PL89668B1 - - Google Patents

Description

The subject of the invention is a method of producing new penicillins that can be used as antibacterials, feed additives, and as medicaments for poultry, animals and humans, for the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, especially Klebsiella bacteria. Antibacterial agents such as arripicillin (U.S. Patent No. 2,965,648) are very effective in treating Gram positive and gram negative bacterial infections. They do not, however, effectively combat infections caused by Klebsiella bacteria. Carbenicillin (US Pat. US Nos. 3,142,673 and 3,282,926) is effective in humans against infections caused by Klebsiella bacteria with prolonged, high dosages which can only be achieved by infusions. The invention relates to 6- (α-3-acyloureftdo) acids. -acetamido-penicylates, in which the hydrogen atom on the nitrogen atom in position 3 is replaced by other ikami. 6 (α-3-acylureidoacetamido) penicillanic acids are described in Dutch Patent Nos. 6,901,646d 6,908,909, US Pat. No. 3,479,399, 3,483,188, 3,481,922 and German Patent Specification No. 195 * 9,920, all of these 3-acylureidoaceta'midopenicylic acids, in contrast to the pendcylate acids obtained according to the invention, are small atoms. hydrogen at the nitrogen atom in position 3 of the acylureido group. It was found that the new penicillins were compounds of the general formula 1, in which A is a group of formula 13, 14 or 15, especially a group of formula 50, 51, 52, 53 or 54, X represents a hydrogen atom, an alkyl radical of up to 10 carbon atoms, an alkenyl radical of up to 10 carbon atoms, a vinyl, cycloalkyl, cycloalkenyl radical of up to 10 carbon atoms, arylvinyl, lower mono- and di-radical - and trihaloalkyl, lower monoalkylammonium, lower dialkylamino, monarylamino, lower aryl-αMloamino, alkoxy with up to 8 carbon atoms, cycloalkoxy with up to 7 carbon atoms, aryl doalkoxy 8 carbon atoms, aryloxy, lower alkyl-O-V- group, lower group aM'lo-SV-, group N- = CV, lower alkyl-O-CO-V group, lower group dialkylamino-CO- V-, group of formula 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, V is a divalent organic radical with 1 to 3 carbon atoms, n is an integer 0-2 d R1, R2 and R3 represent hydrogen atoms, nitro, nlitrile groups, lower dialkylamino groups, lower dialkylaminocaribonyl groups, lower alkanoyl amino groups, lower alkoxycarbonyl groups, lower alkanothiloxy groups, lower alkoxy groups, lower alkyl groups sulfamyl, chlorine, bromine, iodine, fluorine or trifluoro groups, Y is an alkyl radical of up to 10 carbon atoms, an alkenyl radical of up to 10 carbon atoms, vinyl, propenyl, cycloalkyl and cycloalkenyl groups up to 10 carbon atoms, the lower group is a mono-, di- or trihaloalkyl, an arylalkyl radical of up to 8 carbon atoms, an aryl radical or a heterocyclic group, "-Z" denotes a divalent group of the formula WCH 2 -, 27, -hO - CH 2 -, 2 -S - / CK 2 / m-1 - and 28, 29, "- / CH = CH / 2—, m represents an integer of 3-5, the arrow in the bivalent group - <-Z— means that the connection of both free values of the group - <-Z- with the N atom and the C atom in the group of formula 14 is not arbitrary, but proceeds as indicated by the arrow, Q represents a bivalent group of formula 30, 31 or 32, where pg = 0, 1, 2 or 3 a p + g = 1,2 or 3, of the formula 33, of the formulas 34, 36, where pg = 0 or b1, and p + g = 0 or 1, or of the formulas 37, 38 and 39, where in In the above-mentioned formulas, E represents an oxygen or sulfur atom, • G represents a hydrogen atom or a lower alkyl group, R 1 and Rj represent hydrogen atoms, nitro groups, cyano groups, lower dichamino groups, lower dialmalaminocaribonyl groups, lower alkanoylamino groups, lower alkoxycarbonyl groups, lower alkanoyl oxyl groups, lower alkyl radicals, lower alkoxy groups, sulfamyl groups, chlorine, bromine, iodine, fluorine or trifluoromethyl groups, where the arrow in the bivalent group of formula 40 means that the binding of both free values The groups with both nitrogen atoms of the group of formula 15 are not arbitrary but proceed as depicted The marked arrow, M represents the group of formula 41 or 42, where pg = 0, 1 or 2, and p + g = 2 or 3, or formula 43, where pg = 0, 1 or 2, and p + g = = 2 or 3 and of which E and G are as defined above, B represents the groups of the formulas 44, 45, 46 or 47, where in formula 44 R4, R5 and R6 are hydrogen atoms, halogen atoms, lower radicals alkyl, lower alkoxy groups, lower alkylthio groups, lower alkylsulfonyl groups, nitro groups, lower dialkylamino groups, lower alkanoylamino, hydroxyl groups, lower alkandyloxy groups, the compounds of formula the configuration of one of the two possible diastereoisomers of the R 1 S 11 b configuration being a mixture of both diastereoisomers and their niletoxic salts used in the pharmaceutical formulation, "is obtained by reacting 6-aminopenicillanic acid of the formula II with the reaction product of the compound of formula V with the compound of the general formula [TW] + W—, in which T is represented by Although the group of the general formula 6, 7, 8 or 9, in which the formulas R9 is as defined above, R10 is R * or a phenyl radical, Rn is a divalent radical of the formulas - / CH2 / 4 -, - / CH2 / s- or - / CH2 / 2-0- / iCH2 / 2-Ia W denotes a halogen atom or an azide group, in anhydrous or water-containing, inert organic solvents in the presence of a base. The reactions according to the invention are carried out by reacting carboxylic acids having a carboxylic acid group, preferably in the form of a solution in an anhydrous inert organic solvent with a solution of 6-aminopenicillanic acid in water, in anhydrous or water-containing solvents in the presence of a base . As solvents for carboxylic acids having a carboxyl-converted group, they are used in the reaction medium containing water, for example, acetone, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and hexamethylphosphoric acid triamide, and preferably chloride in the anhydrous chloroform reaction medium. 6-aminopenicyanic acid is reacted, preferably in the form of a solution of its salt with a base in water or a mixture of water with a water-miscible solvent, or in an anhydrous organic solvent. Suitable solvents, in addition to water, are: acetone, tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric triamide, and isopropanol for the reaction medium containing water, and for an anhydrous environment, in addition to the solvents mentioned above, preferably methylene chloride and chloroform. In order to convert 6-aminopenicylic acid into its salt with a base, dissolved in a solvent, a suitable base is used as an aqueous or water-containing reaction medium, for example inorganic bases such as sodium carbonate , sodium hydroxide, acidic sodium carbonate, and suitable potassium and calcium compounds, magnesium oxide or magnesium carbonate, or buffer substances, and preferably triethylamine, pyridine, diethylamine, N-ethylpiperidine or'N-ethylmorpholene in the anhydrous reaction medium. Reactions of the carboxylic acids product of the reaction of the compound of formula 5 with the compound [TW] + W-, with a converted carboxyl group, with 6-aminopenicillanic acid, in a water or water-containing environment, can be carried out at a pH value preferably of 6.5 ° C. 8, or at a pH of about 3. As in most chemical reactions, temperatures higher or lower than those indicated in the examples may be used. When using temperatures significantly different from those given in the examples, side reactions occur to an increasing extent, which reduce the yield and adversely affect the purity of the products. An excessively lowered reaction temperature reduces the reaction rate very quickly, resulting in a reduction in yield. In the reaction of the carboxylic acids with a transformed carboxylic acid group with 6-aminopenicillanic acid or silalated 6-amlnopenicyanoic acids of general formulas 3 and 4, the preferred temperature is -20 ° C to 30 ° C. Only in cases where the carboxylic acids with the converted carboxyl group is not sufficiently stable or there is a danger that racemization may occur at the optically active center adjacent to the carboxyl group, the reactions are preferably carried out at a temperature below -20 ° C. 40 45 50 51 605 In the reaction of the carboxylic acid carboxylic acids (the reaction product of the compound of formula 5 with the compound of formula [TW] + W) with 6-Haminopenicillanic acid or with compounds of general formulas 3 and 4, the reaction components introduce in equimolar numbers. However, one of the reaction components may be added in excess to facilitate purification or to obtain the desired penicillin clean and increase its yield. For example, the 6-aminopenicillanic acid or the compounds of general formulas 3 and 4 can be introduced in an excess of 0.1 to about 0.4 molar equiv, and thus better utilization of the carboxyl converted carboxylic acids can be obtained. In the final workup of the reaction mixture and in the isolation of penicillin, the 6-aminopenicillanic acid possibly present can be easily removed, taking advantage of its very good solubility in aqueous mineral acids. The residues of the carboxylic acid present, having a converted carboxyl group, are much more difficult to separate from the penicillin formed. By reaction of the carboxylic acids having the converted carboxyl group with the 6-aminopenicylate acid of formula II or the compounds of general formulas 3 and 4 the amount of the introduced bases depends on the maintenance of the desired pH value. In case the measurement and adjustment of the pH value is not carried out, or if such measurements cannot be made due to the lack of sufficient water in the diluent, it is introduced when using 6-aminopenicylic acid and 1.5-2.5 equivalents of the base of the anhydrous reaction medium. The final treatment of the reaction feeds for the preparation of the penicillins according to the invention or their salts is carried out in a manner generally known and used in the isolation of penicillins. Carboxylic acids with a carboxyl-converted group are prepared by reactions of the compound of formula 5 with the compound of formula [T-WJ + W-, used in an amount 1 molar equivalent in an anhydrous inert organic solvent, in the presence of about 1 molar equivalent of a third-order organic base, at a temperature of about -60 ° C to 30 ° C, preferably -30 ° C to ° C. The reaction obtained in this reaction Carboxylic acids with a carboxylic conversion are preferably not isolated, but are used together with their solvents to react with 6-aminopenicillanic acid or a compound of general formulas 3 or 4. Carboxylic acids of general formula 5 The carboxylic acid derivatives of the formula (10) are converted by first converting the compounds of the general formula (11) in a dry, inert organic solvent, for example acetone, tetrahydrofuran, methylene chloride, dioxane, chloroform or dimethylformamide. , in the presence of at least and preferably 1 equivalent of a tertiary base, preferably triethylamine, at a temperature of about -25 ° C to 25 ° C, preferably - 10 ° C., with 668 6 g of thionyl chloride, to form the molar equivalent of the base hydrochloride, into an unknown intermediate compound which is not isolated but then reacted with 1 equivalent of canboxylic acid of formula 5 in the presence of an additional molar equivalent of an organic base, preferably three to one ammonia, at a temperature from about -25 ° C to 25 ° C, preferably from -10 ° C to ° C. After filtering off the hydrochloride of the base, the corresponding compound of formula 10 can be isolated by evaporating the solvent and, if necessary, overtaking the crystallization from inert solvents, or, if the substance is not crystalline, it can be purified by brief washing, for example with an ethereal or benzene solution with an aqueous acidic solution. sodium carbonate at the lowest possible temperature. The 6-aminopenicillanic acid used as starting material in the process of the invention can be obtained in a known manner by N penicillin G cleavage or by fermentation or by chemical cleavage (Dutch (Patent Specification 67 / H3 809). Carboxylic acids of general formula 5 are prepared from amino acids of general formula 12 by reacting them with compounds of general formula A-CO-W, in which A, B, W and C have the meaning given above. Compounds of the general formula ^ A-OO-W when W is a halogen atom are obtained according to the methods described in German patent DOS No. 1,793,287, UftN patent No. 1,259,871, US Pat. US No. 3,276,618 and No. 3,337,621 and Japanese Patent Laid-open No. 12,921/64. Moreover, some compounds of the general formula A-OO-W in which W is a halogen atom are prepared from the corresponding amides by metallolysis at the amide nitrogen atom with methyllithium and then reacting with phosgene. Compounds of the general formula A-OO-W in which W is a halogen atom and A is a group of formula 15 are obtained, as specifically stated in the examples, by reacting cyclic ureas of formula 48 with phosgene. [T- 45 -W] + W-, in which T represents the group of formula 6, 7 and 9 is described in the literature (J. med. Chem. 9/1966 / page 980, Ber. 96/1963 / page 2681, Tetrahedron 17/1902! / Page 114). The reagent [TW] + W ~, in which T represents a group of general formula 8, is followed by N, N'-dimethylethylenediamine, which is converted to N, N'-bis-trimethylsilyl compounds and / is reacted with phosgene to the corresponding cyclic urea which in turn is reacted with phosgene. 