 (l II) 6.05 (UH), 8. U (3 H) and 8.5 ppm (3 H).

B) 3-Benzoyl-imidazolidin-2-one-1-carbonyl chloride: 0

_ A

This carbamic acid chloride was prepared as described in Example 1B from 1 *, 8 parts by weight of N-benzoylimidazolidone-2, 1 *, 1 * parts by weight of trimethylchlorosilane and 2 *, 8 parts by weight of phosgene.

Yield: 100% Sp. = 153 ° C Calculated: C 52.2 H 3.6 Cl 11 *, 0 N 11.1 Found: C 51.2 H 1 *, 1 * Cl 13.2 N 11.1 IR peaks at 3060 , 1768, 1725 and 1672 cm -1.

NMR signals δ = 2.5 (5 H) and 6.0 ppm (1 H).

C) N-Benzoyl-imidazolidone-2:

n A

x = 'v_ /

To a solution of 8.6 parts by weight of imidazolidone-2 in 100 parts by volume of dry tetrahydrofuran was added a solution of 15.5 parts by weight of benzoyl chloride in 30 parts by volume of tetrahydrofuran over 15 minutes at 5-10 ° C and then stirred for 3 hours. 10 ° C. The solvent was sucked off, the residue was shaken for 15 minutes with a mixture of chloroform and aqueous NaHCO 3, the chloroform was separated, the aqueous layer was extracted once more with chloroform, the combined organic phases were washed with water, dried over MgSO 4 and evaporated to dryness. The residue was recrystallized from ethyl acetate / ether.

U3 56839

Yield: 30% Sp. = 169-170 ° C calculated: C 63.2 H 5.3 N 1H, δ obtained: C 63.0 H 5.3 N IU, 8 IR peaks at 3190, 3110, 17U2, 1718 and 1655 cm-1 .

NMR signals * T-2.2-2.9 (5 H), 3.9 (1H), 6.0 (2 H) and 6.6 ppm (2 H).

Example 13 A) Sodium D-Tot / 13-furoyl (2) -imidazolidin-2-on-1-yl) carbonylamine-7-benzylpenicillin: 0 π n (R) / \ / 0¾ IL „>> - C0-ir This penicillin was prepared as described in Example 1A from 6.0 parts by weight of 3-furoyl (2) -imidazolidin-2-one-1-carbonyl chloride and 12.1 parts by weight of N-CO-NH-CH-COHH. by weight, ampicillin.

Yield: 90% β-lactam content: 97% calculated: C 50.0 H k, k N 11.6 S 5.3 obtained: C 1 * 9.9 HU, 9 N 11.1 S 6.1 IR peaks at 3300, 1770 (shoulder), 17? 0, 1670, 1605 and 1260 cm -1. NMR signals 2.2 (1H), 2.3-2.8 (6H), 3.3 1H), U, 35 (1H), U, 55 (2H), 5.8 (1H), 6.1 (1H), 8.1 * 5 (3H) and 8.5 ppm (3H).

B) 3-furoyl (2) -imidazolidin-2-one-1-carbonyl chloride; 0 cu-A N-C0C1

\ -J

This carbamic acid chloride was prepared as described in Example 1B from 9 parts by weight of N-furoyl (2) -imidazolidone-2, 8.7 parts by weight of trimethylchlorosilane and 6.0 parts by weight of phosgene. Recrystallization from benzene.

t 56839 uit

Yield: 55% Sp. »U9 ° c calculated: C UU, 5 H 2.9 Cl lU, 6 N 11.5 obtained: C U5.0 H 3.6 Cl 13, h M 11.5 IR peaks at 3150, 3100, l800, 17U5, 1715, 1650, 1620 and 1255 cm-1.

NMR signals' T-2.3 (1H), 2.5 (1H), 3.1 U (1H) and 5.9 ppm (U H).

C) N-Furoyl (2) -imidazololidone-2: 0

JLco E ^ r ^ NH

»MMM ·» / This material was prepared as described in Example 12C from imidazolone-2 and furan-oxocarboxylic acid chloride. Post-mixing was performed instead of 10 ° C for three hours at 30 -0 ° C. Recrystallization from nitromethane.

Yield: 53% Sp. 1 H-6 ° C calculated: C 53.2 HU, 5 N 15.6 found: C 51.2 HU, 5 N 15.3 IR peaks at 32U5, 3120, 17U0, 1622, 1560, 1257 and 12Uo cm " 1. NMR signals * 2.25 (1H), 2.6 (1H), 3.35 (1H), 6.0 (2H) and 6. U ppm (2H)

Example lU

A) Sodium D-t-N- (3-n-butyrylimidazolidin-2-on-1-yl) carbonylamino-p-benzylpenicillin:

JL (R> A A

COONa This penicillin was prepared as described in Example 1A from 6.0 parts by weight of 3-n-butyrylimidazolidin-2-one-1-carbonyl chloride and 11.3 parts by weight of ampicillin.

Yield: 100% β-lactam content: 93.5% calculated: C 50.5 H 5.3 N 12.2 S 5.6 obtained: C 50.1 H 6.0 N 11.8 S 6.7 .

1.5 $ 6833 IR peaks at 3310, 3055, 1760, 1730, 1660, 1603, 1265 and 1230 cm -1. NMR signals 2.3-2.8 (5 H), U, U (1H), 1 », 5 (2 II), 5.8 (1H), 6.25 (1H), 7.1 (2H), 8.2 (2H), 8.1» (3H), 8 , Δ (3 H) and 9.0 ppm (3 H).

B) 3-n-Butyryl-imidazolidin-2-one-1-carbonyl chloride: O-CH 2 -CH-CH 2 -C 0 Cl-COCl

3 2 2 \ _J

This carbamic acid chloride was prepared as described in Example 1B from 10.0 parts by weight of N-n-butyrylimidazolidone-2, 11.1 parts by weight of trimethylchlorosilane and 7.0 parts by weight of phosgene. Recrystallization twice from acetone / pentane.

Yield: 65% Sp. 103 ° C

calculated: C U0.2 H l », l» Cl lU, 9 N 11.8 obtained: C 1 »0.2 HH, 8 Cl lU, 7 N 11.7 IR peaks at 3060, 1792, 1722, 1686 and 1220 cm -1 NMR signals T * 6.0 (1 H), 7.1 (2 H), 8.1 (2 H) and 9.0 ppm (3 H).

C) N-n-butyryl-imidazolidone-2: 0 Ϊ

Cl ^ CH-CH ^ CON ^ 'NH

3 2 2 v_y This material was prepared as described in Example 12 C from imidazolidin-2-n and n-butyryl chloride. After stirring instead of 10 ° C for one hour at room temperature and for one hour at 50 ° C. Recrystallization twice from methanol. Yield: 36% Sp. = 96 ° C calculated: C 53.9 H 7.7 N 18.0 found: C 53.5 H 7.6 N 18.3 IR peaks at 3200, 3120, 17U0, 1662 and 1262 cm-1.

NMR signals δ = 6.15 (2H), 6.5 (2H), 7.2 (2H), 8.1 »(2H) and 9.1 ppm (3H) 1.6 56839

Example 15

Sodium Du [- (3-phonylimidazolidin-2-on-1-yl) carbonylamine] -benzylpenicillin: N, N-aminobenzylpenicillin (5.7 wt.%) parts) was suspended in 80 Essay of aqueous tetrahydrofuran (60 volumes) and then added dropwise at 20 ° C with stirring just enough triethylamine to give a clear solution and the pH of the mixture remained between 7.5 and 8.2 (glass electrode ). It was then cooled to 0 [deg.] C. and a solution of 3-formylimidazolidin-2-one-1-carbonyl chloride (2.2 parts by weight) in tetrahydrofuran (20 parts by volume) was added dropwise. In this case, the pH of the mixture was maintained between 7.5 and 8.0 by the addition of triethylamine, respectively. It was then stirred for 30 minutes at 0 ° C. In this case, it was no longer necessary to add triethylamine to maintain the pH between 7.5 and 8.0. After the addition of water (60 volumes), the pH was adjusted to 6.5 with dilute hydrochloric acid and most of the tetrahydrofuran was removed on a rotary evaporator. The remaining aqueous solution was shaken once with ether (the ether extract was discarded), then a 1: 1 (v / v) mixture of ether and ethyl acetate was poured on and the pH was adjusted to 1-2 with dilute hydrochloric acid under stirring and ice-cooling. . The organic phase was then separated, washed with water, dried over magnesium sulphate at 0 ° C for about one hour and, after filtration, diluted with ether using half the volume of the mixture. The sodium salt was then precipitated by the addition of about 1 molar ethereal solution of sodium 2-ethylhexanoate in methanol. The precipitate was first oily, but could be converted to an amorphous solid after decantation of the supernatant solution and stirring with ether.

Yield: 0.9 parts by weight (crude product) β-lactam content: 77% Based on the NMR spectrum, the substance contains 3.5 moles of UgO 2 and 0.3 moles of sodium 2-ethylhexanoate per mole. This was taken into account when calculating the I intelligence values: 1.7 66839 calculated: C 1 * 5.1 H 5.1 * N 11.2 S 5.1 obtained: C 1 * 5.2 H 5.3 N 11.0 S 5, 3 NMR signals 1.0 (1H), 2.1 * -2.8 (5H), 1 *, 3 ~ M (3H), 5.0 (1 II), 6.1-6, ; (* t H) and 8.3-8.5 ppm (6 H).

Efficacy against E. coli strain C 165: 8

Efficiency Prot.morg. Against position 932: 8

Efficiency Psdm. Against the F l * l strain: 8

Efficiency Klebs. Against strain K10: 32 The 3-phonylimidazolidin-2-one-1-carbonyl chloride used in the preparation of this penicillin was obtained as follows: N-Fonnylimidazolidin-2-one: ° \ Λ \ __ y

Imidazolidin-2-one (8.6 parts by weight) was suspended in tetrahydrofuran (100 parts by volume), formic acid-acetic anhydride (10 parts by weight) was added with stirring at room temperature, followed by stirring for 3 hours at the same temperature. The precipitate formed was filtered off, washed with tetrahydrofuran and dried.

Catch: 6.1 * parts by weight.

Melting point: 156-158 ° C calculated: C 1 * 2.1 H 5.3 H 2 U, 6 found: C 1 * 2.2 H 5A N 25.3.

NMR signals = 1.2 (1H) and 5.9-6.5 ppm (1 * H). 3-Formylimidazolidin-2-one-1-carbonyl chloride: ° C-N-C-H-N-Cl

A mixture of N-formylimidazolidin-2-one (6.0 parts by weight), benzene (1 * 0 parts by volume) and triethylamine (11.8 parts by volume) was refluxed and then a solution of trimethylchlorosilane (8.5 parts by weight) in benzene (20 parts by volume). It was then boiled for a further 5 hours, after which the mixture was allowed to stand overnight at room temperature, the precipitate formed was filtered off and washed with benzene. Additional precipitate separated from the combined benzene solutions overnight, which was filtered off. A solution of phosgene (15.6 parts by weight) in dichloromethane (30 parts by volume) was then added dropwise to the filtrate, and the mixture was then allowed to stand in a refrigerator overnight. The mixture was then completely evaporated to dryness on a rotary evaporator. The residue, which was not a completely solidified mass, was then used in the reaction with ampicillin.

Example 16

Sodium Dio-E (3-pivaloyl-imidazolidin-2-on-1-yl) -carbonylamino-benzylpenicillin: -CO (R) / (CH 2), -C-CO-N N-CO- NH-CH-CO-NH-γ —— / \ 3 w 6 COONa This penicillin was prepared as described in Example 15 from ampicillin (9.8 parts by weight) and 3-pivaloylimidazolidin-2-one-1-carbonyl chloride (U, 9 parts by weight).

Yield: 8.6 parts by weight β-lactam content: 97.8%. calculated: C 50.3 H 5.6 N 12.2 S 5.6 obtained: C 50.6 H 5.9 N 11.6 S 5.6 NMR signals T = 2.2, U-2.8 (δ H), U, 3-U, 7 (3 H), 5.8 (1H), 6.0-6.1 * (1 * H) and 8.3-8.9 ppm (15 H).

Efficacy against E.coli strain C 165: 1 *

Efficiency Prot.morg. Against strain 932: <^ 1

Efficiency Psdm. F against Ul position: 1 *

Efficiency Klebs. K against strain 10: 8 N-pivaloylimidazolidin-2-one: / co \

(CHJ-TC-CO-N N-H

33 1.9 56839 To a suspension of imidazolidin-2-one (17.2 parts by weight) in tetrahydrofuran (200 parts by volume) cooled to 0 ° C was added dropwise pivaloyl chloride (2U, 2 parts by weight) over one hour at the same temperature. then for a further 3 hours at 0 [deg.] C., after which triethylamine (27.8 parts by volume) was added dropwise, which was cooled with ice water and then allowed to stand overnight at room temperature, the separated triethylamine hydrochloride was then filtered off and the filtrate was evaporated to dryness. in a rotary evaporator under vacuum and the residue was heated for a further hour in vacuo at a bath temperature of 60 [deg.] C. The oily product (yield of crude product: 32.8 parts by weight) was worked up as it was, and strong decomposition occurred when the product was distilled in vacuo.

