DD91496B3 - PROCESS FOR PRODUCING NEW PENICILLINE - Google Patents

Description

For this 10 pages formulas and tables

The invention relates to a process for the preparation of novel synthetic compounds which are useful as antibacterial agents, food additives in animal feed and as therapeutic agents in poultry and animals and in humans in the treatment of Gram-positive and Gram-negative bacteria and in particular of Klebsiella bacteria caused infectious diseases are valuable. Antibacterial agents such as ampicillin (U.S. Pat. No. 2,985,648) have been shown to be very effective in the therapy of Gram-positive and Gram-negative bacterial infections. However, they are unable to effectively fight Klebsiella infections.

Carbenicillin (U.S. Pat. Nos. 3,124,673 and 3,228,226) is effective in humans for infection by Klebsiella bacteria only when given in sustained high dosage as achieved only by infusion. The invention relates to a process for the preparation of penicillins of the general formula I, wherein A is a group, a, b or c, X is hydrogen, alkyl having up to 10 carbon atoms, alkenyl having up to 10 carbon atoms, vinyl, cycloalkyl and cycloalkenyl with up to 10 carbon atoms, arylvinyl, mono-, di- and trihalogeno-lower alkyl, mono-lower alkylamino, di-lower alkylamino, monoarylamino, aryl-lower alkylamino, alkoxy of up to 8 carbon atoms, cycloalkoxy of up to 7 carbon atoms, aralkoxy of up to 8 carbon atoms, aryloxy, a group of lower alkyl OV, Lower alkyl-SV, N ^ CV, lower alkyl-O-CO-V, di-lower alkylamino-CO-V-, d to n, V is a bivalent organic radical having 1 to 3 carbon atoms, η is an integer from 0 to 2 inclusive and R ₁ , R ₂ and R _{3 are} each hydrogen, nitro, nitrile, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chloro r, bromine, iodine, fluorine or trifluoromethyl, Y is alkyl of up to 10 carbon atoms, alkenyl of up to 10 carbon atoms, vinyl, propenyl, cycloalkyl and cycloalkenyl of up to 10 carbon atoms, mono-, di- and trihalogeno-lower alkyl, aralkyl of up to 8 Carbon atoms, aryl or a heterocyclic radical, ο is a divalent group Ͽ to v, m is an integer from 3 to 5, the arrow in the divalent group ν is intended to express that linking the two free valencies of ο with the N and C atom of the group w is not arbitrary, but in the manner indicated by the arrow, Q is a divalent group, namely of the type aa to jj, wherein E is oxygen or sulfur, G is hydrogen or lower alkyl, R ₁ and R _{2 is} hydrogen, nitro, nitrile, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chloro, bromo, iodo, fluoro or trifluoromethyl t, the arrow in the divalent group kkzum express that the linkage of the two free valencies of kk with the two N atoms of the group c should not be arbitrary, but in the manner indicated by the arrow, M is a group II, B is a group of the formulas oo, pp, qq, rr, R ₄ , R ₅ and R _{6 is} hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylthionyl, lower alkylsulphonyl, Nitro, Diniedrigalkylamino, Niedrigalkanoylamino, hydroxy, lower alkanoyloxy and which may be with respect to the chiral center C of the two possible diastereomers with the R or S configuration or may be present as a mixture of these two diastereomers and their non-toxic, pharmaceutically acceptable salts, characterized in that 6-aminopenicillanic acid of the formula II or compounds of the general formula IV in which R ₇ , R ₈ and R _{9 are} alkyl with up to 6 carbon atoms, with by reaction of carboxylic acids of general formula V with about one molar equivalent of the compounds of general formula Vl, VII, VIII or IX, wherein R _{9 has} the meaning given above, R _{10 has} either the same meaning as R. or phenyl, R _{11 is} a divalent organic radical - (CH ₂ ) 4, - (CH ₂ ) B or -CH ₂ I ₂ -O- (CH ₂ J ₂ -, and W is halogen, in an anhydrous indifferent organic solvents in the presence of about one molar equivalent of a base at a temperature of -60 to +30 ⁰ C obtained at the carboxyl carboxylic acids of the formula Voder carboxylic acid derivatives of the formula X, wherein A, B and C ^{+ have} the abovementioned meaning and U den The reaction in the case of using the 6-aminopenicillanic acid in anhydrous or hydrous solvents in the presence of a base and in the case of using the Ver compounds of general formula IV in anhydrous and hydroxyl-free solvents with or without addition of a base at a temperature in the range of -30 to +50 ⁰ C is performed.

The non-toxic pharmaceutically acceptable salts mentioned above include salts of the acidic carboxyl group such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts and non-toxic substituted ammonium salts with amines such as di- and tri-lower alkylamines, procaine, dibenzylamine, ο, ο'-dibenzylethylenediamine, N-benzyl / 3-phenylethylamine, N-methyl- and N-ethylmorpholine, 1-epenamine, dehydroabietylamine, N, N'-bis-dehydroabietylethylenediamine, N-lower alkylpiperidine and other amines which have been used to form salts of penicillins , By the term "lower alkyl" is meant in the invention both a straight-chain and a branched alkyl group having up to 6 carbon atoms In connection with other groups, as in "lower alkylamino", the term "lower alkyl" refers only to the alkyl portion of the group in question In the reaction according to the invention of the carboxylic acids of the general formula V with 6-aminopenicillanic acid, the carboxylic acids modified at the carboxyl group are preferably in the form of a solution in an anhydrous indifferent organic solvent with a solution of 6-aminopenicillanic acid in water, water-containing or anhydrous organic solvents Suitable solvents for the carboxylic acids which have been modified at the carboxyl group are, for example, for an aqueous reaction medium acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulphoxide and hexamethylphosphoric triamide anhydrous reaction medium, preferably methylene chloride and chloroform. The 6-aminopenicillanic acid is preferably used as a solution of its salt with a base in water or in a mixture of water with a water-miscible solvent or in an anhydrous organic solvent in the reaction according to the invention. Suitable solvents, other than water, for an aqueous reaction medium are preferably acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide and isopropanol, preferably methylene chloride and chloroform for an anhydrous reaction medium above said solvents. In order to convert the 6-aminopenicillanic acid into the salt of a base dissolved in a solvent, suitable bases in the case of an aqueous or aqueous reaction mixture are, for example, inorganic bases such as sodium carbonate, sodium hydroxide, sodium carbonate, the corresponding potassium and calcium compounds, magnesium oxide or magnesium carbonate or buffer mixtures, in the case of an anhydrous reaction medium preferably triethylamine, pyridine, diethylamine, N-ethylpiperidine or N-Athylmorpholin use.

The reaction according to the invention with carboxylic acids of the general formula V which have been modified on the carboxyl group and with the silylated 6-aminopenicillanic acids of the general formulas III and IV is carried out in hydroxyl-free, indifferent organic solvents, for example in carbon tetrachloride, methylene chloride, chloroform, tetrahydrofuran, benzene, diethyl ether and toluene executed.

The reaction according to the invention of the carboxylic acids of the general formula V, in the form modified with the carboxyl group, with the 6-aminopenicillanic acid in an aqueous or aqueous medium can take place at a pH of preferably 6.5 to 8.0 or else at a pH be carried out by about 3

 As with most chemical reactions, higher or lower temperatures than those in the examples

be used specified. However, if one goes considerably beyond the values given therein, side reactions will increasingly take place which reduce the yield or adversely affect the purity of the products. On the other hand, excessively lowered reaction temperatures reduce the reaction rate so much that yield reductions may occur. In the reaction according to the invention, therefore, the carboxylic acids of the general formula V which have been modified on the carboxyl group are with the 6-aminopenicillanic acid or the silylated 6- <

Aminopenicillansäuren the general formula III and IV reaction temperatures of -20 to + 30 ° C are preferred. Only in cases where the carboxylic acids modified at the carboxyl group are not sufficiently stable or there is a risk of racemization occurring at an optically active center adjacent to the carboxyl group, it may be expedient, preferably at reaction temperatures below -20 ° C to work. In the reaction according to the invention of the carboxylic acids of the general formula V which have been modified on the carboxyl group with the 6-aminopenicillanic acid or on the compounds of the general formulas III and IV, the reactants can be reacted in equimolecular amounts. However, it may be desirable to use one of the two reactants in excess to facilitate the purification or purification of the desired penicillin and to increase the yield. Thus, for example, the 6-aminopenicillanic acid or the compounds of the general formulas III and IV can be used with an excess of from 0.1 to about 0.4 molar equivalents and thereby achieve better utilization of the carboxylic acids of the general formula V. In the workup of the reaction mixture and isolation of the penicillin, any existing 6-aminopenicillanic acid can be easily removed because of their good solubility in aqueous mineral acids. By contrast, any carboxylic acid present (see formula V) is much more difficult to separate from the penicillin formed. The amount of the modified carboxylic acids of the general formula V with the 6-aminopenicillanic acid or the compounds of the general formulas III and IV added bases in the inventive reaction of the carboxyl group is determined for example by the desired maintenance of a specific pH. Where a pH measurement and adjustment is not made or is not possible or sin η is full due to the lack of sufficient amounts of water in the diluent, in the case of using the compounds of general formula III and IV, about 0.5 to 2.0 Molar equivalents of base, in the case of using 6-aminopenicillanic acid and an anhydrous reaction medium about 1.5 to 2.5 molar equivalents of base added.

The work-up of the reaction mixtures for the preparation of the penicillins according to the invention and their salts is carried out consistently in the manner well known in the penicillins.

The carboxylic acids of general formula V are thereby converted into the forms of the invention modified to the carboxyl group, that they with about one molar equivalent of the compounds of general formula Vl, VII, VIII or IX in an anhydrous, indifferent organic solvent in the presence of about one molar equivalent a tertiary organic base, at a temperature of about -60 to + 3O ⁰ C, preferably -30 to +5 ⁰ C for reaction brings. The forms of the carboxylic acids which have been changed at the carboxyl group are preferably not isolated but used together with the solvent in which they are present for the reaction with the 6-aminopenicillanic acid or the compounds of the general formulas III or IV. If the reaction mixture contains water in the reaction with the aminopenicillanic acid, organic solvents which are preferably water-miscible as solvents for the reaction of the carboxylic acid V with the compounds VI, VII, VIII or IX, for example acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric triamide used. If the reaction mixture contains no water in the reaction with 6-aminopenicillanic acid or is the reaction mixture in the reaction with compounds of the general formulas III or IV, then such as preferably methylene chloride or chloroform are used in addition to the solvents mentioned.

The carboxylic acids of general formula V are thereby converted into the carboxylic acid derivatives of the general formula X according to the invention, that first compounds of general formula XI in an anhydrous, indifferent organic solvent, for example acetone, tetrahydrofuran, methylene chloride, dioxane, chloroform or dimethylformamide, in the presence of at least and preferably one mole equivalent of a tertiary base, preferably triethylamine, at temperatures of about -25 to +25, preferably -1O ⁰ C, with one molar equivalent of thionyl chloride to form one molar equivalent of basehydrochloride converted into an unknown compound, this intermediate is not isolated but then in the presence of a further molar equivalent of an organic base, preferably triethylamine, with a molar equivalent of the carboxylic acid V at a temperature of about -25 to +25, preferably -10 to + 1O ⁰ C, to implement brin gt. After removal of the base hydrochloride by filtration, the corresponding compound of general formula X can be isolated by evaporation of the solvent and optionally by recrystallization from indifferent solvents or, if the substance is not crystalline, by briefly washing an example ethereal or benzene solution with an aqueous bicarbonate solution Clean at the lowest possible temperature.

The 6-aminopenicillanic acid used as starting material in the invention was obtained by known methods by cleavage of penicillin-G, either by fermentative processes or by a chemical cleavage (see Netherlands Patent 67/13809). The carboxylic acids of general formula V were prepared from the amino acids of general formula XII by reaction with the compounds of general formula XIII in which A, B, W and C have the abovementioned meaning. The compounds of general formula XIII, as far as W is halogen, have been obtained by methods disclosed in West German Patent Application P 1793287.5, Federal Republic of Germany Patent 1 259871, United States Patents 3275618 and 3337621 and Japanese Application 12921/64 are described. In addition, some of the compounds of general formula XIII, as far as W is halogen, from the corresponding amides by metallation with M ethyl lithium amide nitrogen and subsequent reaction with phosgene. The compounds of generally Formula XIII, when W is halogen and A is Group C, were recovered from the Group vv cyclic ureas and phosgene, as further described in the Examples.

The preparation of the reagents of the general formulas VI, VII and IX used is described in the literature (compare J. Med. Chem. 9 [1966] S.980; Bar. 96 [1963] S. 2681; Tetrahedron 17 [1962 ] P. 114). The reagent of general formula VIII was obtained from ο, ο'-dimethylethylenediamine after conversion into the ο, ο'-Bistrimethylsilylverbindung, their reaction with phosgene to give the corresponding cyclic urea and its reaction with phosgene.

The penicillins according to the invention can also be prepared from the carboxylic acids of the general formula V and 6-aminopenicillanic acid or the silylated 6-aminopenicillanic acids (see the general formulas III and IV) by the customary methods of peptide chemistry (compare E.Schröder, K. Lübke, The Peptids, Methods of Peptide Synthesis, Vol. 1, pp. 76 to 128), but only in a less advantageous manner win.

In an attempt to recover some of the penicillins of the present invention by the acid chlorides and 6-aminopenicillanic acid prepared in the usual way from the acids (general formula V) with thionyl chloride, a mixture of several penicillins is obtained, among which the sought-after and otherwise unequivocal ( from ampicillin and the associated acid chlorodi A-CO-CI, see general formula V) penicillin either not at all or only in very small amount was present. This results from the comparison of the "in vitro" bacterial spectra and the thin layer chromatogram In an attempt to obtain the penicillins according to the invention via the mixed anhydrides and aminopenicillanic acid prepared in the usual way from the acids with ethyl chloroformate, it was possible to obtain only in a yield of 20% Isolate% ethoxycarbonylpenicillin.

The chemotherapeutic efficacy of the new penicillins was tested in vivo and in vitro. The determination of the in vitro inhibition values (MIC minimal inhibition concentration) was carried out in liquid medium in the tube serial dilution test, the reading being carried out after incubation at 37 ° C. for 24 hours (Tables see pages VI to X). The MIC is indicated by the turbidity-free tube in the dilution series. The nutrient medium used was a whole medium of the following composition: Lab Lemco (OXOID) 10 g, peptone (DIFCO) 10 g, NaCl 3 g, D - (+) - dextrose (MERCK) 10 g, buffer pH 7.4 1 000 ml. The spectrum of action includes both gram-negative and gram-positive bacteria. The particular advantage of the penicillins according to the invention is that they are active both against in vitro (see Table 1) and in animal experiments against penicillin and carbenicillin-resistant Klebsiella bacteria and against ampicillin-resistant proteus bacteria. In addition, penicillin-resistant Pseudomonas species are detected in vitro and in vivo. The concentrations necessary for the killing are reached in the serum after parenteral administration.

The generally excellent effect is achieved both with single and repeated administration. Resorption of the new penicillins is very rapid after subcutaneous administration and peak levels are reached within 10 minutes. The excretion is usually just as fast. The penicillins according to the invention are acid-stable. They remain microbiologically active at pH 1 for 1 hr. Some of the new penicillins are excellently tolerated, which is made particularly clear by the extremely high dose, which in these cases is tolerated without complications when administered intravenously into the tail vein. The penicillins according to the invention can be formulated and administered alone or in combination with a pharmaceutically acceptable carrier according to the usual pharmaceutical procedure. For oral administration, they may be in the form of tablets, e.g. In addition, starch, lactose, certain types of alumina, etc., or in the form of capsules, drops or granules, may be added alone or together with the same or equivalent additives. They may also be given orally in the form of juices or suspensions, which may contain common flavoring agents or coloring agents for such purposes.

Furthermore, the penicillins of the invention may be administered by parenteral administration, e.g. intramuscularly, subcutaneously or intravenously, possibly as a drip infusion. In the case of parenteral administration, this is best done as a sterile solution which may contain other components of the solution, such as sodium chloride or glucose, to render the solution isotonic. To prepare such solutions, it is expedient to use these penicillins in the form of dry ampoules. For oral or parenteral administration, a dosage of 25,000 to 1 million E / kg body weight / day is appropriate. It can be given as a single dose or as a continuous drip or distributed over several doses. For a local treatment, one can prepare and use the procedural penicillins as ointments or powders.

The following examples are intended to illustrate the invention without limiting it.

The / 3-lactam content of the penicillins was determined by iodometry. All of the substances described here showed an IR spectrum corresponding to their constitution. The NMR spectra of the penicillins were recorded in CD ₃ OD solution; the signals given in the examples correspond to the T-scale; they agree with the respective constitution. The numbers given in the efficacy against certain bacteria (E / ml) are minimal inhibitory concentrations in the tube serial dilution test after 24 hours of incubation. In the statement "efficacy in animal studies", "A" means that the affected penicillin in the mouse when administered subcutaneously to Proteus vulgaris 1017 is more effective than ampicillin and "B" is more effective against ampicillin and carbinicillin against Klebsiella aerobacter 63 The analysis of the analytical data took into account the water content of the penicillins.

Example 1:

D-a- (3-acetyl-3-allyl reido) -benzylpenicillin sodium

With exclusion of moisture, 5.5 parts by weight of di- (3-acetyl-3-allylureido) -a-phenylacetic acid were dissolved in 50 parts by volume of dichloromethane and, with cooling, 2.0 parts by weight of triethylamine were added. It was then cooled to -5 to -10 ° C and 3.6 parts by weight of tetramethylchloroformamidinium chloride added in a few portions over a few minutes. The mixture was then stirred for 30 min. At this temperature, sucked from the possibly unsolved, without the solution over O ⁰ C heated. The filtrate was cooled to -10 ° C and added it all at once to the -10 ⁰ C cold solution of 4.1 parts by weight of 6-aminopenicillin and 3.4 parts by weight of triethylamine in 50 parts by volume of dichloromethane. (The aminopenicillanic acid was stirred with the triethylamine and 2 parts by weight of crushed molecular sieve [zeolite VS 10-2] at room temperature for 1.5 hours, then sucked with exclusion of moisture and the filtrate was used for the reaction.) The combined solutions were left for 1 hr. At ^{0 0} C and then poured into 100VoI.-parts of water. The pH was adjusted to 6.5, the dichloromethane phase was separated off and the aqueous phase was covered with 200 parts by volume of a 1: 1 mixture of ethyl acetate and ether. With vigorous stirring and ice-cooling, the mixture was treated with enough 2N hydrochloric acid to adjust the pH to 2.0 in the aqueous layer. The organic phase was separated with 2 χ 40VoI.-Parts of water and dried over MgSO ₂ 2 hrs. In a refrigerator. It was then mixed with 20 parts by volume of a 1 M solution of sodium 2-ethylhexanoate in methanol-containing ether, concentrated the mixture largely in vacuo at ^{0 0} C, took in the just sufficient amount of methanol and precipitated the sodium salt of penicillin by adding excess ether while shaking vigorously.