55 In an attempt to prepare some penicillins according to the invention in a known manner from acid chlorides obtained from acids of general formula 5 and thionyl chloride, and from 6-aminopenicillanic acid, a mixture of several penicillins was obtained, in which there was no or there was only a small amount sought for penicillin produced in a different uniform manner from ampicillin and the corresponding A-OO-Cl acid chloride, general formula. This was due to the comparison of the bacterial spectrum "in vitro" and the thin-layer chromatogram. When trying to obtain penicillin according to the invention in a known manner from mixed anhydrides obtained from acids and ethyl chloroformate, and from aminopenicillanic acid, it is possible to - to obtain only 20% yield of ethoxycarbonyl-penicillin. The chemotherapeutic effectiveness of the new penicillins was tested in vivo and in vitro. In vitro inhibitory values (MHK - minimum inhibitory concentration) were determined in a liquid environment in test tubes with decreasing dilution, with the reading was carried out after 24-hour incubation at 37 ° C. MHK occurs in a test tube from a series of dilutions, in which there is no turbidity. The medium was used as a medium with the following composition: Lab Lemco / OXOiD / 10 g, peptone / DiFOO / 10 g , NaCl 3 g, D - + / - de-stro (Merck) 10 g and buffer pH 7.4 1000 ml. The activity spectrum covers both gram-positive and gram-negative bacteria. A general advantage of penicillins according to the invention is their efficacy in vitro (Table 1) and in animal experiments against penicillin and carbenicillin resistant Klebsiella bacteria and ampicillin resistant Proteus bacteria. Moreover, they are effective in vitro and in vivo against penicillin resistant pseudomonos species. The concentration necessary for destroying the bacteria is reached in the serum after parenteral administration. Excellent action is obtained both in a single dose and in multiple doses. The resorption of new penicillins after subcutaneous administration is very rapid and the peak concentration is reached after 10 minutes. Precipitation is usually also rapid. The penicillins obtained according to the invention are resistant to acids. At pH = 1, they maintain microbial activity within 1 hour. Some of the new penicillins are well-tolerated, which is particularly evident in the intravenous administration of a very high dose, which is tolerated without complications. According to the invention, penicillins can be used alone or administered after preparation in a known manner with in pharmacy a substrate material. For oral use, they may be administered in the form of tablets, which may additionally contain starches, milk sugar, certain species of alumina, etc., or in the form of capsules, drops or granules, alone or with the same or They may also be administered orally in the form of juices or suspensions which may contain flavor-correcting substances or dyes for such purposes. In addition, penicillins according to the invention may be administered parenterally, e.g. intramuscularly, subcutaneously or intravenously, or as a drip infusion. extended. For parenteral administration, sterile solutions are best used, which may contain other ingredients, such as sodium chloride or glucose to render the solution isotonic. For the preparation of such solutions, penicins are used in dry form, contained in ampoules. For oral and parenteral administration, the dosage is preferably 25,000-1,000,000 E / body weight unit / day. It can be given once or as a prolonged infusion or it can be divided into several smaller doses. For local treatment, the preparation of penicillins, ointments or powders according to the invention, can be used. The following examples illustrate more closely the preparation of new penicillins. The 0-lactam content of penicillin is determined iodometrically. All substances mentioned herein have infrared spectra corresponding to their structure. Penicillin NMR spectra were established in CDfOD solution; the signals given in the examples correspond to the T-scale and they conform to the relevant structure. The numbers (E / ml) indicating the efficacy against the specified bacteria are the minimum inhibitory concentrations, determined after 24 hours of incubation in a test tube dilution sequence. In the animal efficacy test, "A" indicates that the corresponding penicillin in the mice test when administered subcutaneously against Proteus vulgaris 1017 is more effective than ampicillin, and "B" indicates that when used against Klebsiella, aerobacter 63 is more effective. from ampicillin and carbenicillin. When calculating the analytical data, the water content of penicillins was taken into account. Example I. Da- (3-acetyl-3-allylureido) -benzylureido / benzylpenicillin sodium salt Dissolves without moisture 5.5 parts by weight of Da- / 3-acetyl acid -3-allylureido--a-phenylacetic acid in 50 parts by volume of dichloromethane and 2.0 parts by weight of triethylamine are added with cooling. It is then cooled from -S ° C to -10 ° C and 3.6 parts by weight of tetramethylchloroformamidinium chloride are added in several portions over a period of several minutes. Stirring is carried out for 30 minutes at the temperature indicated, any insoluble components present are filtered off, preventing the solution from heating to a temperature above 0 ° C. The slurry is cooled to -10 ° C and is introduced in one portion into a cooled to -10 ° C solution of 4.1 parts by weight of 6-aminopenicillanic acid and 3.4 parts by weight of triethylamine in 50 parts. by weight of bisMoromethane. To this end, amainopenicillanic acid is mixed for 1.5 hours at room temperature with triethylamine and 2 parts by weight of a molecular sieve (Zeolith VS 10-2) grinded in a mortar, then filtered without moisture and the filtrate is introduced into the reaction. The combined solutions are left for 1 hour at 0 ° C and then poured into 100 parts by volume of water. The pH is adjusted to 6.5, the dichloromethane phase is separated and the water phase is covered with 200 parts by volume of a 1: 1 mixture of ethyl acetate and ether. With vigorous stirring and cooling with ice, a sufficient amount of 2N hydrochloric acid is added to bring the aqueous layer to pH = 2.0. The organic phase is separated, washed with 2 x 40 volumetric parts of water and dried in the refrigerator with MgSO 4 for 2 hours. It is treated with 20 volume parts In of a solution of the sodium salt of 2-ethylhexanecarboxylic acid in ether containing 40 45 50 55 6089 668 9 10 o CU W 8 = AA 1 g CM o 3 AT § 3 cu 5 h cont. D "a cont + - »CO a to Ph cd & I 7 ii AI i — IOO CO t- sai AAAAAAA and AAAATAAA 4 A 9 1 IIO CM iH 1 O * M iH I 8 | g AA <3 00 I 7 3 l U i i — i 2 i-H I O 1 A A I i cd a -S ¦ CU - £ "fl u o I l-H 1 I I A A A89 668 11 12 <* 12 | 13 r o l — i Oi 00 t- co LO - ^ co Cd 1—1 —100 00 o V 1 o I o CVI i o CM 1 O o r-H 1 O o CV! and O I o "T o" ° LO And every 100-500 what; o V 1 oo 7 o CVJ o 1-1 1 o cvi oo 1-1 1 o § 7 o cvi o 7 ° CVI o 7 8 ° cvi 1 10 AM o "LO every 100. iH! o 10 o LO o 10 o LO LO cg ° LÓ «K io es co" LÓ what o "V ° LO cvT 1—1 CM oo iH ooo 1— (iH LO *! co" LO * vl A LO *! cvi ° LO every 1—1 oo CVI LO cvi LO CVI o LO o LO LO CM cvf iH ° LO ° A 8 co co ° LO co t- V oo cvi LO, cvp LO ^ cvT iH o LO oo iH ooo LO LO co "10 cvi A cvi co "LO cvi co V CM LO ^ cvT i ^ H LO CM o LO ooo LO LO cvi LO CM co" LO Cvf A CM co " <LO LO every V LO ^ CM "LO ^ cm" o LO O o LO CM 8 LO ^ cm "iH LO esT TH 9 CM co" every 1 00 LV oo CM LO ^ cm "LO ^ cm" I oo 1 1 LO *! every "LO cm" ° A CVI i — 1 every "12,5 00 LOV oo CM LO ^ cvT LO CM every" LO CM cm "iH LO every" LO ^ cm "iH LO CM every" «CM co" O 10 ° 00 LV CM LO CM LO ^ cm "oooooo 1—1 o 3 every" KA LO co "1 — I LO ° LO 00 V oo CM ^ 3 CM cm" i ^ H ° iH ° O ol — 1 LO ^ cm "1—1 LO CM <* A LO CM ^ co "CM LO89 668 13 14 methanol, the mixture is largely concentrated under reduced pressure at 0 ° C, also dissolved in a sufficient quantity of methanol, and the penicillin sodium salt is precipitated with vigorous shaking by introducing excess ether. Yield: tf7%; P-lactam content: 81% Calculated: 51.4% C, 5.3% H, 10.9% N, 6.2% S, found: 51. 5% C, 6.0% H, 10.3% N, 5% S. The product is identical according to the infrared spectrum and the thin layer chromatogram with the reference preparation made from ampicillin and N-acetyl chloride N-allylcarbate - minic acid Example II Da- (3--chlorotoutyryl-3-methylureido) -benzylpenicidin sodium salt According to example I, a solution is obtained from 6.25 parts by weight of the acid D - "-" 3-Y-chlorobutyr- l-3-methylureido-phenylacetic acid and 3.6 parts by weight of tetramethylchloroformamidinium chloride, and it is kept for 1.5 hours at a temperature of -8 ° C to -10 ° C. Then it is combined with solution 4, 1 parts by weight of 6-aminopenicillanic acid and 3.4 parts by weight of triethylamine in dichloromethane, which was previously held at room temperature for 1 hour, and then proceeded as in Example I. Yield: 62%; β-lactam content 84%. Calculated: 48.0% C, 5.1% H, 6.4% - Cl, 10.2% N,. 8% S; found: 48.1% C, 5.2% H, 5.8% Cl, 9.9% N, 6.4% S. NMR signals at T = 2.3-2.9 (5H), 4, 45 <1H), 4.55 (2H), 5.8 (1H), 6.4V (2H), 6.75 (3H), 7.3 (2H), 7.9 (2H) and 8.5 ppm (OH). Example III. Example II is followed with the difference that the Da- (3-Y-chlorobutyryl-3-methylureido) -phenylacetic acid used therein is replaced by 0.02 moles of the following acids in each case: -p-chloropropionyl-3-methylureido) -phenylacetic acid, D-thyryl-3-methylureido) -phenylacetic acid, Ba- (3- -Y-trichlorolbutyryl-3-methylureido) -phenylacetic acid, Da- (3- Y-trichIorobutyryl-3-β-chloroethyl-ureddo (-phenylacetic acid, Da- (3-cinnamoyl-3-methylureido) (n-phenylacetic acid, D-hydrobenzoyl] -3-methylureido) -phenylacetic acid or Da- (3-) hexahydrobenzoyl-3-methylureido) -phenylacetic acid. Correspondingly, the following penicillins are obtained in the form of their sodium salts: Da- (3-P-chloropropionyl-3-methylureido) -toenzylpenicillate, Da- (3-Y-trifluorobutyryl-3-methylureido) -benzylpenicillin, D -aH / 3-Y-trichlorobutyryl -3-methylureido / -1benzylpenicillin, D-cin / 3-Y-trichloroibutyryl-3-P-chloroethylureido / ^ benzylpenicillin, Da- (3-cinnamoyl ^ -methylureido / -benzyl-penicillin, Da- (1,2,5,6-tetrahydrobenzoyl] -3- • -methylureido-Z-toenzylpenicillin, or Da- (3-hexahydrobenzodlo-3-methylureido) -benzylpenicillin. Example IV. Sodium D, L- -3nme'tylyiureido / -p-methylbenzyllope (these Penicillin nicillins are prepared according to examples I and II from 5.5 parts by weight of D, La- (3-benzoyl-3-methylureido) acid) p-tetyl acetic acid, 3 parts by weight of tetramethylchloroformamidinium chloride and 4.35 parts by weight of 6-aminopenicylanic acid Yield: 59%; β-lactam content: 84% Calculated: 54.5% C, 5.3 % H, 9.7% N, 7.9% S, Found: 54.9% C, 5.9% H, 9.5% (5.6%) S. Signals N (MR at * T = 2.5 (5H), 2.5-3.0 (4H), 4.3-4.65 (3.0H), 5.8 (1H), 6.9 <3H) and 8.2-8.5 ppm (6H). Animal test performance: A 13.Example 5 D1- (3-Y-chloroibuttyryl-3-methyl-teido-and (2-tenyl) -methylpenicillin Penicillin sodium salt are prepared according to Examples I and II with 5.9 parts by weight of D, L- (3-Y-chlorobutyryl-H3-methylureido) -2-tenyyl) -acetic acid, 3.5 parts by weight of tetramethylchloroformamidinic chloride and 4.06 parts by weight of acid 6 -amino-penicillate. Efficiency: © 4%; 0-lactam content: 95.5%. NMR signals at T = 2.5-3.2 <3H), 4.1 X 1 H), 4.4 &Lt; 2H), 5.8 (1H), 6.3 (2H), 6.7 &Lt; 3H), 7.2 (2H), 7.9 <2H) and 8.4 ppm <OH). Efficacy in animal trials: B. Example VI. Example I is followed, with the difference that instead of Da- (3-acetyl-3-allylureido (phenylacetic acid), 0.02 n moles of the following acids are used: methylureido / -p-tolyl acetic acid, a - (3-acetyl-3-methylureido), n-α -Morophenylacetic acid, α-n-3-acetyl-3-methylureido-p-methylsulfenylphenylacetic acid, α- (3-acetyl-3-methylureido) -β-me - Toxy-phenylacetic acid, α- (3-acetyl-3-methylureido) -o-chlorophenylacetic acid, α- (3-acetyl-3-methylureido) -m-iodophenylacetic acid, (α- (3-acetyl -3-methylureido / -2,6-dichlorophenylacetic acid, α- (3-acetyl-3-methylureida) -2,6-dimethoxy-phenylacetic acid, α- (3-acetyl-3-methylureido) -2,4-dibromophenylacetic acid, loureido, m-methylphenylacetic acid, α- (3-acetyl-3-methylureido) -2,6-dimethylphenyl acetic acid, α- (3-acetyl-3-methylureido) -2 -chloro-6Hrlyiorophenylacetic acid, α- (3-acetyl-3-methylureido) -2-teinylacetic acid or α- (3-Hacetyl-3-methylureido) - -3-thenylacetic acid. The following penicillins: α- (3-acei; yl-3-methylureido), p-methylbenzylpenicillin, 40 idoZ-p-chlorobenzylpenicillin, α- (3-acetyl-3-methylureido) -p-methylsulfenylbenzylpenzyl α- (3-acetyl-3-methylureMo) -β-methoxylbenzyl-penicillin, α- (3-acetyl-3-methylureid), o / -o-chlorobenzyl-penicillin, 45 zylpenicillin, -dichlorobenzylpenicillin, and - (3-acetyl-3-methyl-ureido) -2f, 6-dimetholxybenzylpenicillin, α- (3-acetyl-3-methylureido) 2,4-dibromoiben-2-ylpenicillin, α- (3-acetyl-3-methyllaureido) - ! m-methylbenzyIopeni <- 50 ciline, α- (3-acetyl-3-methylureido / J2-6-dimethylbenzylpenicillin, -chloro-6-ifluorobenzylpenicillin, ct- (3-acetyl-3-methylureido) - "- 2-rtenylmethylpenicillin or -acetyl -3-methylureido) -α-3-tenylpenicillin. 