3-pivaloyl-imidazolidin-2-one-l-carbonyl chloride:

To a boiling mixture of N-pivaloylimidazolidin-2-one (17.5 parts by weight), benzene (100 parts by volume) and triethylamine (23 parts by volume) were added dropwise over 1 hour a solution of trimethylchloroilane (16.65 parts by weight). ) in benzene (15 volumes) was boiled for a further 6 hours and then the separated triethylamine hydrochloride was filtered off. The filtrate was combined with phosgene (13 parts by weight) and benzene (20 parts by volume) and the mixture was then allowed to stand at room temperature overnight. The reaction mixture was then evaporated to dryness in vacuo and the oily residue was dried over sodium hydroxide in a desiccator. Raw product catch 22.2 parts by weight. The product was reacted in this form with ampieillin.

Example 17

Sodium D- [((3- (ethoxycarbonylaminosulfonyl) imidazolidin-2-on-1-ylcarbonylamino) benzylpenicillin:

(R) g CH

CoH „0-CO-NH-SO-N N-CO-NH-CH-CO-NH - / \ s' J

COONa This penicillin was prepared as described in Example 15 from ampicillin (9.8 parts by weight) and 3- (ethoxycarbonyl-trimethylsilylaminosulfonyl) -imidazolidin-2-one-1-carbonyl chloride (8.0 parts by weight).

Yield: 2.8 parts by weight β-lactam content: 76.8%. % 56839 50 NMR signals c = 2.1 * -2.7 (5H), 6.3-6.7 (3H), 5.8 (1H), 5.85-6, k (6 H), 8.3-8.6 (6 H) and 8.6-8.95 ppm (3 H).

The 3- (ethoxycarbonyl-trimethylsilylaminosulfonyl) -imidazolidin-2-one-1-carbonyl chloride used in the preparation of this penicillin was obtained as follows: 3- (Ethoxycarbonyl-trimethylsilylaminosulfonyl) -imidazolidin-2-one-1-carbonyl-1-carbonyl ca .0 / V ^ C_HcO-CO-N-SO -N NC ^ f 5 V_v

Si (CH 3) 3

A mixture of ethyl (carboxyBulfamoyl) triethylanimony hydroxide inner salt (GMAtkins, EMBurgers) (12.5 parts by weight) and imidazolidin-2-one (U, 0 parts by weight) was heated in a 100 ° C bath for 2 hours. the resulting thick oil was dissolved in dichloromethane (80 parts by volume), triethylamine (10.9 parts by volume) was added, this solution was then heated to reflux while adding a solution of trimethylchlorosilane (15.8 parts by weight) in benzene (30 parts by volume) dropwise. . Thereafter, it was further boiled under reflux for another 3 hours. After overnight at 20 ° C, the solvent was distilled off under normal pressure until the boiling point was 70-75 ° C, after which the mixture was still hot, the triethylamine hydrochloride was filtered off and the filtrate was combined with a solution of phosgene (5.3 parts by weight) after cooling. in benzene (20 parts by volume). This mixture was allowed to stand tightly for 2 hours at 20 ° C. The insoluble matter was then filtered off and the filtrate was evaporated to dryness on a rotary evaporator. An oil remained with a double line in the carbonyl region of the IR spectrum with peaks at 1790 and 1730 cm-1 (in dichloromethane). The material was used in the reaction with ampfa-HUjnt without further purification.

Example 18

Sodium D- (N, N-cyclohexyloxycarbonylimidazolidin-2-on-1-yl) carbonylamino] -7-Benzylpenicillin: N-N (R) N (R)

<γ-O-CO-N N-CO-NH-CH-CO-HH-1 -S

N-N-J-COONa 51 56839 This penicillin was prepared as described in Example 15 from ampicillin (6.6 parts by weight) and 3-cyclohexyloxycarbonylimidazolidin-2-one-1-carbonyl chloride (U, 0 parts by weight).

Yield: 1.6 parts by weight β-lactam content: 63.7% calculated: C U8.3 H 5.8 N 10.5 SU, 8 obtained: C U7.5 H 7.0 N 10.5 S 5.1 NMR signals T = 2.5-2.7 (5 H), U, 3-U, 7 (3 H), 5.8 (1 L), 6.0-6.3 (5 H) and 8.1-9.2 ppm (16 H).

3-Cyclohexyloxycarbonylimidazolidin-2-one-1-carbonyl chloride: 0-o-co-

To a mixture of imidazolidin-2-one-1-carbonyl chloride (7.1 parts by weight), tetrahydrofuran (50 parts by volume) and cyclohexanol (5.5 parts by weight) were added dropwise with stirring and ice-cooling triethylamine (5.8 parts by weight). then the mixture was stirred slowly overnight at room temperature, then boiled for a further hour and filtered hot apart from triethylamine hydrochloride. The filtrate was evaporated to dryness in vacuo, the residue was taken up in cyclohexane, the solid product was filtered off and dried for 3 days in a desiccator. Catch: 5.0 parts by weight.

This material (5.0 parts by weight) was then suspended in tetrahydrofuran, triethylamine (5.2 parts by volume) was added, the mixture was boiled, and a solution of trimethylchlorolanane (3.8 parts by weight) in tetrahydrofuran (10 parts by volume) was added dropwise. It was then boiled overnight and the insoluble material was then filtered off while hot. A solution of phosgene (2.6 parts by weight) in tetrahydrofuran (10 parts by volume) was slowly added to the filtrate at room temperature, and the mixture was allowed to stand at room temperature for 2 hours. The precipitate formed (mostly triethyl arai hydrochloride) was filtered off and the filtrate was evaporated to dryness in vacuo. The crystalline residue was dried in a desiccator. The carbonyl region (Nujol) of the IR spectrum of the substance has a wide absorption point between 1680 and 1820 cm. It was reacted in this form with ampicillin.

52 56839

Example 19

Sodium D (p - [(3-ethanesulfonylimidazolidin-2-on-1-yl) carbonylamino] -benzylpenicillin:

CH-SO-N N-CO-NH-CH-CO-NH ____ / \ / J

25 _ / I I / ^ CH

o COONa This penicillin was prepared as described in Example 15 from ampicillin (9.1 * parts by weight) and 3-ethanesulfonylimidazolidin-2-one-1-carbonyl chloride (5 * 0 parts by weight).

Catch: 5.7 parts by weight.

^ -lact Aarni content: Ö9 »l%

Penicillin contains about 3 * 3% sodium 2-ethylhexanoate and 6.7% water. This was taken into account in the calculated values of the analysis figures.

calculated: C U3.2 H 5.1 N 11.0 S 10.0 found: C 1 * 3.3 H 5.8 N 10.8 S 9.9 3-Ethanesulfonyl-imidazolidin-2-one-1-one carbonyl chloride: s'co \

c2h5-s ° 2-b H-C

N-Ethanesulfonyl-imidazolidin-2-one:

A mixture of imidazolidin-2-one (21.5 parts by weight) and ethanesulfonic acid chloride (32.5 parts by weight) was heated for 1 hour in a bath at 150-180 ° C. The development of HCl had by then largely ceased. The reaction product was then boiled in a water bath successively twice with benzene, acetone and ethyl acetate, pouring the extracts apart after each time. The combined extracts were evaporated to dryness in vacuo and the residue was recrystallized once from ethyl acetate and once from acetone (with the addition of carbon powder). Catch 8.1 parts by weight. Melting point: 11 ° C.

The N-ethanesulfonylimidazolidin-2-one was then suspended in dichloromethane, to which a large excess of phosgene was introduced at 0 ° C, some pyridine was added and the mixture was allowed to stand overnight. Thereafter, most of the 53,56839 excess reagent used was removed by introducing dry air into the vessel and the product was slurried in dichloromethane and filtered off. Melting point: 17 * t ° C. calculated: C 30.0 H 3.8 Cl 1, 8 N 11.6 S 13.3 found: C 30.1 H 3.8 Cl 1U, 7 N 11.8 S 13.3.

Example 20 A) Sodium D-o (- [[2-oxo-3-propionyl-1-imidazolidinyl) carbonylamino] benzylpenicillin:

a. 0 .e CH

CH »CH-CO-N N-CONH-CH-CONH-jf, ^ n3 w, ΡνΛ COOKa This penicillin was prepared as described in Example 1A from 9 parts by weight of 1-chlorocarbonyl-2-oxo-3-propionylimidazolidine and 17 .5 parts by weight of ampicillin.

Yield: 38% β-lactam content: 89% calculated: (taken into account water content 2%) i C 50.1 H 5.0 N 12.7 S 5.8 obtained: C 1 + 9.8 H 6.3 N 12.7 S 5.6.

IR peaks at 3290, 170, 1732, 1670, 1603, 1525 and 1250 cm -1 (in Nujol).

NMR signals δ 2.3-2.8 (5H), U, 35 (1H), U, 5 (2H), 5.8 (1H), 6.0-6.3 (UH), 7.1 (1H), 8, U (3H), 8.5 (3H) and 8.8 ppm (3H).

5l * 56839 Β) 1-Chlorocarbonyl-2-oxo-3-propionyl-imidazolidine:

O

X

CH0CH -CO-N N-COCl 3 2 w

A mixture of 12 parts by weight of 1-propianyl-2-oxoimidazolidine, 18.5 parts by weight of trimethylchlorosilane, 15.1 parts by weight of triethylamine and 80 parts by volume of toluene was boiled under stirring overnight and, after cooling, the precipitate was filtered off and filtered off. washed with toluene. To the combined solutions was added 9 parts by weight of phosgene, allowed to stand overnight, evaporated to dryness in vacuo and the residue dried using an oil pump. The product was reacted in this form with ampleillin (Example 20 A).

IR peaks at 1822, 1770-1680, 1385 and 1280-1210 cm-1.

C) 1-Propionyl-2-oxo-imidazolidine: 0

CH-CH CON NH

3 2 w This material was prepared as described in Example 1 C from 17.2 parts by weight of 2-oxoimidazolidine and 20, k parts by weight of propionic acid chloride.

Sp. = 147 ° C (from chloroform).

Yield: U5% calculated: C 50.7 H 7.0 N 19.7 obtained: C> 9.2 H 7.1 N 20.2 IR peaks at 32Uo, 1760-1736, 1678 and 1280 cm-1.

NMR signals 3.8 (1H), 6.1 (2H), 6 (2H), 7.1 (2H) and 8.8 ppm (in CDCl 3) (3H).

Example 21

Sodium D- (N, N-oxo-3-benzenesulfonyl-1-imidazolidinyl) carbonylamino-benzylpenicillin: Λ 9 (N) -SO 2 -N-N-CO-NH-CH-CONH 3 COONa 55 56839 This penicillin was prepared as described in Example 1A from 5 parts by weight of 1-chlorocarbonyl-2-oxo-3-benzenesulfonylimidazolidine and 7.5 parts by weight of ampicillin.

Yield: 9h% β-lactam content: 95% calculated (observed water content 3.5%) · C 1 * 8.0 H 1 *, 1 * M 10.8 S 9.9 obtained: C 1 + 8.1 H 1 *, 6 II 10.9 S 10.5.

IR peaks at 3300, 1770, 17 ^ 0, 1680, 1610, 1530, 1260, 1181 * and 1136 cm -1 NMR signals = 1.8-2.1 (2H), 2.2-2.8 ( 8 H), 1 *, 1 * (1H), 1 *, 5 (2 H), 5.8 (1H), 6.15 (1 * H), 8.1 * 5 (3 H) and 8.5 ppm (3H).

B) 1-Chlorocarbonyl-2-oxo-3-benzenesulfonyl-imidazolidine: A mixture of 0 (f X) -SO -N-N-COCl W-0 ° C with 80 parts by weight of 1-benzenesulfonyl-2- oxoimidazolidine, 69 parts by weight of phosgene, 31.6 parts by weight of pyridine and 350 parts by volume of dichloromethane were stirred overnight at room temperature and then evaporated to dryness. The residue was then slurried in 500 volumes of ice water, filtered, the residue dissolved in 500 volumes of dichloromethane, dried over MgSO 4, filtered, the solution re-evaporated to dryness and recrystallised from acetone / petroleum ether. Sp. = 161 ° C.

Yield: 61 *% calculated: C 1 + 1.6 H 3.5 Cl 12.3 N 9.7 S 11.1 obtained: C 1 + 1.6 H 3.0 Cl 12.2 N 9.7 S 10.7 IR peaks at 1802, 1732, 1318 and 1200 cm -1 (in Nujol).

NMR signals = 1.8-2.1 (2H), 2.1-2.5 (3H) and 5.7-6.1 ppm (UH).

C) 1-Benzenesulfonyl-2-oxo-imidazolidine: «k

(f SO -N NH

2W

A mixture of 86 parts by weight of 2-oxoimidazolidine, 19 I * parts by weight of benzenesulphochloride, 800 parts by volume of tetrahydrofuran, 500 parts by volume of chloro-formulation and 101 parts by weight of triethylamine was stirred overnight at 50 ° C and evaporated. after drying under vacuum. The residue was gradually added with stirring to 1,000 volumes of ice water, filtered and the residue was recrystallized from ethanol. Sp. = 155 ° C. Yield: 35% · calculated: C 1 + 7.7 H UN 12.1 * S 1U, 2 obtained: C 1 + 7.8 H 1 +, 5 N 12.2 S 1U, 3 IR peaks at 3280, 17 ^ 0, 1700, 1280, 1178, 1095 and 1060 cm-1 (in Nujol).