Yield 67%, / 3-lactam content 81%.

Calc .: C 52.4 H 5.3 N 10.9 S 6.2% F. C 51.5 H 6.0 N 10.3 S 5.5%

The product was identical to one from ampicillin and N-acetyl-N according to IR spectrum and thin-layer chromatogram.

Allylcarbaminsäurechlorid hergestellen comparison preparation. ι

Example 2:

D-a- (3-y-chlorobutyryl-3-methyl-1-propyl) benzyl penicillin sodium

As described in Example 1, from 6.25 parts by weight of di (3-7-chlorobutyl-3-methylureido) -phenylacetic acid and 3.6 parts by weight of tetramethylchloroformamidinium chloride, a solution was prepared which was allowed to stand for 1.5 hours. 5 to -10 ⁰ C was held.

Subsequently, it was combined with a solution of 4.1 parts by weight of 6-aminopenicillanic acid and 3.4 parts by weight of triethylamine in dichloromethane, which was stored for 1 hr. At room temperature. Subsequently, one worked as in Example 1

described on. Yield 62%, / 3-lactam content 84%.

Calc .: C 48.0 H 5.1 Cl 6.4 N 10.2 S 5.8% Found: C 48.1 H 5.2 Cl 5.8 N 9.9 S 6.4%

NMR signals at τ = 2.3 to 2.9 (5H), 4.45 (1H), 4.55 (2H), 5.8 (1H), 6.4 (2H), 6.75 (3H), 7.3 (2H), 7.9 (2H), and 8.5ppm (6H).

Example 3:

If one replaces in the procedure of Example 2, there used D-a- (3-y-chlorobutyryl-3-methylureido) -phenylacetic acid

by 0.02 mol each:

Da- (3- / 3-Chloro-propionyl-3-methyl-ureido) -phenylacetic acid, Da (3-y-trifluorobutyryl-3-methyl-ureido) -phenylacetic acid, DaPy-trichlorobutyryl-S-methyl-ureido-J-phenylacetic acid, Dapy -Trichlorbutyryl-S-.beta.-chloroethyl-ureidol-phenylacetic acid.

Da-fS-.beta.-cinnamoyl-S-methyl-ureidoJ-phenylacetic acid, Do; - (3-cinnamoyl-3-methyl-ureido) -phenylacetic acid or Da- (3-hexahydrobenzoyl-3-methyl-ureido) -phenylacetic acid so the following penicillins are obtained in the form of their sodium salts:

Da-IS-β-chloropropionyl-S-methylureido-benzylpenicillin, Da-fS-y-trifluorobutyryl-S-methyl-ureido-benzylpenicillin, DaPy-trichlorobutyryl-S-methyl-ureido-benzylpenicillin, Da-fS-y-trichlorobutyryl- S-.beta.-chloroethyl-ureidot-benzylpenicillin, D-oHS-cinnamoyl-S-methyl-ureido-benzylic penicillin, Da-f S -n-S-tetrahydrobenzyl-S-methyl-ureido-benzylpenicillin,

D-A-P-S-methyl-Hexahydrobenzoyl ureidoi-benzylpenicillin.

Example 4:

DJL-a-tS-benzoyl-S-methyl-ureidol-p-methylbenzylpenicillin sodium

As described in Examples 1 and 2, this penicillin was prepared from 5.5 parts by weight D, La (3-benzoyl-3-methyl-ureido) -ptolyl-acetic acid, 3Gew parts tetramethyl chloroformamidinium chloride and 4.35 wt. Share 6-aminopenicillanic acid

manufactured. Yield 59%, β-lactam content 84%.

calc .: C 54.5 H 5.3 N 9.7 S 7.9% Found: C 54.9 H 5.9 N 9.5 S (5.6)%

NMR signals at τ = 2.5 (5H), 2.5 to 3.0 (4H), 4.3 to 4.65 (3.0 H), 5.8 (1H), 6.9 (3H ), 7.7 (3H) and 8.2 to 8.5 ppm (6H).

Efficacy in animal experiments: A and B

Example 5:

D, L- (3-y-chlorobutyryl-3-methyl-ureido) - (2-thenyl) -methylpenicillin sodium

This penicillin was prepared in the manner described in Examples 1 and 2 from 5.9 parts by weight of D, L- (3-Y-chlorobutyryl-3-methyl-ureido) - (2-thenyl) -acetic acid, 3.5Gew. Parts of tetramethylchloroformamidinium chloride and 4.06 parts by weight of 6

Aminopenicillanic acid produced. Yield 64%, β-lactam content 95.5%.

NMR signals at T = 2.5 to 3.2 (3H), 4.1 (1H), 4.4 (2H), 5.8 (1H), 6.3 (2H), 6.7 (3H), 7.2 (2H), 7.9 (2H) and 8.4ppm (6H).

Efficacy in animal experiments: B.

Example 6:

If, in the procedure of Example 1, the D-a- (3-acetyl-3-allyl-ureido) -phenylacetic acid used there is replaced by je

0.02 mol:

"- (S-acetyl-S-methylureido-1-p-tolylacetic acid, a- (3-acetyl-3-methylureido) -p-chlorophenylacetic acid, α- (3-acetyl-3-methylrido) -p-methylsulfeny I phenylacetic acid, α- (3-acetyl-3-methyl-propyl) -p-methoxyphenylacetic acid, α-α-acetyl-S-methylureidol-o-chlorophenylacetic acid, α- (3-acetyl-3-methylrido) - m-Iodo-phenyl acetic acid, α- (3-acetyl-3-methylureido) -2,6-dichloro-phenylacetic acid, α- (3-acetyl-3-methylureido) -2,6-dimethoxy-phenylacetic acid, α- ( 3-acetyl-3-methylureido) -2,4-dibromo-phenylacetic acid, "- (S-acetyl-S-methylureidol-m-methyl-phenylacetic acid, e- (3-acetyl-3-methylureido) -2,6- dimethyl-phenylacetic acid, α- (3-acetyl-3-methylureido) -2-chloro-6-fluoro-phenylacetic acid,

a- (3-acetyl-3-methylureido) -2-thenyl-acetic acid or a-P-acetyl-S-methylureido-S-thenyl-acetic acid, the sodium salts of the following penicillins are obtained:

alpha-beta-acetyl-S-methylureidol-p-methylbenzylpenicillin,

α-O-acetyl-S-methylureidol-p-chlorobenzylpenicillin,

«- (S-acetyl-S-methylureido) -J-p-methylsulfenylbenzylpenicillin, a-fS-acetyl-S-methylureidol-p-methoxybenzylpenicillin, oHS-acetyl-S-methylureidoJ-o-chlorobenzylpenicillin, oHS-acetyl-S-methylureidoJ-m -iodobenzylpenicillin, α-acetyl-S-methylureido-1-dichlorobenzylpenicillin, α- (3-acetyl-3-methylureido) -2,6-dimethoxybenzylpenicillin, α- (3-acetyl-3-methylureido) -2,4-dibromobenzylpenicillin , OHS-acetyl-S-methylureidol-m-methylbenzylpenicillin, α- (3-acetyl-3-methylureido) -2,6-dimethylbenzylpenetrillin, α-acetyl-S-methylureidol-1-chloro-S-fluorobenzylpenicillin, "- (S-acetyl-S-methylureidol-a ^ -thenylmethylpenicillin or aO-acetyl-S-methylureidoJ-aS-thenylmethylpenicillin.

Example 7:

D-a-IS-methoxycarbonyl-S-methyl-ureidol ^^ - dichlorobenzyl-penicillin sodium

1,35Gew. Part Tetramethylchlorformamidiniumchlorid were dissolved in 15VoI. portions of dichloromethane and cooled under exclusion of moisture at 0 C ^c. To this solution was added 2.4 parts by weight of di (3-methoxycarbonyl-3-methyl-ureido) -2,6-dichloro-phenylacetic acid in a little dichloromethane. At -5 ^C C the solution of 1,04Vol. parts of triethylamine was now over 30 min. Then added dropwise in 5VoI. portions of dichloromethane. After a further 40 min. At -5 ° C was combined with the -20 ° C cold solution ofTriäthylaminsalzes from 2.22 parts by weight of 6-aminopenicillanic acid and 1.6 parts by volume of triethylamine in 25Vol parts of dichloromethane. Now 30 min. Was stirred at 0 ⁰ C, wherein after 15 min. Added again 0.4Vol.-parts of triethylamine. The mixture was then stirred for 30 min. At room temperature, poured into water, separated at pH 6.5, the aqueous layer and the sodium salt of penicillin, as described in Example 1, isolated. Yield 28%, β-lactam content

NMR signals at τ = 2.6 (2.1 H), 2.7 (0.9 H), 3.4 (0.7 H), 3.8 (0.3H), 4.35 to 4, 50 (2H), 6.8 (1H), 6.15 (3H), 5.8 (2.1H), 6.85 (0.9H) and

8,45ppm (6H).

Example 8:

L-a-iS-methoxycarbonyl-S-methylureidoJ ^^ - dichlorobenzyl-penicillin sodium

This penicillin was prepared in the manner described in Example 7 from 3.1 parts by weight of L-α- (3-methoxycarbonyl-3-methylureido) -2,6-dichlorophenylacetic acid, 1.74 parts by weight of tetramethylchloroformylamidinium chloride and 2.87 parts by weight

6-aminopenicillanic acid produced.

Yield 47%, β-lactam content 92%.

NMR signals at r = 2.6 (1.8H), 2.7 (1.2H), 3.35 (0.6H), 3.8 (0.4H), 4.4 (2H), 5.75 (1H), 6.15 (3H), 6.8 (1.8H), 6.85 (1.2H) and 8.4ppm

Example 9:

D, L-a- (3-methoxycarbonyl-3-methyl-ureido) -2,6-dichloro-benzylpenicillin sodium

To the slurry of 3,0Gew. parts feingemörsertem Tetramethylchlorformamidiniumchlorid in 20VoI. parts of dry acetone were added dropwise at 0 ⁰ C a solution of 5,0Gew. parts D, La (3-methoxycarbonyl-3-methyl-ureido) -2,6 dichlorophenylacetic acid in 10 parts by volume of acetone. After 5 min. Was cooled to -5 ° C and dripped slowly and evenly over 30 min. 2.1 Vol. Parts of triethylamine in 10VoI.-parts of acetone with exclusion of moisture. With stirring, ⁰ C for 1 hr. And then kept sucked from the precipitate without the solution was warmer than 0 ° C in O. The filtrate was then added to the 0 ⁰ C cold solution of 3.23 parts by weight of 6-aminopenicillanic acid in 25VoI.-parts of 80% aqueous tetrahydrofuran [addition of sufficient 2 N NaOH until just solution occurs (pH 8.2 )] in a few portions, the pH being kept between 7.5 and 8.0 by the addition of 2N NaOH. With stirring, it was allowed to come to room temperature, where stirring was continued until no more sodium hydroxide solution was required to maintain the pH of 7.5 to 8.0 (1 to 2 hours). The pH was then brought back to 6.5 with a little dilute hydrochloric acid, 20VoI.-parts of water were added and the tetrahydrofuran was evaporated in vacuo at room temperature. The remaining aqueous solution was extracted once with 25 vol. Parts of ether and coated with 50VoI.-parts of a 1: 1 mixture of ethyl acetate and ether. Under ice-cooling was acidified with dilute hydrochloric acid to pH 2.0 and the organic phase separated. This was washed twice with 10VOI.-portions of water, dried over MgSO _{4 for} 4 hrs. At 0 ⁰ C and filtered. By addition of 15VoI.-parts of a 1 molar solution of sodium 2-ethylhexanoate in methanol-containing ether was precipitated from the sodium salt of penicillin. The solvent was almost distilled from the mixture in vacuo at ⁰ ° C., taken up in the smallest possible amount of methanol, and the product was precipitated by the addition of ether. After 1 hour at ^{0 0} C had left, was filtered off, washed with methanol-containing ether and then dried in a vacuum desiccator over P ₂ Os for several days

 Yield 71%, / 3-lactam content 68%

 Calc. 41.3 H4.2 Cl 12.2 N 9.6 S5.5% 41.1 H 5.0 Cl 14.0 N 9.0 S 4.9%

NMR signal at τ = 2.5 (1.95H), 2.6 (1.05H), 3.35 and 3.40 (0.65H), 3.8 (0.35H), 4.45 ( 2H), 5.8 (1H), 6.2 (3H), 6.75 (1.95H), 6.8 (1.05H) and 8.4ppm (6H).

Example 10:

A) D-α-O-methoxycarbonyl-S-methyl-u'reidol-phenylacetic acid

15.1 parts by weight of D (-) - C-phenylglycine were stirred for 15 minutes with 20.2 parts by weight of triethylamine in 180 parts of a 3: 1 mixture of dimethyl sulfoxide and water. In the course of 30 min., 15.2 parts by weight of N-methoxycarbonyl-N- were now.

Methyl-carbaminsäurechiorid in 30 parts by volume of dry acetone was added dropwise so that the temperature did not rise above 2O ⁰ C. Man ₍ stirred for 2 hours after, then added 200 parts by volume of water and acidified with dilute hydrochloric acid to pH 2. It was then extracted three times with 120 parts by volume of ethyl acetate, the organic phase with 50VoI.-parts of water washed and dried over MgSO _4. The solvent was distilled off after filtration in vacuo residues of dimethyl sulfoxide at 80 ⁰ C and

0.1 Torr deducted. The glassy oil remaining in 73% yield was pure methoxycarbonylmethyl-ureidophenyl-acetic acid according to the NMR spectrum.

C 54.0 H 5.3 N 10.5% C 54.9 H 5.6 N 9.6% NMR signals at τ = 0.4 (1H), 2.4 to 2.8 (5H), 4.65 (1H), 6.2 ( 3H) and 6.9ppm (3H).

B) D-α-iS-methoxycarbonyl-S-methyl-ureidot-benzylpenicillin sodium

This penicillin was prepared as described in Example 7 from 5.3 parts by weight of D-α- (3-methoxycarbonyl-3-methylureido) -phenylacetic acid, 3.4 parts by weight of tetramethylchloroformamidinium chloride and 4.0 parts by weight of 6-aminopenicillanic acid. Yield 63%, / 3-lactam content 69%. NMR signals at τ = 2.3 to 2.9 (5 H), 4.45 (1 H), 4.5 and 4.55 (2 H), 5.8 (1 H), 6.2 ( 3H), 6.85 (3H) and 8.45ppm (6H). ·

In the following table, the antibacterial activity of this product A is compared with the penicillin B prepared from ampicillin and N-methoxycarbonyl-N-methyl-carbamic acid chloride as well as with the product prepared according to the procedure of Example 27 C:

bacteria A Efficacy [E / ml] 6.25 C 100.00 12.50 B 25,00 200.00 Escherichia coli 14 50,00 25,00 > 400.00 Escherichia coli 183/58 50,00 25,00 > 400.00 Pseudomonasaerug. Bonn 50,00 200.00 > 400.00 Pseudomonasaerug. Walter 200.00 200.00 > 400.00 KlebsiellaKIO 200.00 1.56 6.25 Klebsieila 63 1.56 Staphylococcusaureus133

Example 11:

A) D-α- (3-isopropoxycarbonyl-3-methylureido) -phenylacetic acid

15.1 parts by weight of D (-) - C-Phenylcjlycin were dissolved by addition of sufficiently dilute sodium hydroxide in 250VoI.-parts of 50% aqueous dioxane. The pH was then adjusted back to 7.8 with 2N HCl, with some of the phenylglycine precipitated in finely divided form. The mixture was cooled to ⁰ ° C. and 18.0 parts by weight of N-isopropoxycarbonyl-N-methylcarbamic acid chloride in 30 parts by volume of anhydrous dioxane were added dropwise over the course of 30 minutes, the pH being from 7.5 to 8.0 by simultaneous addition of 2 η-soda lye was maintained. The mixture was then stirred at room temperature until no addition of alkali was required to maintain the pH constant. Then 300 parts by volume of water were added and the solution was extracted once in 150 parts by volume of ether. Subsequently, the mixture was acidified to pH 2 with 2N HCl and the precipitated oil was taken up in several portions of ethyl acetate. The combined organic solutions were washed once with 100 parts by volume of water and dried over MgSO _{4 for a} few hours. After filtration, it was evaporated and the oily residue freed from dioxane at 60 to 80 ° C and 0.1 Torr. The glassy product was obtained in 48% yield. It was completely pure according to the NMR spectrum and the thin-layer chromatogram, calc .: C 57.1 H 6.1 N 9.5% Found: C 56.9 H 5.7 N 9.8% NMR signals at τ = -0.3 (1H), +0.4 (1H), 2.3 to 2.8 (5H), 4.6 (1H), 5.0 (1H), 6.9 ( 3H) and 8.75ppm (6H).

B) the following a-ureido-arylacetic acids were prepared as described in Example 11A:

1. D-a- (3-acetyl-3-allylureido) -phenylacetic acid containing 8.1 parts by weight of N-acetyl-N-allylcarbamic acid chloride and 7.5 parts by weight of D (-) - C-phenylglycine. Yield 100%.

Calc .: C 60.8 H 5.9 N 10.1% Found: C 60.3 H 6.1 N 9.8% NMR signals at τ = 0.0 (1H), 2.6 ( 5H), 3.75 to 4.5 (1H), 4.6 (1H), 4.7 to 5.15 (2H), 5.5 to 5.9 (2H) and 7.7ppm (3H ).

2. D-α- (3-y-chlorobutyryl-3-methylureido) -phenylacetic acid from 9.9 parts by weight of N-y-chlorobutyryl-N-methylcarbamic acid chloride and 7.5 parts by weight of D (-) - C-phenylglycine. Yield 99%.

Calc .: C 53.8 H 5.5 Cl 11.3 N 9.0% Found: C 53.9 H 5.8 Cl 10.8 N 9.4% NMR signals at τ = -0.1 (1H), 2.6 (5H), 4.6 (1H), 6.3 (2H), 6.8 (3H), 7.2 (2H) and 7.9ppm (2H).

3. DL-c * - (3-benzoyl-3-methylureido) -4-tolylacetic acid from 3.2 parts by weight of N-benzoyl-N-methylcarbamic acid chloride and 3.8 parts by weight of D, LC- (4-tolyl) glycine. Yield 90%.

NMR signals at τ = 2.5 (5H), 2.6 (2H), 2.8 (2H), 4.5 (1H), 6.85 (3H) and 7.7ppm (3H).