55 Example VII. D-α- (8-rhethoxycarbonyl-3-methylureidb) -2,6-dichlorobenzyl-penicillin sodium salt. 1.35 parts by weight of tetramethylchloroformamidinium chloride are dissolved in 15 parts of 60 weight by weight of dichloromethane and cooled to 0 ° C. 2.4 parts by weight of Dna- (3-methoxyTibonyl-3-methylureido) -2.6% dihydrogen phenylacetic acid in a small amount of dichloromethane are added to this solution. 65 At a temperature of -5 ° C, a solution of 1.04 parts by weight of triethylamine in parts by weight of dichloromethane is added dropwise within 30 minutes to 15 89 668 16 notes. After 40 minutes, it is combined at -5 ° C with a solution of the triethylamine salt, cooled to -20 ° C, obtained from 2.22 parts by weight of 6-aminopenicillanic acid and 1.6 parts by weight of triethylamine. in 25 parts by volume of dichloromethane. Stirring is carried out for 30 minutes at 0 ° C., after which, after 15 minutes, 0.4 part of triethiamine by volume is added. Then it is stirred for 30 minutes at room temperature, poured into water, a water layer is separated at pH = 6.5 and the sodium salt of penicillin is formed according to example I. Yield: 28%. β-lactam content: 94%. NMT signals at T = 2.6 (2.1G), 2.7 <0.9H), 3.4 (0.7H), 3.8 (0.3H), 4.35 ^, 50 (2H), 5.8 (1H), 6.15 (3H), 6, 8 (2.1H), 6.85. (0.9H) and 8.46 ppm (6H). Example VIII. L-gt- (3-methoxycarbonyl-3-methylureid and -2f, 6-dis-Morobenzyl-penicillin sodium salt). The above penicillin is prepared according to clause VII from 3.1 parts by weight of La- (3-methoxy-bonyl-3-methylureido) -2,6-dichlorophenyl acetic acid, 1.74 parts by weight of tetramethylchloroformylamidinium chloride. and 2.87 parts by weight of 6-aminopenkylanic acid. Efficiency: 47%; β-lactam content: 92%. NMR signals at T = 2.6 <1.8H), 2.7 <1.2H), 3.35 (0.6H), 3.8 (0.4H), 75 (1H), 6.15 (3H), 6.8 (1.1H), 6.85 <1.2H) and 8.4 ppm (6H). f Example IX. D, La- (3-methoxy-caribonyl-3-methylureido) -2,6-d-chlorobenzyl-penicillin sodium salt For the suspension of 3.0 parts by weight of tetramethylchlorobenzyl-penicillin ground in a mortar in 20 parts by volume dry acetone is added dropwise at 0 ° C. to a solution of 5.0 parts by weight of D, La- (3-methoxytearbonyl-3-non-ylureido) -2,16-dichlorophenylacetic acid in 10 parts by volume of acetone. After 5 minutes, it is cooled to -5 ° C and the dropwise addition is slow and even, over 30 minutes, without the access of moisture, 2.1 parts by volume of triethylamine in 10 parts by volume of acetone. The mixture is then stirred for 1 hour at 0 ° C, then the sediment is drained, not exceeding the temperature of the solution 0 ° C. The porcine is introduced in several portions into the solution at 0 ° C, 3.23 parts by weight of 6-aminopenicillanic acid in 25 parts by volume of 80% aqueous tetrahydrofuran with the addition of sufficient 2n NaOH to re-form a solution with a pH value of 8.2 while maintaining a pH value of 7.5 - - «, 0 by adding '2n NaOH. . The mixture is brought to room temperature, while stirring, until the addition of sodium liquor is no longer required to maintain the pH value at 7.5-8.0 (1-2 hours). In the last step, a small amount of dilute hydrochloric acid is acidified until a pH of 6.5 is reached, 20 parts by volume of water are added and the tetrahydrofuran is evaporated under reduced pressure at room temperature. The remaining aqueous solution is extracted once with 25 parts by volume of ether and covered with 50 parts by volume of a 1: l mixture of ethyl acetate and ether. It is acidified with dilute hydrochloric acid to a pH of 2.0 under cooling with ice and the organic phase is separated. These phases are washed twice with 10 parts by volume of water, dried with MigSO 4 for 4 hours at 0 ° C and filtered. The penicillin sodium salt is precipitated by adding 15 volumetric parts of a 1 molar solution of 2-ethylipentanecarboxylic acid sodium in an ether containing methanol. The mixture is almost completely distilled off under reduced pressure at 0 ° C., dissolved in as little methanol as possible, the product is precipitated by the addition of ether and left for 1 hour at 0 ° C. It is then filtered off, washed with ether containing methanol and then dried in a desiccator under vacuum against Pz06 for several days. Efficiency: 71%; content. P-dactam: 68%. Calculated: 41.3% C, 4.2% H, 12.2% Cl, 9.6% N, 5.5% S; found: 41.1% C, 5.0% H7, 14.0% Cl, 9.0% N, 4.9% S. NMR signal at t = 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 8.4 ppm <6H). Example X. A) Da- (3-methoxycarbonyl-3-methylureido) -phenylacetic acid Mix 15.1 parts by weight of D (- / - C-phenylglycin) for 15 minutes with 20.2 parts by weight of triethylamine in 180 parts by volume of a 3: 1 mixture of dimethyl sulfoxide and water. Within 30 minutes, 15.2 parts by weight of N-methoxycarbinyl-N-methylcarbamic acid chloride in 30 parts by volume of acetone were added dropwise in such a way that the temperature did not exceed 20 ° C. Stirring for 40 2 hours, then 200 parts by volume of water are added and acidified with dilute hydrochloric acid to pH = 2. Then extracted three times with 120 parts by volume of ethyl acetate, the organic phase is washed with 45 50 parts by volume. volumetric water and dried over MgSO 4. After filtering, the solvent is distilled off under reduced pressure and the residual dimethyl sulfoxide is stripped off at 80 ° C. and 0.1 torr. This gives M with a yield of 73% a glassy oil which is pure methoxycarphinylureido-phenylacetic acid according to the NMR spectrum. Calculated: 54.0% C, 5.3% H, 10.5% N; found: 54.9% C, 5.6% H, 9.6% N NMR signal at t = 0.4 <1H), 2.4 ^ 2.8 (5H), 4, fl 55 (1H), 6.2 (3H) and 6.9 ppm (3H). B) D-Loureido / nbenzylpenicillin Penicillin sodium salt produces according to example 60 VII with 5.3 parts by weight of D- (3-methoxycarbonyl-3-methylureido) -phenylacetic acid, 3.4 parts by weight of tetramethylcMoroformamidinic chloride and 4.0 parts by weight of 6-amino-penicillanic acid. Yield: 63%; P-lactate 65 content: € 9%. NMR signals at t = 2.3 ^ 2.9 (5H), 89-17 4.45 (1H), 4.5 and 4.55 (2H), 5.8 (1H), 6.2 (3H), 6.85 (3H) and 8.45 ppm (6H). The table above compares the antimicrobial effect of product A) with penicillin obtained from ampicillin and N-meth-Ixycarbonyl-N-methyl chloride. carbamic acid B) and with the product prepared according to the example XXVII C). Table 2 Genus of Escherichia coli 14 Escherfchia coli 183/58 Pseudomonas aerug.Bonn Pseudomonas aerug.Wolter Klebsiella K 10 Klebsiella 63 Stophylococcus aureus 133 Efficacy [E / ml] ~ ^ T ~ 12.5 50 50 50 200 200 1.56 B) 6.25 200 200 1.56 O 100 200 400 400 400 400 6.25 Example XI. A) D-α- (3-isopropoxycarbonyl-3-methylur.eido) -phenylacetic acid 15.1 parts by weight of D-Mphenylenydglycine are dissolved in 250 parts by volume of 50% aqueous dioxane by adding sufficiently diluted sodium hydroxide solution. The pH is then adjusted to 7.8 with 2N HCl, and part of the phenylglycine is precipitated out in a finely divided form. It is 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 are added dropwise within 30 minutes, the pH value being maintained at 7.5. 8.0 by simultaneous addition of 2 N sodium hydroxide solution, then stirred at room temperature until no addition is needed to keep the pH constant. 300 parts by volume of water are added and the solution is extracted with 150 parts by volume of ether at a time, then acidified with 2N HCl to pH =? = 45 = 2 and the precipitated oil is dissolved with several portions of ethyl acetate. The combined organic solutions are washed once with 100 parts by volume of water and dried over MgSO 4 for several hours. After filtering, the oily residue is evaporated and the dioxane is freed at 60-80 ° C. under a pressure of 0.1 torr. A glassy product is obtained with a yield of 48%. According to the NMR spectrum and the thin layer chromatogram it is completely pure. Calculated: 57.1% C, 6.1% 55 H, 9.5% N; found: 5 * 6.9% C, 5.7% H, 9.8% N NMR signals at t = 0.3 (1H), 0.4 (1H), 2.3 ^ 2.6 (5H ), 4.6 <1H), 5.0 (1H), 6.9 (3H) and 8.75 ppm, (6H). B) According to example A) the following α-ureidaryl acetic acids are produced: 60 1. D acid - you. Prepared from 8.1 parts by weight of N-acetyl-N-allylfearbamic acid chloride and 7.5 parts by weight of D1 - C - phenylglycine. Yield: 100%. Calculated: 60.8% C, 5.9% H, 10.1% N; found: 65 18 60.3% C, 6.1% H, 9.8% N. NMR signals at t = 0.0 (1H), 2, and 6 <5H), 3.75 → 1.5 <1H), 4.6 <1H), 4.7-5.15 (2H), 5.5 ^ 5.9 (2H) and 7.7 ppm <3H). 2. D-α- (3-N-chloroibutyryl-3-methylureido) -phenylacetic acid. Prepared from 9.9 parts by weight of N-Y-chlorobutyryl-N-methyl-carbamoyl chloride and 7.5 parts by weight of D (-) - C-phenylglycine. Yield: 99%. Calculated: 53.8% C, 5% H, 11.3% Cl, 9.0% N; found: 53.9% C, 8% H, 10.8% a, 9.4% N. Signal NMR at t = -0.1 (1H), 2.6 (5H), 4.6 &Lt; 1H), 6.3 (2H), 6.8 &Lt; 3H), 7.2 (2H) and 7.9 ppm (2H). 3. D-α- (3-benzoyl-3-methylureido) -4-tolyl acetic acid. It is prepared from 3.2 parts by weight of N-benzoyl-N-methylcarbamic acid chloride and 3.8 parts by weight of D, L-C- (4-tolyl) -glycine. Yield: 90%. NMR signals at t = 2.5 (5H), 2.6 &Lt; 2H), 2.8 (2H), 4.5 <1H), 6.85 (3H) and 7.7 ppm <3H). 4. K4 as D-α- (3-methoxycarbonyl-3-methylurei to (-2,6-dichlorophenylacetic acid). Prepared 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. Probably an acid prepared in a known manner from 2, 6 ^ of dichlorobenzaldehyde by hydentoine, after acylation of the amino group by cleavage of the racemate with optically active bases and cleavage of the acylating group, it exists in the left-handed and right-handed form, the left-handed form belongs to the well-known right-handed C-phenylglycin system, and to the L series. Yield: 90%; melting point: 149 ° C; [a] D = -28.1 °. NMR signals at t = 0.2 (1H), 2.5 (3H), 3.6 (1H), 6.2 (3H) and 6.9 ppm (3H). ¦. L-α- (3-methoxycarbonyl-3-methylurci- to:) - 2,6-dichlorophenylacetic acid. It is prepared from 1.6 parts by weight of N-methoxycarbonyl-N-methylcarbamic acid chloride and 3.01 parts by weight of 2 (+) - C- (2,6-diorophenyl) -gaicine hydrobromide. Efficiency: 100%; [NMR as set out in example IX. 6. D, L-α- (3-methoxycyribonyl-3-methylureido) -2,6-dichloroacetic acid. Prepared from 3.03 parts by weight of N-methoxycarnyl-HN-methyl-anbamic acid chloride and 4.4 parts by weight of D, LC- (2,6-dichlorophenyl) -glycine. Yield: 78% , mp: 216 ° 6. NMR signals as set out in Example IX. 7. D-α - f; 3-nH-butoxycarbonyl (-3-methylureido) -phenylacetic acid. Prepared from 9.7 parts by weight of N-n-butoxycarlbonyl-N-methylcarbamic acid chloride and 7.1 parts by weight of D-C-phenylglycine. Yield: 100%. Calculated: 58.4% C, 6.5% H, 9.1% N; found: 58.6% H, 9.5% N NMR signal at t = 0.5 (1H), 2.6 <5H), 4.65 (1H), 8 (2H), 6.9 (3H), 8.0-9.0 (4H) and 9.05 ppm <3H). . 8.. D, L-α- (3-benzoyl-3-αMoureido, M-methoxyiphenylglycine). Prepared from 4.5 parts by weight of N-i-benzoyl-N-allylcarbamic acid chloride and 3.6 parts by weight of D, L-C- (4-methoxyphenyl) -glycin. Yield: 70%. NMR signals at t = 0.6 (1H), 2.5 (5H), 2.7 (2H), 3.0 (& H), 3.8 ^ 4.5 (1H), 4.6 - - ^ 5.2 (3H), 5.6 ^ -5.8 (2H), and 6.2 ppm {ni). 