NMR signals λmax 1.8-2.6 (6h), 6.1 (2H) and 6.7 ppm (2H) (in DMSO-d 6).

Example 22 A) Sodium D-c - (- (3- (methylsulfonylaminocarbonyl) imidazolidinon-2-yl-1-7-carbonylamino) benzylpenicillin:

<R> /.S

CH -SCL-MH-CO-N H-CO-NH-CH-CO-HHt-f. “3

w rS

This penicillin was prepared as described in Example 15 from 10.0 parts by weight of ampicillin and 5 to 9 parts by weight of 3- (methylsulfonylaminocarbonyl) -1-chlorocarbonylimidazolidinone (2).

Yield: 9.8 parts by weight β-lactam content: 82% NMR signals 'S' = 2.1 + -2.8 (5H), i +, 3-U, 65 (3H), 5.8 (1H) , 6.05-6.1 + 5 (Uh), 6.95 (3H) and 8.35-8.75 ppm (6h).

calculated (taking into account 5.8 JS sodium 2-ethylhexanoate content and 10% water content): C i + 0.1 H 5.2 N 11.7 S 8.9 obtained: C 1 + 0.1 + H 5, 2 N 11.7 S 8.8

Electrophoresis of penicillin yielded only one spot, (microbiological evaluation, subtilis bacterium).

56839 57 B) 1- (methylsulfonylaminocarbonyl) -3-chlorocarbonylimidazolidone- (2): CH3? -imidazolidino- (2) was dissolved or suspended in 50 volumes of tetrahydrofuran, 5.7 parts by weight of methanesulfonyl isocyanate were added, and the mixture was first stirred for 26 hours at room temperature. Since virtually no reaction had taken place, 5 drops of pyridine were added and stirring was continued for a further 65 hours at room temperature. The crystalline precipitate was then filtered off.

Yield: 10.5 parts by weight Sp. = 218-220 ° C.

Calculated: C 26.7 H 3.0 Cl 13.1 N 15.6 S 11.9 Found: C 27.2 H 3.2 Cl 12.8 N 15.5 S 11.9 NMR signals *? * = 5.8-6.2 (multipl.) (1+ H) and 6.7 ppm (3 H).

IR spectra: 1800 and 1730 cm -1 (C = O).

Example 23 A) Hatrium D-N- - (3-methylsulfonyl-U- or 5-methyl-imidazolidin-2-on-yl-1-) carbonylamino-7-benzylpenicillin:

/ CQS. (R) CE

CH -SO -N N-CO-NH-CH-CO-NH-i-f X> n3

y a7X> X

This penicillin was prepared as described in Example 15 from 12.0 parts by weight of ampicillin and 7.7 parts by weight of 1-methylsulfonyl-3-chlorocarbonyl-U- or 5-methylimidazolidin-2-one.

Catch: 9.3 parts by weight. OF

Β-lactam content: 9 * +% calculated: (1.33 moles of H 2 O): C 1 * 1 *, 0 H 1 », 8 N 11.7 S 10.7 obtained: C UU, 0 H 5.0 N 11, US 10.6

Specific rotation: + 135.9 ° (methanol-water) MMR signals 2.3-2.65 (5H), U, 25-6.6 (3H), 5.75 (1H), 5.8 -6, U (3 H), 6.6 (3 H), 8.3-8.5 (6 H) and 8.6-8.8 ppm (3 H).

B) 1-Methylsulfonyl-3-chlorocarbonyl-U- or -5-methylimidazolidin-2-one: v 1 · 58 56839

CHo-SO-N N-C

3 .mu.l of CH313.U parts by weight of 1-methanesulfonyl-U- or 5-imidazolidin-2-one were added to a solution of 15.0 parts by weight of phosgene in 60 parts by volume of dichloromethane and 0 ° C: 6.1 parts by volume of pyridine were added dropwise. The mixture was then allowed to stand overnight at room temperature, the phosgene was removed from the mixture by a stream of dry air, and then the solution was evaporated to dryness in vacuo. The oily residue was dried in a desiccator over PgO 2.

Yield: 27 parts by weight of IR peaks in the carmonyl region: 10000, 1760 and 1720 cm-1.

C) 1-Methanesulfonyl-h- or -5-methyl-imidazolidin-2-one / CO 2.

CH - SO - N NH

V

CH3

A mixture of 53.8 parts by weight of U-methylimidazolidin-2-one and 6 kg of 6 parts by weight of methanesulfonic acid chloride was heated in a bath at 90 ° C until the evolution of HCl was complete (about 7 hours). The obtained crude product (yield 3U, 2 parts by weight) melted at 131-133 ° C. Recrystallization from water with a water bath gives a product with a melting point of 135 ° C.

Calculated: C 33.7 H 5.7 N 15.7 S 18.0 Found: C 33.5 H 5.5 N 15.3 S 18.2 MR signals f - 5.9-6.7 (multipl .) (3H), 6.75 (3H) and 8.65 8.75 ppm (3H) (dubl.).

D) Methylimidazolidin-2-one:

C/O

/ N

HN NH

This compound was obtained by heating in an autoclave at 180 ° C for 10 hours a mixture of 383 parts by weight of 1,2-diaminopropane and 611 parts by weight of carbonic acid diethyl ester and recrystallizing from isopropanol and methanol.

Catch 109 parts by weight. Sp. 130 ° C.

59 56839

Example 2h A) Sodium D-Q (- (N- (thienyl- (2) -sulfonyl) -imidazolidin-2-on-1-ylcarbonylamino) -7-benzylpenicillin: O

(R) CH

SCL-N N-CONH-C H-C ONH-Γ X v 3 'w 0- + V- This penicillin was prepared as described in Example 1A i.

3.3 parts by weight of 1-chlorocarbonyl-2-oxo-3- (thienyl- (2) -sulfonyl) -imidazolidine and 5.0 parts by weight of ampicillin.

Yield 89% β-lactam content: 83% calculated (water content taken into account in calculating the analytical values 6, ¾% and sodium 2-ethylhexanoate content 2.1%): C 1 + 3, ¾ H 1 +,! + N 10 , 2 S 11 +, 1 obtained: C 1 + 3.7 H 1 +, 2 N 10.0 S 11 +, 1.

IR peaks at 3320, 171 + 2, 1680, 1610, 1530, 1258 and 1188 cm -1. IMR signals = 2.0-2.2 (2H), 2.1 + -2.9 (6h), 1 +, 1 + (1H), »+, 5 (2H), 5.8 (1H), 6.2 (UH), 8.1 + 5 (3H) and 8.5 ppm (3H).

B) 1-Chlorocarbonyl-2-oxo-3- (thienyl- (2) -sulfonyl) -imidazolidine:

/ Γ \ κ A

This carbamic acid chloride was prepared as described in Example 21B from 2.9 parts by weight of 1- (thienyl- (2) -sulfonyl) -2-oxoimidazolidine and 2.7 parts by weight of part of phosgene. Yield: 80%, m.p. = 166 ° C, IR peaks at 3080, 1800, 1728, 1300 and 1178 cm -1 (in Nujol).

6ο S6839 C) 1- (Thienyl (2) -sulfonyl) -2-oxo-imidazolidine: 0

^ X

//% -SO -N NH

V \ _ /

A mixture of 1¾ parts by weight of 2-chlorosulfonylthiophene and 6.6 parts by weight of imidazolidone-2 was heated with stirring at 150 ° C until the evolution of HCl was complete (about k hours). It was then cooled, shaken with 150 volumes of chloroform / water (2: 1), the chloroform layer separated, dried over MgSO 4, boiled with charcoal, filtered and evaporated to dryness. The residue was recrystallized from acetone.

Hall: 20.2 ί, sp. = 171 ° C.

calculated: C 36.1 H 3.5 »12.0 S 27.5 obtained: C 35» 8 H 3.5 N 11.9 S 27.5 IR peaks at 3230, 3080, 1738, 1705, 1172 and 1062 cm-1 (in Nujol).

NMR signals λ: 2.1-2, ¾ +2 H), 2.8-3.0 (11 H), U, 0 (1H), 5.9-6.2 (2 H) and δ , 3-6.7 ppm (2H) (in CDCl 3).

D) 2-Chlorosulfonyl-thiophene: <> - SO2cl

The compound was obtained according to the instructions for the preparation of methylthiophene sulfochloride (disclosed in J. Org. Chem. 33, 1357 (1968)), thiophene, chlorosulfonic acid and PCl 2 in Saudi Arabia as a low melting solid. Kpg »117 ° C.

Calculated: C 26.3 H 1.6 Cl 19, ¾ S 35.0

Found: C 25.9 H 2.6 Cl 19, ¾ S 3¾, 2 IR peaks at 3110, 1196, 1032 and 7 cm -1 NMR signals λ = 2.08 (2 H) and 2.75 ppm (l H).

Example 25 A) Sodium D-β - (- [2-oxo-3-acetyl-1,3-diazacyclohex-1-yl) -carbonylamino] -benzylpenicillin: 56839 6ι o

JL (R) s CH

CH.CO-N N-CONH-CH-CONH / [6 COONa This penicillin was prepared as described in Example 1A from 7.6 parts by weight of 1-chlorocarbonyl-2-oxo-3-acetyl-1,3-diazate. cyclohexane and 16.5 parts by weight of Ample Ulin *.

Yield: 93% β-lactam content: 91 »% calculated (water content taken into account when calculating 6%): C 1 * 8.1 H 5.2 N 12.2 S 5.5 obtained: C 1 * 8.0 H 5.5 N 12.2 S 6.2.

IR peaks at 3250, 1772, 1700, 1615, 1520, 1305 and 1180 cm -1. NMR signals »2.3-2.8 (5 H), U, U (1H), 1 *, 5 ( 2 H), 5.8 (1H), 6.0-6.1 »(UH), 7.5 (3 H), 7.8-8.3 (2 H), 8.1» (3 H) and 8.5 ppm (3H).

B) 1-Chlorocarbonyl-2-oxo-3-acetyl-1,3-diazacyclohexane: This carbamic acid chloride was prepared as described in Example 21B from 7.1 parts by weight of 1-acetyl-2-oxo-1,3-diazacyclohexane. cyclohexane and 10 parts by weight of phosgene. Oil.

Catch: 89% ·

Calculated: C Ul, l H U, U Cl 17.1 »N 13.7

Found: C 1 * 1.1 H U, 5 Cl 17.1 N 13.3.

IR peaks at 2950, 1800, 1730, 1706, 11 * 00, 1376, 1320, 1295, 1202, 1178 and 1051 * cm -1.

WMR signals = 5.9-6.3 (1 * H), 7.1 * 5 (3 H) and 7.65-8.15 ppm (2 L).

62 56839 C) 1-Acetyl-2-oxo-1,3-diazacyclohexane: 0 Λ

CH-CO-N NH

A mixture of 10 parts by weight of 1,3-diazacyclohexan-2-one, 11.8 parts by weight of acetyl chloride, 8.7 parts by weight of pyridine, 50 parts by volume of tetrahydrofuran and 50 parts by volume of chloroform was stirred at room temperature for 2 hours. , filtered and washed with tetrahydrofuran / chloroform (1: 1). The combined solutions were evaporated to dryness, recrystallized from acetone / ethanol, 50 parts by volume of half-saturated NaHCO 3 solution were added and extracted three times with 50 parts by volume of ethyl acetate. The extracts dried over MgSO 4 were evaporated to dryness; the residue was recrystallized from acetone / petroleum ether.

Yield: 53%. Sp. = 132 ° C.

Calculated: C 50.7 H 7.0 N 19.7

Found: C 50.5 H 7.1 N 20.1.

IR peaks at 33 ^ 5, 1708, 166U, 1320, 1281, 1250, 1175, 1130 and 1022 cm -1 (in Nujol) NMR signals 6.1-6.1 * (2H), 6.6 -6.85 (2H), 7.5 (3H) and 7.8-8.3 ppm (2H) (in CD 2 O).

Example 26 A) Sodium N, N-formyl-1,3-diazacyclohexan-2-on-1-yl) carbonyl-Amino-N-benzylpenicillin: 1 »

HC0-N N-CONH-CH-CONH. .S

kk J

O 0 ^ Υ ^ 0Η3 COONa This penicillin was prepared as described in Example 1A from 8.1 parts by weight of 1-chlorocarbonyl-2-oxo-3-formyl-1,3-diazacyclohexane and 18.9 parts by weight of ampieillin.

Yield: 1 * 1% β-lactam content: 9 *%.

63 56839

Calculated (water content 3% was taken into account in the calculation): C 1 * 8.7 H 1 *, 8 N 12.9 S 5.9

Found: C 1 * 8.1 * H 5.1 * N 11.3 S 6.5 IR peaks at 3270, 1765, 1700, 1675, 1603, 1310 and 1183 cm -1.

NMR signals * Γ = 0.6 (1H), 2.3-2.8 (5H), U, U (1H), 1 », 5 (2H), 5.8 (1H) , 6.0-6.5 (UH), 7.75 (2H), 8, U (3 II) and 8.5 ppm (3 H).