4. Da- (3-methoxycarbonyl-3-methylureido) -2,6-dichlorophenylacetic acid from 1.75 parts by weight of N-acetyl-N-methylcarbamic acid chloride and 3.31 parts by weight of D (-) - C- (2 , 6-dichlorophenyl) glycine hydrobromide. (We assume that the recoverable from the 2,6-dichlorobenzyldehyde via the hydantoin in a conventional manner acid present after acylation of the amino group by racemate resolution with optically active bases and subsequent cleavage of the acylating group in a left-handed and a dextrorotatory form , in the left-handed form based on the known conditions in the C-phenylglycine of the D series, heard in the dextrorotatory form of the L series).

Yield 90%, mp. 149 ⁰ C [a] _D = -28.1 "C.

NMR signals at T = 0.2 (1H), 2.5 (3H), 3 ~ 6 (1H), 6.2 (3H) and 6.9ppm (3H).

5. LaO-methoxycarbonyl-S-methyl-ureido-1-dichloro-phenylacetic acid from 1.6 parts by weight of N-methoxycarbonyl-N-methylcarbamic acid chloride and 3.01 parts by weight of L (+) - C- (2,6-dichlorophenyl ) -glycine hydrobromide, yield 100%, [a] _D = +29.3 ⁰ C.

NMR signals as given in Example 9B4.

6. D 1 -O-Methoxycarbonyl-S-methylureido ^^ -dichlorophenylacetic acid from 3.03 parts by weight of N-methoxycarbonyl-N-methyl-carbamic acid chloride and 4.4 parts by weight of D, LC- (2,6-dichlorophenyl) - glycine. Yield 78%, mp. 216 ° C, NMR signals as given in Example 9B 4.

7. D-a- (3-n-butoxycarbonyl-3-methylureido) -phenylacetic acid, 9.7 parts by weight of N-n-butoxycarbonyl-N-methylcarbamic acid chloride and 7.1 parts by weight of D-C-phenylglycine. Yield 100%.

Calc .: C 58.4 H 6.5 N 9.1% Found: C 58.6 H 6.9 N 9.5%. NMR signals at τ = 0.5 (1H), 2.6 (5H), 4.65 (1H), 5.8 (2H), 6.9 (3H), 8.0 to 9, 0 (4H) and 9.05ppm (3H).

8. D, La (3-benzoyl-3-allyl-ureido) -methoxyphenyl-glycine from 4.5 parts by weight of N-benzoyl-N-allyl-carbamic acid chloride and 3.6 parts by weight of D, LC- (4- methoxyphenyl) glycine.

Yield 70%.

NMR signals at τ = 0.6 (1H), 2.5 (5H), 2.7 (2H), 3.0 (2H), 3.8 to 4.5 (1H), 4.6 to 5.2 (3H), 5.6 to 5.8 (2H) and 6.2ppm (3H).

9. Da- (3-acetyl-3-benzylureido) -phenylacetic acid from 8.5 parts by weight of N-acetyl-N-benzyl-carbamic acid chloride and 6.0 parts by weight of DC-phenylglycine. Yield 92%, mp 183 to 185 ^° C.

Calc .: C 66.3 H 5.6 N 8.6% Found: C 66.3 H 5.7 N 8.6% NMR signals at τ = -0.1 (1H), 2.6 (5H), 2.7 (5H), 4.55 (1H), 5.0 (2H) and 7.8ppm (3H).

10. D, La (3-benzoyl-3-allylureido) -2,6-dichlorophenylacetic acid from 4.5 parts by weight N-benzoyl-N-allyl-carbamic acid chloride and 4.4 parts by weight D, LC- (2 , 6-dichlorophenyl) glycine. Yield 97%.

Calc .: C 56.0 H 4.0 Cl 17.4 N 6.9% Found: C 55.6 H 4.4 Cl 16.0 N 6.5% NMR signals at τ = 0 (1 H ), 2.3 to 2.65 (8H), 3.6 (1H), 3.9 to 4.5 (1H), 4.8 to 5.3 (2H) and 5.6 to 5, 9ppm (2H).

11. D, Lo: - (3-acetyl-3-allylureido) -2-thenylacetic acid from 3.2 parts by weight of N-acetyl-N-allylcarbamic acid chloride and 2.9 parts by weight of D, LC- (2-thenyl) - glycine. Yield 99%. NMR signals at r = 2.5 to 3.1 (3H), 3.7 to 4.4 (1H), 4.3 (1H), 4.6 to 5.1 (2H), 5, 5 to 5.7 (2H) and 7.7ppm (3H).

12. D, La- (3-dimethylaminocarbonyl-3-methylureido) -2,6-dichlorophenylacetic acid from 3.3 parts by weight of N-dimethylaminocarbonyl-N-methyl-carbamic acid chloride and 4.4 parts by weight of D, LC- (2, 6-dichlorophenyl) glycine. Yield 86%. Mp 205 ⁰ C.

NMR signals at T = 1.6 (1H), 2.5 (3H), 3.7 (1H), 7.0 (3H), and 7.1 ppm (6H).

13. D, La (3-methoxycarbonyl-3-methylureido) -4-methoxyphenylacetic acid from 3.0 parts by weight of N-methoxycarbonyl-N-methylcarbamic acid chloride and 3.6 parts by weight of D, LC- (4-methoxyphenyl) - glycine. Yield 87%.

NMR signals at T = 2.6 (2H), 3.05 (2H), 4.6 (1H), 6.2 (6H) and 6.8ppm (3H).

14. D, La (3-dimethylaminocarbonyl-3-methylureido) -4-methoxyphenylacetic acid from 3.3 parts by weight of N-dimethylaminocarbonyl-N-methylcarbamic acid chloride and 3.6 parts by weight of D, LC- (4-methoxyphenyl) - glycine. Yield 100%.

NMR signals at τ = 2.0 (1H), 2.6 (2H), 3.05 (2H), 4.6 (1H), 6.2 (3H), 6.95 (3H) and 7.1 ppm (6H).

15. D, La- (3-Methoxycarbonyl-3-methylureido) -2-thenyl-acetic acid from 3.0 parts by weight of N-methoxycarbonyl-N-methylcarbamic acid hydrochloride and 2.9 parts by weight of D, LC- (2-thenyl ) glycine. Yield 100%.

NMR signals at τ = 0.4 (1H), 2.5 to 3.1 (3H), 4.25 (1H), 6.2 (3H) and 6.8ppm (3H).

16. D, La (3-dimethylaminocarbonyl-3-methylureido) -phenylacetic acid from 3.3 parts by weight of N-dimethylaminocarbonyl-3-methyl-carbamic acid chloride and 2.9 parts by weight of D, LC- (2-thenyl) glycine. Yield 84%.

NMR signals at τ = 1.9 (1H), 2.5 to 3.1 (3H), 4.3 (1H). 6.9 (3H) and 7.1 ppm (6H).

17. D, La (3-benzoyl-3-allylureido) -a-2-thenylacetic acid from 4.5 parts by weight of N-benzoyl-N-allyl-carbamic acid chloride and 2.9 parts by weight of D, LC- (2- thenyl) glycine. Ausbeute96%. NMR signal = 2.5 (5H), 2.5 to 3.1 (3H) to 4.5 (2H), 4.8 to 5.3 (2H) and 5.5 to 5.8ppm (2H).

18. D, La- (3-y-chlorobutyryl-3-methylureido) -2-thenylacetic acid from 4.0 parts by weight ο-γ-chlorobutyryl-N-methylcarbamic acid chloride and 2.9 parts by weight D, La (2 -Thenyl) -glycine, yield 99%.

NMR signals at τ = 2.5 to 3.1 (3H), 4.2 (1H), 6.35 (2H), 6.7 (3H), 7.2 (2H) and 7.9ppm ( 2H).

19. D, La- (3- [2-furoyl] -3-methyl-ureido) -2-thenylacetic acid from 5.6 parts by weight N- (2-furoyl) -N-methyl-carbamic acid chloride and 4.7 g. Parts D, LC- (2-Tenyl) -glycine. Yield 100 ^° C.

20. D-α- (3-Allyloxycarbonyl-3-methylureido) -phenylacetic acid from 15.8 parts by weight of N-allyloxycarbonyl-N-methylcarbamic acid chloride and 15.1 parts by weight of D-C-phenylglycine. Yield 88%.

NMR signals at τ = -1.8 (1H), +0.4 (1H), 2.6 (5H), 3.7 to 4.3 (1H), 4.4 to 4.9 (3H), 5.3 (2H) and 6., 85ppm (3H).

21. Da (3- [3-nitro-4-methylbenzoyl-3-methyl-ureido) -phenylacetic acid from 8.0 parts by weight of N- (3-nitro-4-methylbenzoyl) -N-methyl-carbamic acid chloride and 4 , 7 parts by weight of DC-phenylglycine. Yield 46%.

NMR signals at τ = 1.6 to 2.8 (8H), 4.6 (1H), 6.8 (3H) and 7.4ppm (3H).

22. D-α- (3- [4-methylbenzoyl] -3-methylureido) -phenylacetic acid from 13 parts by weight of N-p-methylbenzoyl-N-methylcarbamic acid chloride and 9.2 parts by weight of D-C-phenylglycine. Yield 85%.

NMR signals at τ = 0.2 (1H), 2.4 to 2.9 (9H), 6.65 (1H), 6.9 (3H) and 7.6ppm (3H).

23. D, La (3-Benzoyl-3-methylureido) -2,6-dichlorophenylacetic acid from 7.2 parts by weight N-benzoyl-N-methylcarbamic acid chloride and 8.0 parts by weight D, LC- (2.6 -Dichlorphenyl) glycine. Yield 100%, mp. 200 ° C. NMR signals at τ = -0.4 (1H), 2.2 to 2.7 (8H), 3.5 (1H) and 6.9 (3H).

24. D, La (3-benzoyl-3-methylureido) -4-methylsulfenylphenylacetic acid from 10.0 parts by weight of N-benzoyl) -N-methylcarbamic acid chloride and 10.0 parts by weight of D, LC- (4-methylsulfenylphenyl) glycine. Yield 73%. NMR signals at τ = 0.2 (1H), 2.3 to 2.8 (9H), 4.65 (1H), 6.9 (3H) and 7.5ppm (3H).

25. D ^ -ap-ethoxycarbonyl-S-methylureidoM-methylsulfenyl-phenylacetic acid from 16.8 parts by weight of N-ethoxycarbonyl-N-methyl-carbamic acid chloride and 20.0 parts by weight of D, LC- (4-methylsulfenyl-phenyl) -glycine , Yield 85%, mp. 120 to 122 ° G. NMR signals at τ = 0.4 (1H) 2.4 to 2.9 (4H), 4.65 (1H), 5.75 (2H), 6.85 (3H) and 7.55 ppm ( 3H).

26. D, La (3 - ^ - Chloropropionyl-3-methylureido) - (1,2,5,6-tetrahydrophenylacetic acid from 18.4 parts by weight N- / 3-chloropropionyl-N-methylcarbamic acid chloride and 15.5 wt. Parts D, LC- (1,2,5,6-tetrahydrophenyl) -glycine, yield 73%, NMR signals at τ = 0.6 (1H), 4.3 (2H), 5.7 (1H), 6.2 (2H), 6.8 (2H) and 7.7 to 8.8ppm (7H).

27. D -a- (3- [2-thenoyl] -3-methyl-ureido) -phenylacetic acid from 9.0 parts by weight of N-fS-ThenoyO-N-methyl-carbamic acid chloride and 6.6 parts by weight of D-C-phenylglycine. Yield 50%.

.28. D-a- (3- [3,5-dimethyl-isoxazol-4-oyl] -3-methyl-ureido) -phenylacetic acid from 8.5 parts by weight N- (3,5-dimethylisoxazole-4-

oyl) -N-methylcarbamic acid chloride and 5.9 parts by weight of D-C-phenylglycine. Yield 32%.

C) D-α-iso-S-isopropoxycarbonyl-S-methylureido-benzyl-penicillin sodium

This penicillin was prepared as described in Example 9 from 5.9 parts by weight of D-α- (3-isopropoxycarbonyl-3-methylureido) -phenylacetic acid, 3.7 parts by weight of tetramethylchloroformamidinium chloride and 4.0 parts by weight of 6-aminopenicillanic acid

manufactured. Yield 45%, β-lactam content 86%.

calc .: C 48.8 H 5.6 N 10.4 S 5.9%

Found: C48.7 H 5.9 N 10.8 S 5.8%

NMR signals at τ = 2.3 to 2.8 (5H), 4.4 (1H), 4.55 (2H), 5.0 (1H), 5.8 (1H), 6, 85 (3H), 8.5 (6H) and 8.7ppm (6H).

The following table shows the antibacterial activity of this product (A) with that of ampicillin and N-i-

Propyloxycarbonyl-N-methylcarbamic acid chloride (B) and the product obtained from D-α- (3-i-propoxycarbonyl-3-methyl-ureido) -phenylacetic acid as described in Example 28 (C).

Bacterial activity [E / ml]

(A) (B) (C)

Escherichia coli 14 6.25 6.25 100 Escherichia coli C165 50,00 25,00 200 Escherichia coli 183/58 12.50 6.25 400 Pseudomonasaer. Bonn 50,00 25,00 > 400 Pseudomonas aer. Walter 100.00 50,00 > 400

Example 12:

D-a-fs-butoxycarbonyl-S-methylureidoi-benzylpenicillin sodium

This penicillin was prepared in the manner described in Example 9 from 5.6 parts by weight of di- (3-n-butoxycarbonyl-3-methyl-ureido) phenylacetic acid, 3.3 parts by weight of tetramethyl-chloroformamidinium chloride and 3.6. Parts of 6-aminopenicillanic acid. Ureidoacetic acid was treated with tetramethylchloroformamidinium chloride at -5 ° C in acetone for 20 min.

touched. Yield 38%, α-lactam content 61%.

calc .: C48.1 H 6.0 N 9.7 S 5.6%

Found: C 48.4 H 5.5 N 9.4 S 5.5%

NMR signals at τ = 2.3 to 2.8 (5H), 4.45 (1H), 4.55 (2H), 5.8, 6.85 (3H), and 8.1 to 8.9 ppm (13H).

Example 13:

If, in the procedure of Example 10, the D-α- (3-methoxycarbonyl-3-methylureido) used there is used,

phenylacetic acid by 0.018 mol each:

Da- (3-ethoxy'carbonyl-3-methyl-ureido) -phenylacetic acid, Da (3-dimethylaminocarbonyl-3-methyl-ureido) -phenylacetic acid, Da (3-dimethylaminocarbonyl-3-ethyl-ureido) - pheny! acetic acid, Da-1-dimethylaminocarbonyl-S-propyl-ureidol-phenylacetic acid, Dap-dimethylaminocarbonyl-Si-propyl-ureidol-phenylacetic acid, Da- (3-dimethylaminocarbonyl-3-n-butyl-ureido) -phenylacetic acid, DaO- Dimethylaminocarbonyl-S-allyl-ureido-phenylacetic acid, Dap-dimethylaminocarbonyl-S-cyclohexyl-ureido-phenylacetic acid, DaO-dimethylaminocarbonyl-S-phenyl-ureido-phenylacetic acid, Da-is-t-pyrrolidylcarbonyl-S-methyl-ureidot-phenylacetic acid, DaPn-piperidylcarbonyl-S-methyl-ureido-J-phenylacetic acid, DaO-diethylaminocarbonyl-S-methyl-ureido-phenylacetic acid, Da (3-ethylaminocarbonyl-3-methyl-ureido) -phenylacetic acid, Da (3-methyl la minocarbonyl-3-methyl-ureido) -phenyl, acetic acid, Da (3-phenyl-la-carbonyl-3-methyl-ureido) -phenyl, acetic acid, Da- (3- [4-morpholinyl] approx rbonyl-3-methyl-ureido) -phenylacetic acid, DaO-ti-pyrrolidylcarbonyl J-S-ethyl-ureidol-phenylacetic acid, DaO-II-piperidylcarbonyl-S-ethyl-ureidol-phenylacetic acid, Da-diethylaminocarbonyl-S-ethylureido-J-phenylacetic acid, DaO -Ethylaminocarbonyl-S-ethylurido-J-phenylacetic acid, D-oHS-methylaminocarbonyl-S-ethylurido-J-phenylacetic acid, DaO-phenylaminocarbonyl-S-ethylurido-phenylacetic acid, Da (3- [4-morpholinyl] carbonyl-3-ethyl-acidido) -phenyl! acetic acid, Da-tS-n-pyrrolidylJ-carbonyl-Sn-propylureido-benzylpenicillin, Da-t-piperidyl-carbonyl-Si-propyl-ureidoJ-benzylpenicillin, DaO-diethylaminocarbonyO-Sn-butyl-ureidol-benzylpenicillin,

D-α- (3-dimethylaminocarbonyl) -3-cyclohexyl-ureido-benzylpenicillin to give the sodium salts of the following penicillins:

D-a-fS-ethoxycarbonyl-S-methyl-ureidol-benzylpenicillin, D-α-p-dimethylaminocarbonyl-S-methyl-ureidol-benzylpenicillin,

Daβ-dimethylaminocarbonyl-S-ethylurido-benzyl-penicillin, ₍

DaO-dimethylaminocarbonyl-S-propyl-ureidol-benzylpenicillin, Da-IS-dimethylaminocarbonyl-Si-propyl-ureidoJ-benzylpenicillin, Da-fS-dimethylaminocarbonyl-Sn-butyl-ureidol-benzylpenicillin, Da-t-dimethylaminocarbonyl-S-allyl- ureidol-benzylpenicillin, Da (3-dimethyl-aminocarbonyl-3-cyclohexyl-ureido) -benzylpenicillin, Da-fS-dimethylaminocarbonyl-S-phenyl-ureidol-benzylpenicillin, DaO-t-pyrrolidylcarbonyl-S-methyl-ureidol-benzylpenicillin, D-aO-II-piperidylcarbonyl-S-methyl-ureidoJ-benzylpenicillin, DaP-diethylaminocarbonyl-S-methyl-ureidoJ-benzylpenicilin, Da-fS-ethylaminocarbonyl-S-methyl-ureidoJ-benzylpenicillin, Da-fS-methylaminocarbonyl-S- Methyl-ureidol-benzylpenicillin, Da-fS-phenylaminocarbonyl-S-methyl-ureidoJ-benzylpenicillin, Da - ^ - morpholinyl-carbonyl-S-methyl-ureidol-benzylpenicillin, Da- (3- [1-pyrrolidylcarbonyl] -3-ethyl-ureido) - benzylpenicillin.