9. D-α- (3-acetylc-34) enzylureido / -phenyl acetic acid. Prepared from 8.5 parts by weight of N-acetyl-N-benzylcarbamic acid chloride and 6.0 parts by weight of D-L-phenylglycine. Efficiency: 92%; mp: 183-1850C. Calculated: 66.3% C, 5.6% H, SfiVO N; found: 66.3% C, 7% H, 8.6% N. NMR signals at t = -0.1 (KH), 2.6 (5H), 2.7 (5H), 4.55 <1H), 5.0 (2H) and 7.8 ppm (3H) .. D, L-dichlorophenylacetic acid is prepared from 4.5 parts by weight of N-benzoyl-N-allylcarbamic acid chloride and 4.4 parts by weight of D, LC- (2,6-Di-MorophenylZ-glycine). Yield: 97%. Calculated: 56.0% C, 4.0% H, 17.4% Cl, 6.9% N; Found: 55.6% C, 4.4% H, 16.0% Cl, 6.5% N. NMR signals at t = 0 (1H), 2.3-2.05 (8H), 3, 6 (1H), 3.9-4.5 (1H), 4.8-5.3 (2H) and 5.0 ^ 5.9 ppm <2H). (11. D, L-α- (3-aceto-allylureido) 2-phenyl acetic acid is prepared from 3.2 parts by weight of N-acetyl-N-allylcarbimic acid chloride and 2.9 parts by weight D, L <: - / 2-ienyl / -glycine.y Yield: 99%. NMR signals at x => = 2.5-3.1 (3H), 3.7-4.4 (1H), 4.3 (1H), 4.6-5.1 (2H), 5.5 —5.7 (2H) and 7.7 ppm (3H). '12. The acid D, La- (3-dimethylaminocytibonyl-3-methylureido) -2,6-di-chlorophenylacetic acid is prepared from 3.3 parts by weight of N -dimume chloride; ylamino-tibonyl-N-methylbaminic acid and 4.4 parts by weight of D, L-CV2, [beta] -dichlorophenylZ-glycine. Efficiency: 86%; melting point: 205 ° C. NMR signals @ t = 1.6 (1H), 2.5 &Lt; 3H), 3.7 (1H), 7.0 (3H) and 7.1 ppm &lt; 6H). 13. D, La- (3-methoxycarlbonyl-3-methylureid and M-methoxyphenylacetic acid) is prepared from 3.0 parts by weight of N-methoxycartonyl-N-methylcarbamic acid chloride and 3.6 parts by weight of D, L? C- (4-methoxyienyl) -glycine. Yield: 87%. NMR signals @ t = 2.6 (2H), 3.05 (2H), 4.6 (1H), 6.2 ("H) and 6.8 ppm (3H). 14. D, L-α- (3-dimethylalminocarbonyl-3-methylureido-M-metaxyphenylacetic acid). Prepared from 3.3 parts by weight of N-dimethylaminocarbolnyl-N-methylcarbamnic acid chloride and 3.6 parts by weight of D, LC- / 4-metolxy (phenyl / glycine. Yield:} 00%. NMR signals at t = 2.0 &Lt; 1H), 2.6 (2H), 3.05 (2H), 4.6 (1H), 6.2 (3H), 6.95 (3H), and 7.1ppm 6H) .. Acid D, Lai (A) - methoxycarbonyl-3-methylureido-2-phenyl acetic acid. Prepared from 3.0 parts by weight of N-methoxycanbonyl-N-methylcarfoamic acid chloride and 2.9 parts by weight of D, L-, [mu] C "(2-tenyl) -glycine. Yield: 100%. NMR signals at x = 0 , 4 (1H), 2.5-3.1 (3H), 4> 5 (1H), 6.2 (3H), and 6.8 ppm (3H). 16. Acid D, La- (3-dimethylaminocarbonyl) -3-MethylureidoZ-phenylacetic acid Prepared from 3.3 parts by weight of N-diaminocarbonyl-3-methylcaribaminic acid chloride and 2.9 parts by weight of I, LC- (2-retenyl) -glycine Yield: 84%. NMR signals at x = 1.9 (, 1H), 2.5 ^ 3.1 <3H), 4.3 (1H), 6.9 (3H), and 7.1 ppm (6H). 17. D, L-α- (3-benzoyl-t3-allylureido) -a-, 2-thenylacetic acid. Prepared from 4.5 parts by weight of N-benzoylOHN-allylcarbamic acid chloride and 2.9 parts by weight of D, L-C- (2-tenyl) -glycine. Yield: 96%. NMR signals @ x = 2 $ (5H), 2.5-9668 7.7-8.8 ppm (7H). * —3.1 (3H), 3.8-4.5 (2H), 4.8-5.3 (2H), and 5.5-5.8 ppm (2H). 18. D, L-α- (3-Y-chlorobutyryl-3-'methylureido) -2-thhenylacetic acid. Prepared from 4.0 parts by weight of N-Y-chloroibutyryl-N-methylcarbamic acid chloride and 2.9 parts by weight of D, L-α- (2-thenylZ-glycine). Yield: 99%. NMR signals at x = 2.5- ^ 3.1 (3H), 4.2 (1H), 6.35 (EH), 6.7 &Lt; 3H), 7.2 (2H) and 7.9 ppm (2fH). 19. The acid D, La- (3- [2-furoyl] H3-methylureido) -2-thenylacetic acid is prepared from 5.6 parts by weight of N- (2-furoyl) -N-methylcarbamic acid chloride and 4, 7 parts by weight of D, LC- (2-tenyl) -glycine. Yield: 100%. Da- (3-αUHoxyfcanbonyl-3-methylurei) n-phenylacetic acid is prepared from 15.8 parts by weight of N-allyloxycarbonyl-N-methylcarbamlinic acid chloride and 15.1 parts by weight of D, C-phenylglycine. Yield: 88%. NMR signals with t = -1fi (1H), +0.4 (ilH), 2.6 (5iH), 3.7 ^ 4.3 (1H), 4.4-4.9 (3H), 5, 3 (2H) and 6.85 ppm (3H). 21. D4a-3- [3-Nitro-4-methylbenzoyl] -3-methylureido / n-phenylacetic acid is prepared from 8.0 parts by weight of N- (3-nitro-4-methyl-benzoyl) Z-N acid chloride -methylcarbamic acid and 4.7 parts by weight of DC-phenylglycine. Yield: 46%. NMR signals at x = 1fi-2fi &Lt; 8H), 4.6 (1H), 6.8 (3H) and 7.4 ppm (3H). . 22. Da- (3- [4-methylbenzoyl] -3-mei; ylureitot) -phenylacetic acid is prepared from 13 parts by weight of N-p-methylbenzoyl-N-methylcarbamic acid chloride and 9.2 parts by weight of DC -phenyl-glycine. Yield: 05%. NMR signals @% = 0.2 (1H), 2.4 ^ 2.9 (9H), 6.65 (1H), 6.9 (3H) and 7.6 ppm (3H). 23. 'Acid D, La- (34enzoyl-3-' methylureildo) -2,6-dichlorophenylacetic acid is prepared from 7.2 parts of N-benzoyl-methylcarbamic acid chloride 40 and 8.0 parts by weight of D, LC- / T 2, i 6, dichoMorotfeiriyl) - rglycine. Efficiency: 100%; melting point: 200 ° C. NMR signals @ x = -0.4 (1H), 2.2-2.7 <8H), 3.5 (1H) and 6.9 (3 'H). 24. D, La- (3-benzoyl-3-methylureido) -4-45-methylsulfenylphenylacetic acid is prepared from 10.0 parts by weight of N-benzoyl-N-methylcarbamic acid chloride and 10.0 parts by weight of D4 LC- (4-methylsulfenyl) H-glycine. Performance: . 73%. NMR signals at x = 0.2 (1H), 2.3-2.8 (9H), 4.65 (1H), 6.9 (3H) and 7.5 ppm (3H) .. D, La- (3-ethoxycarbonyl-3Hmethyl) rheido) -4-methylsulfenhenylacetic acid is prepared from 16.8 parts by weight of N-ethoxycarbonyl-N-methylcarbamic acid chloride and 20.0 parts by weight of 55 D, LC- (4-methylsulfenyl) H-glycine. Efficiency: 85%; melting point: 120-122 ° C. NMR signals at t = 0.4 <1H), 2.4-2 ° C (4H), 4.65 (1H), 5.75 &Lt; 2H), 6.85 (3H) and 7.55 ppm (3H). 26. DJ1-α- (3-P-chloropTOipionio-3-methyl-eureido) -x, l, 5-6-tetrahydrophenylacetic acid is produced from 18.4 parts by weight of N- - or - chloropropionyl chloride -N-methylcarbamic acid and 15.5 parts by weight of D, LC- (1,2,5,6-tetrahydrophenyl) glycin. Yield: 73%. NMR signals at 6, x = 0fi (1H), 4.3 (2H), 5.7 (1H), 6, (2H), 6.8 (2H) i, 89 668 21 22 27. Da- (3- [2-tenoyl] -3-methylureido) -phenylacetic acid is prepared from 9.0 parts by weight of N chloride - 4 - tenoylZ-N-methylcarbamlin and 6.6 parts by weight of D, C-phenylglycine. Yield: 50%. 28. Da- (3- [3,5-dimethyl-4-isoxazolyl] -3-methylureido) -phenylacetic acid is prepared from 8.5 parts by weight of N - (p. 3,5-dimethyl-4-iso) chloride. xazoloyl-N-methylcarbamate and 5.9 parts by weight of D, C-phenylglycine. Yield: 32%. C) Da- (3-isopropoxy-carbo.nyl-3- -methytoureteto) -Jbenzylpenicillin sodium salt. These penicillines are prepared according to Example IX from 5.9 parts by weight of D-carbonyl -3-methylureido acid / - £ of enoacetic acid, 3.7 parts by weight of tetramethylhloroformannidinium chloride and 4.0 parts by weight of 6-amino-penicillanic acid. Yield: 45%, content (3-lactam: 86%. Calculated: 48.8% C, 5.5% H, 10.4% N, 5.9% S, found: 48.7% C, 5) , 9% H, 10.8% N, 8% S. NMR signals at t = 2.3-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.0 ( 1H), 5 ^ 8 (1H), 6.85 (3H), 8.5 (6H) and 6.7 ppm (6H). Table 3 compares the antimicrobial activity of the obtained product (A) with that of the penicillin produced from ampicillin and Ni-propyloxycarbonyl-N-methylcarbarryic acid chloride (B) and with the action of product A obtained according to example XXVIII from D- - (3-i-propolxycarlbonyl-3-methylurethiido) -phenylacetic acid (C Table 3 Type of bacteria Escherichia coli 14 Escherichia coli C 165 Escherichia coli 183/58 Pseudomonas aer. 1 Boun Pseudomonas aer.Walter Efficacy (E / ml) 1 (A) 6.25 50 12.5 50 100 (B) 6.25 6.25 50 (C) 100 200 400 400 1 »400 ¦ Example XII Da- (3-n-butoxycarbonyl-3-methylureido) -benzylpenicillin sodium salt These penicillins are prepared according to example IX of 5 6 parts by weight of D-ct- / 3-n-ibuto acid xycarbonyl-3-methylureido) -ienylacetic acid, 3.3 parts by weight of tetramethylchloroibrmamidinium chloride and 3.6 parts by weight of 6-aminopenicylanic acid. Ureidoacetic acid is mixed with tetramethylchloroformamidinium chloride at -5 ° C in acetone for only 5 minutes. Yield: 36%; β-lactam content: 61%. Calculated: 48.1% C, 6.0% H, 9.7% N, 5.6% S; found: 48.4% C, 5.5% H, 9.4% N, 5.5% S. NMR signals at t = 2.3-2.8 (5H), 4.45 (1H) , 4.5-5 (2H), 5.8 (3iH), 6.85 (3H), and 8.1 ^ 8.9 ppm (13H). Example XIII. The procedure is followed in the case of clade X with the difference that the Da- (3-methoxycarbonyl-3-methylureido) -phenylacetic acid used in it is replaced by 0.018 moles of the following acids in each case: 3-ethoxycarbonyl-3-methylureido / -phenylacetic acid, Da- (3-dimethylaminocarpoonyl-3-methylureido) -phenylacetic acid, Da- (3-dimethylaminocarbonyl-3-ethylureido) -phenylacetic acid, Da- (3-dimethylaminocaribonyl-3-propyl ureido) -phenyl acetic acid, Da- (3-dimethylaminocarbonyl-3-i-propyloureido) -phenylacetic acid, Da- (3-dimethylaminocTbonyl-3-n-butyl leureido) -phenylacetic acid, Da- (3-dimethylaminocarbonyl-3-allylureido) -phenylacetic acid, Da- (3-dimethylaminocartonyl-3-c-, clohexylureido) -phenylethic acid, Da- (3-dimethylaminocaribonyl-3-acid) -phenyl-ureido, -phenylacetic acid, D- to N-phenylacetic acid, Da- (3- [1-piperidylcaribonyl] -3-methylureido) -phenylacetic acid, D- (3- [1-piperidylcaribonyl] -3-methylureido) -phenylacetic acid, Da- (3-methylaminocarfoonyl-3-methylurethane idoMenhenylacetic acid) , Da- (3-ethyl) acid laminocarbonyl-3-methylureido, - -phenylacetic acid, Da- (3-methylaminocarbonyl-3-methylurei, Z-phenylacetic acid, D, -a- (3-phenylaminocarbonyl-3-methylureido) to -phenylacetic acid, Da- (3- [4-morpholinyl] -banbonyl-3-methylureido) -phenylacetic acid, D4α- (3- [pyrrolidinylcartonyl] -3-ethylureido) - -phenylacetic acid, Da- (3- [1-piperidylcaribonyl] ] -3-ethylureido) -phenylacetic acid, Da- (3-diethylaminocarbonylcK-3-ethylureidoZ-phenylacetic acid, Da- (3-ethylaminocarbonyl-3-ethylureido) - -phenylacetic acid, Da-ZS-methylaminoicarbonyl-S-ethylureido-S-ethylureido (phenylacetic acid, Da-ZS-phenylamino-carbonyl-S-ethylureido) -ienylacetic acid, Da- (3- [4-morpholinyl] carbonyl-3-ethylureido) -phenylacetic acid, Da- (3- [1) -pyrrolidyl] -carbonyl-3-n-propylureido) -nbenzylpenicillin, Da -Il-piperidyl-carbonyl-Si-propylureado (- -benzylpenicillin, Da- (3-diethylaminocarbonyl) -3-n-1-butinylurebenicillin-3-n-1butylurelopenic-yl Da- (3-dimethylaminocarbonyl) -3-cyclohexylureidobenzylene icillin. The sodium salts of the following penicillins are obtained: Da- (3-ethoxyicarbonyl-3H-methylureido) -benzyl-penicillin, Da- (3-dimethylaminocarbonyl-3-methylureido) - benzylpenicillin, - »23 Da-S-dimethylureido -ethylureido / - -4) enzylpanicylmy, Da-ZS-dimethylaminocarbonyl-SHproipylouireado / - -benzylpenicillin, Da-ZB-dimethylaminofearbanyl-oSi -pyropyropyrine-to / nbenzylipeniicillin, Da-ZS-dimethylaminocarbonyl-SHproipylouireado D6 α- (3-dimethylamino-3-allylouTeido) - (beinzylpecillin, D-ar (3-dimethylamino-3-cycloheixylureido) -benzylpendcyline, Da- (3-dimethylamino, carbonyl-3) -penyajOureido (- nbenzylpenicillin, Da-y3-IlH-pyrrolysylpenicillin, E) _a_ (3_ [1,3-pyrroleidylcarbonyl] -3-non-typhyloureido) - -bemzylpenicillin, Dai (3-diethylaminocaribonyl-3-dibenicaribonyl-3-dibenicaribonyl) Da- (3-ethylaminolcarbonyl) -3-methylLoureido) -benzylpendcillin, s Da-ZS-methylamokaribonyl -S-non-ethyliireido) -3-methyl-penicillin, P- α- (3-phenylylami) jiocarbo'nyl-3-methylureido (-beinzylpenicillin), • Da- (3- [4-morpholinyfo] -carbonyl- 3-methyl, loureido) - 4-enzyiopenicillins, Da- (3-i [ l-pyrollidyiocarbonyl] -3-ethylureido, -I-benzylpenicillin, Da- (3- [l-piperidyl-tibonyl] -3-ethylureisylpenicillin, .. Ba- (3-diethylamino-carbonyl-3-ethylurel-3-ethylureyl), Da- (end-benzyl) (3-ethylaminociarbonyl-3-ethylureido, Z-benzyl-penicillin, Da- (3-methylalminolcarbonyl-3-ethylureido) - 'benzylolpeniicillin, Da- (3-phenylaminolcaribonyl-3-ethylureido) - (benzyl, Da-penicillin) 3- [4-moa-foQiinyl] -carbonyl-3-ethyloureldo (- -benzyl penifcyl), * DTa, -flipii-Throlidyl-yl-arbonyl-Sn-propyioureido (- -Jbenzyl endcyline, Da - -? -? -PiperidylolH - carbonyl-Si-loureido) benzylpenicillins, Da- (3-diethylammonium) rbonyl (H3-n-ibutylureido) - -ibenzylpenicillin, or * - Da - ^^ diethylaTniincarbonyl (^ - cycloihexylureido) -ibenzylpenicillins. Example XIV. Sodium D, La- (3H-benzoyl -3-allyloureido) -4-methoxybenzylpenicidin. These penicillines are prepared according to example IX from 4.4 parts by weight of D, L-enzooyl-3-iallylouTeido / -4-methoxyphenylacetic acid, 2.26 parts by weight of tetramethylchloroformamidate chloride and 2.6 parts by weight of 6-aminopenicylanic acid. Yield: 5.1%; P-lactam content: 65%. Calculated: 55.4% C, 5% H, 9.2% N, 3%, S .; found: 55.4% C, 4.8% H, 8.1% N, 4.5% S. NMR signals at t = 2 ^ 6 (5H), 2.7 (2H), 3.2 (2H ), 3.9-4.5 (1H), 4.55 (3H), 4.7-5.2 (2H), 5.6-5.9 (3H), 6.25 (3H) and " 8.4 ppm <«H). Example XV. The sodium salt of D, .