B) 1-Chlorocarbonyl-2-oxo-3'-formyl-1,3-diazacyclohexane: O HCO-H 2 O · N-COCl 3 This carbamic acid chloride was prepared as described in Example 21B from 5 parts by weight of 1-fornyl. -2-oxo-1,3-diazacyclohexane and 6 parts by weight of phosgene. The oil thus formed was reacted, as described in Example 26A, immediately with ampleillin.

IR peaks at 1790, 1685, 1300 and 1165 cm -1.

C) 1-Formyl-2-oxo-1,3-diazacyclohexane: 0 k / *

A mixture of 10 parts by weight of 1,3-diatea-cyclohexan-2-one, 1 to 9 parts by weight of trimethylchlorosilane, 25 parts by weight of triethylamine and 150 parts by volume of dioxane was boiled under stirring and protected from moisture for 3 days, followed by filtration, was concentrated to 50 parts by volume in vacuo and mixed with 11.5 parts by weight of formic acid-anhydride at room temperature overnight. The mixture was evaporated to dryness in vacuo and the residue was recrystallized from ethanol / ether.

Yield: kO%. Sp. = 100 ° C.

Calculated: C 1 + 6.9 H 6.9 N 21.9

Found: C 1 * 6.7 H 6.3 N 22.0.

IR peaks at 3250, 3120, 1690, 1312 and 1166 cm-1 (in Nujol).

611 56839

Example 27 A) Sodium D - N - (C3-mesyl-1,3-diazacyclohexan-2-on-1-yl) carbonylamino] benzylpenicillin:

O

JL <r> s CH3SO2-N N-COHH-CH-CONH Λ / CH3

^ 6 XOX

COONa This penicillin was prepared as described in Example 1A from 5.6 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-1,3-diazacyclohexane and 10 parts by weight of ampoule.

Yield: 52% γ-lactam content: 9U% ·

Calculated (The analytical values were calculated taking into account a water content of 2.9% and a sodium content of 2-ethylhexanoate of 2.9%): C Uit, 8 HU, 8 N 11, US 10, U Found: C UU, 9 H 5.1 N 11 .0 S 10.3.

IR peaks at 3300, 1765, 1705-1665, 1605, 1515, 13U5 and 116U cm-1. NMR signals T = 2.3-2.8 (5 H), U, U (1H), U, 5 (2 H), 5.0 (1H), 6.0-6.U

(U H), 6.6 (3 H), 7.7-0.3 (2 H), 8, U (3 H) and 8.5 ppm (3H).

B) 1-Chlorocarbonyl-2-oxo-3-mesyl-1,3-diazacyclohexane: CH 2 SO-H N-COCl This carbamic acid chloride was prepared as described in Example UB from 5 parts by weight of 1-mesyl-2-oxo- 1,3-diazacyclohexane, 6.9 parts by weight of trimethylchlorosilane and 5.2 parts by weight of phosgene. The oily crude product was used as such in a reaction with ampicillin (Example 27 A).

Yield: 83% · IR peaks at 2980, 2950, 1790, 1760-1680, IU72, 1355, 1215, 1162, 982 and '855 cm-1.

65 S6839 C) 1-Mesyl-2-oxo-1,3-diaza-cyclohexane: 0 Λ

CH_SO -N NH

This compound was prepared as described in Example 26 C from 10 parts by weight of 1,3-diazacyclohexan-2-one, 9 parts by weight of trimethylchloro-ylane and 30 parts by weight of mesyl chloride. The yield of product recrystallized from acetone and then acetone / ethanol at low temperature was 3%. Sp. = 172 ° C.

IR peaks at 3210, 3070, 1692, 13 ^ 0 and 1170 cm-1. (Nujol'issa). NMR signals T = 6.25 (2H), 6.5-6.8 (2H), 6.7 (3H) and 7.8-0.3 ppm (2H) in CD 2 D ).

Calculated: C 33.7 H 5.6 N 15.8 S 18.0 Found: C 33, U H 5.7 N 15.6 S 17.3.

Example 28 A) Disodium D-o-N- (3-phenylsulfonyl-1,3'-diazacyclohexan-2-on-1-yl) carbonylamino] benzylpenicillin: O

/ = \ 1 (R) S

<„,) - 30 -ΓΓ N-CONH-CH-CONH / \, CH

COONa This penicillin was prepared as described in Example 1A from 2.6 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenylsulfonyl-1,3-diazacyclohexane and 3.8 parts by weight of ampicillin.

Hall: 82 1.

γ-lactam content: 85%.

IR peaks at 3300, 1770, 1695, 1610, 1520 and 1180 cm-1.

NMR signals T- 1.9-2.1 (2H), 2.3-2.6 (3H), 2.6 (5H), U, 5U (II), kt6 (2H) , 5.65 (1H), 5.9-6.5 (1H), 7.8-8.25 (2H), 8.1-7 (3H) and 8.52 ppm (3H). B).

B) 1-Chlorocarbonyl-2-oxo-3-phenylsulfonyl-1,3-diazacyclohexane: O-SO 2-^ S-COC 66 56839 This carbamic acid chloride was prepared as described in Example 21B from 6 parts by weight of 1-phenylsulfonyl-2 -oxo-1,3-diazacyclohexane and 5 parts by weight of phosgene. The product recrystallized from acetone / petroleum ether, m.p. was = 123 ° C, yield was 35% · IR peaks at 3350, 1790, 1692 and 1162 cm -1 (in Nujol).

C) 1-Phenylsulfonyl-2-oxo-1,3-diazacyclohexane: 0

, —V I

(f H —- SO0 "N

W- *

To a stirred mixture of 10 parts by weight of 1,3-diazacyclohexan-2-one, 80 parts by volume of tetrahydrofuran and 80 parts by volume of chloroform were added dropwise over 15 minutes at 10-15 ° C 20 U parts by weight of benzenesulfonic acid chloride dissolved in 20 parts by volume of tetrahydrofuran , and then at the same temperature 10.1 parts by weight of triethylamine. Stirred for 30 minutes at 10-15 ° C and then overnight at 50 ° C. It was then evaporated to dryness, the residue was taken up in 100 volumes of water, filtered, slurried once more in water, filtered and washed with ethanol.

Yield: 29%. Sp. = 207 ° C.

Calculated: C 50.0 H 5.0 N 11.7 S 13.3

Found: C 1 + 9.0 H 5.0 N 11.7 S 12.5 IR peaks at 3320, 1665, 13 ^ 8, 1300 and 1175 cm -1 (in Nujol).

HMR signals 1.8-2.2 (2H), 2.3-2.7 (3H), 6.0 (2H), 6.7 (2H) and 8.0 ppm (2H) ) (In CDCl 3).

Example 29

Sodium D-no * [3- [3-methylsulfonylimidazolidinon- (2) -yl-1 -) - carbonylamine] -7.1'-cyclohexadien-yl-1-methylpenicillin: SO-N-N-CO-NH-CH-CO-NH _ / \ / ° H3

k-k A

^ 11 X COONa 61 56839 This penicillin was prepared as described in Example 15 from 2.5 parts by weight of D-α-amino-1,4-cyclohexadien-1-methyl-penicillin and 1.6 parts by weight of 1-methylsulfonyl-3 -kloorikarbonyy-li-imidazolidinone (2) copies.

Catch: 2.6 parts by weight.

β-lactam content: 87%.

NMR signals T = 4.0 (1H), 4.3 (2H), 4.4 (2H), 4.0 (1H), 5.8 (1H), 6.0 (4H) ), 6.6 (3 H), 7.2 (4 H) and 8.2-8.4 ppm (6 H).

Example 30 Do * · / (2-Oxo-3-phenylsulfonyl-imidazolidin-1-yl) -carbonylamino] -p-hydroxy-Benzyl-penicillin-sodium: O (R) 5 - SO 2 N-CONH-CH-CONH -1- (V, CH 3 ^ w φ

OH

This penicillin was prepared from 0.69 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenylsulfonylimidazolidine and 1.0 part by weight of D-OC amino-p-hydroxybenzylpenicillin as described in Example IA. 60% in the hall.

Penicillin content by NMR and IR spectra: 82%.

IR peaks at 3325, 1770, 1735, 1673, 1605, 1660-1510, 1258, 1184, 1134 and 768 cm-1 (in nujol).

NMR signals 1.8-2.05 (2H), 2.2-2.6 (3H), 2.8 (2H), 3.25 (2H), 4.6 (3H), 5.85 ( 1H), 6.15 (4H), 8.45 (3H) and 8.5 ppm (3H).

According to the NMR spectrum, the product contains 9% sodium 2-ethylhexanoate, 7% water and 2% ether.

Example 31 D-6ft-Z '(2-Oxo-3-methylsulfonyl-imidazolidin-1-yl) -carbonylamino} -p-hydroxy-benzylpenicillin sodium: Λ ου ^ CH3-SO2-N N-CO-NH- CH-CO-NH-j-1 \ / CH3 A, I 1_ ^ ch3 | J 0 \ 00Na

OH

68 56839 This penicillin was prepared from 1.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylsulfonylimidazolidine and 2.5 parts by weight of D-o-amino-p-hydroxybenzylpenicillin as described in Example 15. Catch: 1.3 parts by weight.

Β-lactam content: 86% IR peaks in the carbonyl region at 1770, 1730-40, 1650-80, 1580-1610 and 1520-1560 cm-1 (in nujol).

Efficacy against E. coli 14: 2-4 D / ml Efficacy against Klebsiella K 10: 32-64 U / ml Efficacy against Klebsiella 63: 32-64 U / ml Example 32 DW- / 2-oxo-3-ethylsulfonylimidazolidine -1-yl) -carbonyl-amino-β-hydroxy-benzylpenicillin sodium: 0 <R> s C, H.-SO, -N N-CO-NH-CH-CO-NH-i- \, CH3 w A, J3_>.

C00Na%

V

OH

This penicillin was prepared from 0.9 parts by weight of 1-chlorocarbonyl-2-oxo-3-ethylsulfonylimidazolidine and 1.5 parts by weight of D - N - amino-p-hydroxybenzylpenicillin as described in Example 15.

Yield: 1.6 parts by weight -actam content: 85%

Calculated (water content taken into account): C 40.5 H 5.1 N 10.7 S 9.8 Found: C 40.8 H 5.1 N 10.3 S 9.5 NMR signal tr = 2.7 (2H) , 3.2 <2H), 4.4-4.6 (3H), 5.8 (1H), 6.1 (4H), 6.3-6.6 (2H) and 8.3-8, 7ppm (9H).

IR peaks in the carbonyl region at 1770, 1740, 1680, 1610 and. 1525-60 cm * (in nujol).

69 56839

Example 55.

D-Of - ["(2-Oxo-3-ethylsulfonyl-imidazolidin-1-yl) -carbonyl-amino] -1,4-cyclohexadien-yl-1-methyl-penicillin: A (R) C2H5-SO2-M N-CO-NH-CH-CO-NH -, - ✓SN ^ CHj w rA / -Lo® »LJ COONa This penicillin was prepared from 1.0 part by weight of 1-chlorocarbonyl-2-oxoethylsulfonylimidazolidine and 1, 5 parts by weight of D-Of-amino-1,4-cyclohexadienyl-1-methylpenicillin as described in Example 15.

Yield: 2.0 parts by weight β-lactam content: 56% NMR signals T = 4.0 (1H), 4.2 (2H), 4.4 (2H), 4.9 (1H), 5.7 ( 1H), 6.0 (4H), 6, 2-6.5 (2H), 7.2 (4H), 8.3-8.4 (6H), and 8.45-8.65 ppm (3H ).

Example 34 AQ y CH3-NHSO2N NCONH-CH-CONH — If \ xh3 w <*> J_n-0: h3 0 COONa This penicillin was prepared as described in Example 1 from 4.5 parts by weight of ampicillin trihydrate and 2.7 parts by weight 1-Chloro carbonyl-2-oxo-3-methylaminosulfonyl-imidazolidine.

Yield: 2.0 parts by weight of D-c * - [(2-oxo-3-methylaminosulfonylimidazolidin-1-yl) carbonylamino] -benzylpenicillin sodium.

IR peaks at 3220, 1760, 1715, 1660, 1600, 1508, 1375, 1250, 1175, 1124 and 1090 cm-1 (in nujol) NMR signaltr δ 2.3-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.85 (1H), 6.15 (4H), 7.25 (3H), 8.45 (3H) and 8.5 ppm (3H) (in CD 3 OD) ).

X

CH, NHSO 2 NCNCl 7.0 parts by weight of 1-methylaminosulfonylimidazolidone-2 were dissolved in 70 parts by volume of methylene chloride, and 4 parts by weight of phosgene in 15 parts by volume of methylene chloride were added dropwise with stirring at 10 ° C. Thereafter, 3.15 parts by weight of pyridine was added dropwise, and 70,56839 was gradually stirred for 30 minutes at 10 ° C and 4 hours at room temperature. Evaporated to dryness, redissolved in methylene chloride, shaken with water, dried over MgSO 4, evaporated to dryness and recrystallized from benzene.

Yield: 3.8 parts by weight of 1-chlorocarbonyl-2-oxo-3-methylaminosulfonylimidazolidine.

IR peaks at 1790, 1712 and 1160 cm -1 (in Nujol).