Da-fS-ti-piperidylcarbonyl J-S-ethylureidolbenzylpenicillin, Da-IS-diethylaminocarbonyl-S-ethyluridolbenzylpenicillin, Da-fS-ethylaminocarbonyl-S-ethyluridolbenzylpenicillin, DaO-methylaminocarbonyl-S-ethylureidolbenzylpenicilHn, DaO- Phenylaminocarbonyl-S-ethyluridoJ-benzyl penicillin, Da-fS-I ^ morpholin-carbonyl-S-ethyluridoJ-benzylpenicillin, Da-IS-pyridyl-J-carbonyl-Sn-propylureidol-benzylpenicillin, Da-fS-t-piperidyl-carbonyl -Si-propylureido-benzylpenicillin, Da-IS-diethylaminocarbonyl-Sn-butylureidoJ-benzylpenicillin

D-a-IS-Diäthylaminocarbonyl-S-cyclohexylureidoj-benzylpenicillin.

Example 14:

D, L-a- (3-benzoyl-3-allyl-ureido) -4-methoxybenzylpenicillin sodium

This penicillin was prepared in the manner described in Example 9 from 4.4 parts by weight of D, La (3-benzoyl) -3-allylureido) -4-methoxyphenylacetic acid, 2.26 parts by weight of tetramethylchloroformamidinium chloride and 2.6 parts by weight 6

Aminopenicillinic acid produced. Yield 51%, / 3-lactam content 65%.

calc .: C55.4 .H 5.2 N 9.2 S 5.3%

gel: C55.4 H4.8 N8.1 S4.5%

NMR signals where T = 2.6 (5H), 2.7 (2H), 3.2 (2H), 3.9 to 4.5 (1H), 4.55 (3H), 4.7 to 5.2 (2H), 5.6 to 5.9 (3H), 6.25 (3H) and 8.4 ppm

Example 15:

D ^ -a-O-benzoyl-S-allyl-ureidol ^^ - dichlorbenzylpenicillin sodium

This penicillin was prepared in the manner described in Example 9 from 7.2 parts by weight of D, La (3-benzoyl-3-allylurido) -2,6-dichlorophenylacetic acid, 4.05 parts by weight of tetramethylchloroformamidiniumchloride and 3.86 parts by weight Parts 6-aminopenicillanic acid

manufactured. Yield 46%, β-lactam content 83%.

Calc .: C49.5 H4.3 Cl 10.8 N8.6 S4.9% Found: C49.9 H5.1 Cl 11.3 N8.2 S4.4%

NMR signals at τ = 2.4 to 2.9 (8H), 3.4 (1H), 3.8 to 4.4 (1H), 4.4 to 4.6 (2H), 4.8 to 5.2 (2H), 5.5 to 5.8 (2H), 5.85 (1H) and

8.5ppm (6H).

Example 16:

If, in the procedure of Example 4, the D, L-α- (3-benzoyl-3-methylureido) -p-tolyl-acetic acid used there is replaced

Jeo, 015mol:

Da- (3-benzoyl-3-methylureido) -phenylacetic acid, Da (3-benzoyl-3-ethylureido) -phenylacetic acid, D-aHS-benzoyl-S-methylureidoM-chlorophenylacetic acid, Da (3-benzoyl-3-methylureido ) -4-methoxyphenylacetic acid, Da (3-benzoyl-3-methylureido) -2-chlorophenylacetic acid, Da (3-benzoyl-3-methylureido) -3-iodophenylacetic acid, Da (3-benzoyl-3-methylureido) - 2,6-dimethoxyphenylacetic acid, Da (3-benzoyl-3-methylureido), 2,4-dibromophenylacetic acid, Da (3-benzoyl-3-methylureido) -3-thenylacetic acid, Da (3-Benzoyl-3-methylureido ) -m-tolylacetic acid, Da (3-benzoyl-3-methylureido) -2,6-dimethylphenylacetic acid, Da (3-benzoyl-3-methylureido) -2-chloro-6-fluorophenylacetic acid, Da (3-benzoyl 3-methylureido) -2-thenylacetic acid, La (3-benzoyl-3-methylureido) -phenylacetic acid, Da (3- [3-nitro-4-methoxyphenyl] -3-methylureido) -phenylacetic acid, DaOp-chlorobenzoyl S-äthylureidol-phenylacetic acid,

Da- (3-o-bromobenzoyl-3-n-propyl-ureido) -phenylacetic acid, Da (3-p-methoxybenzoyl-3-methyiureido) -phenylacetic acid, DaOp-methoxycarbonylaminobenzoyl-S-methylureidol-phenylacetic acid, Da (3 -p-Methylsulfenylbenzoyl-3-methyl-ureidophenylessigsäure,

Da- (3- [2-chloro-5-methoxybenzoyl] -3-n-butyl-ureido) -phenylacetic acid, >

Da- (3-p-nitrobenzoyl-3-methyl-ureido) -phenylacetic acid, Da (3- [2-chloro-4-ethylsulfenylbenzoyl] -3-methylureido) -phenylacetic acid _/ Da-IS-m-cyanobenzoyl-S; methyl-ureidol-phenylacetic acid, Da (3- [3,5-dimethylbenzoyl] -3-methyl-ureido) -phenylacetic acid, Da (3-benzoyl-3-allyl-ureido) -phenylacetic acid, Da (3 -m-iodobenzoyl-3-metyl-ureido) -phenylacetic acid, Da (3-benzoyl-3-phenyl-ureido) -phenylacetic acid,

D-a- [3-naphthoyl (1) -3-methyl-ureido] -phenylacetic acid, the sodium salts of the following penicillins are obtained:

Da-benzoyl-S-methylureido-benzylpenicillin, Da (3-benzoyl-3-ethylurido) -benzylpenicillin, DaO-benzoyl-S-methylureidoM-chlorobenzylpenicillin, Da (3-benzoyl-3-methylureido) -4-methoxybenzylpenicillin, DaP- Benzoyl-S-methylureido-chlorobenzylpenicillin, DaO-benzoyl-S-methylureidol-S-iodobenzylpenicillin, Da (3-benzoyl-3-methylureido) -2,6-dimethoxybenzylpenicillin, Da (3 Benzoyl-3-methylureido) -2,4-dibromo-benzylpenicillin, DaP-benzoyl-S-methylureidol-S-thenylmethylpenicillin, DaO-benzoyl-S-methylureidol-S-methylbenzylpenicillin, Da (3-benzoyl-3-methylureido) 2,6-dimethylbenzylpenicillin, Da (3-benzoyl-3-methylureido) -2-chloro-6-fluorobenzyl penicillin, Da (3-benzoyl-3-methyl-ureido) -2-theny1-methyl penicillin, La- (3-Benzoyl-3-methylureido) benzyl penicillin, DaO-IS-nitro ^ -methoxyphenyl J-S-methylureidolbenzylpenicillin, Da-f-methoxybenzoyl-S-methylureidolbenzylpenicillin, DaOp-methoxycarbonylaminobenzoyl-S- methylureidoJ-benzylpenicillin, DaOp-chlorobenzo yl-S-ethyluridoJ-benzylpenicillin, Da-IS-o-bromobenzoyl-Sn-propyl-ureidoJ-benzylpenicillin, Da- (3- [2-chloro-5-methoxybenzoyl] -3-n-butyl-ureido) -benzylpenicillin, Da-fS-p-methylsulfenylbenzoyl-S-methylureidolbenzylpenicillin, Da-t-nitrobenzoyl-S-methylureidolbenzylpenicillin, Da- (3- [2-chloro-4-ethylsulfenylbenzoyl] -3-methylureido) -benzylpenicillin Da- (3-m-cyanobenzoyl-3-methyl-ureido) -benzylpenicillin, Da-fS-IS ^ -dimethylbenzoyl-S-methyl-ureidol-benzylpenicillin, Da-IS-benzoyl-S-allyl-ureidol-benzylpenicillin, Dapm Iodobenzoyl-S-methyl-ureidol benzylpenicillin, Da (3-benzoyl-3-phenylureido) benzylpenicillin

D-a-O-NaphthylfiJ-S-methyl-ureidol-benzylpenicillin.

Example 17:

D ^ -a-O-acetyl-S-allylureidoJ ^ -thenylmethylpenicillin sodium

This penicillin was prepared in the manner described in Example 9 from 5.0 parts by weight of D, La (3-acetyl-3-allyl-ureido) -2-thenylacetic acid, 3.6 parts by weight of tetramethylchloroformamidinium chloride and 3.9% by weight. Share 6-aminopenicillanic acid prepared.

Yield 53%, / 3-lactam content 72%.

Calc .: C46.2 H4.9 N 10.8 S12.3% Found: C46.6 H5.3 N 10.4 S 12.3%

NMR signals at τ = 2.5 to 3.2 (3H), 3.8 to 4.4 (1H), 4.2 (1H), 4.5 (2H), 4.6 to 5, 0 (2H), 5.5 to 5.7 (2H), 5.8 (1H), 7.7 (3H) and

8,4ppm (6H).

Example 18:

D ^ -a-O-methoxycarbonyl-S-methylureidol ^ -methoxybenzylpenicillin sodium

3.04 parts by weight of tetramethylchloroformamidinium chloride in 20 parts by volume of dry dichloromethane were added at ⁰ ° C. and admixed with the solution of 4.8 parts by weight of D, La (3-methoxycarbonyl-3-methylureido) -4- methoxyphenylacetic acid in 10 parts by volume of dichloromethane. Then, in the course of 30 min. At 0 ° C with exclusion of moisture 2.24Vol.-parts of triethylamine in 10VoI.-parts were added dropwise dichloromethane. The mixture was then stirred for 20 min. At +5 "C, filtered from undissolved without the solution was heated above 5 ⁰ C and cooled to - 20 ° C. To this was added the likewise prepared -20 ⁰ C cold as described in Example 1 Solution of 5.0 parts by weight of 6-aminopenicillin acid and 3.5 parts of triethylamine in 20 parts by volume of dichloromethane were then stirred for 30 minutes at ⁰ ° C. for a further 30 minutes at room temperature and finally dissolved in 150 vol. The ice water was poured in and adjusted to a pH of 6.5 with 2N sodium hydroxide solution After separation of the organic layer and mixing with 150 parts by volume of a 1: 1 mixture of ethyl acetate and ether, the procedure was as in

Example 1 described and isolated the sodium salt of penicillin.

Yield 54%, / 3-lactam content 75%.

NMR signals at τ = 2.6 (2H), 3.1 (2H), 4.3 to 4.9 (3H), 5.8 (1H), 6.2 (6H), 6.85 ( 3H) and 8.5ppm (6H).

Efficacy in animal experiments: B

Example 19:

DJL-a-fs-dimethylaminocarbonyl-S-methyl-ureidoM-methoxybenzyl penicillin sodium

This penicillin was prepared as described in Example 18 from 6.0 parts by weight of D, La (3-dimethylaminocarbonyl-3-methylureido) -4-methoxyphenylacetic acid, 3.8 parts by weight of tetramethylchloroformamidinium chloride and 6.2 parts by weight 6-aminopenicillanic acid produced. Yield 23%, / 3-lactam content 59%. ·

NMR signals at τ = 2.65 (2H), 3.1 (2H), 4.4 to 4.8 (3H), 5.65 (1H), 6.2 (3H), 6.9 ( 3H), 7.05 (6H) and 8.4ppm (6H).

Example 20:

D, L-a- (3-methoxycarbonyl-3-methyl-ureido) -2-thenylmethylpenicillin sodium

This penicillin was prepared as described in Example 18 from 4.5 parts by weight of D, L-α- (3-methoxycarbonyl-3-methylureido) -thenylacetic acid, 3.2 parts by weight of tetramethylchloroformamidinium chloride and 5.2 parts by weight of 6-aminopenicillanic acid

manufactured. Yield 62%, / 3-lactam content 84%.

NMR signals at τ = 2.5 to 3.2 (3H), 4.2 (1H), 4.5 (2H), 5.8 (1H), 6.2 (3H), 6.8 (3H) and 8.4ppm (6H).

Efficacy in animal experiments: A

Example 21:

D, L-a- (3-benzoyl-3-allylureido) -2-thenylrnethylpenicillin sodium

This penicillin was prepared as described in Example 18 from 6.0 parts by weight of D, La (3-benzoyl-3-allylureido) -2-thenylacetic acid, 3.4 parts by weight of tetramethylchloroformamidinium chloride and 5.5 parts by weight of 6 -Aminopenicillanic acid produced. yield

45%, / 3-lactam content 77%.

NMR signals at τ = 2.5 (5H), 2.5 to 3.1 (3H), 3.7 to 4.4 (2H), 4.5 (2H), 4.7 to 5.2 ( 2H), 5.5 to 5.9 (3H) and 8.4ppm (6H).

Efficacy in animal experiments: B

Example 22:

D, L-a- (3- [2-furoyl] -3-methyl-ureido) -2-thenylmethylpenicillin sodium

This penicillin was prepared as described in Example 18 from 11.6 parts by weight of D, La (3- [2-furoyl] -3-methylureido) -2-thenylacetic acid, 6.5 parts by weight of tetramethylchloroformamidinium chloride and 8.2 parts by weight. Share 6-aminopenicillanic acid

manufactured. Yield 39%, / 3-lactam content 88%.

NMR signals at τ = 2.2 (1H), 2.5 to 3.1 (4H), 3.35 (1H), 4.1 (1H), 4.45 (2H), 5, 8 (1H), 6.55 (3H) and 8.4ppm (6H).

Efficacy in animal experiments: A and B

Example 23:

D, L-a- (3-dimethylaminocarbonyl-3-methyl-ureido) -2-thenylmethylpenicillin sodium

The slurry of 3.9 parts by weight of tetramethylformamidinium chloride in 30 parts by volume of dry acetone was added at -20 ⁰ C within 5 min. With the solution of D, La- (3-dimethylaminocarbonyl-3-methylureido) -2 -thenylacetic acid in 10 parts by volume of acetone and then added dropwise within 30 min. 2.1 parts by volume of triethylamine in 5 parts by volume of acetone to. After 1 hr. Was stirred at -20 ° C, was sucked off so that the temperature of the solution did not rise above -10 ⁰ C The mixture was cooled again to -20 ⁰ C and combined with the vigorously stirred to -5 ° C cooled solution of 3.9 parts by weight of 6-aminopenicillanic acid in 50 ml of 60% aqueous tetrahydrofuran (solution was added after addition of sufficient 2N NaOH, to to set a pH of 8.2). By adding 2 η-soda lye a pH range of 7.5 to 8.0 was maintained. After 15 minutes, the mixture was allowed to come to room temperature and stirred until no change in the pH value was observed. The subsequent work-up of the reaction mixture and the isolation of the penicillin was carried out in the manner indicated in Example 9. Yield 43%, / 3-lactam content 54%. NMR signals at τ = 2.5 to 3.2 (3H), 4.5 (3H), 5.8 (1H), 6.9 (3H), 7.05 (6H) and 8.4ppm ( 6H).

Example 24:

D-a-O-y-chlorobutyryl-S-methyl-ureidoi-benzylpenicillin sodium

5.1 parts by weight of Da (3-y-chlorobutyryl-3-methylureido) -phenylacetic acid and 3.0 parts by weight of tetramethylformamidinium chloride were reacted in dichloromethane as described in Example 18. The resulting solution was combined with the solution of 6,5Gew. parts of N-trimethylsilyl-beta-aminopenicillanic acid-trimethylsilylesterin 33VoI. parts of dry dichloromethane at 0 ⁰ C. 1.3 parts by weight of pyridine were added and the mixture was stirred under exclusion of moisture for 1 hour at ⁰ ° C., then 2 × 2 hours. at room temperature. It was then poured into 120 parts by volume of ice water, adjusted to a pH of 7 to 8 and the dichloromethane removed in vacuo. The aqueous phase was shaken with 50 parts by volume ether, which was then discarded while the aqueous phase was freed from solid by filtration. Now was covered with 200Vol.-parts of a 1: 1 mixture of ether and ethyl acetate, cooled to 0 ⁰ C and acidified to pH 2 with 2 η hydrochloric acid with vigorous stirring. The separated organic solution was washed twice with 50 parts by volume of water, dried over MgSO ₄ , filtered and precipitated by adding 15 ml of a 1 M solution of sodium 2-ethylhexanoate in methanol-containing ether, the sodium salt of penicillin. The entire mixture was concentrated at ⁰ ° C. to near dryness, rapidly dissolved in as little methanol as possible and precipitated by the addition of excess ether. Non-crystalline solid, yield 29%, / 3-lactam content 49%. Position of the NMR signals as indicated in Example 2.

The crude product still contained D-α-IS-y-chlorobutyryl-S-methylureidol-phenylacetic acid, which can be removed by fractional extraction of the aqueous penicillin saline solution at pH values of 5.5 to 6.5. ,

Example 25

If, in the procedure of Example 1, the D-a- (3-acetyl-3-allyl-ureido) -phenylacetic acid used there is replaced by each

0.02 mol:

D-a-O-acetyl-S-methylureidol-phenylacetic acid,

D-α- (3-acetyl-3-ethylurido) -phenylacetic acid,

DaO-acetyl-S-vinyl-ureido-phenylacetic acid, Dc * - (3-acetyl-3-n-propyl-ureido) -phenylacetic acid, di (3-acetyl-3-propenyl-ureido) -phenylacetic acid, CaO-acetyl -Si-propyl-ureidol-phenylacetic acid, D-aHS-acetyl-Sn-butyl-ureidol-phenylacetic acid, Da-fS-acetyl-S-β-methoxyethyl-ureidol-phenylacetic acid, Da- (3-acetyl-3- / 3 -dimethylaminoethyl-ureido) -phenylacetic acid, dap-acetyl-S-cyclohexyl-ureido-phenylacetic acid, Da-IS-acetyl-S-cyclobutyl-ureido-J-phenylacetic acid, Da (3-acetyl-3-benzyl-ureido) -phenylacetic acid, Da- (3-Formyl-3-methyl-ureido) -phenylacetic acid, Do! - (3-formyl-3-ethyl-ureido) -phenylacetic acid, D-ar (3-formyl-3-propyl-ureido) -phenylacetic acid, DTa- (3-Formyl-3-i-propyl-ureido) -phenylacetic acid, Da-iS-acetyl-St-butyl-ureidol-phenylacetic acid, D ^: a- (3-formyl-3-n-butyl-ureido ) -phenyl, acetic, di- (3-formyl-3-ayl, -u-reido) -phenylacetic acid, DOO-phosphoryl-3-benzyl-ureido) -phenylacetic acid, D-ar (3-formyl) 3-phenylureido) -phenylacetic acid, di-a-O-formyl-S-cyclop ropyl-ureidol-phenylacetic acid, DaO-formyl-S-cyclobutyl-ureidol-phenylacetic acid, D.-a-fS-formyl-S-cyclopentyl-ureidol-phenylacetic acid

Q ^ -P-formyl-S-cyclohexyl-ureidoJ-phenylacetic acid, the following penicillins are obtained in the form of their sodium salts:

DaO-acetyl-S-methyl-ureidol-benzylpenicillin, Da-fS-acetyl-S-ethyl-ureidol-benzylpenicillin, DaO-acetyl-S-vinyl-ureidol-benzylpenicillin, DaO-acetyl-Sn-propyl-ureidol-benzylpenicillin, DaO-acetyl-S-prop-i-enyl-ureidol-benzylpenicillin, Da-fS-acetyl-Si-propyl-ureidol-benzylpenicillin, D ^ aO-acetyl-Sn-butyl-ureidol-benzylpenicillin, Da-fS-acetyl- St-butyl-ureidol-benzylpenicillin, Dra-IS-acetyl-S-zS-methoxy-ethyl-ureidol-benzylpenicillin, D-of-IS-acetyl-S-β-dimethylaminoethyl-ureidol-benzylpenicillin, D> a- (3-acetyl 3-cyclohexyl-ureido) -benzylpenicillin, Da- (3-acetyl-3-cyclobutyl-ureido) -benzylpenicillin, DaO-acetyl-S-benzyl-ureidol-benzylpenicillin, Da- (3-formyl-3-methyl-ureido ) benzyl penicillin, & a- (3-formyl-3-ethyl-ureido) -benzylpenicillin, D'-aO-formyl-S-propyl-ureidol-benzylpenicillin, Da-β-formyl-Si-propyl-ureidoJ-benzylpenicillin, D> α- (3-Formyl-3-n-butyl-ureido) -benzyl-penicillin, Cta-O-formyl-S-allyl-ureidol-benzylpenicillin, Da-fS-formyl-S-benzyl-ureidol-benzylpenicillin, D ^L a- (3-Formyl-3-phenylureido) -benzylpenicillin, DaO-formyl-S-cyclopropyl-ureidolbenzylpenicillin, DaO-formyl-S-cyclobutyl-ureidolbenzylpenicillin, D ^ a-fS-formyl-S- cyclopentyl-ureidol-benzylpenicillin

D-a-fS-formyl-S-cyclohexyluridol-benzylic penicillin.