- [alpha] - (3-benzoyl- - ^ - allylureido (-2.6-1668) The penicillin is prepared according to example IX from 7.2 parts by weight of the acid D, L-a- (3-ibenzodio-). -3-allylureido (-2,6-disMoxophenylacetic acid), 4.05 parts by weight of tetramethylchloroformamidinium chloride and 3.86 parts by weight of 6-amino-penicillanic acid. Yield: 46%, content (3-lactam: 83%. Calculated: 49.9% C, 4.3% H, 10.8% Cl, 8.6% N, 4.9% S; found: 49 , 9% C, 5.1% H, 11.3% GI, 8.2% N, 4.4% S. NMR signals at x = = 2.4 ^ 2.9 <8H), 3.4 (1H), 3.8-4.4 (1H), 4.4-1.6 (2H), 4.8-5.2 (2H), 5 ^ 5-5, 8 (2H), 5.85 (1H) and 8.5 ppm (6H). Example XVI. Proceeding from Example IV, with the difference that instead of D, La- (3-benzoyl-3-methylureido) -p-tolylacetic acid, 0.015 moles of the following acids are introduced: Da- (3-toenzoyl-3) acid -methylureido (-phenylacetic acid, Da- (3-ibenzoyl-3-ethylureido) -iphenylacetic acid, Da- (3-benzoyl-3-methylureido) -4-chlorophenylacetic acid, Da- (benzoyl-3-methylureido) -4-methoxyphenylacetic acid, Da- (3-benzolyl-3-methylureido) - '2-chlorophenylacetic acid, Da- (3-benzoyl-3-methylureido) 3-iododium enyl' acetic acid Da- (3H-benzoal-3-methylureido) -2,6-dimethoxyphenylacetic acid, Da- (f3Jbenzoyl-3-methylureido) -2,4-dibromophenylacetic acid, Da- (3-benzodl-3-methylureido) - 3-tenoacetic acid, Da- (3-ibenzoyl-3-methylurea! Ido) -m-toHloacetic acid, Da- (3-: benzoyl-3-methylureido) -2,6-dimethylphenylacetic acid, D- -fluorophenylacetic acid, | D-αV3-benzoyl-3-methylureido-2-tenylacetic acid, La- (3-benzo; yl-3-methylureido) -phenylacetic acid, Da- (3- [3-nitro-4-methoxyphenyl] -3-methylureido / -phenylacetic acid, Da- (i3-p-chlorobenzoyl-3-ethylureido) -phenylacetic acid, Da- (3, N-o-bromobenzodl-3-n-propy) acid! Tourei to i-phenylacetic acid, Ba- (3-p-methoxylbeinzoyl-3-methylureidot) -phenylacetic acid, Da- (3Hp-methoxycarbonylamino-benzodlo-3- 50-methylreddo, Z-phenylacetic acid, * * Da- (3-p) acid -methylsulfenyl! benzoyl-3-methylureido, Z-phenylacetic acid, * Da- (3- (2-chloro-5-methoxybenzoyl) -3Hn-butylureido) phenylacetic acid, 55 Da- (3Hp-nitrobenzoyl-3-methylureido acid) (phenylacetic acid, Da- (3-2-chloro-4-ethylsulfenylbenzoyl) -3-methyluretho) -phenylacetic acid, para- (3-m-cyanobenzolyl-3-methyl) acid, rheido (phenylacetic acid) 80 nylacetic acid, Da- (3- [3,5-dimethyl (benzoyl] -3-methylureido) -phenylacetic acid, 'Da- (3-benzoyl ^ 3- alldloureido) -tphenyloacetic acid,' Da4 acid) 3-m-iodo, benzolyl-3-methylureido) -phenyl-acetic acid y, 25 89 668 26 Da- (3-benzoyl-3-phenylureido) -phenylacetic acid, Da- (3-naphthoyl (1) -3-methylureido) -phenylacetic acid. The sodium salts of the following penicillins are obtained: ** Da- (3-benzoyl-3-methylureido) - | benzylpenicillin, Da- (3-benzoyl-3-ethylhereddi) -ibenzylpenliicillin J Da- (3-benzOil-3-methylureiido) -4-chloroibenlzylpenicillin, Da- (3-benzodl-3-methylureido) -4-methoxyibenzyl-penicillin, Da- (3-benzoyl-3-methylureido) -2-chlorobenzyl-penicillin, Da - (3-1-benzoyl-3-methylureido) -3 - iodo! benzylpenicillin, v Da- (3-benzoyl-3-methylurea: iJdo / -2J6-dimethcyx-benzylpenicillin, Da- (3-be! nzooyl-3-methylureido) -2,4-dibromo (ben- zylpenicillins, Da- (3-be'nzo, yl-3-methylU'reido) -3-tenylmethylp-nicillin, Da- (3- benzoyl-3-methylureido) -3-methylibenzylperenicillins, Da- (34enzoyl-3) -methylureido (-2,6-dimethylcyl, benzylpenicillin, Da- (3-ibenzoylO'-3-methylureido) -2-l-chloro-6-fluoro-benzylpenicillin, Da- (3-benzo, l-3-meltylureiido) -2-tenylmethylope - nicillin, La- (3-benzoyl, 3-meltylureido) -benzylpenicillin, Da-ZS-1B-nitro-methoxyphenyl] -S-methylureido) - -benzyl semicillin, Da- (3-p-methoxycarbonylaminoibenzoyl-3-methylpenicillin) , Da- (3-p-methoxybenzoyl-3-methylureido) -beinzy-loureido / -benzylipeni'cyline, Da-ZS-p-tchlorobenzoyl-S-ethylureido (enzylopenicylim, Da- (3-o-bromoibenzoyl-3-) n-propylureido (- * benzy-l-cpenicillins, Da- (i3- [2-Cihi10: ro-5-methoxybenzoyl] -3-n-butyl.ureido) -benzylpenicillins, Da- (3; p-methyl; sulfenylbenzoyl) -3-methylouxeid-benzylpenicillin, Da- (3-p-n-trrolbenzoyl! Lo-3-methylureido) -be'nzylpenicillin, Da- (3- [2-chloro-4-ethylsulfenyl (benzoyl] -3-methyl) - loureido Z-benzylpenicillin, Da- (3-m-cyja! nobenzoyl-3-methylure, ido / -benzyl-penicillin, Da-ZS-CSyS-dimethylbenzoyl J-S-methylureido / - -benzylpenicillin, Da- / 3- b € nzolillo-3-a! lylurei'do / -benzylpenicillin, D-αV3-m-iodoibenzoyl-3-methyl-uireido) -benzyl-penicillin, Da- (3''benzoyl-3-phenylureido) -benzylpenicillin or D-α- (3-naphthyl- (l / -3-methylureido) -benzylpenI-cillin. Example XVII. D, La- (3-acetyl-3-allylureido) -2-tenylmethylpenicillin sodium salt These penicillin are prepared according to example IX from 5.0 parts by weight of D, L-allylureido / -2-te'nylacetic acid, Three to six parts by weight of tetramethylchloroformamidinium chloride and 3.9 parts by weight of 6-aminopenicillic acid. Efficiency: 53%; (3-lactam content: 72%. Calculated: 46.2% C, 4.0% H, 10.8% N, 12.3% S; found: 46.6% C, 5.3% H, 10 , 4% N, 12.3% S. NMR signals at t =; 2.5-3.2 (3H), 3.8 ^ 1.4 (1H), 4.2 (1H), 4.5 ( 2H), 4.6-5.0, (2H), 5.5-5.7 (2H), 5.8 (1H), 7.7 (3H), and 8.4 ppm (iGH). Example XVIII D, La- (3-methoxycarbonyl-3-methyl nicillin sodium salt) 3.04 parts by weight of tetramethylchlorofiramidinium chloride are introduced into 20 parts by volume of dry dichloromethane at 0 ° C and treated with a solution of 4.8 parts by weight of DrL-metVlpureido / -4-methoxythenylacetic acid in 10 parts by volume of dichloromethane Then instilled in 30 minutes at 0 ° C without moisture, at 0 ° C, 2.24 parts by volume of triethylamine in 10 parts by volume of dichloromethane, then stirred for 20 minutes at 5 ° F, the insoluble components are filtered off at a temperature not exceeding / ° C and cooled to -20 ° C. Cooling is added to this A solution at a temperature of - 20 ° C obtained according to example I from 5.0 parts by weight of 6-aminopenicillanic acid and 3.5 parts by weight of triethylamine in 20 parts by volume of dichloromethane. It is stirred at 0 ° C for 30 minutes, then at room temperature for 30 minutes, then poured into 150 parts by volume of ice-cold water and adjusted to pH = 6.5 with 2N sodium hydroxide solution. After separating the organic layer and treating with 150 parts oibvolume. 1: 1 mixture of ethyl acetate and ether, a final treatment according to Example 1 is carried out and the penicillin sodium salt is isolated. Efficiency: 54%; content of | 3-lactam: 75%. NMR signals at t = 2.6 (2H), 3.1 (2H), 4.3-4.0 (3H), 5.8 (1H), 6.2 (GH), 6.85 (3H ) and 8.5 ppm (6H). Effectiveness in an animal trial: B. Example XIX. D, L-methylaminocarbonyl-3-methylureido (-4-methoxyibenzylpenicillin) sodium salt. 45 These penicillines are prepared according to Example 18 from 6.0 parts by weight of acid D; La- (3-dimethylaminocarbonyl-2-methylureido) -methoxy-phenylacetic acid, 3.8 parts by weight of tetrafluoro-formamidinol chloride and 6.2 parts by weight - 50 g of 6-aminopenicillanic acid. Efficiency: 23%; phMactam content: 59%. NMR signals with t = I 2.65 (2H), 3.1 (2H), 4.4-4.8 <3H), 5.65 (1H), 6.2 (3H), 6.9 (3H), 7.05 <6H) and 8.4 ppm (6H). Example XX. The sodium salt of D, La- (3-methoxy-3-carbonyl-3-ny. Penicillin is prepared according to Example 18) from 4.5 parts by weight of the acid D, La- (3-imethoxy: ribonyl-3-methylureido) - tenoacetic acid, 3.2 parts by weight of tetramethylchloroformamidinium chloride and 5.2 parts by weight of 6-amino-penicillanic acid. Yield: 62%, content of | 3-lactam: 84%. Signals at x = 2.5-3.2 (3H), 4.2 (1H), 4.5 (2H), 5.8 (1H), 6.2 (3H), 6.8 (3H) and 8.4 ppm 65 (6H). Effectiveness in animal trials: A.89 668 27 28 Example XXI. Sodium salt of D, L-benzoyl-3-allylureido-1-2-tenylmethylpenicillin. These penicillins are prepared according to example XVIII from 6.0 parts by weight of D, L-zooyl-3-allylureido / -2-tenylacetic acid, 3 , 4 parts of 5 parts by weight of tetramethylchloroformamidinium chloride and 5.5 parts by weight of 6-aminopenicylic acid. Efficiency: 45%; P-lactam content: 77%. NMR signals at t = 2.5 (5H), 2.5-3.1 (3H), 3.7 ^, 4 (2H), 4.5 (2H), 4.7 ^ 5.2 (2H) , 5.5-5.9 (3H) and 8.4 ppm (6H). Effectiveness in an animal trial: B. Example XXII. Sodium D, L-rolyl] -3-methylurefido (-2-tenylmethyl'penicillin). The penicillin is prepared according to Example 18 from 11.6 parts by weight of the acid D, La- (3- [2-furoyl] -3) -methylureido (-2-, tenylacetic acid), 6.5 parts by weight of tetramethylchloroform: nidinium chloride and 8.2 parts by weight of 6-amino-penicillanic acid. Yield: 39%, content of | 3-20-lactam: 88%. NMR signals at x = 2.2 <1H), 2.5 ^ 3.1 (4H), 3.35 (1H), 4.1 (1H), 4.45 (2H), 5.8 (1H), 6.55 (3H) and 8.4 ppm (6H). Efficacy in animal trials: A and B. Example XXIII. Sodium salt of D ^ -a - ^^ wutethylaminocarbonyl-3-'methylure! Ido (-2-1ienyl-methylpenicillin). A suspension of 3.9 parts by weight of tetramethylchloroformamidinium chloride in 30 parts by weight of dry acetone is treated in the form of - 30 ° C for 5 minutes with a solution of D, La- (3-dimethylaminocarbonyl-3-imethyl-ureido) -2-thhenylacetic acid in 10 volumetric parts of acetone and then dripped thereto over the course of 30 minutes 2.1 parts by volume of triethylamine in 5 parts by volume of acetone. It is stirred for 1 hour at -20 ° C, then filtered so that the temperature of the solution does not exceed -10 ° C. It is cooled again to the temperature of -20 ° C, combined with an intensely stirred and cooled to a temperature of -5 ° C a solution of 3.9 parts by weight of 6-aminopenicylanic acid in 50 ml of 60% aqueous tetrahydrofuran. prepared by adding sufficient 2n NaOH to obtain a pH value of 8.2. . A pH value in grammes of 7.5-8.0 is obtained by adding 2N NaOH. After 1 & minutes, the mixture is brought to room temperature and stirred until no change in the pft value is detected. Final treatment of the reaction mixture and the isolation of penicillin are carried out according to Example IX. Yield: 43%; β-lactam content: 54%. NMR signals with t = I 2.5-3.2 (3H), 4.5 (3H), 5.8 (1H), 6.9 (3H), 7.05 (6H) and 8.4 ppm (6H). Example XXIV The sodium salt of Da- (3-Y-chlorobutyryl-3-methylureido) -benzylpenicillin is reacted (in dichloromethane 5.1 parts by weight of D -a-) 3-Y-chlorobutyryl-3- methylureido (phenylacetic acid) with 3.0 parts by weight of tetramethylformamidinium chloride The obtained solution is mixed at 0 ° C with a solution of 6.5 parts by weight of N-trimethylsilyl-6-aminopenicillanic acid trimethylsilyl ester in 33 parts by volume of dry dichloromethane Add 0.5 parts by weight of pyridine and mix without moisture for 1 hour at 0 ° C, then for 2.5 hours at room temperature. Pour into 120 parts by volume. The water phase is adjusted to a pH value of 7-8 and the dichloromethane is stripped off under reduced pressure. The water phase is shaken with 50 parts by volume of ether, which is then discarded, and the water phase is released into solids by drainage. cover is made with 200 parts of a 1: 1 mixture of ether and ethyl acetate, cooled to 0 ° C and acidified with hydrochloric acid to pH = 2 with intensive stirring. The separated organic solution is washed twice with water, 50 parts by volume each. They are dried over MgSO 4, filtered and the sodium salt of penicillin is broken down by adding 15 ml of 1 m solution of sodium 2-ethylpentanoicarboxylate in ether containing methanol. The entire mixture is concentrated at 0 ° C to almost dry, dissolved in as little methanol as possible and the non-crystalline solid is precipitated by adding excess ether. Efficiency: 29%; P-lactam content: 49%. ' Location of NMR signals as in example II. The crude product still contains D-α- (3-Y-chloro-butyryl-3-imethylureido) -phenylacetic acid, which can be removed by fractional extraction of an aqueous solution of penicillin salt at a pH value of 5.5-6.5. Example XXV. The procedure is as in Example I using 0.02 mole of the following compounds in place of D6 α- (3-acetyl-3-allylureido) -phenylacetic acid: Da- (3-acetyl-3-methylureido) -phenyl acetic acid , Da- (3-acetyl-3-ethylureido) -phenylacetic acid, Da- (3-acetyl-3-vinylureido) -phenylacetic acid, Da- (3-acetyl-3-n-propylureido) -phenylacetic acid, s Da- (3-acetyl-3-propeinylureido) -phenylacetic acid, Da- (3-acetyl-3-i-propylureido) -phenylacetic acid, Da- (3-acetyl-3-n-butylureido acid) N-phenylacetic acid, Da- (3-acetyl-3- | 3-methoxyethylO'ureido) -phenylacetic acid, m D -a-) -a (3-acetyl-3-P-dimethylatminoethylureidoI -ienylacetic acid, Da- (3-acetyl-3-cyclohexylureido) -phenylacetic acid, Da- (3-aoethyl-3-cyclobutylreido) -phenylacetic acid, Da- (3-acetyl-3-benzylureido) -phenylacetic acid, Da - (3Hformyl-3-methylureido) -phenylacetic acid, D- Da- (3-foyrmyIo-3-propylureido) -phenylacetic acid, Da- (3-formyl-3-i-pro, pylureido) -phenylacetic acid, Da- (3-acetyl-3-II acid) I-pre-butylureido) -phenylacetic acid, Da- (3-formyl-3-n-butylureido) -phenylacetic acid, Da- (3-fbrmyl-3-allylureido) -phenylacetic acid, 89668 29 Da- (3-formyl-3-banzylureido) -phenylacetic acid, Da- (3-foirmyl'-3-pheinylureido) -menoacetic acid, Da-ZS-formyl-S-cyMopinopyO-uireido, phenyl-acetic acid, "Da- / 3-formyl-3-cyclobutyaoureido / - (phenyl acetic acid, D -a- / 3-formlo- <3-cycloperitylou'redido / -feTiyl- "acetic acid or D ^ a-ZS-formyl-3-cyclohexylourfeidoZ-phenyl-acetic acid. The following penicillins are obtained in the form of their sodium salts: * / Da-y3-acetyl ^ - me1; yloureido / -lbenzyl-eniijcyline, ¦ Da- (3-acetyl-3-ethylurephido