0

A

CH, NH-SO 2 NH

W

To 8.6 parts by weight of imidazolidone-2 in 70 parts by weight of acetonitrile was added dropwise over 30 minutes 13 parts by weight of N-chlorosulfonylmethylamine (Weiss u. Schulze, Ann. 729, MO (1969)) at 10 ° C. with stirring. Stirred for 30 minutes at 10 ° C and 60 minutes at 50 ° C, evaporated to dryness in vacuo and the residue recrystallized from acetone. Sp. = 184 ° C.

Yield: 7.8 parts by weight of 1-methylaminosulfonyl-2-oxoimidazolidine. Calculated: C 26.8 H 5.0 N 23.2 S 17.9 Found: C 27.0 H 5.1 N 23.3 S 17.6 IR peaks at 3240, 1708, 1350, 1264, 1170 and 1080 cm 1 (in Nujol). Example 55

A Q

H 2 NNSO 2 N 2 NCO NH-CH-CONH-β-CH 2 (R) -N-CH 2 COONa This penicillin was prepared as described in Example 1 from 4.0 parts by weight of ampicillin trihydrate and 2.3 parts by weight of 1-chlorocarbonyl. -2-oxo-3-aminosulfonyl-imidazolidine.

Yield: 3.5 parts by weight of D - <* - / (2-oxo-3-aminosulfonylimidazolidin-1-yl) carbonylamino] -benzylpenicillin IR peaks at 3250, 1765, 1715, 1655, 1505, 1370 and 1255 cm -1 (in Nujol).

NMR signals T = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.2 (4H), 8.4 (3H) and 8.5 ppm (3H) (in CD 3 OD).

1-Chlorocarbonyl-2-oxo-3-aminosulfonyl-imidazolidine was prepared as described in Example 3¾ from 1-chlorocarbonyl-2-oxo-3-methylaminosulfonyl-imidazolidine from 1-aminosulfonyl-2-oxo-imidazolidine, 1-aminosulfonyl oxoimidazolidine was prepared as described in Example 34 from 1-methylaminosulfonyl-2-oxo-7i 56839 imidazolidine from imidazolidine-2 and amidosulfonic acid chloride. Example 36 This penicillin was prepared as described in Example 1 from 1.5 parts by weight of amoxicillin trihydrate and 0.86 parts by weight of 1-chloro. -rikarbonyyli-2-oxo-3-metyyliamiinisulfonyyli-imidazolidine.

Yield: 1.3 parts by weight of D-o (- [(2-oxo-3-methylaminosulfonylimidazolidin-1-yl) carbonylamino] -p-hydroxy-benzylpenicillin sodium.

IR peaks at 3280, 1765, 1715, 1660, 1600, 1370, 1280 and 1175 cm-1 (in Nujol).

NMR signals T "= 2.7 (2H) 3.2 (2H), 4.5 (2H), 4.6 (1H), 5.8 (1H), 6.15 (4H), 7.2 (3H) , 8.4 (3H) and 8.5 ppm (3H) (in CH 2 OD).

Example 37

Λ V χ * CH

v_y <*> XT_A «3 σ COONa This penicillin was prepared as described in Example 1 from 1.5 parts by weight of D-O (-amino-o (^ (1,4-cyclohexadien-1-yl) methyl) penicillin and 1.03 parts by weight of part of 1-chlorocarbonyl-2-oxo-3-methylaminosulfonylimidazolidine.

Yield: 1.6 parts by weight of Do (- (2- (2-oxo-3-methylaminosulfonylimidazolidin-1-yl) carbonylamino) -o (- (1,4-cyclohexadien-1-yl) methyl). lipenisilliini-sodium.

IR peaks in the carbonyl zone at 1770, 1720, 1670 and 1610 cm-1 (in Nujol).

NMR signals T = 4.1 (1H), 4.2-4.5 (4H), 5.0 (1H), 5.7 (1H), 6.15 (4H), 7.2 (3H), δ , 3 (4H), 8.3 (3H) and 8.45 ppm (3H) (in CDgOD).

Example 38 A. D-Ot- (if (2-Oxo-3-ethylaminosulfonyl-imidazolidin-1-yl) -carbonylamino-7-benzylpenicillin sodium 72 S6839

X O

ch3ch2nh-so2n nconh-Ch-conh-jf \ yd N / (R) JN _ / ^ 0Η3 0 COONa This penicillin was prepared as described in Example IA from 23 parts by weight of ampicillin trihydrate and 14.5 parts by weight of 1-chlorocarbonyl-2 -oxo-3-ethylaminosulfonyl-imidateolidine in 91% yield. β-lactam content: 88%.

Calculated: C 44.7 H 4.6 N 14.2 S 10.8 Found: C 44.0 H 4.9 N 13.3 S 10.5 IR peaks at 3350, 3220, 1785, 1718, 1667, 1608, 1505, 1312, 1244, 1172, 1125 and 778 cm -1 (in Nujol).

NMR signals 2.3-2.8 (5H), 4.4 (1H), 4.54 (2H), 5.8 (1H), 6.15 (4H), 6.85 (2H), δ .45 (3H), 8.5 (3H) and 8.8 ppm C3H).

B. 1-Chlorocarbonyl-2-oxo-3-ethylaminosulfonyl-imidazolidine.

0 Λ.

CH-CH, NH-SO-N NCCO 3 3 2 2 \ uy This carbamic acid chloride was prepared from 1-ethylaminosulfonyl-2-oxoimidazolidine and phosgene in methylene chloride as described in Example 19. Recrystallization from benzene.

Yield = 91%.

Sp. 118 ° C.

Calculated: C 28.2 H 3.9 Cl 13.9 N 16.4 S 12.5 Found: C 28.5 H 4.0 Cl 14.4 N 16.3 S 12.6 C. 1-ethylaminosulfonyl- 2-oxoimidazolidine 0 A.

CH ~ CHONHSO «N NH

This product was prepared from equimolar amounts of imidazolidone-2 and N-chlorosulfonylethylamine in 50 ° C acetonitrile.

After chromatography on an Al 2 O 3 column, the product was obtained in analytical purity in 18% yield.

Sp. = 110 ° C.

Calculated: C 31.1 H 5.7 N 21.7 S 16.6 Found: C 31.0 H 5.6 N 21.7 S 16.6.

73 56839

Example 39 D - <* - E (2-Oxo-3-furoyl (2) -imidazolidin-1-yl) carbonylamino] -p-hydroxybenzylpenicillin sodium

OH

0 Hl

f \ _ sK Λ CH

Cy — CON NCONH-CH-CONH-iS \ / 3 '-1 (W J-1 - (^ Hj 0 COOMa This penicillin was prepared as described in Example IA from 2.5 parts by weight of amoxillin and 1.7 parts by weight of 1- chlorocarbonyl-2-oxo-3-furoyl (2) -imidazolidine in 84% yield.N-lactam content: 88%.

Calculated: (taking into account the NMR spectroscopically determined acetic acid, water and sodium 2-ethylhexanoate content) C 49.2 H 4.4 N 11.0 S 5.0 Found: C 48.4 H 5.3 N 11.0 S 5.2 IR peaks at 3400, 3300, 1770, 1722, 1680, 1650, 1600, 1500 1315, 1295 and 1240 cm-1 (in Nujol).

NMR signals δ = 2.2 (1H), 2.5 (1H), 2.65 (2H), 3.15 (2H), 3.33 (1H), 4.41 (1H), 4, 46 (2H), 5.8 (1H), 6.0 (4H), 8.33 (3H) and 8.4 ppm (3H).

Example 40 D-Of - [* (2-Oxo-3-furoyl (3) -imidazolidin-1-yl) carbonylamino] -benzylpenicillin sodium.

AP / s CON NCONH-CH-CONH —- f 3 <rC W (R) uS ™ »<fN” Ac00N This penicillin was prepared as described in Example IA from 4.03 parts by weight of ampicillin trihydrate and 2.43 parts by weight of 1-chlorocarbonyl 2-oxo-3-furoyl (3) -imidazolidine (prepared analogously to 1-chlorocarbonyl-2-oxo-3-furoyl (2) -imidazolidine as described in Example 13) in 74% yield.

Β-lactam content: 92%.

IR peaks at 3260, 1760, 1730, 1652, 1597, 1505, 1320, 1245, 1190, 1151, 1025 and 1003 cm-1 (in Nujol).

τ * S 6 θ 39 NMR signals = 1.83 (1H), 2.5-2.9 (6H), 3.26 (1H), 4.48 (1H) H, 63 (2H), δ , 91 (1H), 6.18 (1H), 8.48 (3H) and 8.54 ppm (3H).

Example 41 D-c (- [(2-Oxo-3-furoyl (3) -imidazolidin-1-yl) carbonylamino] -p-hydroxy-benzylpipicillin sodium.

. Λ

^ V> 3. CH

CON NCONH-CH-CONH— | -S H3 ^ (R> OJ - ^ (C} i3'O / COONa) This penicillin was prepared as described in Example IA from 1.5 parts by weight of amoxillin and 1.0 part by weight of 1-chlorocarbonyl - 2-oxo-3-furoyl (3) -imidazolidine in 86% yield. Β-lactam content: 90%.

IR peaks at 3290, 1760, 1730, 1650, 1595, 1498, 1322, 1247, 1192, 1156, 1003, 878 and 762-733 cm-1 (in Nujol). NMR signals δ = 1.7 (1H), 2.45 (1H), 2.7 (2H), 3.12 (1H), 3.2 (2H), 4.4-4.6 (3H), 5.83 (1H), 6.1 (4H), 8.42 (3H) and 8.48 ppm (3H).

Example 42 2-Oxo-3-furoyl (3) -imidazolidin-1-yl) carbonylamino-7-O - (- (cyclohexa-1,4-dien-1-yl) -methylpenicillin sodium.

0 AV / 3 zri \ -t <*> <A3 () ^ "A ™ 3 o COONa This penicillin was prepared as described in Example IA from 1.0 part by weight of <X-amino-af- (cyclohexa-1,4-diene). -1-yl) -methyl-penicillin and 0.7 parts by weight of 1-chlorocarbonyl-2-oxo-3-furoyl (3) -imidazolidine in 91% yield.

Β-Lactam content: 92%.

IR peaks at 3300, 3150, 1770, 1730, 1657, 1597, 1505, 1320, 1247, 1193, 1155, 1004, 957, 869 and 758-740 cm-1 (in Nujol).

75 56839 NMR signal δ = 1.7 (1H), 2.48 (1H), 3.16 (1H), 4.08 (1H), 4.3 (2H), 4.51 (2H), δ .0 (1H), 5.8 (1H), 6.08 (4H), 7.32 (4H), 8.36 (3H) and 8.46 ppm (3H).

Example 43 D-Ro- [2-Oxo-3- (isothiazol-4-ylcarbonyl) -imidazolidin-1-yl) -carbonylamino] -benzylpenicillin sodium.

A (R>.

cl w δ AA

S COONa This penicillin was prepared as described in Example IA from 1.61 parts by weight of ampicillin trihydrate and 0.92 parts by weight of 1-chlorocarbonyl-2-oxo-3- (isothiazol-4-ylcarbonyl) imidazolidine (prepared analogously to Example 1). -chlorocarbonyl-2-oxo-3-furoyl (2) -imidazolidine as described in Example 13) in 83% yield. Β-lactam content: 87%.

IR peaks at 330Q, 3150, 1770, 1730, 1657, 1597, 1505, 1320, 1247, 1193, 1155, 1004, 957, 869 and 750 cm -1 (in Nujol).

NMR signals T "= 0.5 (1H), 1.1 (1H), 2.35-2.85 (5H), 4.4 (1H), 4.55 (2H), 5.84 (1H) , 6.06 (4H), 8.43 (3H) and 8.5 ppm (3H).

Example 44 D-O- (2-Oxo-3- (isothiazol-4-ylcarbonyl) -imidazolidine-1-carbonylamino) -p-hydroxy-Benzylpenicillin sodium.

OH

q r'S

o CON NC0NH-CH-C0NH —- f V'yCH3 f \ W <R> J-'N - <> «3 \ / 0 COONa

S

This penicillin was prepared as described in Example IA from 1.5 parts by weight of amoxillin and 0.92 parts by weight of 1-chlorocarbonyl-2-oxo-3- (isothiazol-4-ylcarbonyl) imidazolidine in 81% strength. yield.

β-lactam content: 90%.

IR peaks at 3290, 1765, 1725, 1655, 1595, 1500, 1242 and 759-728 (in Nujol).

NMR signals C-0.53 (1H), 1.2 (1H), 2.7 (2H), 3.2 (2H), 4.49 (1H), 4.53 (2H), δ Δ (1H), 6.05 (4H), 8.4 (3H) and 8.48 ppm (3H).

Example 45 D-q ['- [(3-Cyclopropylcarbonylimidazolidin-2-one-1-yl) carbonylamino] -benzylpenicillin sodium.

76 56839

O

K <R> ^ c IY-CO-N N-CO-NH-CH-CO-NH-τ-f \ CH3 w ö COONa This penicillin was prepared as described in Example 15 from ampicillin (4.0 parts by weight) and 3- cyclopropylcarbonylimidazolidin-2-one-1-carbonyl chloride (2.16 parts by weight).

Yield: 4.4 parts by weight.