Example 26:

If, in the procedure of Example 1, the D-a- (3-acetyl-3-allyl-ureido) -phenylacetic acid used there is replaced by each

0.02 mol:

DaO-methoxyacetyl-S-methyl-ureidol-phenylacetic acid, Da (3-propionyl-3-methyl-ureido) -phenylacetic acid, Da-fs-methylsulfenyl-acetyl-S-methyl-ureidol-phenylacetic acid, Dra- (3-propionyl-3 ethyl-ureido) -phenylacetic acid, Da (3-propionyl-3-vinyl-ureido) -phenylacetic acid, Da (3-n-butyryl-3-methyl-ureido) -phenylacetic acid, D ^ a-is- Methoxycarbonylacetyl-S-methyl-ureido-J-phenylacetic acid, Da (3-i-butyryl-3-methyl-ureido) -phenylacetic acid, Da-i-acryloxy-S-methyl-ureidol-phenylacetic acid, Da- (3-pivaloyl-3 -methyl-ureido) -phenylacetic acid,

D-a-O-cyanomethyl-acetyl-S-methyl-ureidoJ-phenylacetic acid,

D-alpha-beta-acetyl-S-phenyl-ureidol-phenylacetic acid,

D-α- (3-propionyl-3-phenylureido) -phenylacetic acid, '

D-a-hexadecahydroazepin ^ -one-i-yl-carbonylaminol-phenylacetic acid, ·;

or. ,

D-α- (pyrrolid-2-one-ylcarbonylamino) -phenylacetic acid;

this gives the following penicillins:

D-a-O-methoxyacetyl-S-methyl-ureidol-benzylpenicillin,

D-a-O-propionyl-S-methyl-ureidol-benzylpenicillin,

D-a-O-Methylsulfenylacetyl-S-methyl-ureidoj-benzylpenicillin,

D-a-O-propionyl-S-ethyl-ureidol-benzylpenicillin,

D-alpha-beta-propionyl-S-vinyl-ureidoJ-benzylpenicillin,

D-a-p-n-butyryl-S-methyl-ureidol-benzylpenicillin,

D-a-IS-IVlethoxycarbonylacetyl-S-methyl-ureidol-benzylpenicillin,

D-a-fS-i-butyryl-S-methyl-ureidol-benzylpenicillin,

D-a-fS-acryloyl-S-methyl-ureidol-benzylpenicillin,

D-a-fS-pivaloyl-S-methyl-ureidoj-benzylpenicillin,

D-a-O-Cyanmethylacetat-S-methyl-ureidol-benzylpenicillin,

D-a-IS-acetyl-S-phenyl-ureidol-benzylpenicillin,

D-a-fS-propionyl-S-phenyl-ureidol-benzylpenicillin,

D-oHHexahydroazepin ^ -one-i-yl-carbonylaminot-benzylpenicillin,

D-a- (pyrrolid-2-on-l-yl-carbonylamino) -benzylpenicillin.

Example 27:

Attempting to prepare D-a-fS-methoxycarbonyl-S-methyl-ureidol-benzylpenicillin-natrium:

5.2 parts by weight of D-oHS-methoxycarbonyl-S-methyl-ureidolphenylacetic acid were added by slurrying in a mixture of 10 parts by weight of benzene, 5 parts by weight of thionyl chloride and 0.05 parts by weight of dimethylformamide, followed by careful heating magnetic stirring. At about 60 ⁰ C was held until completion of gas evolution, then in a water jet vacuum, finally at 0.1 Torr and 50 ⁰ C thionyl chloride and benzene removed. The remaining product showed the IR spectrum strong bands at 1 805.1725 and 1175cm ^-1. Yield 5.5 parts by weight.

Calculated as D-α-O-methoxycarbonyl-S-methyl-ureidol-phenyl-acetic acid chloride:

Calc .: C50.55 H 4.56 Cl 12.47 N 9.84%

Found: C47.57 H4.29 CI11.60 N9.68%

5 parts by weight of the product thus obtained, dissolved in 10 parts by volume of dry tetrahydrofuran, were added to the ice-cooled solution ^:

von3,8Gew.-parts of 6-aminopenicillanic acid (in 50VoI. parts 80% aqueous tetrahydrofuran addition of sufficient [

2N sodium hydroxide solution until the solution has entered at pH 8.2) are added dropwise with stirring. By simultaneous addition of further 2N sodium hydroxide solution while keeping the pH between 7 and 8. Then was still 30min. at O ⁰ C and stirred at room temperature until the pH of von'7 to 8 no more sodium hydroxide solution was required. 100 parts of water were then added, the tetrahydrofuran was removed at 0 ° C. in vacuo and the remaining aqueous solution was removed with 50 parts by volume of ether to remove neutral constituents. It was then coated with 150Vol.-parts of a 1: 1 mixture of ether and ethyl acetate and then acidified with dilute hydrochloric acid with ice cooling and stirring to pH 2.0. After separating the organic phase, it was dried over MgSO ₄ after washing with 50 parts by volume of water. Subsequently, 17 parts by volume of a 1 mM solution of sodium 2-ethylhexanoate in methanol-containing ether were added, and the mixture was evaporated to near dryness in vacuo and dissolved in as little methanol as possible. Addition of excess ether precipitated a colorless, noncrystalline product which, after decanting off the supernatant solution, was digested with ether, filtered off with suction and dried over P ₂ O ₅ in a vacuum extender. Yield 6 parts by weight, / 3-lactam content

Calculated as methoxycarbonyl-methylureido-benzylpenicillin:

Calc .: C49.3 H4.7 CIO ₁ ON 11.5 S6.6%

Found: C47.5 G6.0 CI0.1 N 9.9 S7.0%.

The thin layer chromatogram of the product (silica gel, 10: 3: 1 mixture of n-butanol, n-pentane and glacial acetic acid, running time 1 h 2 h) showed spots at Rf values of 0.045, 0.11 to 0.3 and 0.56 , Authentic Da (3-methoxycarbonyl-3-methylureido) benzylpenicillin, prepared either by the method of Example 8 or by acylation of ampicillin with N-methoxycarbonyl-N-methyl-carbamic acid chloride, showed an Rf of 0.45 under the same conditions , An electrophorogram developed with Bacillus subtilis indicated the presence of several antibiotic active substances, none of which, however, matched the authentic material. Finally, on the basis of the NMR spectrum, the presence of larger amounts of the desired methoxycarbonyl-methylureido-benzylpenicillin could be ruled out, but rather the assumption of a mixture of several different substances was confirmed. For antibacterial efficacy of this product see table in example 8.

Example 28:

In the reaction of Da- (3-i-propyloxycarbonyl-3-methylureido) -phenY-l-acetic acid and of Da- (3-n-butoxycarbonyl-3-methylureido) -phenylacetic acid with thionyl chloride and then with 6-aminopenicillanic acid in the manner described in Example 11c Were also obtained in each case products which proved to be mixtures of several antibiotically active substances, but none of which with the authentic, prepared according to the instructions of Examples 9c and 10 Da- (3-i-propyloxycarbonyl-S-methyl-ureidol-benzylpenicillin The Rf values of the thin-layer chromatograms developed on silica gel with a 9: 3: 1 mixture of n-butanol, pentane, and glacial acetic acid were 0.080 and 0, respectively , 35 and 0.078, 0.46 and 0.75, respectively, under the same conditions, the authentic products showed Rf values of 0.56 and 0.64, respectively. Products of the reaction of Da (3-i-propyloxycarbonyl-3-) methyl-ureido) -phenylacetic acid:

For antibacterial efficacy see table in Example 9c.

Products of the reaction of D-a-tS-n-butoxycarbonyl-S-methylureidolphenylacetic acid:

The following table shows the antibacterial activity of this product (A) with those of ampicillin and N-n-butoxycarbonyl-N-

methyl carbamic acid prepared penicillins (B):

bacteria Efficacy (E / ml) (B) 3.12 (A). 6.25 Escherichia coli 14 100.0 6.25 Escherichia coli C165 200.0 25,00 Escherichia coli 183/58 400.0 12.50 Proteus 3400 > 400.0 12.50 Proteus 1017 > 400.0 25,00 Pseudomonas aerug. Bonn > 400.0 <0.78 Pseudomonasaerug. Walter > 400.0 Staphylococcusaur. 133 12.5.

Example 29:

D-a- (3-cyclohexyloxycarbonyl-3-methyl-ureido) -benzylpeniciliin sodium

4.5 parts by weight of 6-aminopenicillanic acid were suspended in 60 parts by volume of 50% strength aqueous tetrahydrofuran, which was added to dissolve the aminopenicillanic acid just required amount of triethylamine, the resulting solution having a pH of 8.0 ( Glass electrode) to OX, the solution of 8.0 parts by weight of O- [Dc * - (3-cyclohexyloxycarbonyl-3-methylureido) -phenylacetyl] -C-cyano-C-ethoxycarbonyl-formaldehyde oxime in 25 parts of tetrahydrofuran was added dropwise and kept by appropriately adding triethylamine, the pH of the solution to 7.5. Then 90 min. Was stirred at 22 ° C, 100 parts by volume of water, the solution adjusted to pH 6.5, the tetrahydrofuran in vacuo in a rotary evaporator largely removed, the remaining aqueous solution with a 1: 1 mixture Overlaid from ether and ethyl acetate, stirred and cooled to 0 to 5 ° C and acidified by 2 η hydrochloric acid to pH 1.5. The organic phase was then separated, washed with water, dried over sodium sulfate in a refrigerator and precipitated the sodium salt of penicillin using a 1 M solution of sodium 2-ethylhexanoate in methanol-containing ether. The supernatant solution was decanted from the initially oily precipitate and converted by trituration with dry ether in a colorless powder. / 3-lactam content 82%.

NMR signals at τ = 2.4 to 3.0 (5H), 4.3 to 4.7 (3H), 5.2 (1H), 5.8 (1H), 6.8 (3H) and 7.9 to 9.0ppm (16H). The biological activity of this penicillin (A) and the penicillin (B) prepared from ampicillin and N-cyclohexyloxycarbonyl-N-methyl-carbamic acid chloride were identical within the error limit as shown in the table below.

Minimal inhibitory concentration (E / ml): (B) (A) 1.56 E. coli 14 3.12 400.00 E.COÜA261 400.00 6.25 E.COÜC165 6.25 1.56 E. coli 183/58 3.12 6.25 Proteus 3400 12.50 6.25 Proteus 1017 12.50 25,00 Pseudomonas aerug. Bonn 25,00 50,00 Pseudomonas aerug. Walter 50,00 100.00 KlebsiellaKIO 200.00 100.00 Klebsiella63 100.00 400.00 Staphylococcus aureus 1777 E 200.00 <0.70 StaphylococcusaureusiSS <0.70 100.00 Enterococcus ATCC 9790 100.00

Example 30:

D-a-O-Allyloxycarbonyl-S-methylureidol-benzylpenicillin sodium

7.1 parts by weight of 6-aminopenicillanic acid were dissolved in the mixture of 120 parts by volume of methylene chloride and 10 parts by volume of triethylamine, 12.4 parts by weight of O- [Da- (3-allyloxycarbonyl-3-methylureido) - phenylacetyl] -C-cyano-C-ethoxycarbonylformaldehyde oxime added, the solution 24h. allowed to stand in a refrigerator, diluted with 150Vol.-parts of methylene chloride, exhaustively shaken with saturated sodium carbonate solution, the combined bicarbonate extracts with a 1: 1 mixture of ether and ethyl acetate, while stirring with 2N hydrochloric acid, the pH in the aqueous phase to 5 , 0, the organic phase separated, the aqueous phase overcoated with fresh ether-ethyl acetate mixture, the aqueous phase is then acidified to pH 1.5 with 2N hydrochloric acid with stirring and cooling with ice, the organic phase separated and precipitated and isolated in the manner described in Example 29, the sodium salt of penicillin. Yield 30%,

/ 3-lactam content 74%.

Calc .: C 49.7 H 5.2 N 10.5 S 6.1% Found: C49.9 H6.1 N 10.4 S5.6%

NMR signals at τ = 2.4 to 2.8 (5H), 3.7 to 4.3 (1H), 4.4 to 4.9 (5H), 5.1 to 5.4 (2H) , 5.8 (1H), 6.8 (3H) and 8.45ppm (6H).

The biological activity of this penicillin (A) and that of ampicillin and N-allyloxycarbonyl-N-

penicillin (B) represented by methylcarbamic acid chloride were within the error limit, as shown in the table below,

identical.

Minimal inhibitory concentration (E / ml): (B) 3.12 (A) > 400.00 E. coli 14 0.8 to 4.0 12.50 E. coli A 261 100.0 to 500.0 6.25 E. coli C165 4.0 to 20.0 25,00 E. coli 183/58 4.0 to 20.0 12.50 Proteus 3400 20.0 to 100.0 12.50 Proteus 1017 20.0 to 100.0 12.50 Pseudomonas aerug. Bonn 4.0 to 20.0 50,00 Pseudomonas aerug. Walter 20.0 to 100.0 25,00 KlebsiellaKIO 20.0 to 100.0 0.78 Klebsiella63 20.0 to 100.0 50,00 Staphylococcus 133 0.8 to 4.0 Enterococcus ATCC 9790 20.0 to 100.0

Example 31:

a- (3-benzoyl-3-methyl-ureido) -2,6-dichlorbenzylpenicillin sodium

This penicillin was prepared in the manner described in Example 30 from 2.82 parts by weight of 6-aminopenicillanic acid, 6.0 parts by weight of 0- [α- (3-benzoyl-3-methylureido) -2,6-dichlorophenylacetyl]. -C-cyano-C-ethoxycarbonyl-formaldehydroxime, 50 parts by volume

Methylene chloride and 4 parts by volume of triethylamine. Yield 40%, / 3-lactam content 80%.

calc .: C 47.4 H 4.3 N 8.8 S 5.0% Found: C 47.1 H 4.7 N 8.9 S 5.4%

NMR signals at τ = 2.4 to 2.9 (8H), 3.3 (0.6H), 3.8 (0.4H), 4.45 (2H), 5.8 (1H), 6.8 (0.6H), 6.85 (0.4H) and 8.45ppm (6H).

Example 32:

a-f S-benzoyl-S-methyl-ureido ^^ - dichlorbenzylpenicillin sodium

There were 6,6Gew. Part a- (3-benzoyl-3-methyl-ureido) -2,6-dichlorophenylacetic acid in a mixture of acetone and dry 70Vol. parts 2,5Vol. parts triethylamine at -5 to -10 ⁰ C solved. 2.9 parts by weight of i-methyl ^ -chloro-pyrrolinium chloride added, 45 min. stirred, the precipitate formed (triethylamine hydrochloride) was filtered off with suction, the filtrate with a cooled to -1OX, prepared by means of triethylamine solution of 4.3 parts by weight of 6-aminopenicillanic acid in water, which had a pH of 7.5 , combined, then stirred for 2 hrs. At -5 ° C and the pH while kept by appropriate addition of triethylamine to 7.5. The mixture was then diluted with 130 parts by volume of water, the pH was adjusted to 6.5 by means of 2N hydrochloric acid, the acetone was removed in vacuo and the remaining solution was adjusted to pH 7.5 with a 1: 1 mixture shaken out of ether and ethyl acetate, the aqueous phase separated, covered with fresh organic phase and acidified with stirring to ice with 2N hydrochloric acid to pH 1.5, the organic phase separated, washed with water, over sodium sulfate 2h. dried in a refrigerator and precipitated in the manner described in Example 27, the sodium salt of penicillin and isolated. Yield 33%, / 3-lactam content 78%. NMR signals at τ = 2.4 to 2.75 (8H), 3.3 (0.7H), 3.7 (0.3H), 4.4 (2H), 5.75 (1H), 6.8 (3H) and 8.45ppm (6H)

 Efficacy in animal experiments: A and B

Example 33:

a- (3-benzoyl-3-methyl) -4-methylsulfenylbenzylpenicillin sodium

This penicillin was prepared as described in Example 32 from 6.0 parts by weight of a- (3-benzoyl-3-methylureido) -4-methylsulfenylphenyl-acetic acid dissolved in 70 parts by volume of acetone and 2.3 parts by volume. Parts of triethylamine, after reaction with 2.7 parts by weight of 1-methyl-2-chloro-pyrroliniumchlorid, prepared by combining with a prepared by the addition of triethylamine solution of 6-aminopenicillanic acid in water of pH 7.5. Yield 45%, / 3-lactam content 72%. NMR signals at τ = 2.4 to 2.9 (9H), 4.4 (1H), 4.5 (2H), 5.8 (1H) 6.9 (3H), 7.6 ( 3H) and 8,45ppm (6H)

 Efficacy in animal experiments: A and B

Example 34:

a- (3-ethoxycarbonyl-3-methyl) -4-methylsulfenylbenzylpenicillin sodium

This penicillin was prepared in the manner described in Example 32 from 6.0 parts by weight of a- (3-ethoxycarbonyl-3-methylureido) -4-methylsulfenylphenyl-acetic acid, 80VoI.-parts acetone, 2.6VoI.-parts triethylamine and 3.0 parts by weight of 1-methyl-2-chloropyrrolinium chloride were prepared by combining with a prepared by the addition of triethylamine solution of 4.4 parts by weight of 6-aminopenicillanic acid in 70VoI.-parts of 50% aqueous acetone. Yield 44%, / 3-lactam content 78%. NMR signals at τ = 2.6 (2H), 2.75 (2H), 4.5 (1H), 4.55 (2H), 5.5 to 5.9 (3H), 6.85 ( 3H), 7.55 (3H), 8.4 (6H) and 8.6ppm (3H).