Z-Ibenzylpenicyline, Da- (3-iacetyl-3-vinylureido) -beinzylpenicyline, Da- (3-acetyl-3-n-propy) ( loureido / Hbenzylipenicillin, Da- (3-acetyl-3-prop-1-enylureido) - (benzylpen'iciline, Da- (3-acetyl-i-roipylureid), benzylpenicillin, Da - - acetyl- Sn-ibutylureido (3-dimethylaminopenicyline., Da- (3-acetyl-3-11HTzed.Hbutylureido) Hbenzylpenicylime, Da- (3- "acetyl-3- (3-dimethylaminoethylureido) - -benzylpenicyline, Da- (3-aoethyl) -Qjcykló: hek: sylO'Ure, ildo / -ibenzylipen (i-cyline, Da- / 3-acetyl-3-cylklobutylureido / -benzylpenicyline, Da- ^ 3-acetyl-3 ^ benzylouireddaZ-benzylpenicyline, Da- / 3-formyl-3-methylureido, Z-benzylpenicyline, Da- (3-formyl-3-ethylureido) -benzylpenicyline, Da- (3-formyl-3-tops (loureido) -ben zylopenicillin, Da- (3-foiiyl-34Hpixpyloux-ido) -benzylpenicillin, Dai (3-formyl-3-n-butylureidoZ-benzylpenicillin, DHx- (3-pho-tyl-allyl) to / -benzylpenicillin! line, Da- (3-foitnyl-3-benzylureido) -ibenzylpenicine, Da-ZS-ooniayl-S-enylureido) -beinzylpenicyline, Da- (3- formyl-3-cyclopropylureido) -ibenzylpenicilline, D-an / 3 -foaimyl-3-yphelobutylureiido / -tbenzyiopenicylicline, Da- (3-formyl-3-cylclopentylureido / -ibenzylpenicilline or Da- / 3-foa: myl-3Jcyclo'heixylour, eido / -benzylpeni-cyldme. . The procedure is as in Example I using 0.02 moles of the following acids in place of the D-acetic acid used in this example: D-(3-methoxyacetyl-3-methylureido) -phenylacetic acid, D-acid, - Da- (3-methylsulfenylacetyl-3-methylurei to-phenylacetic acid, Da- (3-propionyl-3-ethylureido) -phenylacetic acid, Da- (3-propionyl-3-vinylureido) -phenylacetic acid , Da- (3-n-bu-yryl-3-methylUreido) -phenylacetic acid, Da- (3-methoxycarbonylacetyl-3-methylureido) -phenylacetic acid, Da- (3-i-ibutyTyl) acid -3-methylureido-phenylacetic acid, Da- (3-acryloyl-3-methylureto) -phenylacetic acid, Da- (13- pivaloyl-3-methyl.ureido) -phenylacetic acid, Da- / 3-cyanoimethyl-acetyl-3-methylureido) -phenylacetic acid, D-Qc- (3-acetyl-3-phenylureido) -phenylacetic acid, Da- (3-propionyl-3-phenylureido) -phenylacetic acid, Da- 6-hydroazepdn-2-one-1-yl-carbonylamino-Z-phenylacetic acid or Da- (pyrrolid-2-one-1-yl-carlbonylamino) -phenylacetic acid. and the following penicillins: D-nicyline, Da- (3-propionyl-3Hmethylureido) -! benzylene, icyllin, Da-Z3-methylureido / - -benzylpenicillin, M Da- (3-propionyl-3-ethylureido) / - »benEylipenicyline, Da-ZS-propionyl-S-vinylureido (benzylpenicillin), Da- (3-n-butyryl-3-methylureido) / 4) eiizylpenicyline, Da4 / 3-m € teteycarbonylacetyl-3- methylureido) - 3-benzylpenicillin, Da- (3-i-butyryl- -methylureido-Z-benzylpenicillin, Da- (3-i-butyryl-3-methylureido) -Jbenzylpenicillin, Da-ZS-pivaloyl-S-methylureidoZ -benzylpenicillin, Da- (3-cyanomethylacetyl-3H-methylureido) / 4-enzylpeniciline, Da-Z3Hpropionyl-3-phenylureido-Z-benjzylpenicillin, * Da- (hexahydroreazepin-.2-on-ubzyl-lylcarbonyl) Da- (pyrrolid-2-one-1-yl-carbonylamino), benzyl-penicyline. Example XXVII. Attempt to prepare the sodium salt of Da-Z3-methoxycarbonyl-3-methylureidoZ-benzylpenicillin. 5.2 parts by weight of Da-Z3-meftoxycarbonyl-3-methylureido (phenylacetic acid) are crushed in a mixture of 10 parts by weight benzene, 5 parts by weight of thionyl chloride and 0.05 parts by weight of dimethylformimide, and then carefully heated while stirring with a magnetic stirrer. The temperature is kept at 60 ° C until gas evolution ceases, then thionyl chloride and benzene are removed under a vacuum produced by a water pump and finally at 50 ° C and 0.1 torr. in the infrared spectrum of the band at 1805, 17125 and 1175 cm-1. Yield: 5.5 parts by weight. : Calculated from Da-Z3-metho'xycaribonyl-3-non-ethyl-ureido-Z-phenylacetic acid chloride calcd: 50.55 ° Zo C, 4.56 ° Zo H, li 2.47 ° Zo Cl, 9.84 ° Zo N; got: 47.57 * Zo C, 4.29 * Zo H, 11, 6 ° Zo Cl, 9.66 ° ZoN. 55 5 parts by weight of the product thus obtained are dissolved in 10 parts by volume of dry tetrahydrofuran and added dropwise with stirring to an ice-cooled solution of 3 to 8 parts by weight of 6-aminopenicillanic acid in 50 parts by volume of aqueous tetrahydrofuran with the addition of sufficient the amount of sodium liquor until a solution is formed at a pH value of 8.2. By adding an additional amount of 2 N sodium liquor, the pH value is maintained between 7 and 8. Then stirring is continued for 30 minutes at temperature 0 ° C, then at room temperature until it is found that there is no need to add sodium liquor to maintain the pH value of 7-8. 100 parts by volume of water are added, the tetrahydrofuran is removed at 0 ° C under reduced pressure and the remainder is extracted. an aqueous solution of 50 parts by volume of ether to remove the inert components and then covered with 160 parts by volume of a 1: 1 mixture of ether and ethyl acetate and acidified with dilute hydrochloric acid, cooling with ice and stirring, to a pH value of 2. After separation of the organic phase, it is dried over MgSO 4 after washing with 50 parts by volume of water, then treated with 17 parts of water. by volume of the solution of 2-ethylpentanecarboxylic acid sodium in an ether containing methanol, it is evaporated under reduced pressure to almost dry and dissolved in as little methanol as possible. After By adding an excess of ether, a colorless, non-crystalline product is precipitated, which, after decanting the solution, is thermally macerated with ether, filtered off and dried in a vacuum desiccator against P 3 Os. Yield: 6 parts by weight, content (3-lactam: 88%. Calculated as methoxycarbonylmethyl-ureidopenicilline: 49.3% C, 4.7% H, Cl, 11.5% N, 6.6% C) ; found: 47.5% C, 6.0% H, 0.1% Cl, 9.9% N, 7.0% S. Thin-shell chromatogiram of the product (silica gel, 10: 3: 1 mixture of n-butanol, n-pentane and glacial acetic acid, 1.5 hour run-out time) showed spots at JRI values of 0.045, 0.11-0.3, and 0.56. Authentic Da- (3-methoxycarbonyl-3-methyl) ureido-ibenzylpenicidine prepared according to example VIII or by acylating ampicillin with N-imethoxy-airboinyl-N-methylcarbamic acid chloride under the same conditions has a value of R 1 = 0.45. with Becillus subtilis, it shows the presence of several antibiotically active substances, none of which is identical to the authentic material.Moreover, on the basis of the NMR spectrum, the presence of a greater amount of the prescribed methoxycar-bonylmethylureidopene is excluded icillin and it is confirmed that a mixture of several different substances is present. The table in Example VIII. Example XXVIII shows the antimicrobial efficacy of this product. The reaction of Dai (3-n-butoxycarbonyl-3-methylureido) -phenylacetic acid according to example XIc of Dai (3-n-butoxycarbonyl-S-methylureido) -phenylacetic acid with thionyl chloride and then with 6-aminopenic acid. In each case, pro) 668 32 products are obtained, which are mixtures of several antibiotically active substances, none of which are identical to the authentic ones, obtained according to Examples IX and X, Da- (3-and-propyloxycarbonyl). 3-methylureido) -benzylpenicillin or Da- (3-n- #toxisy-carbonyl-3-methylureido) -benzylpenicillin. The Rf values in a thin-layer chromatogram developed with a 9: 3: 1 mixture of n-butanol, pentane and glacial 'acetic acid' on a silica gel are 0.080 and 0.35 or 0.078, 0.46 and 0 respectively. , 75. Under the same conditions, the authentic products show an Rf value of 0.56 or 0.64. The antimicrobial effectiveness of the reaction products of D-(3-i-propyloxycaribonyl-3-methylureido) 7-phenylacetic acid is given in the table in Example IX. Antimicrobial activity of the reaction products of D-phenylacetic acid (product A) in comparison with the action of pouring penicillins (B), prepared from ampicillin and Nn-butoxycarbonyl-N-methyl-carbamic acid chloride, is given in table 4.¦ «¦ '¦ Table 4 Type of bacteria Eschericia coli 14 Eschericia coli C 166 Eschericia coli 183/58 Proiteus 3400 Proteus -1017 Pseudomoinas aerug.Bonn Pseudomoinas aerug.Walter Staphylocoecus aur. 133 Efficacy (E / ml) of products (A) 100 200 400 400 400 400 400 12.5 (B) | 3y12 6.25 6.25 215 12.5 12 "5" 25 <0.78 1 Example XXIX. The sodium salt of α- (3-ibenzoyl-3-methylureido) -2,6-dichlorobenzyiopenicillin. 5.6 parts by weight of α- (3-benzoyl-3-methyl) acid are dissolved: eido (-2,6-dichlorophenylacet-) <5 parts in a mixture of 70 parts by volume of dry acetone and 2.5 parts by volume of triethylamine at a temperature of -5 ° C to -10 ° C, 2.9 parts by weight of 1-methyl-2-chloride are added. - - • chloro-pyrrolidinium, stirring for 45 minutes, sludging, and the precipitate formed (triethylamine hydrochloride, filtration with a solution of 6-aminopenicylamic acid in water, prepared with triethylamine, and cooled to -20 ° C) , having a pH value of 55 7.5, is then stirred for 2 hours at -5 ° C and the pH is maintained at 7.5 by appropriate addition of triethylamine. Then it is diluted with 130 parts by volume of water, pH = 6.5 60 with 2N hydrochloric acid, acetone is stripped off under reduced pressure, the remaining solution is adjusted to pH = 7.5, shaken with a 1: 1 mixture of ether and ethyl acetate, the aqueous layer is separated, the fresh organic phase is covered and with stirring and cooling with ice 89 668 33 acidified with 2N hydrochloric acid to a value of pH = 1.5, the organic phase is separated, washed with water, dried with sodium sulphate in a refrigerator for 2 hours and, according to the example XXVII, precipitated and separated penicillin sodium. Efficiency: 33%; content of | 3-lactam: 78%. NMR signals at t = 2.4-2.75 (8H), 3.3 (0.7H), 3.7 (0.1H), 4.4 (2H), 5.75 (1H), 6, (8 (-3H) and 8 "45 ppm (6H). Effectiveness in tests on animals: A and B. Example XXX. Sodium salt of a- (3) benzoyl-3-m6ityilO'Ure, ido / -i3 -methylsulfenyl: benlzylpenicillin. These penicillines are prepared according to Example XXIX from 6.0 parts by weight of -S-methylureido-M-methylsulfenylacetic acid dissolved in 70 parts by volume of acetone and 2.35 parts by volume of ethylamine by reaction with 2.7 parts by weight of 1-methyl-2-chloropyrrolidinium chloride and then with a solution of 6-amino-penicillanic acid, p'H = 7.5, prepared with the addition of triethylamine. Yield: 45%, p-lactim content: 72 %. NlMR signals at% = 2.4-2.9 (9H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.9 (3, H), 7, 6 (3H) and 8.45 ppm (6H). Animal test efficacy: A and B. Example XXXI. Α- / 3-ethoxycarbonyl-3-! Me, tylourelido-4-methylsullphenylbenzylope- sodium salt Nicillin.Penicylime also produces e according to example XXIX with 6.0 parts by weight of α- (3-ethoxy- ^ carboinyl-3-methylureido) -4-methyl: losulfenylphenyl acetic acid, 80 parts by volume of acetone, 2.6 parts by volume of triethylamine and 3.0 parts by volume by weight of 1-methyl-2-chloropyrrolidinium chloride by reacting them with a solution of 4.4 parts by weight of 6-amino-penicillanic acid in 70 parts by volume of 50% aqueous acetone prepared by adding triethylamine. Yield: 44%; content of | 3-lake! tamu: 78%. NMR signals at t = 2.6 (2H), 2.75 (2H), 4.5 (1H), 4.55 and (and 2H), 5-5.9 (3H), 6.85 &Lt; 3H), 7.55 (3H), 8.4 (6H) and 8.6 ppm <3H). Example XXXII. The sodium salt of α- (3-ethoxycarbonyl-3-methylurei.do) -4-methylsulfenylibenzylpenicillin. 6.0 parts by weight of the acid "- / 3-ethoxic! Ribonyl-3-methylureido" are dissolved to form this penicillin. "" -4-methylsulfenylacetic acid in 80 parts by volume of acetone, adding 2.6 parts by volume of triethylamine, then added at a temperature of -5 ° C to -10 ° C, 3.6 parts by weight of l-meltyl chloride 2-chloro-pyridinium- is stirred at this temperature for 45 minutes, a solution of 4.4 parts by weight of 6-aml-nopenicillamic acid in a mixture of 70 parts by weight of 50% aqueous acetone and triethylamine is added, the pH value is = 7.5, then the mixture is stirred for 2 hours at - 5 ° C, diluted with 50 parts by volume of water and the reaction mixture is subjected to a final treatment according to Example XXIX in order to isolate penicillin sodium. Efficiency: 44%; β-lactam content: 78%. Calculated: 46.7% C, 5.2% H, 9.9% N, 11.3% S; found: 47.0% C, 5.6% H, 9.4% N, 10.8% S. NMR signals such as in the example XXXI, Wi-34 40 45 50 55 dma of both substances are identical. Productivity in animal testing: A. Example XXXIII. Α- (3-13-chloropropionyl-3-methylolUTeido) -cyclohelk! S-3-enyl / -methylpenicillin sodium salt. These penicillines are prepared according to Example XXIX from 5.3 parts by weight of α- / 3- β3-chloropropionyl-3H-methylureido / -cyclonex-3-enoacetic acid, which is reacted with 3.0 parts by weight of lamethyl-2-chloropyrrolidinium chloride in the presence of 2.6 parts by weight of triethylamine, then the total reacts with 4. 