β-lactam content: 92%.

The substance contained 0.5 moles of H 2 O. This was taken into account in the calculated analytical values.

Calculated: C 51.4 H 4.8 N 12.5 S 5.7 Found: C 51.8 H 5.6 N 12.4 S 5.5 NMR signals 7 * s 2.3-2.8 ( 5H), 4.2-4.6 (3H), 5.8 (1H), (CDgOD) 6.0-6.4 (4H) and 8.2-8.7 ppm (6H).

Efficacy against E. coli Neumann strain: 2-4 Efficacy against Klebsiella K10 strain: 8-16 l-cyclopropylcarbonylimidazolidin-2-one: k Λ

> -CO-N NH

To a stirred mixture of imidazolidin-2-one (86 parts by weight), tetrahydrofuran (400 parts by volume), cyclopropanecarboxylic acid chloride (104.5 parts by weight) at 20 ° C was added dropwise triethylamine (101 parts by weight) over 2 hours. dissolved in 200 volumes of tetrahydrofuran. The mixture was then stirred for a further 18 hours at 20 ° C. Dilute with water, extract with ethyl acetate, wash the organic phase with water and recrystallize the residue obtained after extraction with ethyl acetate from ethyl acetate.

Yield: 80 parts by weight, m.p. = 155 ° C Calculated: C 54.6 H 6.5 N 18.2 0 20.8

Found: C 54.8 H 6.5 N 17.9 0 20.9 56839 77 3-Cyclopropylcarbonylimidazolidin-2-one-1-carbonyl chloride: K Jk .0 VCO-N N - v w \ C1

To a mixture of cyclopropylcarbonylimidazolidin-2-one (11.5 parts by weight) and dichloromethane (400 parts by volume) was added condensed phosgene (10.0 parts by weight). Triethylamine (8.0 parts by weight) diluted with a small amount of dichloromethane was then added dropwise at -10 ° C to 5 ° C. The mixture was then allowed to stand for 64 hours at 20 ° C. After all, everything was extracted, the residue was washed with ether and extracted with boiling cyclohexane (about 600 parts by volume) (triethylamine hydrochloride remained insoluble). The material crystallized from cooled cyclohexane. It was recrystallized from toluene / pentane. Yield: 4.6 parts by weight.

Sp. 107-109 ° C.

Calculated: C 44.4 H 4.2 Cl 16.4 N 12.9 Found: C 44.6 H 4.4 Cl 16.0 N 12.8.

Example 46 D- (N- (N-3-Cyclopropylcarbonylimidazolidin-2-one-1-yl) carbonylamino) -p-hydroxybenzylpenicillin sodium.

(R) ly CO-N N-CO-NH-CH-CO-NH-t-

w (S

COONa This penicillin was prepared as described in Example 15 from amoxillin (1.5 parts by weight) and 3-cyclopropylcarbonylimidazolidin-2-one-1-carbonyl chloride (0.77 parts by weight).

Yield: 1.8 parts by weight.

Β-lactam content: 90%.

IR peaks in the carbonyl region: 1755, 1725, 1650, 1680 and 1500 cm -1 (in Nujol).

NMR signals T = 2.7 (2H), 3.2 (2H), 4.3-4.7 (3H), 5.8 (1H), (CD 3 OD) 6.0-6.4 (4H) , 6.6-7.0 (1H), 8.3-8.7 (6H) and 8.8-9.2 ppm (4H).

τ8 56639

Example 47 D - <- E - (3-Cyclopropylcarbonylimidazolidin-2-one-1-yl) carbonylamino [7- (1,4-cyclohexadien-1-yl) methyl] penicillin sodium, | R) / s \ / CH, V CO-N N-CO-NH-CH-CO-NH - S \ X 3 w ό 7V <-.

COONa This penicillin was prepared as described in Example 15 from epicillin (2.0 parts by weight) and 3-cyclopropylcarbonylimidazolidin-2-one-1-carbonyl chloride (1.2 parts by weight).

Yield: 2.4 parts by weight, β-lactam content: 89%, IR peaks in the carbonyl region: 1755, 1725, 1665, 1590 and 1515 cm-1 (Nujol), NMR signals λ = 4.1 (1H), 4, 35 (2H), 4.55 (2H), 5.0 (1H), 5.8 (1H), (CD 3 OD) 6.1-6.4 (4H), 6.7-7.1 (1H) , 7.1-7.5 (4H), 8.25-8.65 (6H) and 8.8-9.2 ppm (4H).

Example 48

Sodium Dd- [T (2-oxo-3-mesylimidazolidin-1-yl) carbonyl-amino] -7-benzyl-penicillin Q / V% CH.SO.N ^ N CO NH-CH 2 CO NH- -f W <»> 1 / \ CH, s Νγ COONa 79 56839 a) Ampicillin trimethylsilyl ester CH.CO0 NH2 o / L_N ^ | CH 3 COO-Si (CH 3) 3 20.2 parts by weight of ampicillin trihydrate, 11 * 1 parts by weight of triethylamine and 20 parts by weight of anhydrous sodium sulfate were stirred in 250 volumes of methylene chloride for 2 hours at room temperature and then filtered off with suction, washed with methylene chloride, 5.5 parts by weight of trimethylchlorosilane in 50 parts by volume of methylene chloride were added dropwise to the organic phases under cold water cooling. The solution was stirred for a further 30 minutes, b) Sodium D - (* * - [N- (2-oxo-3-mesylimidazolidin-1-yl) carbonylamino] -7-benzylpenicillin from ampicillin trimethylsilyl ester

To a solution of ampicillin trimethylsilyl ester obtained in a) in methylene chloride was added portionwise with stirring and protection from moisture over 15 minutes 11.3 parts by weight of solid 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine, stirred for 1 hour at room temperature and then evaporated to dryness. 400 parts by volume of water were added to the solid residue, the pH of the mixture was adjusted to 7, and it was extracted with 200 parts by volume of ethyl acetate, the extract was discarded, 200 parts by volume of ethyl acetate were added to the aqueous phase, the pH was adjusted with 2N HCl to 2, the ethyl acetate was separated and the aqueous phase was extracted. once more with 200 parts by volume of ethyl acetate. The combined ethyl acetate solutions were dried over MgSO 4, after separation of MgSO 4, 50 parts by volume of a 1-M solution of sodium 2-ethylhexanoate in methanolic ether were added, the solvent was evaporated on a rotary evaporator until the evaporation was dissolved. stirring into an ice-cold mixture of 1000 volumes of ether and 100 volumes of methanol, the separated product was filtered off with suction, washed with ether and dried in a vacuum desiccator over P 2 O 3 and paraffin chips. Yield: 27 parts by weight of sodium 56839 rium-D * A-Z7 (2-oxo * 3-mesylimidazolidin-1-yl) carbonylaminobenzylpenicillin with β-lactam content 85%, IR peaks: 3305 , 1760, 1728, 1670, 1605, 1360 and 117 «4 cm-1. NMR signals: T = 2.3-2.7 (5H), δ 4.35 (1H), δ 4.5 (2H), 5.8-6.2 (δ 4Η), 6.65 (3H ), 8, 4 (3H) and 8.5 ppm (3H).

The product is identical to the product of Example «4.

Example 49

Sodium D - N - [(2-oxo-3-mesylimidazolidin-1-yl) carbonylamino] 13-benzylpenicillin λ? CH_SO 0 N CO NH-CH-CO NH - f 3 2 \ _ / <*) 1 / N-h / -V ^ "3

o I

COONa a) N-Trimethylsilyl-ampicillin-trimethylsilyl ester -CH-CO NH - / V / CH3 w · · COO-Si (CH3) 3 20.2 parts by weight of ampicillin trihydrate, 11.1 parts by weight of triethylamine and 20 a part by weight of anhydrous sodium sulfate was stirred in 250 volumes of methylene chloride for 2 hours at room temperature; then filtered off with suction, washed with methylene chloride, and 5.0 parts by weight of triethylamine were added to the combined organic phases, and then 11 parts by weight of trimethylchlorosilane in 100 parts by volume of methylene chloride were added dropwise with cold water under cooling. Stirring was continued for 30 minutes.

si 56839 b) Sodium D-o-C 1-4 -oxo-5-mesylimidazolidin-1-yl) carbonylamino J7-Benzylpenicillin from N-trimethylsilyl-ampicillin-trimethylsilyl ester

To a solution of N-trimethylsilylampicillin trimethylsilyl ester obtained in a) in methylene chloride was added portionwise and protected from moisture over 15 minutes, 11.3 parts by weight of solid 1-chlorocarbonyl-2-oxo-3-mesylimidazolidine were added over 15 minutes, stirring was continued for 1 hour at room temperature. According to Example 48b, 28 parts by weight of sodium D - * - E - (2-oxo-3-mesylimidazolidin-1-yl) carbonylamino-7-benzylpenicillin were isolated, the β-lactam content was 90%. IR and NMR spectra are agree with the spectra of the products of Examples 4 and 48b,

Example 50

Sodium D- [N- (2- (2-oxo-3-phenylsulfonylimidazolidin-1-yl) carbonylamino] -7-benzylpenicillin] = = N, N-SO2NCO2 NH-CH-CO NH - ^ W «> ix \ ch, /“ Ύ COONa a) Ampicillin trimethylsilyl ester __. O CH

Qh-CH-CO NH ..... r- ^

Jh2 / LY

COO-Si (CH3) 3 *, 1.1 parts by weight of ampicillin trihydrate, 2.9 · * parts by volume of triethylamine and 6.0 parts by weight of anhydrous magnesium sulfate were stirred in 80 parts by volume of dichloromethane for 2 hours at 20 ° C, then filtered off with suction, was washed with dichloromethane, and 1.1 parts by weight of trimethylchlorosilane in 30 parts by volume of dichloromethane were added dropwise to the combined organic solutions under cooling (cold water). The solution was stirred for a further 30 minutes, b) Sodium D-c * - [(2-oxo-3-phenylsulfonylimidazolidin-1-yl) carbonylamino] benzylpenicillin ampicillin from trimethylsilyl ester

To a solution of the ampicillin trimethylsilyl ester obtained in a) in dichloromethane was added, with stirring and protection from moisture, 2.9 parts by weight of solid 1-chlorocarbonyl-2-oxo-3-phenylsulfonylimidazolidine, stirring was continued at 20 ° C for 1 hour and then evaporated to dryness. The solid residue was suspended in water, the pH of the solution was adjusted to 7.0-7 | 5 with dilute NaOH with stirring, and the slightly cloudy solution was gently shaken once with ethyl acetate. After separation of the organic phase, a new portion of ethyl acetate was poured onto the aqueous phase and acidified to pH 2 with dilute HCl. with. The organic phase was separated, washed with dilute NaCl solution, diluted with ether to twice the volume, and the sodium salt was mixed with a 1 M solution of sodium 2-ethylhexanoate in methanolic (about 5%) ether. The precipitated substance was initially oily. After complete evaporation of the solvent with the addition of absolute ether, the precipitate became a powder. It was filtered off with suction and washed with 10% methanol in ether and dried in a desiccator above p4 ° 10 *

Yield: 5.9 parts by weight Sodium D - * - E- (2-oxo-3-phenylsulfonylimidazolidin-1-yl) carbonylaminoZ7-benzylpenicillin β-lactam content: 80% IR peaks: 3300, 1770 , 1740, 1680, 1610, 1530, 1260, 1184 and 1136 cm -1, NMR signals: δ = 1.8-2.1 (2H), 2.2-2.8 (8H), 4.4 ( 1H), 4.5 (2H), 5.8 (1H), 6.15 (4H), 8.45 (3H) and 8.5 ppm (3H),

The product is identical to the product of Example 21 83 56839

Example 51

Sodium D - (* (R (2-oxo-3-phenylsulfonylimidazolidin-1-yl) carbonylamino) benzylpenicillin) NH-CH-CO NH -, - f X / vy ^ 'w <., COONa a) N-Trimethylsilyl-ampicillin-trimethylsilyl ester

/ = \ / S / CH

6 y - <: h-co nh - / d ΝΠ J - N CH3

Si (CH3) 3 v T

COO-Si (CH 3) 3 4.1 parts by weight of ampicillin trihydrate, 4.2 parts by volume of triethylamine and 6.0 parts by weight of anhydrous magnesium sulfate were stirred in 80 parts by volume of dichloromethane at 20 ° C for 2 hours. It was then filtered off with suction, washed with dichloromethane, and 2.2 parts by weight of trimethylchlorosilane in 30 parts by volume of dichloromethane were added dropwise to the combined organic solution under cooling (cold water). Stirring of the solution was continued for 30 minutes.

b) Sodium D- [N- (2-oxo-3-phenylsulfonylimidazolidin-1-yl) carbonylamino] -benzylpenicillin from N-trimethyl-ampicillin-trimethylsilyl ester

To a solution of N-trimethylsilylampicillin trimethylsilyl ester obtained in a) in dichloromethane was added 2.9 parts by weight of 1-chlorocarbonyl-2-oxo-3-phenylsulfonylimidazolidine (solid) under protection from moisture and stirring, followed by stirring for 20 hours at 20 ° C. As described in Example 50b, Sodium D- [N- [1- (2-oxo-3-phenylsulfonylimidazole-> 66839 din-1-yl) carbonylamino] -7-benzylpenicillin was obtained as a white powder in a weight of 5.7% by weight. parts. β-lactam content 71% The IR and NMR spectra are consistent with the spectra of the products of Examples 21 and 50b.