Example 35:

a- (ethoxycarbonyl-3-methyl) -4-methylsulfenylbenzylpenicillin sodium

To prepare this penicillin, 6.0 parts by weight of (-3-ethoxycarbonyl-3-methylureido) -4-methylsulfenylphenylacetic acid were dissolved in 80 parts by volume of acetone with the addition of 2.6 parts by volume of triethylamine, at -5 to -10 ⁰ C 3.0 parts by weight of 1-methyl-2-chloro-pyrrolinium chloride added, 45 min. stirred at the same temperature, a solution of 4.4 parts by weight of 6-aminopenicillanic acid in the mixture of 70 parts by volume of 50% aqueous acetone and triethylamine, which had a pH of 7.5, was added, the mixture then 2 hours. stirred at -5 ⁰ C, diluted with 150Vol.-parts of water and the reaction mixture, worked up as in Example 32 until isolation of the sodium salt of penicillin. Yield 44%, / 3

Lactamgehalt78%.

Calc .: C46.7 H 5.2 N9.9 S 11.3% Found: C47.0 H 5.6 N 9.4 S 10.8%.

NMR signals as given in Example 34. The spectra of the two substances are identical.

Efficacy in animal experiments: A

Example 36:

a- (3- / 3-chloropropionyl-3-methyl) cyclohex-3-enylmethylpenicillin sodium

This penicillin was prepared in the manner described in Example 32 from 5.3 parts by weight of a- (3- / 3-chloropropionyl-3-methylureido) -cyclOhex-3-enyl-acetic acid, after reaction with 3.0 parts by weight of i.p. Methyl-2-chloropyrroliniumchlorid in the presence of 2.6VoI .'- parts of triethylamine, by reaction with 4.4 parts by weight of 6-aminopenicillanic acid, which by means of triethylamine in 50% '

aqueous acetone at pH 7.5 was prepared. Yield 44%, / 3-lactam content 78%.

NMR signals at τ = 4.3 (2H), 4.5 (2H), 5.8 (1H), 6.2 (2H), 6.65 (3H), 6.8 (2H), and 7 , 7 to 8.8ppm (13H).

Example 37:

D-a- [3- (2-thenoyl) -3-methylureido3-benzylpenicillin sodium

To prepare this penicillin, 3.9 parts by weight of di [3- (2-thenoyl) -3-methylureido] -phenylacetic acid were dissolved in 55 parts of acetone with addition of 2.0 parts of triethylamine at -5 to -10 ° C2,4Gew.-parts of 1-methyl-2-chlorpyrroliniumchlorid, 45 min. Stirred at the same temperature, a solution of 3.1 parts by weight of 6-aminopenicillanic acid in the mixture of 60VoI.-Parts 90% aqueous acetone and Triethylamine, which had a pH of 7.5, added, the mixture 2Stdt. stirred at -5 ⁰ C and, as described in Example 32, until isolation of the sodium salt of penicillin

worked up. Yield 56%, / 3-lactam content 64%.

NMR signals at τ = 2.1 to 3.0 (8H), 4.35 to 4.8 (3H), 5.8 (1H), 6.55 (3H), and 8.45 ppm (6H).

Example 38:

D-a- [3- (3,5-Dimethylisoxazoloyl-4) -3-methylureido] -benzylpenicillin sodium

To prepare this penicillin, 3.9 parts by weight of di- [3- (3,5-dimethylisoxazoloyl-4) -3-methylureido] -phenylacetic acid in 60 parts by volume of methylene chloride with addition of 2.0 parts by volume of triethylamine dissolved, the solution was cooled to -10 ⁰ C, 2.2 parts by weight of i-methyl-2-chloropyrroliniumchlorid added, the mixture 90Min. at -10 to -35 ⁰ C left standing (solution A).

On the other hand, 3.1 parts by weight of 6-aminopenicillanic acid were suspended in 60 parts by volume of methylene chloride, added 3.4VoI.-parts of triethylamine and the mixture 4h. stirred at 22 ° C (solution B). Then solution B was cooled to 0 to -5 ° C and the solution Aim over 30 min. added with stirring and further cooling in several portions. The mixture was then stirred for 1 h. At 0 to 5 ⁰ C, the solvent was removed in vacuo, the residue taken up in water and a 1: 1 mixture of ether and ethyl acetate, the pH adjusted to 7.5 with stirring, the separated organic phase, the aqueous phase overcoated with fresh ether-ethyl acetate mixture, while stirring and cooling with ice, the pH was brought to 1.5 by means of 2 η hydrochloric acid, the organic phase separated, washed with water, over magnesium sulfate 2TStd. dried in the refrigerator and, as described in Example 32, the penicillin isolated as the sodium salt. Yield 50%,

/ 3-lactam content 80%.

calc .: C 50.7 H 5.0 N 12.3 S5.6% Found: C51.1 H5.4 N 11.6 S5.8%

NMR signals at τ = 2.35 to 2.9 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.8 (3H), 7.6 (3H), 7.75 (3H) and 8.45ppm (6H).

Example 39:

Substituting the procedure of Example 37, there used D-a- [3- (2-thenoyl) -3-methylureido] phenylacetic acid

by 0.012 mol each:

[3- (2-Furoyl-3-methylureido] -phenylacetic acid, Da- [3- (2-furoyl) -3-ethyl-ureido] -phenylacetic acid, Da- [3- (2-furoyl) -3- n-propylureido] -phenylacetic acid, Da [3- (2-furoyl) -3-phenylureido] -phenylacetic acid, Da- [3- (2,5-dimethylfuroyl-3) -3-methylureido] -phenylacetic acid, Da- [. 3- (5-Bromofuroyl-3) -3-methylureido] -phenylacetic acid, Da [3- (5-methoxymethylfuroyl-2) -3-methylureido] -phenylacetic acid, Dap-jSjo-dimethylisothiazole-S-y-carbonyl -S-methylureidol-phenylacetic acid, Da- [3- (isoxazol-4-yl) -carboxylyl-3-methyl-propyl] -phenylacetic acid, Da-β-ilsoxazol-S-yl-J-carbonyl-S-methyl-acididol -phenylacetic acid, Do; - {3- [3-methylthiodiazoJ (1,2,5) -4-yl] carbonyl-3-methyl-ureido} -phenylacetic acid,

D-a- {3- [4-methylthiadiazole (1,2,3) -5-yl] carbonyl-3-methylureido} -phenylacetic acid> to give the sodium salts of the following penicillins:

Da- [3- (2-furoyl) -3-methylureido] benzylpenicillin, Da- [3- (2-furoyl) -3-ethylureido] -benzyl penicillin, Da- [3- (2-furoyl) -3 n-propylureido] benzylpenicillin, Da [3- (2-furolyl) -3-phenylureido] benzylpenicillin, Da [3- (2,5-dimethylfuroyl) -3] -3-methylureido] benzylpenicillin, Da [3- (5-bromo-furoyl-3) -3-methylureido] -benzyl-penicillin, Da [3- (5-methoxymethylfuroyl-2) -3-methylureido] -benzylpenicillin, Da-IS-O, -dimethylisothiazole S-ylJ-carbonyl-S-methylureidol-benzylpenicillin, Da- [3- (isoxazol-4-yl) -carbonyl-3-methylureido] -benzylpenicillin, Da-t-osoxazol-S-yl-carbonyl-S-methylureidol benzylpenicillin, Da-IS-tS-methylthiodaiazole-1-yl-5-yl-carbonyl-S-methylureido-1-benzylpenicillin,

D ^ a- {3- (4-Methylthiodiazol (1,2,3) -5-yl] carbonyl-3-methyl-ureido} -benzylpenicillin.

Example 40:

A) D-α-p-cyclohexyloxycarbonyl-S-methyl-ureidol-phenylacetic acid

13.5 parts by weight of bis-trimethylsilyD-C-phenylglycine were dissolved in 10 parts by volume of partially dry carbon tetrachloride, and a solution of 10.0 parts by weight of N-cyclohexyloxycarbonyl-N-methylcarbamic acid chloride in 30 vol .-% was slowly added dropwise at 0 ° C. with exclusion of moisture. Divide carbon tetrachloride and allowed to stand overnight in the refrigerator. The mixture was then washed 3 times with 50 parts by volume of water and the organic phase was evaporated to dryness in vacuo. Yield on

oily product 95%.

NMR signals at τ = 0.5 (1H), 2.5 (5H), 4.6 (1H), 5.2 (1H), 6.8 (3H) and 7.9-8, 9ppm (10H).

B) 0- [Da (3-Cyclohexyloxycarbonyl-3-methylureido) phenylacetyl] -C-cyano-C-ethoxycarbonylformaldehyde oxime There were added 2.92 parts by weight of C-cyano-C-ethoxycarbonylformaldehyde oxime in 50 parts by volume Dissolved tetrahydrofuran, 2.9 parts by volume of triethylamine, the mixture cooled to -10 ^c C, then slowly added dropwise with stirring and further cooling 1.5VoI.-thionyl chloride and then 15Min. stirred at -10 ° C. Then, the cooled to G ⁰ C solution of 6.88 parts by weight of Da-tS-cyclohexyloxycarbonyl-S-methylureidoPhenylacetic acid in the mixture of 50VoI.-parts of tetrahydrofuran and 2.9VoI.-parts of triethylamine in the course of about 45 min. Under added dropwise cooling and then the reaction mixture after 1 hr. At ^{0 0} C stirred. Then the precipitated triethylamine hydrochloride was filtered off with suction, the filtrate was evaporated in vacuo from a bath of 15 to 2O ⁰ C by means of a rotary evaporator, the residue dissolved in methylene chloride, the solution cooled to ^{0 0} C, once quickly shaken with ice water, then the organic phase at Dried over sodium sulfate, filtered, evaporated in vacuo by means of a rotary evaporator from a bath of 20 ⁰ C, finally evaporated from a bath of 4O ⁰ C. This gives a colorless, paint-like body. Yield 98%. Specific rotation: [a] _5S9

-8.1 ° (54.2 mg, methanol).

The substance showed an IR spectrum corresponding to its constitution.

NMR signals at τ = 0.5 (1H), 2.6 (5H), 4.3 (1H), 5.25 (1H), 5.7 (2H), 6.8 (3H) and 8.0 to 9.0ppm (13H).

Example 41:

0- [Da (3-Allyloxycarbonyl-3-methylureido) phenylacetyl] C-cyano-C-ethoxycarbonylformaldehyde oxime This substance was prepared from 5.86 parts by weight C-cyano C in the manner described in Example 40 -ethoxycarbonylformaldehyde oxime, 100 parts by volume of tetrahydrofuran, 57 parts by volume of triethylamine, 3.0 parts by volume of thionyl chloride and the mixture of 12.0 parts by weight of di- (3-allyloxycarbonyl-3-methylureido) -phenylacetic acid, 100Vol. Parts of tetrahydrofuran and 5.7VoL parts represented triethylamine. This gives a colorless, paint-like body. Yield over 80%. Specific rotation: [a] ₅₈ 9

-19.8 ° (50.6 mg, methanol). The substance showed an IR spectrum corresponding to its constitution.

NMR signals at τ = 0.4 (1H), 2.6 (5H), 3.7 to 4.2 (1H), 4.3 (1H), 4.5 to 4.9 (2H ), 5.3 (2H), 5.65 (2H), 6.8 (3H) and 8.65ppm (3H).

Example 42:

0- [Da (3-Benzoyl-3-methylureido) -2,6-dichlorophenylacetyl] -C-cyano-C-ethoxycarbonylformaldehyde oxime This substance was prepared from 2.85 parts by weight of C in the manner described in Example 40 Cyano-C-ethoxycarbonylformaldehyde oxime, 50 parts by volume of tetrahydrofuran, 2.8 parts by volume of triethylamine, 1.45 parts by weight of thionyl chloride and of the mixture of 7.6 parts by weight of di (3-benzoyl-3-methylureido) 2,6-dichlorophenylacetic acid, 50 parts by volume of tetrahydrofuran and 2.8 parts by volume.

Share represented triethylamine. This gave a colorless, paint-like substance. Yield over 80%.

The IR spectrum of the substance showed the bands corresponding to the constitution.

NMR signals at τ = 0.5 (1H), 2.45 (5H), 3.55 (1H), 5.65 (2H), 6.9 (3H) and 8.7 (3H).

Example 43:

a- (pyrrolid-2-on-1-yl-carbonylamino) -a-p-tolyl-methyl penicillin sodium

This penicillin was prepared in the manner described in Example 1 from 14.5 parts by weight of a-pyrrolid-2-one-1-yl-carbonylamino) -a-ptolylacetic acid, 10.2 parts by weight of tetramethylchloroformamidinium chloride and 15 parts by weight of 6- aminopenicillanic

manufactured. Yield 29%, / 3-lactam content 67%.

NMR signals at τ = 2.5 to 3.05 (4H), 4.5 (3H), 5.8 (1H), 6.1 to 6.4 (2H), 7.4 (2H), 7.7 (3H), 8.0 (2H) and 8.3 to 8.6ppm (6H).

Example 44:

α- (3-o-fluorobenzoyl-3-methyl-ureido) -α-p-tolyl-methyl penicillin sodium

This penicillin was prepared in the manner indicated in Example 2 from 9 parts by weight of N-o-fluorobenzoyl-N-methyl-ureido-N-p-tolylacetic acid, 4.95 parts by weight of tetramethylchloroformamidinium chloride and 8.5 parts by weight of 6-aminopenicillanic acid

manufactured. Yield 59%, / 3-lactam content 87%.

calc .: C53.7 H4.8 N9.7 S 5.5% Found: C53.4 H (6.0) N9.7 S5.9%

NMR signals at τ = 2.3 to 3.1 (8H), 4.5 (3H), 5.8 (1H), 6.3 (3H), 7.7 (3H and 8.2 to 8.5 ppm ( 6H) Efficacy in animal experiment: A

and B.

Example 45:

a - [(imidazolidin-2-on-1-yl) -carbonylamino] -p-methylberizylpenicillin sodium

3.76 parts by weight of tetramethylchloroformamidinium chloride were slurried in 15 parts by volume of dry acetone and stirred for 10 minutes with exclusion of moisture. The mixture was also sucked in with exclusion of moisture, the reagent was slurried in 40 parts by volume of methylene chloride and cooled to ⁰ ° C. 5.53 parts by weight of a - [- (imidazolidin-2-one-1-yl) carbonylamino] -p-methylphenylacetic acid in a little methylene chloride and added dropwise to the mixture with stirring over 30 min. At ^{0 0} C, the solution of 2.0Gew.-parts of triethylamine in 20VoL-TeMe methylene chloride with exclusion of moisture. At +5 ⁰ C was 20 min. Stirred and then cooled to 20 ⁰ C and treated in one portion with the likewise cooled to -20 ⁰ C solution desTriäthylaminsalzes of 6-aminopenicillanic acid in methylene chloride. (This solution was prepared by stirring 5.8 parts by weight of 6-aminopenicillanic acid, 3.4 parts by weight of triethylamine, and 8 parts by weight of anhydrous sodium sulfate in 40 parts by volume of methylene chloride and then aspirating for 2 hours).

The mixture was allowed to come to ⁰ ° C. with stirring, and after a short time it was treated with a further 0.9 part by weight of triethylamine and the mixture was stirred at ⁰ ° C. for 30 minutes and at room temperature for 30 minutes. The mixture was then poured into ice-water, the pH was adjusted to 5.5 and the methylene chloride was removed in vacuo. It was extracted twice with ether and washed out the ether with little water. The combined aqueous solutions were layered with ethyl acetate and adjusted with stirring to pH 1.5 with dilute hydrochloric acid, while cooling with ice. The ethyl acetate phase was separated, the water extracted once more with ethyl acetate and the combined extracts washed with water. It was dried for about 1 hour at ^{0 0} C over MgSO ₄ , added after filtration with 20VoI.-Parts of a 1 molar solution of sodium 2-ethylhexanoate in methanol-containing ether and evaporated in vacuo at room temperature to an oily consistency. Now methanol was dissolved in the required amount and this solution was added dropwise to 500VoI.-parts of a mixture of about 500VoI.-parts of absolute ether and 50Vol.-parts of methanol, being stirred vigorously. The precipitated product was filtered off with suction after brief standing, slurried with dry ether and sucked off again. It was dried in vacuo over P ₂ O ₅ for about 2 days. Yield 70%, / 8-lactam content 86%. NMR signals see Table 2, p. 101. IR bands at 3280.1, 760.1712.1, 655.1, 600.1, 520, 127 and 765 cm ^-1 (in Nujol suspension).

Example 46:

a - [(imidazolidin-2-on-1-yl) -carbonylamino] -p-methylbenzylpenicillin sodium

2.8 parts by weight of a - [(imidazolidin-2-one-1-yl) carbonylamino] -p-methylphenylacetic acid were reacted in the manner described in Example 45 with 1.7 parts by weight of 1-methyl-2-chloro-Al -pyrrolinium chloride instead of tetramethylchloroformamidinium chloride and then reacted with 2.6 parts by weight of 6-aminopenicillanic acid in the form of its triethylamine salt to give the sodium salt of a- [(imidazolidin-1-y-carbonylaminol-benzylpenicillin.] Yield 54%, / 3-lactam content 39 %, NMR signals see

Table 2, page 101.

The location of the IR bands is consistent with that of the penicillin of Example 45.

Example 47:

a - [(imidazolidin-2-on-1-yl) carbonylamino] -p-chlorobenzyl penicillin sodium

This penicillin was prepared in the manner described in Example 45 from 5.95 parts by weight of a - [(imidazolidin-2-one-1-yl) carbonylamino] -p-chlorophenylacetic acid, 3.76 parts by weight of tetramethylchloroformamidinium chloride and 5.8 parts by weight Parts of 6-aminopenicillanic acid. Yield 59%, / 3-lactam content 86%. NMR signals see Table 2, page 101. IR bands at 3300, 1775, 1727, 667.1, 608.1, 540, 128 and 780 cm ^-1 .