4 parts by weight of 6-aminopanicillanic acid dissolved with triethylamine in 50% aqueous acetone, pH = 7.5. Efficiency: 44%; content of (3-lactim: 78%. NMR signals at t = 4.3 tf2H), 4.5 <2H), 5.8 (1H), 6.2 <2H), 6.65 (3H), 6.8 (2H), and 7.7-6.8 ppm (13H). Example XXXIV. Dnoyl (-3-methylureido] -ibenicillin sodium salt. To prepare this penicillin, 3.9 parts by weight of D-methylureidol-phenylacetic acid are dissolved in 55 parts by volume of acetone, with the addition of 2.0 parts by volume. 2.3 parts by weight of 2-methyl-2-chloropyrrolidinium chloride are added at a temperature from -5 ° C to -10 ° C, and mixed at the indicated temperature for 45 minutes, then the a solution of 3.1 parts by weight of 6-aminopenicillanic acid in a mixture of 60 parts by volume of 90% aqueous acetone and triethylamine, showing a pH value of 7.5, stirred for 2 hours at -5 ° C and subjected to final treatment according to example. Xxix for the isolation of penicillin sodium. Efficiency: 56%; content of? -lactam: 64%. NMR signals at t = 2.1-3.0. (? 8H), 4.35-4.8 (3H), .8 (1H), 6.55; (3H ) and 8.45 ppm (GH). Example XXXV. D- dimethylisoxazolyl-4- (3-methylureildp] - iopenicillin sodium salt. 3.9 parts by weight of D-ia- [3- /, 5-dimethyl-isoxazolyl-4 / -3-] acid are dissolved to form this penicillin. methylreido] -phenylacetic acid in 60 parts by volume of methylene chloride with the addition of 2.0 parts by volume of triethylamine, the solution is cooled to -10 ° C, 1.2 parts by weight of l-methyl-2-chloropyridinium chloride are added and the mixture is left for 90 minutes at -10 ° C to -35 ° C (solution A). 3.1 parts by weight of 6-amino-penicillanic acid are dispersed separately in 60 parts by weight of methylene chloride, 3.9 parts by weight of D-a- (3- / 3,5-dimethyl) acid are mixed. for 4 hours at the temperature of 22 ° C (solution B). Then solution B is cooled to the temperature of -5 ° C and solution A is added to it in several portions during 30 minutes with stirring and cooling. at 0 ° C to 5 ° C for 1 hour, the solvent is stripped off under reduced pressure, the residue is dissolved in a 1: 1 mixture of ether and ethyl acetate, the mixture is brought to pH 7.5 with stirring, separated the organic phase, the aqueous phase is covered with a fresh mixture of ether and ethyl acetate, the pH value is brought to 1.5 with 2N hydrochloric acid while stirring and cooling with ice, the organic phase is separated, washed with water, dried with magnesium sulphate in a refrigerator for 2 hours and isolates according to example XXVII penicillin in the sodium salt. Efficiency: 50%; β-lactam content: 80%. Calculated: 50.7% C, 0% H, 12.3% N, 5.6% S; found: 56.1% C, 5.4% H, 11.6% N, 5.6% S. N, MR signals at t = 2.35 - -> 2.9 (5H), 4.4 <1H), 4.5 - (2H), 5.8 (1H), 6.8 (3H), 7.6 (3H), 7.75 (3H) and 8.45 ppm (6H). Example XXXVI . Example XXXIV is followed by using instead of Da- (3- (2-tenoyl) -3-methylureido) -phenylacetic acid 0.012 moles of the following acids: Ia- [3- (2, -fUiroyl) -3 acid -methylureido] -phenylacetic acid, Da .- [37 (2-furoillo) -3-ethylureido] -phenylacetic acid, acid. Da - [- 3- (2-furoyl) -3-n-propylureido] -phenylacetic acid, Da- [3- (2-furoyl) -3-phenylureido] -tenylacetic acid, Da- [3-) 2,5-dimethylfuroyl-3 / -3-methylurei] -phenylacetic acid, Da- [3- (5-bromofuroyl-3- (methylureido]) -phenylacetic acid, Da- [3- (5-methoxy-) ureido] -phenylacetic acid, Da - [- (3,5-dimethyl lisothi! azoyl- (3) -carbonyl) - '3-methylureido] H-phenylacetic acid, Da- [3- (isoxazolyl) -4) -JkaTibonyl (3-methyl-ureido] -phenylacetic acid, Dai [3- (isoxazolyl-3) -kanbonyl-3-methylureido] -phenylacetic acid, ¦ Da- [3- (3-methylthiadiazal) -1,2, 5) -yl- (4) -carbonyl-3-methylureido] -phenylacetic acid or Da- [3- (4-methylthiadiazole / 1,2,3H-yl-5) -carbonyl-3-methylureido ] -phenylacetic. The sodium salt of the following penicillins is obtained: Da- [3- (2-furoyl) -3-methylureido] -benzylpenicillin, Da- [3- (2-furoyl) -3-ethylureido] -lbeinzyiopeni <: ylins, D - "[3- (2-furoyl) -3-n-propylairido / 4enzylpenicillin, Dai [3- (2-fuix) yl] -, 3-phenylureido] 43-enzylpenicillin, Da- [3- (2,5-dimethylfutyl- (3) -3-methylureido] -benzylpenicillin, Da- [3- (5-bromoifuroyl) 3 / -3-methyl, loureido) -benzyl-penicillins, Da- {3- / 5-methoxymethylfuroyl- (2) -3-methylureido] -benzylpenicillin, Da- [3- (3,5-dimethylisothiazolyl- (3H -carbO'nylO-3- - "meltylureido] -toenzylpenicillin, Da-) 3- (isoxazolyl-M) -carbanyl-3-methylureido] - 2 -benzylpenicillin, Da- (3) isoxazolyl- (3) -carboinyl-3-methylureido) - -benzylpenicillin, * Da- [3- (3-methylthiodiazole) ) 1,2,5Mlo- (4'-carbonyl) - -methylureido] -! benzylpenicillin or Dai [3- (4-methylthiadiazole (1r2,3) -yl- (6H-carbonyl-3-methylureido] -benzylpenicillin) . 1668 36 Example XXXVII. A) D-hexylcarbonyl (-3-methylureido) -phenylacetic acid. 13.5 parts by weight of bis (trimethylsilyl) -C-phenylglycin are dissolved in 100 parts by volume of dry carbon tetrachloride, slowly dropwise at 0 ° C without access to moisture solution of 10.0 parts by weight of N-cyclohexyl chloride acid chloride, volumetric carbon tetrachloride and left overnight in the refrigerator. Thereafter, the water is washed three times with 50 parts by volume each and the organic phase is evaporated to dryness under reduced pressure. Yield of an oily product: 95%. NMR signals at t = 0.5 (LiH), 2.5 (5H), 4.6 (1H), 5.2 (1H), 6.8 (3H) and 7.9-8.9 ppm (10H ). '. B) O- [D-ureido-phenylacetyl-C-cyano-C-ethoxycarbonyl-formaldehyde. 2.95 parts by weight of Ocyano-C-ethoxytoa.nbonyi-formaldehyde are dissolved in 50 parts by volume of tetrahydrofuran, 2.9 parts by volume of triethylamine are cooled, the mixtures are cooled to -10 ° C and, while stirring and further cooling, 1.5 parts by volume of thionyl chloride are slowly added dropwise, and the mixture is stirred for 15 minutes at a temperature of - 10 ° C. Then a solution of 6.88 parts by weight of Da- (3-cyclohexyloxycaribonyl-3-methylureido) -phenylacetic acid in a mixture of 50 parts by volume of four parts is added dropwise during about 45 minutes cooled to 0 ° C in about 45 minutes. ¬ Hydrofuran and 2.9 parts by volume of triethylamine and the reaction mixture is stirred for a further 1 hour at 0 ° C. The precipitated triethylamine hydrochloride is filtered off, the filtrate is evaporated under reduced pressure in a rotary evaporator placed in a bath at 15-20 ° C, the residue is dissolved in methylene chloride, the solution is cooled to 0 ° C, shaken quickly once with ice-cold water, then the organic phase is dried with sodium sulphate at 0 ° C, filtered, evaporated in a bath at 20 ° C in a rotary evaporator, and finally in a bath at a temperature of At 40 ° C. A colorless substance similar to lacquer is obtained. Efficiency: 98%; Specificity: [has an infrared spectrum corresponding to its structure. NMR signals at t ^ 0.5 and (1H), 2ph '(5H), 4.3 (1H), 5.25 (1H), 5.7 (2H), 6.8 <3H) and 8.0- → 9.0 µm (13H). Example XXXVIII. O- [D-nyl-3-methylureido] -phenylacetyl] -C-cyano-C-ethoxycarboinylformaldehyde. These substances are prepared from 5.8s6 parts by weight of C-cyano-C-ethoxycarbonylformaldehydeoxime , 100 parts by volume of tetrahydrofuran, 57 parts by volume of triethylamine, 3.0 parts by volume of 60 thionyl chloride, and a mixture of 12.0 parts by volume of Da- (3-aUiloxycarbophyl-3-methylureido) -phenylacetic acid, 100 parts by volume of tetrahydrofuran and 5 , 7 parts by volume of triethylamine. Colorless substances are obtained in the form of a lake. Yield: greater than 80%; 37 Specificity: [a] m = -19 μg (50.6 mg; methanol). The substance has an infrared spectrum corresponding to its structure. NMR signals at t = 0.4 (1H), 2.6 (5H), 3.7-4.2 (1H), 4.3 (1 "), 4.5 ^ 1.9 (2H), 3 &Lt; 2H), 5.65 (2H), 6.8 (3H), [delta] 65 ppm <3H). Example XXXIX. 0- [Du- (3-benzoyl-3-ma * tylourefido / ^^ - dichlorophenylacetylol-C ^ cyano-C- -ethoxykyirtonyl / - (foirmaldehydo! K) sylm These substances are prepared according to example XL from 2.85 parts by weight of C-cyanb-C-ethoxycarbonylformaldehyde oxime, 50 parts by volume of tetrahydrofuran, 2.8 parts by volume of triethylamine, 1.45 parts by volume of thio-chloride. of methyl and a mixture of 7.6 parts by weight of D- -a- (3-ibenzoiao-3-methylureido-2, 6-dichlo-profene) acetic acid, 50 parts by volume of tetrahydrofuran and 2.8 parts by volume of triethylamine. A colorless substance in the form of a lacquer is obtained. Efficiency: more than 80%. The infrared spectrum of this substance shows bands corresponding to its structure. NMR signals at x = 0y5 (TH), 2.45 (5H), 3.55 (1H), 5.6 (5 (2H) 6.9 (3H) and 8.7 (3H). Example XL. Salt Sodium α- (pyrrole Jd-2-one-1-yl-carbonylamino / -ap-tolylmethylpenicilli) (these Penicillines are prepared according to example I from 14.5 parts by weight of α-pyrrolid-2'-one-i- ylo-carbonylamino / - "- p-tolylacetic acid, 10 ^ 2 parts by weight of tetramethylcMoroformamidinium chloride and 15 parts by weight of 6-amnopenicylanic acidic. Yield: 29%; content (Macam: 67%. NMR signals at t = 2.5 ^ 3.05 <4H), 4.5 (3H), 5.8 (1H), 6 ^ 1 ^ 6.4 (2H), 7.4 (2H), 7.7 (3H), 8.0 (2H) and 8.3-8.6 ppm (6H). Example XLI. The sodium salt of α- (3-o-fluoro-benzo, illo-3-methylureido), ap-1xlilome1; ylo! Pe, nic, ylins. These penicillines are prepared according to example II from 9 parts by weight of N-fluoro-methylureido acid. N-tolylacetic acid, 4.95 parts by weight of chioite tetramethylchlorotformamidinate and 8.5 parts by weight of 6-aminopenicylic acid. Efficiency: 59%; β-lactam content: 87%. Calculated: 53.7% C, 4.8% H, 9.7% N, 5.5% S; found: 53.4% C, 6.0% H, 9.7% N, 5.9% S. NMR signal at t = 2.3-3.1 (8H), 4.5. (3H) " 5.8 (1H), 6.3 (3H), 7.7 (3iH), and 8.2- < 8.5ppm (6H). Animal test performance: A and B. Example XLII. The sodium salt of a ^ (imidazolidin--2-o, nl-yl) -car! Bonylamino / -p-me1; ylolbenzylpenicillin, mush 3.76 parts by weight of methylchloroiphonamidinium chloride in 15 parts by volume of dry acetone and mixes in minutes without moisture. It is also drained without the access of moisture, the reagent is mushroomed in 40 parts by volume of methylene chloride and cooled to 0 ° C. Then, 5.53 parts by weight of α - [N - amidazolidin-2-one-1-yl] -bonylamino-p-methylphenylacetic acid dissolved in a small amount of methylene chloride are added to the mixture, and the mixture is added dropwise with stirring without moisture. , at 0 ° C, within 30 minutes a solution of 2.0 parts by weight of triethylamine in 20 parts by volume of methylene chloride. It is stirred at 5 ° C for 20 minutes, 9668 38 are cooled to -20 ° C and treated in a vessel with a solution of triethylaluminum salt of 6-aminopenylate, also cooled to - 20 ° C. This solution was prepared for 12 hours (mixing 5.8 parts by weight of 6-aminopenicylic 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 sipping it thoroughly.) After a short period of stirring to 0 ° C., an additional 0.9 part by weight of triethylamine is added after a short time, and the mixture is stirred for 30 minutes at 0 ° C. and for 30 minutes at room temperature. Chilled water, adjusted to pH 5.5 and stripped off methylene chloride under reduced pressure. Extracted twice with ether and washed, ether is washed with a little water. The combined aqueous solutions are covered with ethyl acetate. and with me The sewing is adjusted to a pH value of 1.5 with dilute hydrochloric acid, and the steaming is cooled with ice. The ethyl acetate layer is separated, the water is back-extracted with ethyl acetate and the combined extracts are washed with water. It is dried for about an hour at 0 ° C. over MgSO 4 and, after filtering, is treated with a 1 molar solution of sodium 2-ethylpenitanecarboxylic acid in ether containing methanol and evaporated under reduced pressure to an oily consistency. Then it is dissolved in the required amount. methanol and the resulting solution are added dropwise, with vigorous stirring, to 500 parts by volume of a mixture consisting of about 500 parts by volume of absolute ether and 50 parts by volume of methanol. / After standing for a short time, the precipitated product is filtered off, mushroomed in dry ether and filtered again. It is dried with P2O5 for 2 days under reduced pressure. Yield: 70%; 0-lactam content: 86%. The NMiR signals are listed in Table 7. Infrared bands at 32280, 1760, 1712, 1055, 1600, 1520, 1270 and 765 cm; -1 (nujol suspension). Example 1 a d XLIII. The sodium salt of a - [/ imlidazolidin--2-one-yl / Jkanbonylamino / -p-methyl ^ benzylpenicillin. According to example XLII, 2.8 5 parts by weight of the acid a - [/ imidazolidin-2-one-l are reacted - -yl (-kaifltonylamino) -p-methylphenylacetic acid with 1.7 parts by weight of 1-imethyl-2Hchloro-Al-pyrrolidinium chloride used in place of tetramethyl chloride. tylchloroformamidinium and then with 2.6 parts by weight of 6-aminopenicillanic acid in the form of its triethylamino salt to obtain α - [(imidazolidin-2-one-1-yl) 11- nylanino] -benzylpenicillin. Efficiency: 54%; P-lactam content: 39%. NMIR signals are given in