Example 52 This penicillin was prepared as described in Example 1A from 7.8 parts by weight of 1-chlorocarbonyl-2-oxo-3-thienyl (2 ) -carbonylimidazolidine and 13.3 parts by weight of ampicillin.

Yield: Sodium D-ou ^. (2-Oxo-3-thienyl (2) -carbonylimidazolidin-1-yl) carbonylamine N, N-benzylpenicillin: 89%, β-lactam content: 90%, IR peaks: 3290, 1770, 1730, 1657 , 1602, 1505, 1340, 1305, 1240 and 763-708 cm-1 NMR signals: T ~ 2.1 (1H), 2.2 (1H), 2.3-2.8 (5H) , 2.9 (1H), 4.4 (1H), 4.55 (1H), 5.8 (1H), 6.1 (4H), 8.4 (3H) and 8 , 5 ppm (3 H).

B) 0

II

- CO 2 COCl 19.6 parts by weight of nl-thienyl (2) -carbonyl-2-oxoimidazolidine In 160 volumes of tetrahydrofuran, 18 parts by weight of phosgene and then 18 parts by weight of triethylamine were added at 0 ° C, and the mixture was stirred for 24 hours. hours at room temperature. The triethylamine hydrochloride was filtered off with suction, the mother liquor was evaporated to dryness and the residue was crystallized from benzene.

Mp 130 ° C, 1-chlorocarbonyl-2-oxo-3-thienyl (2) carbonylimidazolidine yield: 85%, calculated: C 41.9 H 2.7 Cl 13.8 N 10.8 0 18 , 6 S 12.4 found: C 43.5 H 2.6 Cl 13.8 N 10.8 0 17.4 S 12.5> 85 56839 c) o

A

$ y-CON NH

1-Thienyl (2) -carbonyl-2-oxoimidazolidine was prepared in 82% yield from thiophene-2-carboxylic acid chloride and imidazolidone (2)

in tetrahydrofuran in the presence of pyridine. Mp, 110 ° C

calculated: C48.9 H 4.1 N 14.3 0 16.3 S 16.3 found: C 48.8 H 4.0 N 13.2 0 16.4 S 16.7 NMR signals: T = 2 .0 (1H), 2.25 (1H), 2.85 (1H), 6.0 (2H) and 6.5 ppm (2H) (acetone-dg)

Example 53

OH

-CON NCONH-CH-CONH-1f! w ·

o T

COONa This penicillin was prepared as described in Example 1A from 1.77 parts by weight of 1-chlorocarbonyl-2-oxo-3-thienyl (2) -carbonylimidazolidine and 2.5 parts by weight of amoxicillin. Yield of sodium D-ou (2-oxo-3-thienyl (2) -carbonylimidazolidin-1-yl) carbonylamino] -β-hydroxybenzylpenicillin: 72%.

(Β-lactam content: 91%, IR peaks: 3270, 1760, 1730, 1645, 1595, 1500, 1240 and 763-711 cm-1, NMR signals: T = 2? (1H), 2.34 (1H), 2.85 (3H), 3.3 (2H), 4.5-4.8 (3H), 5.9 (1H), 6.2 (4H), 8 , Δ (3 H) and 8.56 ppm (3 H).

0 ^ 86 56839

Example 54

.-. Il V

/ T \ _ I / CH3

Xs v_x 1 X

/ N \ X Xch3

O I

COONa This penicillin was prepared as described in Example 1A from 0.7 parts by weight of 1-chlorocarbonyl-2-oxo-3-thienyl (2) -imidazolidine and 1.0 part by weight of epicillin sodium, Sodium D - 7 (2-Oxo-3-thienyl (2) -carbonylimidazolidin-1-yl) carbonylamino [7-O-t-cyclohexa-1,4-dienylmethylpenicillin yield: practically quantitative.

Β-lactam content: 95%.

IR peaks: 3280, 1760, 1655, 1730, 1590, 1505, 1338, 1304 1240 and 763-708 cm-1.

NMR signals: T = 2.15 (1H), 2.25 (1H), 2.9 (1H), 4.15 (1H), 4.4 (1H), 4.6 ( 2 H), 5.05 (1H), 5.85 (1H), 6.1 (4 H), 7.3 (4 H), 8.38 (3 H) and 8.47 ppm (3 H).

Example 55 ^ A) 0 n X T / \ / CH3 ^ CON NCONH-CH-CONH - / V / w TV ^

o I

COONa This penicillin was prepared as described in Example 1A from 2.6 parts by weight of 1-chlorocarbonyl-2-oxo-3-thienyl (3) -carbonylimidazolidine and 4.5 parts by weight of ampicillin. Yield of sodium D-ol (2-oxo-3-thienyl (3) carbonylimidazolidin-1-yl) carbonylamino] benzylpenicillin: 91% β-lactam content: 86%, IR peaks: 3300, 1775, 1745, 1678, 1615, 1526, 1315 and 1256 cm-1.

87 56839 NMR signals: * E * = 2.0 (1H), 2.4-3.0 (7H), 4.45 (1H), 4.6 (2H), 5.9 ( 1H), 6.15 (4H), 8.47 (3H) and 8.54 ppm (3H).

0

II

NCOC1 "0 w This carbamic acid chloride was prepared as described in Example 52 B from 1-thienyl (3) -carbonyl-2-oxoimidazolidine and phosgene in the presence of triethylamine. Yield of 1-chlorocarbonyl-2-oxo-3-thienyl (3) -carbonylimidazolidine : after crystallization from benzene: 82%

Mp = 125 ° C.

calculated: C 41.9 H 2.7 Cl 13.8 N 10.8 S 12.4 found: C 41.8 H 3.2 Cl 13.7 N 10.8 S 12.5.

C) 1

_______ CON ^ ^ NH

1- (Thienyl-3-carbonyl) -2-oxoimidazolidine was prepared in 57% yield from thiophene-3-carboxylic acid chloride and imidazolidone (2) in tetrahydrofuran in the presence of pyridine. Mp * 130 ° C, calculated: C 49.0 H 4.1 N 14.3 0 16.3 S 16.3 found: C 49.0 H 4.1 N 13.6 0 16.3 S 16.6 .

IR peaks: 3180, 3060, 1740, 1630, 1325, 1302, 1255, 1140, 1065, 857, 804, 743 and 696 cm-1 (Nujol).

NMR signals: T = 2.1 (1H), 2.7 (2H), 6.05 (2H) and 6.55 ppm (2H) (CDgOD),

Example 56 88 56639

OH

0 ό T / ° H3 ^ CON NCONH-CH-CONH--

W I / \ CH

V / / - "v / 3 soy COONa This penicillin was prepared as described in Example 1A from 1.3 parts by weight of 1-chlorocarbonyl-2-oxo-3-thienyl (3) -carbonylimidazolidine and 1.83 parts by weight of amoxicillin. , Yield of sodium DdC (2-oxo-3-thienyl (3) -carbonylimidazolidin-1-yl) carbonylamino-7-p-hydroxybenzylpenicillin: 95%, β-lactam content: 87%, IR peaks: 3290, 1780, 1745, 1675, 1610, 1518, 1317 and 1255 cm -1, NMR signals: T = 1.85 (1H), 2.55 (2H), 2.7 (2H), 3.2 (2H), 4.5 (3H), 5.8 (1H), 6.1 (4H), 8.4 (3H) and 8.5 ppm (3H).

Example 57

. O

ti S

^ \ / CH, _ ^ CON> NCONH-CH-CONH - f 6

S I

COONa This penicillin was prepared as described in Example 1A from 0.7 56839 89 parts by weight of 1-chlorocarbonyl-2-oxo-3-thienyl (3) -carbonylimidazolidine and 1.0 part by weight of epicillin sodium. Sodium-D - <* - £ T (2-oxo-3-thienyl- (3) carbonyl-imidazolidin-l-yl) carbonyl-amino -? ** -! Yield of β-cyclohexadienylmethylpenicillin: practically quantitative, ε-lactam content: 92%.

IR peaks: 3300, 1778, 1765, 1745, 1676, 1612, 1525, 1315 and 257 cm-1, NMR signals: T * = 1.9 (1H), 2.6 (2H), 4, 16 (1H), 4.3 (2H), 4.55 (2H), 5.0 (1H), 5.8 (1H), 6.1 (4H), 7.35 ( 4 H), 8.4 (3 H) and 8.47 ppm (3 H).

Example 58 x 9 COIT ^ NCONH-CH-CONH - f

s o I

COONa This penicillin was prepared as described in Example 5A from 2.6 parts by weight of 1-chlorocarbonyl-2-oxo-3- (1,2,5-thiadiazol-3-ylcarbonyl) imidateolidine and 4.4 parts by weight of ampicillin trihydrate. , Yield: 70% (calculated on the pure sodium D - * - [[2-oxo-3- (1,2,5-thiadiazol-3-ylcarbonyl) -imidazolidin-1-yl] carbonylamino] -benzylpenicillin) The product contained 20% sodium D-α - [* (2-oxoimidazolidin-1-yl) carbonylamino] -7-benzylpenicillin formed by hydrolysis of the title compound 90 56839 NMR signals: Τ = 1.1 (1H), 2.4-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.8 (1H), 5.95 (4H), 8.4 (3H) ) and 8.48 ppm (3H).

B) o Π, _ ^ CON NCOC1

^ W

Nxs-N

This carbamic acid chloride was prepared as described in Example 52 B from 1- (1,2,5-thiadiazol-3-ylcarbonyl) -2-oxoimidazolidine and phosgene in the presence of triethylamine, 1-chlorocarbonyl-2-oxo-3- (1,2 Yield of (5-thiadiazol-3-ylcarbonyl) -imidazolidine: 75%, m.p. 193 ° C, calculated: C 32.3 H 1.9 Cl 13.7 N 21.6 S 12.3 found: C 32.5 H 1.9 Cl 13.3 N 21.4 S 12.1 IR peaks: 3080, 1813, 1726, 1685, 1340, 1252, 1221, 1167, 797 and 724 cm-1.

NMR signals: T = 1.1 (1H) and 5.9 (4H) (CD3CN), C) O

II

v_

N- 'N N

1- (1,2,5-Thiadiazol-3-ylcarbonyl) - <-2-oxoimidazolidine was prepared from 1,2,5-thiadiazole-3-carboxylic acid chloride and imidazolidone in tetrahydrofuran in the presence of pyridine, and the yield after recrystallization was 88% from ethanol. Mp 155 ° C, calculated: C 36.3 H 3.0 N 28.3 S 16.2 found: C 36.4 H 3.0 N 28.5 S 16.3 IR peaks: 3190, 3100, 1745, 1660, 1355, 1255, 1142, 1063 1025, 889, 818, 778, 760, 743, 703 and 679 cm-1.

91

Example 59 56839

I 1 9 CH

Br-U s' C0N NCONH-CH-COHH-f un3 0 W) - γ CH3 COONa This penicillin was prepared as described in Example 1A from 6.2 parts by weight of 1-chlorocarbonyl-2-oxo-3- (5-brcmifuroyl). -2 -) - imidazolidine and 9 parts by weight of ampicillin trihydrate. Yield of sodium DTD? [2- (2-oxo-3- (5-bromofuroyl-2) -imidazolidin-1-yl] carbonylamino] -benzylpenicillin: 96 ί · β-lactam content: 92%.

IR peaks: 3330, 1770, 1735, 166U, 1600, 1510, 1310, 12U5, 75¾, 7 ^ 1, 69¾ cm-1.

NMR signals f = 2.3-2.8 (6 H), 3.35 (1H), k, 35 (1H), U, 5 (2 H), 5.8 (1H), δ .05 (h H), 8.0 (3 H) and 8.5 ppm (3 H).

B) O- [4] This carbamic acid chloride was prepared as described in Example 62 B from 1- (5-bromofuroyl-2) -2-oxoimidazolidine and phosgene in the presence of triethylamine and crystallized from benzene, 1-chlorocarbonyl-2-oxo-3- ( Yield of 5-bromofuroyl-2) -imidazolidine: 83%, 132 ° C, calculated: C 33.6 H 1.9 Br 2¾.9 Cl 11.0 N 8.7 found: C 33.7 H 1.8 Br 2¾.7 Cl 11.1 N 8.6 IR peaks: 31 ^ 0, 1790, 1700, 16U5, 12 ^ 0, 1225, 1160, 1017, 925, 798, 737 and 703 cm-1 (Nujol).

C) 0

Br —1! JLcON ^^ NH

1- (5-bromofuroyl-2) -2-oxoimidazolidine was prepared in 7U yield from 5-bromopyrrolic acid chloride and imidazolidone-2 by stirring overnight in tetrahydrofuran and then crystallizing from methanol. , sp. 15o ° C.

calculated: C 37.0 H 2.7 Br, 30.9 N 10.8 0 18.5 found: C 36.8 H 2.8 Br 31.0 N 10, U 0 19.0 OR peaks: 3280 , 3150, 1730, 1622, 1555, 12 ^ 5, 1232, 1195, 1120, 10U5, 1025, 979, 9 ^ 9, 92U, 863, 811, 7U8 cm-1 (Nujol).