Example 48A:

a - [(imidazolidin-2-on-1-yl) -carbonylamino] -p-chlorbenzylpenicillin sodium

3.6 parts by weight of a - [(imidazolidin-2-on-1-yl) -carbonylamino] -p-chlorophenylacetic acid were mixed with 2.22 parts by weight of 1,3-dimethyl-2-one in the manner described in Example 45. Chloro-A1 imidazolinium chloride and then reacted with 3.02 parts by weight of 6-aminopenicillanic acid to the sodium salt of a - [(imidazolidin-2-one-1-yl) carbonylamino] -p-chlorobenzylpenicillins.

Yield 65%, / 3-lactam content 72%. NMR signals see Table 2, page 101.

The IR spectrum in Nujol is identical to that of the penicillin of Example 47.

Example 48B:

a - [(imidazolidin-2-on-1-yl) -carbonylamino] -p-methylphenylacetic acid

16.5 parts by weight of a- (4-methylphenyl) glycine was dissolved in 200 parts by volume of 50% aqueous dioxane with the addition of sufficient 2 N sodium hydroxide solution. Thereafter, 5N hydrochloric acid was used to bring the pH back to 7 to 8, the amino acid parting off as a fine precipitate. With stirring, the solution was added dropwise to 11.8 parts by weight of 1-chlorocarbonylimidazolidin-2-one in 50 parts by volume of warm acetone while cooling with an ice bath. The pH was maintained by appropriate addition of 2N sodium hydroxide solution between 7 and 8. After the addition was stirred for 15 min. At room temperature, until the pH remained constant. It was filtered from unreacted amino acid (6 parts by weight), the filtrate evaporated to half the volume in vacuo and extracted once with 100 parts by volume of ether. The aqueous phase was adjusted to a pH of 1 to 2 with 2N hydrochloric acid and the precipitated oil was taken up by extraction with 2 times 10Vol parts in ethyl acetate. The combined ethyl acetate extracts were washed with 50 vial of water, dried over MgSO ₄ and then evaporated to dryness. A glassy foam was obtained, which was converted by trituration with petroleum ether into a fine-grained, non-crystalline powder. Yield 48%, NMR signals see Table 2, page 101.

Example 48C:

The following a - [(imidazolidin-2-on-1-yl) carbonylamino] -phenylacetic acid was described as in Example 48B

manufactured.

a - [(imidazolidin-2-on-1-yl) -carbonylamino] -p-chlorophenylacetic acid from 18.6 parts by weight of a- (4-chlorophenyl) -glycine and 11.8 parts by weight of i-chlorocarbonyl-imidazolidine 2-one. Reclaimed, unreacted a (4-chlorophenyl) glycine: 6 parts by weight. Yield of ether-moist product 33 parts by weight. The substance was recrystallized from ethyl acetate / petroleum ether.

1st fraction Yield: 35% based on reacted *

2nd fraction Yield: 15% starting material

Mp. 115 to 120 ⁰ C. NMR signals see Table 2, page one hundred and first

Example 48D:

1-chlorocarbonyl-imidazolidin-2-one

To the vigorously stirred solution of 3.5 parts by weight of imidazolidone (2) (prepared by Fischer and Koch, Ann.232, p.224 [1886]) in 50 parts by volume of absolute tetrahydrofuran was added dropwise 4Gew.-parts of phosgene in 10VoI. Parts of absolute tetrahydrofuran over 15 min. to. Subsequently, at 10 ° C for 3h. stirred and then passed through the reaction mixture, a stream of dry air to blow out the resulting hydrochloric acid and residues phosgene. It was then evaporated to dryness on a rotary evaporator in vacuo and the solid residue was dried over concentrated sulfuric acid and at about 12 torr. Yield 93%.

Mp 150 ° C after recrystallization from acetone-pentane.

Calc .: C32.3 H3.4 N 18.8 CI23.9

Found: C32.3 H (4.5) N18.7 CI23.9

NMR signals at τ = 5.7 to 6.1 (1 H) and 6.3 to 6.7 (2 H), (acetone-d ₆ as solvent) symmetric A ₂ B ₂ system. IR bands

at 3230,1790,1700,1270 and 1150cm " ¹ .

Example 48 E:

If the a-[(imidazolidin-2-on-1-yl) -carbonylamino] used in a procedure of Example 45 is replaced,

methylphenylacetic acid by 0.02 mol each:

a - [(imidazolidin-2-on-1-yl) carbonylamino] thienyl (2) acetic acid, a - [(imidazolidin-2-on-1-yl) carbonylamino] thienyl (3) acetic acid, aI (imidazolidin-2-one-1-yl) carbonylamino] -p-hydroxyphenyl acetic acid, a - [(imidazolidin-2-one-1-yl) carbonylamino] -rn-hydroxyphenylacetic acid, a - [(imidazolidine -2-on-1-yl) -carbonylamino] -o-chlorophenylacetic acid, a - [(imidazolidin-2-one-1-yl) carbonylamino] -o, o'-difluorophenyl acetic acid, α-idmidazolidine ^ -one i-yD-carbonylaminol-o.o'-chlorfluorphenylessigsäure,

"- [(imidazolidin-1-yl-carbonylaminol-p-acetylaminophenylacetic acid, the following penicillins are obtained in the form of their sodium salts:

a - [(imidazolidin-2-on-1-yl) carbonylamino] -thienyl-2-methylpenicillin, α-klmidazolidine-1-yl-carbonylaminol-thienyl-OJ-methylpenicillin, a - [(imidazolidine -2-on-1-yl) -carbonylamino] -p-hydroxybenzylpenicillin, a-hlmidazolidine ^ -one-i-ylJ-carbonylaminol-m-hydroxybenzylpenicillin, a-imidazolidine ^ -on-i-yl-carbonylaminol-o-chlorobenzylpenicillin , a-Klmidazolidine ^ -one-i-yl-carbonylaminol-o.o'-difluorobenzylpenicillin, a - [(imidazolidin-2-one-1-yl) carbonylamino] -o, o'-chlorofluorobenzyl penicillin

-on-i-yli-carbonylaminol-p-acetylaminobenzylpenicillin [(imidazolidine ^ - ".

Example 49:

D-a - [(imidazolidin-2-one-1-yl) carbonylamino] -phenyl acetic acid

9.7 parts by weight of D (-) - C-phenylglycine were suspended in 150 parts by volume of 50% aqueous dioxane, added dropwise at room temperature while stirring so much 40% aqueous sodium hydroxide solution until the phenylglycine was just dissolved. To this solution was then added with stirring about 15% hydrochloric acid until the pH of the solution reached 7.5 to 8.0. The then present fine suspension of phenylglycine was cooled to about +5 ⁰ C, with stirring at this temperature gradually added 10.6Gew.-parts finely powdered imidazolidin-2-one-1-yl-carbonyl chloride while the pH by corresponding addition of about 5N sodium hydroxide kept at 7.5 to 8.0. The phenylglycine went into solution except for a small amount. There were still 60 min. At -5 ⁰ C stirred, while still to maintain the desired pH-value something sodium hydroxide solution had to be added occasionally only in the first 15 min.. Small amounts of insoluble matter were then removed by suction. The filtrate was largely freed from dioxane by means of a rotary evaporator, covered with ethyl acetate, acidified with 2N hydrochloric acid to pH 1.5 to 2.0, carried out, then the organic phase was separated, washed twice with water, dried over magnesium sulfate and completely evaporated in a rotary evaporator. The residue, a colorless clear foam, was dried for 2 days in a desiccator with open tap over P ₄ Oioan of the oil pump. Yield 7.9 parts by weight. In the IR spectrum (solvent: dimethyl sulfoxide), the substance shows two double bands in the region left open by the solvent, namely at 1720 and 1670 and at 1525 and 1480 cm ^-1 . NMR signals see Table 2, page 101.

Example 50:

a - [(imidazolidin-2-on-1-yl) carbonylamino] -4-methylthiophenylessigsäure

a) a-amino-4-methylthiophenylacetic acid

This amino acid was obtained by conventional procedure starting from 4-methylthio-benzaldehyde over the cyanohydrin and a-aminonitrile and saponification with boiling 20% hydrochloric acid. Melting point> 260 ⁰ C on the Kofler heating bench. The IR spectrum (Nujol) shows a single band in the carbonyl region at 1740cm " ¹ and a broad absorption between 1 570 and 1 670cm" ¹ with a main peak at 1 590cm " ^1. The NMR spectrum (NaOD / D ₂ O) is found Signals at τ = 2.5 to 2.8 (4H) (AB system), at 5.6 (1 H) and at 7.6ppm (3H).

b) a - [(imidazolidin-2-one-1-yl) -carbonyiamino] -4-methylthiophenylacetic acid

This compound was prepared from 13 parts by weight of the above-described amino acid and IOGew part 1-imidazolidin-2-one-i-.ylcarbonyl chloride in the manner described in Example 49. Yield 6.7 parts by weight of a yellowish hard foam. In the IR spectrum (solvent: dimethylsulfoxide), the substance in the region left open by the solvent shows two double bands, namely at 1760 and 1660 as well as 1 520 and 1480 cm ^-1 , NMR signals see Table 2, page 101.

Example 51:

a - [(imidazolidin-2-on-1-yl) carbonylamino] -benzylpenicillin sodium

3.8 parts by weight of the dinuclidazolidine ^ -one-i-y-carbonylaminol-phenylacetic acid were dissolved in 65 parts by volume of dichloromethane, 2.7 parts by weight of 1-methyl-2-chloro-A1-pyrrolinium chloride were added and then Cooling to -10 ° C. 2.0 parts by volume of triethylamine added little by little. This reaction mixture was then stirred for 1 hr. At -5 ° C (mixture A). ₍ 4.0 parts by weight of 6-aminopenicillanic acid were stirred in 80 parts by volume of dichloromethane after addition of 4.4 parts by volume of triethylamine and 4.0 parts by weight of anhydrous sodium sulfate for 2 hours at room temperature. cooled 2O ⁰ C and combined with the mixture A. the reaction was allowed mixture of alone 0 ⁰ C come and still stirred for 1 hr. at ⁰ ° C according to. Now the solvent was removed in a rotary evaporator, the residue dissolved in water, the solution covered with ice water and acidified with dilute hydrochloric acid to pH 1.5 with stirring and at 0 ° to 5 ° C. The organic phase was then separated, washed with water, dried over magnesium sulfate with cooling, filtered and, after dilution with the same Amount of ether in the filtrate precipitated the sodium salt of penicillin by addition of a methanol-containing ethereal solution of 2-ethylcapronic acid sodium yield 1.3 parts by weight, / 3-lactam content 34%. Band at 1775crrT ¹ NMR signals see Table 2, page 101.

Example 52:

Da - [(Imidazolidin-2-one-1-yl) carbonylamio] benzylpenicillin (free acid and sodium salt) In a manner similar to Example 51, from 3.8 parts by weight of Da - [(imidazolidin-2-one -1-yl) -carbonylamino] -phenylacetic acid, 65VoI.-parts dichloromethane, 3.0 parts by weight of 1,3-dimethyl-2-chloro-A1-imidazoliniumchlorid and 2, OVoI.-parts triethylamine prepared the mixture A and with prepared from 4.0 parts by weight of 6-aminopenicillanic acid, 80VoI.-parts of dichloromethane, 4.4 parts by volume of triethylamine and 4.0 parts by weight of Na ₂ SO ₄ prepared dried solution reacted. After removal of the solvent and the distribution of the reaction product between an aqueous phase of pH 1.5 and ethyl acetate, a precipitate which was neither soluble in the acidic aqueous phase nor in the organic phase was formed, which was filtered off with suction, washed with water and dried , This was the free acid of the desired penicillin. Yield 1.5 parts by weight. The ethyl acetate phase present over the acidic aqueous phase was separated, washed with water, dried over magnesium sulfate, diluted with ether and precipitated the sodium salt of penicillin. Yield 1.9 parts by weight, / 3-lactam content (free acid) 92%, / 3-lactam content (sodium salt) 89%. The two penicillins show an IR spectrum corresponding to their constitution. NMR signals see Table 2, page 101.

Example 53:

Da - [(Imidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin (free acid and sodium salt) In a manner similar to Example 52, the penicillin was prepared from 3.8 parts by weight of Da - [(imidazolidin-2-one 1-yl) carbonylamino] -phenylacetic acid, 50 parts by volume of dichloromethane, 1.2 parts by weight of tetramethylchloroformamidinium chloride and 1.0 part by mole of triethylamine as mixture A and 2.0 parts by weight of 6-aminopenicillanic acid in 50 parts by volume. Parts of dichloromethane and 2.2VoI.-Parts triethylamine and 2.0Gew.-Sodium sulfate prepared. There were obtained O.2 parts by weight of penicillin as the free acid and 1.9 parts by weight of the sodium salt. / 3-lactam content (free acid) 90%, / 3-lactam content (sodium salt) 25%.

The free acid showed an IR spectrum corresponding to its constitution.

Example 54:

a - [(imidazolidin-2-on-1-yl) carbonylamino] -4-methylthiobenzylpenicillin sodium This penicillin was prepared in a manner similar to Example 51 from 4.5 parts by weight of a - [(imidazolidin-2-one 1-yl) carbonylamino] -4-methylthio-phenylacetic acid, 80 parts by volume of dichloromethane, 2.7 parts by weight of 1-methyl-2-chloro-A1-pyrrolidinium chloride and 2.0 parts by weight of triethylamine for mixture A and 4.0 parts by weight of 6-aminopenicillanic acid, 80 parts by volume of dichloromethane, 4.4 parts by volume of triethylamine and 4.0 parts by weight of sodium sulfate. Yield 4.2 parts by weight of sodium salt, / 3-lactam content 36%.

NMR signals see Table 2, page 101.

Example 55:

a - [(imidazolidin-2-on-1-yl) carbonylamino] -4-methylthiobenzylpenicillin sodium In a manner similar to Example 51, this penicillin was prepared from 1.9 parts by weight of a - [(imidazolidin-2-one 1-yl) carbonylamino] -4-methylthio-phenylacetic acid, 40 parts of dichloromethane, 1.2 parts of tetramethylchloroformamidinium chloride and 0.98 part of triethylamine for mixture A and 173 parts of 6-aminopenicillanic acid, 40 vol Parts of dichloromethane, 1.9 parts by weight of triethylamine and 1.5 parts by weight of sodium sulfate for the mixture B obtained. Yield: 2.0 parts by weight of sodium salt, / 3-lactam content 61%.

The penicillin showed an IR spectrum corresponding to its constitution.

NMR signals see Table 2, page 101.

Example 56:

1,3-dimethyl-2-chloro-A1-imidazolinium

a) N, N'-dimethyl-N, N'-bis-trimethylsilyl-ethylenediamine

The mixture of 176 parts by weight ο, ο'-dimethylethylenediamine, 1 OOOVol.-parts of benzene and 552Vol.-parts of triethylamine was stirred at room temperature while 434 parts by weight of trimethylchlorosilane, diluted with 500 parts by volume of benzene, within 3 hours dripped. It was 3.5 hours. stirred, left to stand overnight, the precipitate sucked off and washed with benzene. The combined filtrates were evaporated in a rotary evaporator and the residue was distilled in vacuo. Yield 364Gew. parts, Kp. _0, i = ₅ 55 to 6O ⁰ C.

The NMR spectrum (solvent CCI ₄ ) showed signals at -160 (40) and -149 Hz (6H), with the signal of trimethylsilyl (9H) at 0Hz.

Analysis:

calc .: C 51.7 H 12.1 N 12.1%

Found: C51.1 H 11.9 N 12.1%

b) N, N'-Dimethylimidazolidone- (2)

The solution of 363 parts by weight, parts N, N'-dimethyl-N, N'-bis-trimethylsilylethylenediamine in 440 parts by volume dichloromethane and the solution of 170 parts by weight phosgene was added, simultaneously and separately, to 800 parts by volume dichloromethane while stirring at room temperature in 700Vol. parts of dichloromethane within 4V2Std. dropwise. Then, the reaction mixture was allowed to stand overnight, the unreacted phosgene blown out with dry air, the solvent removed on a rotary evaporator and the residue distilled in vacuo. Yield 119Gew. parts, Kp. ₁₀ _ _{10, 5} Torr = from 95 to 95.5 ° C.

c)!, S-dimethyl ^ -chloro-AI-imidazolinium chloride

To dissolve 156 parts by weight of phosgene in 330 parts of toluene was added the solution of 150 parts by weight of 1,3-dimethylimidazolidone- (2) in 200 parts by volume of toluene and allowed to stand at room temperature overnight. The then crystallized product was filtered off, washed with tetrachloromethane and dried in a desiccator over P4O10. Yield 177Gew. parts, melting point about 95 to 100 ⁰ C (Kofler hot bench). The product is crystalline and very hygroscopic. The NMR spectrum (solvent: chloroform) shows signals at τ = 5.6 (4H) and 6.65 ppm (6H).