Example 60 OH

m Φ

Bi-IL JJ-CONH-C H-CONH-CH, COONa This penicillin was prepared as described in Example 1A from 1.8 parts by weight of 1-chlorocarbonyl-2-oxo-3- (5-bromofuroyl-2) -imidazolidine and 2.0 parts by weight of amoxicillin. Yield of sodium D2-oxo-3- (5-bromofuroyl-2) -imidazolidin-1-yl] carbonylamino-β-hydroxybenzylpenicillin: 60%.

fi-lactam content: 88%.

IR peaks: 3280, 1760, 1730, 1650, 1595, 1500, 12U3 cm -1.

NMR signal t ** ** 2.65 (1H), 2.85 (2H), 3.3 (2H), 3.5 (1H), U, UU, δ (3H), 5.9 (1H), 6.2 (UH) and 8.5 ppm (6H).

Example 6l

rm a CH

° w J-VN

COONa This penicillin was prepared as described in Example 1A from 0.9 parts by weight of 1-chlorocarbonyl-2-oxo-3- (furyl-2-sulfonyl) imidazolidine and 1.0 part by weight of ampicillin trihydrate. Yield of sodium D-O- [2 / oxo-3- (furyl-2-sulfonyl) -imidazolidin-1-yl] -carbonylamino] -benzylpenicillin: 91.5%.

Β-lactam content: 92%, 93 56839 IR peaks: 3300, 31U0, 1775, 17½, 1682, 1613, 1525, 1255, 1209, 117o, 1136 cm-1. NMR signals: δ 2.25 (1H) , 2.5-3.0 (6h) 3, ¾ (1H), ί +, 53 (1H), 1 +, 62 (2H), 5.9 (1H), 6.17 (UH), 8, 1 + 8 (3H) and 8.55 ppm (3H).

B) n-> -SO0 NCOC10 This carbamic acid chloride was prepared as described in Example 52 B from 1- (furyl-2-sulfonyl) -2-oxoimidazolidine and phosgene in the presence of triethylamine and crystallized from benzene.

Yield of 1-chlorocarbonyl-2-oxo-3 '(furyl-2-sulfonyl) -imidazolidine: 91% · M.p. 139 ° C.

IR peaks: 3105, 1808, 1723, 1380, 1295, 1208, 1169, 1133, 1012, 960, 783, 71 + 8 and 727 cm-1 (Nujol).

NMR signals 1% = 2.1 (1H), 2.7 (1H), 3.3 (1H) and 5.9 ppm (1 + H).

c) 56839 9h o ._,

U J SO - N KH

0 w 5.9 parts by weight of furan-2-sulfochloride and 3.0 parts by weight of imidazolidone-2 were heated for 30 minutes at 70-80 ° C, the mixture was cooled and a little water was added. The crystalline precipitate was filtered off with suction and crystallized from methanol,

Yield: 12%, mp = 174 ° C, IR peaks: 3200, 3090, 1715, 1488, 1268, 1208, 1171, 1132, 1085, 1059, 1007, 919 cm -1, NMR signals: T = 2 , 2 (1H), 2.8 (1H), 3.35 (1H), 4.2 (1H), 6.05 (2H) and 6.6 ppm (3H), (CD ^ CN).

D) T 2 SO 2 Cl 2 2-Bromofuran and n-butyllithium in ether / hexane were prepared at -70 ° C to give 2r.furyllithium and dropped at -70 ° C into an equivalent amount of sulfuryl chloride. Stirring was continued at -70 ° C for 30 minutes, then the mixture was allowed to warm to room temperature, shaken once with water, the organic solution was dried over MgSO 4 and distilled, Furan-2-sulfochloride distilled at 14 torr at 94 ° C, Yield: 42 %, Gas chromatographic uniform, calculated: C 28.8 H 1.8 Cl 21.3 0 28.8 S 19.2 Found: C 29.5 H 2.0 Cl 21.1 0 29.6 S 18.4 IR peaks: 3100, 2900, 1535, 1460, 1380, 1202, 1155, 1120, 1050, 1005, 912, 877 and 763 cm-1.

Example 62 6: fi il Sf / S \ / CH3 l! SO0N NCONH-CH-CONH - ^

\ / I

N '/) - oy * COONa 95 S6839 This penicillin was prepared as described in Example 1A from 0.8 parts by weight of 1-chlorocarbonyl-2-oxo-3- (furyl-2-sulfonyl) imidazolidinine and 1.04 parts by weight amoxicillin, Yield of sodium Dc-C2-oxo-3- (furyl-2-sulfonyl) -imidazolidin-1-yl-7-carbonyl-amino-p-hydroxybenzylpenicillin: 77%. Β-lactam content: 91%, IR peaks: 3295, 3135, 1770, 1742, 1680, 1615, 1518, 1255, 1209, 1170, 1136, 759 cm -1 NMR signals: T = 2.1 (1H) , 2.55 (1H), 2.7 (2H), 3.2 (2H), 3.3 (1H), 4 ^ 5 (3H), 5.8 (1H), 6 , 1 (4 H), 8.44 (3 H) and 8.5 ppm (3 H).

Example 63 A) n i / CHa

.so9-n NCONH-CH-CONH - / V

0 W

COONa This penicillin was prepared as described in Example 1A from 1.24 parts by weight of 1-chlorocarbonyl-2-oxo-3- (furyl-3-sulfonyl) imidazolidine and 2.0 parts by weight of ampicillin, Sodium D-α-jc2 Yield of oxo-3- (furyl-3-sulfonyl) -imidazolidin-1-yl-7-carbonylamino-benzylpenicillin: 92%, β-lactam content: 90%, IR peaks: 3300, 3130, 1770, 1740, 1682, 1613 , 1525, 1260, 1240, 1168 and 1128 cm -1, NMR signals: * T = 1.65 (1H), 2.25 (1H), 2.4-2.8 (5H), δ , 1 (1H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.1 (4H), 8.4 (3H) and 8.45 ppm (3H), B) 0

II

This carbamic acid chloride was prepared as described in Example 52 B from 1- (furyl-3-sulfonyl) -2-oxoimidazolidine (prepared analogously to 1- * (furyl-2-sulfonyl) -2-oxoimidazolidine; m.p. 170 ° C) and phosgene in the presence of triethylamine, crystallization was performed from benzene, yield of 1-chlorocarbonyl-2-oxo-3-furyl-3-sulfonyl) -imidazolidine: practically quantitative, mp 154 ° C, calculated: C 34.6 H 2 .5 Cl 12.8 N 10.1 0 28.7 S 11.5 found: C 3 * 1.5 H 2.6 Cl 12.8 N 9.8 0 27.8 S 11.1 * IF peaks : 3130, 1810, 1730, 1500, 1380, 1302, 1238, 1207, 1167,

1126, 1082, 1008, 975, 890, 887, 750 and 723 cm-1, NMR signals: T = 1.8 (1H), 2.4 (1H), 3, 15 (1H) and δ .0 ppm (4 H), Example 61+ OH

o (S

Y / K / CHs

j-w2 ", NCONH-CH-CONH-S

This penicillin was prepared as described in Example 1A from 1.39 parts by weight of 1-chlorocarbonyl-2-oxo-3- (furyl-3-sulfonyl) imidazolidine and 1.82 parts by weight of amoxicillin. Sodium DA- [C2-oxo-3- (furyl-3-sulfonyl) -imidazolidin-1-yl] -7-carbonylamino] -β-hydroxybenzylpenicillin yield: 79%, β-lactam content: 88%, IR peaks: 3298, 3120, 1780, 1765m 1739, 1676, 1613, 1516, 1250 and 1167 cm-1.

NMR signals: X- 1.65 (1H), 2.3 (1H), 2.75 (2H), 3.1 (1H), 3.2 (2H), 4.4- 4.65 (3H), 5.85 (1H), 6.15 (4H), 8.45, (3H) and 8.5 ppm (3H),

Example 65 9

_ / SO 2 N NCONH-CH-CONH - f Y

COONa This penicillin was prepared as described in Example 1A 97,66839 from 0.55 parts by weight of 1-chlorocarbonyl-2-oxo-3- (furyl-3-sulfonyl] -imidazolidine and 1.0 part by weight of epicillin sodium. Yield of -O- [2-oxo-3- (furyl-3-sulfonyl) -imidazolidin-1-yl] -carbonylamino] -c (-1H-cyclohexadienylmethylpenicillin): 82%, β-lactam content: 89%, IR peaks: 3280, 3120, 1770, 1739, 1678, 1612, 1522, 1248, 1166 cm -1. NMR signals; T * 1.65 (1H), 2.25 (1H), 3.1 1H), 4.1 (1H), 4.3 (2H), 4.5 (2H), 5.0 (1H), 5.8 (1H), 6.1 (4H) ), 7.3 (4H), 8.4 (3H) and 8.45 ppm (3H).

Example 66 A) Sodium D-tf-ZT (3-nicotinoylimidazolidin-2-on-1-yl) carbonylamino-17-benzylpenicillin 0 11 (R) S / CH3 CO-N2-N-CO- NH-CH-CO-NH_Γ ~ | This penicillin was prepared as described in Example 1A from 4.0 parts by weight of ampicillin and 2.5 parts by weight of 1-chlorocarbonyl-2-oxo-3-nicotinoyl. imidazolidine, it was extracted from an aqueous solution adjusted to pH 3.0 with a large amount of ethyl acetate and precipitated from the extract as the sodium salt as described above by diluting with ether

Yield: 1.8 parts by weight * mp, 198- *. 220 ° C, decomposes, β-lactam content: 85%, NMR signals: T = 1.2-1.4 (2 H), 1.8- 2.1 (1H), 2.3-2.8 (6H), 4.3-4.7 (3H), 5.85 (1H), 5.9-6.1 (4H) and 8.3- 8.7 ppm (6 H), B) 1-Chlorocarbonyl-2-oxo-3-nicotinoyl-imidazolidine

II

aCO-N -C0-C1

To a mixture of 5.0 parts by weight of 1-nicotinoyl-2-oxoimidazolide-98,56839, 2.9 parts by weight of triethylamine and 80 parts by weight of tetrahydrofuran was added dropwise at 0 ° C a solution of 3.1 parts by weight of part of phosgene in 20 volumes of tetrahydrofuran, then stirred overnight at 20 ° C and evaporated to dryness in vacuo. The dark, semi-solid residue containing the acid chloride formed mixed with the resulting triethylamine hydrochloride was extracted several times with ethyl acetate. The combined extracts were evaporated to dryness in vacuo. An amorphous mass was obtained which was used as such for further reaction with ampicillin, C) 1-nicotinoyl-2-oxoimidazolidine 0

(I

- CO-N 2 NH

ζ JJ \ - /

Pyridine-2,3-dicarboxylic anhydride (298 parts by weight) was heated to 160 ° C, and imidazolidin-2-one (172 parts by weight) was added so that the temperature rose to 200 ° C (gas evolution). the temperature was maintained at 175-200 ° C for 2 hours. After cooling to 100 ° C, 150 volumes of ethanol were added, decanted, the same amount of ether was added, filtered off with suction, the ethereal filtrate was stirred with 700 volumes of ether, and the resulting precipitate was filtered off with suction. and the ethereal filtrates were combined, evaporated in vacuo, the residue treated with nitromethane and the precipitate formed filtered off with suction. This precipitate (85 parts by weight) was boiled in 800 volumes of nitromethane, the mixture was allowed to slowly cool to 45 ° C, the precipitate formed was filtered off with suction and discarded, and the filtrate was cooled to 5 ° C. The precipitated precipitate (58 parts by weight) was then boiled in a mixture of isopropanol (700 parts by volume) and ethanol (50 parts by volume), all precipitated above 50 ° C was filtered off with suction and discarded, and the desired product precipitated from solution on cooling to 0 ° C in 29.3% yield. parts by weight, Sp. 178-180 ° C, calculated: C 56.5 H 4.7 N 22.0 found: 55.9 4.9 22.1,

Claims (1)

0. N ^ COOH color A är 0 M Cv RXn / nN- V color R betyder derivative, dä X = CO, alkyl med 1-1 + cholatomer, cycloalkyl med 3-6 chol atom, alkoxy med 1-1 + cholatomer , when X = CO, cyclohexyloxy, when X = CO, phenyl, phenoxy, when X = CO, amino, mono- or dialkylamino with 1-1 + cholatomic groups alkyl group, phenylamino, tetra-eller pentamethylenimino, ethoxycarbonylamino, methylsulfonylamino , optionally substituted with halogen, furyl, thienyl, isothiazolyl, isoxazolyl or pyridyl, X is CO or SO2, optionally with methyl substituents - (CH2Jg- e- ^ er "(CH2J2- group, and B is phenyl, Hydroxyphenyl or cyclohexa-1, U-dien-1-yl, single penicillin derivatives of the base of the chiral center Cx are used in the R-configuration and in the form of a mixture of the diastereomeric residue, which is the same as the parent compound. därav, att en förening med formuleln * s. T-NH-CH-CO-NH-jS CH3 B CH_ II 0 ^ - »^ 3 COOT color B har ovan anförda betydelse, och T och bäda fig sig betyder en väteatom eller en grupp med formuleln y -Si ^ -E5 \ r6