Example 57:

By replacing the a - [(imidazolidin-2-one-1-yl) -carbonylamino] -p- used in the procedure of Example 45

methylphenylacetic acid by 0.02 mol each:

Da - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] phenylacetic acid, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p-methylphenylacetic acid, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p-chlorophenylacetic acid, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p- methylthio-phenylacetic acid, a - [(diazacyclohexan-2-one-1-yl) carbonylamino] -p-hydroxyphenylacetic acid, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] thienyl ( 2) -acetic acid, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -thienyl (3) -acetic acid, Da - [(benzimidazolon-1-yl) carbonylamino] -phenylacetic acid, "- [(benzimidazolon-1-yl-carbonylaminol-p-methyl-phenylacetic acid, α-catenoimidazolon-1-ylj-carbonylaminol-p-chlorophenylacetic acid," - [(benzimidazolon-1-yl-carbonylaminol-p-methylthiophenylacetic acid, a - [(benzimidazolone-1-yl) carbonylarnino] -p-hydroxy-phenylacetic acid, a - [(benzimidazolon-1-yl) -carbonylamino] -thienyl (2) -acetic acid, "- [(benzimidazolone-i) ylJ-carbonylaminol-thienyl-ol-acetic acid, Da - [( 5-methylimidazolidin-2-one-1-yl) carbonylamino] phenylacetic acid, a - [(4-methylimidazolidin-2-one-1-yl) carbonylamino] -p-methylphenylacetic acid, a - [(5- Methylimidazolidin-2-one-1-yl) carbonylamino] -p-chlorophenylacetic acid, o - [(5-methylimidazolidin-2-one-1-yl) carbonylamino] -p-methylthio-phenylacetic acid, "- [(o-) 1-Dimethylimidazolidine-1-yl-carbonylaminol-p-hydroxy-phenylacetic acid, a - [(5-methylimidazolidin-2-one-1-yl) carbonylamino] -thienyl (2) -acetic acid, a - [(5- Methylimidazolidin-2-one-1-yl) carbonylamino] thienyl (3) acetic acid, Da - [(5,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] phenylacetic acid, a - [(5 , 5-Dimethylimidazolidin-2-one-1-yl) carbonylamino] -p-methylphenylacetic acid, a - [(5,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] -p-chloro -phenylacetic acid, a - [(4,5-dimethylimidazolidin-2-on-1-yl) carbonylamino] -p-methylthio-phenylacetic acid, a - [(5,5-dimethylimidazolidin-2-one-1-yl) - carbonylamino] -p-hydroxy-phenylacetic acid, a - [(5,5-dimethylimidazolidin-2-one-1-yl) carbonylamine o] -thienyl (2) acetic acid

a - [(4,4-dimethylimidazolidin-2-one-1-yl) carbonylamino] thienyl (3) acetic acid, the following penicillins are obtained in the form of their sodium salts:

Da - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p-methylbenzylpenicillin, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p-chlorobenzylpenicillin, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p- methylthio-benzylpenicillin, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -p-hydroxybenzylpenicillin, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino ] -a-thienyl (2) -methylpenicillin, a - [(1,3-diazacyclohexan-2-one-1-yl) carbonylamino] -a-thienyl (3) -methylpenicillin, Da-KBenzimidazolone-i- yl-carbonylaminol-benzylpenicillin, a-tl-benzimidazolone-i-yl-carbonyl-aminol-p-methylbenzylpenicillin, a-lfbenzimidazolone-i-y-carbonylaminol-p-chloro-benzylpenicillin, a-KBenzimidazolon-i-yD-carbonylaminol-p- methyl-thiobenzylpenicillin, α-catenoimidazolone-i-ylcarbonylaminol-p-hydroxy-benzylpenicillin, a - [(benzimidazolon-1-yl) carbonylamino] -a-thienyl (2) -methylpenicillin, "- [(benzimidazolone-i -ylJ-carbonylaminol-a-thienyHSJ-methylpe nicillin, Da - [(5-Methylimidazolidin-2-one-1-yl) carbonylamino] benzylpenicillin, a - [(4-methylimidazolidin-2-one-1-yl) -carbonylamino] -p-methylbenzylpenicillin, a - [(5-Methylimidazolidin-2-one-1-yl) carbonylamino] -p-chlorobenzylpenicillin, a - [(5-methylimidazolidin-2-one-1-yl) carbonylamino] -p-methylthiobenzylpenicillin, a - [(5-methylimidazolidin-2-on-1-yl) carbonylamino] -p-hydroxybenzylpenicillin, a - [(5-methylimidazolidin-2-on-1-yl) -cafbonylamino] -a-thienyl (2 ) -methylpenicillin, "- [(S -methylimidazolidine) -one-i-yl-carbonylaminol-a-thienyl-O-methylpenicillin, Da - [(5,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] benzylpenicillin .

a4 (5,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] -p-methylbenzylpenicillin, a - [{5,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] -p- chloro-benzyl penicillin, "-t (4,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] -p-methylthiobenzylpenicillin," - [(SS-dimethylimidazolidin-1-ylj-carbonylaminol) p-hydroxybenzylpenicillin, a - [(5,5-dimethylimidazolidin-2-one-1-yl) carbonylamino] -a-thienyl (2) -methylpenicillin

e - [(4,4-dimethylimidazolidin-2-on-1-yl) carbonylamino] -a-thienyl (3) -methylpenicillin.

Example 58:

By replacing the a - [(imidazolidin-2-on-1-yl) carbonylamino] -p- used in the procedure of Example 45

methylphenylacetic acid by 0.02 mol each:

Da-n-imidazolidine ^ -one-i-ylJ-carbonylamino-p-methoxyphenylacetic acid, La-climidazolidine ^ -one-i-y-carbonylaminol-p-methoxyphenylacetic acid, DXra-E-imidazolidine ^ -on-1-ylcarbonylaminol-p-methoxyphenylacetic acid , Da - [(Imidazolidin-2-one-1-yl) carbonylamino] -o, o'-dichloro-phenylacetic acid, La-illmidazolidine ^ -one-i-ylJ-carbonylaminoI-o'-dichlorophenylacetic acid

D.L-α-methylimidazolidine-1-ylj-carbonylamino-o.o-dichloro-phenylacetic acid, the following penicillins are obtained in the form of their sodium salts:

Da - [(im idazolidin-2-on-1-yl) -ca-carbonylamiono] -p-methoxybenzyl penicillin, La - [(imidazolidin-2-one-1-yl) carbonylamino] -p-methoxybenzylpenicillin, D ^ - α-imidazolidine ^ -on-1-ylcarbonylaminol-p-methoxybenzylpenicillin, Da-flavidazolidine ^ -on-1-ylcarbonylamino-o'-dichlorobenzylpenicillin, La-klmidazolidine-1-yl-carbonylaminol-o ^ '- dichlorbenzylpenicillin

D, L-a-Klmidazolidin ^ -on-i-yll-carbonylaminol-o.o'-dichlorbenzylpenicillin.

A-CO-NH-CH-CO-NH-CH - CH

X-CO-N-, Y

CO-N or

cb)

R ₂

CH COOH

(C)

(F)

(G)

Ch) U)

(I)

CH,

CH ₃ , CK,

and

(Ic)

(1) (τη)

(Η)

-Z- a divale-ftte group (ο)

Low igyl CH ₂ - (X)

-CH ₂

(£) CO N

Ct) (v)

(W)

Ί, £, 3 or 4,

(A3).

or 1 ^{w V v} or 2,

(Vb)

and g = 0, 1, .2, or Ͽ + g = 1, 2 or 3

(Cc)

or 1

ti *

C =

(there)

Cee)

C C

(M)

or 1

Q and g = 0 or Ͽ + g = 0 or 1

(Ii)

(Ic It)

or

or

⁷ p

(nti)

E Il C-

/ Ip ^- OTId g = O, / od.

(Mtn)

/ p ~ and g = 0, 1 or 2 J / P + S = 2 or 3 /

_J

(OO)

(PP)

(Irr)

H, N-CH-CH / CH ₃

C COOH (II)

H _a N-CH-CH / CH ₃ (III)

ul

CH

c _v / Nh ₃

(IV)

A-CO-NH-CH-COOH I B

10 #

(VI)

Ί1

ι V V ^

(VII)

CJi ο CHo W

C-)

H ₂

(IX)

IV

* ^ o: h-c ^ u (χ)

) ^ OC CH ₂ ) ₂ -

H ₂ N-CK-COOH B

A-CO-V (XIII)

^(s> general formula I, VV)

E. CoIi 25 A 261 C 165 183/58 Proteus vulg Table 1 : 3400 Klebsiella 63 50 100 PSDM. aerug Walter Staph. aureus 133 Streptoc. Faecal. ATCC 9790 14 3.1 > 400 100 100 1017 (MHK 200 K 10 50 100 Bonn 200 177.7 E 1.6 0.8 to 4 400 12.5 12.5 400 : in E / ml) 25 50 20 to 400 100 ~ 0.8 Peni cillin No. 100 to 500 4 to 20 4 to 20 100 bacterial strains 4 to 20 50 20 to 100 20 to 100 > 0.8 1 100 to 500 100 to 500 4 to 20 4 to 20 20 to 100 20 to 100 ' > 500 20 to 100 20 to 100 > 0.8 200 2 > 500 > 500 100 to 500 100 to 500 100 to 500 > 500 > 500 0.8 to 4 200 4 ' 20 to 100 > 500 > 50O> 500 ^ 500 > 500 > 500 > 500 100 to 500 > 500 100 to 500 4 to 20 100 to 500 5 12.5 > 50O 100 to 500 100 to 500 > 500 > 500 > 500 50 > 500 > 500 100 to 500 0.8 to 4 100 to 500 7 6.3 > 400 50 50 > 500 200 > 500 100 100 > 500 200 , 1.6 100 * o to 500 ^ 8th 6.3 > 400 50 12.5 200 100 50 100 200 200 400 1.6 > 500 Ov 9 4 to 20 > 400 50 12.5 100 100 50 20 'to 100 400 200 400 1.6 ^ 500 10 B 20 to 100 > 500 20 to 100 20 to 100 100 ~ 100 50 > 500 100 400 100 to 500 400 0.8 to 4 100 11 C 4 to 20 > 500 100 to 500 100 to 500 100 to 500 > 500 20 to 100 20 · to 100 to 50O > 500 0.8 to 4 200 12 4 to 20 > 500 20 to 100 20 to 100 > 500 100 to 500 > 500 20 to > 500 10O to 500 <0.8 200 14 > 500 20 to 100 20 to 100 > 500 100 to 500 20 to 100 100 to 500 100 to 500 0.8 to 4 100 to 500 15 100 to 500 20 to 100 100 to 500 > 500 17 20 to 100 18 ^ 100;

E. CoIi A 261 C 165 183/58 Proteus vulg Table 1 (Continuation) 3400 Klebsiella : • 63 20 to 100 PSDM. aerug Walter Staph. aureus Streptoc. Faecal. ATCC 9790 i O 14 > 500 20 to 100 1017 bacterial strains 100 to 500 K 10 20 to 100 Bonn 100 to 500 1777 E 133 20 to 100 Peni cillin No. > 500 20 to 100 20 to 100 20 to 100 100 to 500 <0.8 100 500 20 > 500 4 to 20 4 to 20 > 500 20 to 100 <0.8 ^ 20 21 > 500 100 to 500 > 500 100 > 500 <0.8 100 to 500 22 > 400 25 25 50 > 400 100 0.8 to 4 200 23 6.3 > 400 200 200 100 > 400 50 > 400 100 > 400 -v, 1.6 > 400 24 100 > 400 200 400 > 400 > 400 > 400 100 > 400 > 400 > 400 6.3 > 400 ( 27 100 > 400 6.3 3.1 > 400 12.5 > 400 100 to 500 > 400. 50 > 400 12.5 100 28 3.1 > 500 20 to 100 20 to 100 12.5 100 to 500 200 100 to 500 25 100 to 500 200 <0.8 20 to 100 29 4 to 20 > 500 100 to 500 20 to 100 100. up to 500 100 to 500 100 to 500 about 100 100 to 500 100 to 500 0.8 to 4 > 500 30 20 to 100 > 500 20 to 100 20 to 100 100 to 500 100 to 500 100 to 500 4 to 20 about 500 100 to 500 a, 8 to 4 100 to 500 31 about 20 100 to 500 4 to 20 about 100 100 to 500 20 to 100 100 to 500 4 to 20 about 0.8 20 to 100 32 100 to 500 20 to 100 4 to 20 4 to 20 20 to 100 about 20 <0.8 20 to 100 33 about 4 20 to 100 20 to 100 4 to 20 <0.8 35

Table 1 (continued): Bacterial strains

Penicillin no.

E. CoIi

14

A 201

Proteus vulg.

C 165

183/56

3400

Klebsiella

K 10

63

PSDM. aerug.

Bonn

Walter

Staph. aureus

1750

133

Streptoc. Faecal. ATCC 9790

> 500

<0.8> 500

0.8 to 4> 500

100 to 500 ..> 500> 500> 500

0.8 to 4 0.8 to 4 4 to 20 4 to 20 20 to 100 4 to 20 4 to 20 4 to 20

to

until 20

44 6.25 400 - 25 45 6.25 > 400 25 46 6.25 > 400 50 47 3.12 > 400 25 48 A 3.12 > 400 12.5 51 3.12 400 12.5 52 3.12 > 400 12.5 53 3.12 400 6.25 54 6.25 > 400 25 55 6.25 > 400 25

4 to

25

6.25

12.5

6.25

6.25

12.5

6.25

12.5

6.25

12.5 to 100 20 to 100 20 to 100 20 to 100 20 to 10.0 20 to 100

25

100

50

100

50

25

12.5 100 100

,

100

100

100

100

100

100

50

100

100

50

100

50

50

50

50

25

100

100

50

25

25

12.5

25

12.5

12.5

6.25

12.5

12.5

50

12.5

25

12.5

12.5

12.5

12.5

12.5

25

25

400 200 200 200 400 200 200 200 200

<0.8 <0.8

1.6

<0.78 1.56

<0.78 <0.78

<0.78

<0.78 <0.78 <0.78 <0.78

100 to

20 to

100 to

100

50

50

50

25

25

12.5

50

50

Table 2:

NMR data of some penicillins of the general formula I. Position of the signals in the τ-scale indicated [ppm], solvent CD3OD,

Example NMR signals at

(Intensity of the signals with deduction of Precursorsäuresignale) visible in the spectrum impurities

45 2.4 to 3.0 (4H), 4.3 to 4.6 (3H),

5.8 (1H), 5.9 to 6.4 (2H),

6.4-6.9 (2H), 7.7 (3H) and 8.4 (6H) 15 wt% α- (imidazolidin-2-one-1-ylcarbonylamino) -p- methylphenylacetic acid

46 like example

47 2.6 (4H), 4.3 to 4.6 (3H), 5.8 (1H),

5.9 to 6.8 (4H) and 8.3 to 8.6 (6H)

48 A as example

60% by weight of α- (imidazolidin-2-one-1-ylcarbonylamino) -p-methylphenylacetic acid

10 wt _^0/0 a- (imidazolidin-2-on-1-yl-carbonylamino) -p-chloro-phenylacetic acid

25% by weight of α- (imidazolidin-2-one-1-ylcarbonylamino) -p-chlorophenylacetic acid

Acetone-d ₉ as / solvent

Acetone-de as

solvent

0.9 (1H), 2.6 (2H) ₁ 2.8 (3H), 4.5 (1H) ₁ 6.2 (2H), 6.6 (2H) and 7, 7 (3H)

0.9 (1H) ₁ 2.55 (4H), 4.5 '(1H) ₁ 6.2 (2H) and 6.5 (2H)

IX

Table 2 (continued):

Example NMR signals' at

(Intensity of the signals with deduction of the prazuric acid signals) Impurities visible in the spectrum

2.4 to 2.75 (5H) ₁ 4.45 to 4.6 (1H), 6.0 to 6.85 (4H)

2.55 to 2.8 (4H), 4.55 to 4.7 (1H), 5.95 to 6.8 (4H), 7.55 (3H)

2.35 to 2.75, 4.35 to 4.55, 5.75, 5.95 to 6.85, 8.3 to 8.55 58% by weight of di (imidazolidin-2-one-1 -yl-carbonylamino) - phenylacetic acid

(free acid) 2.4 to 2.7 (H),

4.3-4.6 (3H), 5.55 (1H), 5.9-6.7 (4H), 8.25-8.5 (6H) (Na-SaIz) 2, 45 to 2.75 (5H), 4.3 to 4.6 (3H), 5.8 (1H), 5.95 to 6.75 (4H), 8.3 to 8.6 (6 H)

2.45 to 2.9, 4.35 to 4.6, 5.8, 5.9 to 6.85, 7.6, 8.3 to 8.55

2.4 to 2.9, 4.35 to 4.65, 5.8, 5.95 to 6.8, 7.6, 8.3 to 8.6 60 wt .-% a- (imidazolidin-2 -on-1-yl-carbonylamino) -p-methylthio-phenylacetic acid

40% by weight of α- (imidazolidin-2-one-1-ylcarbonylamino) -p-methylthio-phenylacetic acid

Claims (1)

A process for the preparation of penicillins of general formula I in which A is a group a, berberc, X is hydrogen, alkyl having up to 10 carbon atoms, alkenyl having up to 10 carbon atoms, VinyC cycloalkyl and cycloalkenyl having up to 10 carbon atoms, arylvinyl, mono- , Di- and tri-halo-lower alkyl, mono-lower alkylamino, di-lower alkylamino, monoarylamino, aryl-lower alkylamino, alkoxy of up to 8 carbon atoms, cycloalkoxy of up to 7 carbon atoms, aralkoxy of up to 8 carbon atoms, aryloxy, a group of lower alkyl OV, lower alkyl SV, N = CV, Niedrigalkly-O-CO-V, Diniedrigalkylamino-CO-V, d to n, V is a bivalent organic radical having 1 to 3 carbon atoms, η is an integer from 0 to 2 inclusive and R ₁ , R ₂ and Each R ₃ is hydrogen, nitro, nitrile, di-lower alkylamino, di-lower alkylaminocarbonyl, lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chloro, bromo, iodo, fluoro or trifl methyl, Y is alkyl of up to 10 carbon atoms, alkenyl of up to 10 carbon atoms, vinyl, propenyl, cycloalkyl and cycloalkenyl of up to 10 carbon atoms, mono-, di- and trihalogeno-lower alkyl, aralkyl of up to 8 carbon atoms, aryl or a heterocyclic radical, ο a divalent one Group Ͽ to ν, m is an integer from 3 to 5, the arrow in the divalent group ν is intended to express that linking the two free valences of ο with the N and C atom of the group w is not arbitrary, but in the manner indicated by the arrow, Q is a divalent group, of the type aa to jj, wherein E is oxygen or sulfur, G is hydrogen or lower alkyl, R ₁ and R _{2 is} hydrogen, nitro, nitrile, Diniedrigalkylamino, Diniedrigalkylaminocarbonyl , Lower alkanoylamino, lower alkoxycarbonyl, lower alkanoyloxy, lower alkyl, lower alkoxy, sulfamyl, chloro, bromo, iodo, fluoro or trifluoromethyl, the arrow in the divalent one Let group kk express that the linkage of the two free valencies of kk with the two N atoms of the group c is not arbitrary, but in the manner indicated by the arrow, M is a group II, mm or nn, wherein E and C are as defined above, B is a group of the formulas oo, pp, qq, rr, R ₄ , R ₅ and R _{6 are} hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylthionyl, lower alkylsulfonyl, nitro, lower alkylamino, lower alkanoylamino, Hydroxy, lower alkanoyloxy and which may be with respect to the chiral center C ⁺ one of the two possible diastereomers with the R or S configuration or may be present as mixtures of these two diastereomers and their non-toxic, pharmaceutically acceptable salts, characterized in that 6-aminopenicillanic acid of the formula II or compounds of the general formula IV in which R ₇ , R ₈ and R _{9 are} alkyl having up to 6 carbon atoms in which R _{10 has} either the same meaning as R or denotes phenyl, by reaction of carboxylic acids of the general formula V with about one molar equivalent of the compounds of the general formulas Vl, VII, VIII or IX in which R _{9 has} the meaning indicated above; Ri _{1 represents} a divalent organic residual (CH ₂ H, - _(CH2) 5- or- (CH _{2) 2} -O- (CH -darstellt _{2) 2} and W is halogen, in an anhydrous inert organic solvent in the presence of about one molar equivalent of a base at a temperature of -60 to +30 ⁰ C obtained at the carboxyl group modified carboxylic acids of the formula V or carboxylic acid derivatives of FormefX, wherein A, B and C ^{+ have} the meaning given above and U is the radical CN and / wherein the reaction in the case of using the 6-aminopenicillanic acid in anhydrous or aqueous solvents in the presence of a base and in the case of the use of the compounds of the general formulas l is carried out in water-free and hydroxyl group-free solvent, with or without the addition of "a base at a temperature in the range of -30 to +50 ⁰ C IV.