the table. The position of the infrared bands is consistent with the positions of the penicillin bands in Example XLII. Example d XLIV. Ra - {(imIdazolidin--2-one-1-yl) -cartoonylamino] -p-chlorobenzylopeailylcline sodium salt. 65 These penicillines are prepared according to the method described in Example XLII and 5.96 parts by weight of α - [(itnidazoidin-2K) n-17yl] -carboTiylamino] -p-chlorophenylacetic acid, 3.76 parts by weight of chlorine Tetramethylchloroformamidinium acid and 6.8 parts by weight of 6-amino-penicillanic acid. Yield: 59%; content of (3-lactim: < 6%. NMR signals are given in the table. Infrared bands at 3300, 1775, 1667, 1608, 1540, 1287 and 780 ohm - *. Example XLV A. Sodium salt of a - {/ imidazolidine " -on-1-yl - / - carbonylamino] -p-chlorobenzyl-penicillins. According to the example XLII, 3.6 parts by weight of α - [/ ii, midnitrogen.idin-2-one-i-yl) 4car (bonylamino] -p-chloro'phenylacetic acid with 2.22 parts by weight of 1,3-dimethyl-2-chloro-A-imidazolidinium chloride and then 3.01 parts by weight of 6-minopenicillanic acid to the sodium salt of t- [ (imidazolidyin-2-one-1-yl) -caribonylamino] -p-chlorolbenzyl-65%; content of β-lactam: 72% NMR signals are given in the table. The infrared spectrum of nujol is identical to the penicillin spectrum in example XLVII. Example XLV B. a - [/ imidazolidin-2-one-1-ylZ-carbonylaminol-p-imeitylphenylacetic acid. Ii6.5 parts by weight of a- (4-methylphenyl) -glycine are dissolved in 200 parts by volume of 50% of dioxane for use with the additive are sufficient more than 2 liters of sodium hydroxide solution. The pH is then adjusted to 7-8 with 5N hydrochloric acid, a fine residue of the amino acid is partially precipitated. * Then a solution of 11.8 parts by weight of 1'-chlorocaribonylimidazolidine in 50 parts is added dropwise with stirring. of warm acetone and then cooled in an ice bath, maintaining the pH value at 7-8 by the appropriate addition of 2N sodium liquor. After the addition is complete, stirring is continued for 15 minutes. at room temperature to a constant pH value. The unreacted amino acid is filtered off (6 parts by weight), the effluent is evaporated under reduced pressure to half its volume and extracted with 100 parts by volume of ether at a time. The aqueous phase is acidified with 2N hydrochloric acid to a pH value of 1-2 d, the precipitated oil is dissolved by extraction with 2 × 100 parts by volume of ethyl acetate. The combined ethyl acetate extracts are washed with 50 parts by volume of water, dried over MgSO 4 and then evaporated to dryness. A glassy foam is obtained which, when rubbed with petroleum ether, turns into a fine-grained, non-crystalline powder. Yield: 48%. The NMR signals are given in Table 7. Example XLV C. According to the example XLV B, a - {(imidazolidin-2-one-1-yl) -caribonylaminol-and 1 -chlorophenylacetic acid is produced from 18 ^ 6 parts by weight a- / 4-chlorophenyl / glycine and 14.8 parts by weight of 1-chlorocanbonyldimiidazolidinone-2 • 6 parts by weight of unreacted α- (4-chlorophenyl) -glycine are recovered. Yield of product soaked in ether: 33 parts by weight. The substances are recrystallized from an ethyl acetate / petroleum ether mixture. Based on reacted starting materials. The yield of 1 fraction is 35% and the yield from 2 to 15%. Mp 115-120 ° C. The -NMR signals are given in Table 7. Example XLV D. 1-Chlorocarbonylimidazolidin-2-one. To a vigorously stirred solution of 3.5 parts by weight of imidazolidin-2-one (prepared according to the method of Fischer and Koch, Ann. 232, page 224) / l886 /) in 50 parts by volume of absolute tetrahydrofuran, 4 parts by weight of phosgus are instilled in 10 parts by volume of tetrahydrofuran within 15 minutes. The mixture is then stirred at 10 ° C. for 3 hours and dry air is blown through the reaction mixture to remove any hydrochloric acid formed and any residual cphosgene. It is evaporated to dryness in a relational evaporator and the solid residue is dried with concentrated sulfuric acid and under a reduced pressure of about 12 torr. Efficiency: 93%; mp 150 ° C, after recrystallization from acetone / pentane. Calculated: 32.3% C, 3.4% H, 18.8% N, 23.9% C1; found: 32.3% C, 4.5% H, 18.7% N, 23.9% Cl. NMR signals at t = 5.7 ^ 6.1 &Lt; 2H) and 6.3 ^ 6.7 (2H). (Acetone -d6 as solvent) A2B2 symmetrical system. Infrared band at 3230, 1700, 1700, 1270 and 1150 cm1-1. Example XLV E. The example XLII is followed by replacing the acid a - [/ imidazolidin-2-one-l-yl] used in this example [beta] -Cairbonylaiminol-p-methylphenylacetic acid with the following acids in an amount of 0 * 2 moles: [alpha] - [(imlidazolidin-2-one-1-yl] -carbonylamino] -2-thienyl (and 2) -acetic acid, a - [(imidazolidin-2-one-1-yl) -caribonylamino] -thienyl- (3) K) ctow, y, x acid a - [(imidazolidin-2-one-1-yl) -carbonylamino] - -p-hydroxyphenylacetic acid, α - [(amidazolidin-2-pn-1-yl) -kylrbonylamino] - N -hydroxyphenylacetic acid, 4o | a - [(d-dimazolidin-i2-one-1-yl) -carbonylamino] -o-chlorophenylacetic acid, a - [(amidazolidin-2-oin-1-yl) -carbonylamino] - -oo, -dwTi .fluorofluorophenylacetic acid, α - [(imidazolidin-2-one-1-yl) -carbonylamino] - 45-o-o'-chlorofluorophenylacetic acid, or α - [/ im, idazolidin-2-one-1-yl) -carbonylamino ] - -p-acetylaminophenylacetic acid. The following penicillins are obtained in the form of their sodium salts: 50 α - [(imidazolidin-2-one-1-yl) -car; bonylammo] - -thiehyl- (2) -methiophene! icillin, and - [(imidazolidin-2-one-1-yl) -carbonylamino] -thienyl- (3) -me1; ylpenicillin, [alpha] - [(imidazolidin-2-one-1-yl] -canbonylamino] - 55-p- hydroxyHbenzylpenicillin, α - [(imidazolidin-2-one-1-yl) -carbonylamino] - -m-hydroxyibenzylpenicillin, α - [(imidazolidin-2-one-1-yl) -carlbonylamino] - -o-chlorobenzylpenicillin, 60 a - [(imidazolidin-2-one-1-yl) -cathphbonylamino] - -oo-bifluorobenzylpenicillin, and - [(imidazolidin-2-one-1-yl) -car1bonylamino] -o-o'-chlorofluorophenzylpenicillin or a - [/ imidinase -2-on-1-yl) -caribo nylamino] - 65 -β-acetylamlinophenzylpenicillin. 89 668 41 42 Example XLVI. Da -, [(imidazolidin-2-one-yl) -carbonylamino] -phenylacetic acid. 9 I parts by weight of D / - / - C-phenyglycine are dispersed in 15; 0 parts by volume 30% aqueous of dioxane, add dropwise at room temperature, while stirring, 40% aqueous sodium liquor in an amount necessary to dissolve the phenylglycine. Then, about 15% hydrochloric acid is added to this solution with stirring until it is dissolved. produces pH values of 7.5-6.0. 10 The resulting fine suspension of phenylglycine is cooled to a temperature of about 5 ° C, and at this temperature, while stirring, 1 · 0.6 parts by weight of finely powdered imidazolidin-2-nl-yl-caribonyl chloride is slowly added to the pH value is 7.5-8.0 by the appropriate addition of a small amount of 5 N sodium hydroxide solution, the phenylglycine being dissolved. Stirring is continued for 60 minutes at a temperature of 5 ° C, but only in the first 15 minutes it is necessary to add 20 sulfuric liquor until the desired pH value is obtained. Small amounts of insoluble components are found, the permeate is largely released from dioxane in a rotary evaporator, then covered with ethyl acetate, acidified with 2N hydrochloric acid to pH = 1.5-2.0, then the organic phase is separated, washed twice with water, dried over magnesium sulphate and evaporated It completely in the rotary evaporator. The colorless, clear foam residue is dried over P4O10 for 2 days in an open desiccator with an oil pump tap. Yield: 7.9 parts by weight. In the infrared spectrum [solvent: dimethyl sulfoxide] the substance shows in the region beyond the solvent spectrum two double bands at 1720 and 1670 or 1525 and 1480 cm-1. NMR signals are listed in Table 7. Example XLVII. Α - [/, imlidazolidin-2-one-1-yl) -carbonylamino] -4-methylthiophenylacetic acid. A) α-Amino-4-methylthiophenylacetic acid is prepared in a known manner starting from 4-methylthiobenzaldehyde by cyamhydrins and α-aminonitrile and its saponification with boiling 20% hydrochloric acid. Melting point 260 ° C (in Kofler block). The infrared spectrum (nujol) shows in the carbonyl band at 1740 cm-1 single band and at 1570 - '1670 cm- 1 broad adsorption with peaks, mainly at 1) 590 cm-1. In the NMR spectrum / NaOD / D20 / there are signals at x = 2.5-2.8 (4H) (System AB), at 5.6 <1H) and at 7.6 (3H). 50 b) α - [(imidazolides, n-2-one-1-ylb) -carbonylamino] -4-methylthiophenylacetic acid is prepared according to Example XLIX from 13 parts by weight of the amino acid described above and 10 parts by weight of chloride imidazolidin-2-one-1-yl-cariboinyl. Yield: 6.7 parts by weight of a yellowish hard foam. In the infrared spectrum (solvent: dimethyl sulphoxide), the substance shows in the region outside the solvent two double-bands at 1710 and 1660 and 1520 and 110 [mu] cm-1. 60 Signals, NMR are given in Table 7. Figure XLVIII. D-α - [(Imidazolridin-2-one-1-yl) -carbonylamino / Hbeiizylpenicilline sodium salt. 65 45 3.8 parts by weight of D-ct-I / imidazolidin-2-one -1-yW-carbonylamino] -phenyl-acetic acid are dissolved in 65 parts by volume of dichloromethane, 2.7 parts by weight of l- chloride are added. methyl-2-chloro-Al-pyrrolidinium and then, after cooling to -10 ° C, 2.0 parts by volume of triethylamine are added. The obtained reaction mixture is stirred for a further 1 hour at a temperature of -5 ° C (mixture A). It is stirred at room temperature for 2 hours. 4.0 parts by weight of tf-aminopoeicylic acid in 80 parts by volume of dichloromethane with the addition of 4.4 parts by weight of triethylamine and 4.0 parts by weight of anhydrous sodium sulphate. After filtering, the solution is cooled to -20 ° C and combined with mixture (A). The reaction mixture was brought to 0 ° C. and stirred at this temperature for another hour. The solvent is then removed on a rotary evaporator, the residue is dissolved in water, the solution is covered with ethyl acetate and, with stirring, acidified at 0-5 ° C. with dilute hydrochloric acid to. pH values = = 1.5. The organic phase is separated, washed with water, dried by cooling over magnesium sulphate, filtered and, after dilution with the same amount of ether, the penicillin sodium salt is precipitated from the filtrate by adding an ethereal solution of sodium 2-ethyl caproic acid containing methanol Yield: 1.3 parts by weight; content of (3-lafcim: 34%. Infrared bands at 1775 cm-1. NM1R signals are given in Table 7. Example XLIX. D- 1 -imidazollidin-2-one-1-yl) carbonylamino] - benzylpenicillin (free acid and sodium salt). According to Example XLVIII, nine A is mixed with 3.8 parts by weight of D - "- [(iinidazolidin-2-one-1-yl) -car (bonylamino) -phenylacetic acid. - 65 parts by volume of dichloromethane, 3.0 parts by weight of 1,3-dimethyl-2-chloro-A-1-imiidazoline chloride, and 2.0 parts by volume of thiriethylamine and reacted with the dried solution prepared from 4.0 parts by weight of i6-amlinopenicillanic acid, 80 parts by volume of dichloromethane, 4.4 parts by volume of triethylamine and 4.0 parts by weight of NAGSO4. After removal of the solvent and separation of the reaction product between an aqueous phase of pH = 1.5 and ethyl acetate is formed a precipitate that is insoluble neither in the water nor in the organic phase, which is filtered off, washed with water and dried. It is a free acid prescription penicillin. Yield: 1.5 parts by weight. The ethyl acetate phase above the acidic aqueous phase is separated, washed with water, dried over magnesium sulphate, diluted with ether and the penicillin sodium salt is precipitated. Yield: 1.9 parts by weight; content of (3-lactam (free acid): 92%, content of (3-lactam (sodium salt): 89%. Both penicillins show an infrared spectrum corresponding to their structure. NMR signals are given in Table 7. [(Limidazolidin-2-one-1-yl) -carbonylamino] -benzylpenicillin (acid and sodium salt). 89 668 43 According to Example XLIX, penicillins are prepared from 3 to 8 parts by weight of Da - [/ imidazolium] acid. dyn-2-on-l-yW-kairbonylanT! in ^^ 50 parts by volume of dichloromethane, 1.2 parts by weight of tetramethylcoroformamidinium chloride and 1.0 part by volume of triethylamines, constituting mixture A, and 2.0 parts by weight of acid 6 of aminopenicylate in 50 parts by volume of dichloromethane and 2.2 parts by volume of triethylamine and 2.0 parts by weight of sodium sulphate. 0, -2 parts by weight of pearillin as free acid and 1.9 parts by weight of sodium sulphate are obtained. % by weight of the sodium salt. β-lactam content (free acid): 90%; β-lactam content (sodium salt):%. infrared light corresponding to its "structure. Example LI. A - [/ imddazolidin-2- * -on-1-yl / 4-carbonylamino] -4-methylthiobehzylpenicillin sodium salt. The penicillin is prepared according to Example XLVIII from 4.5 parts by weight of the acid a - [/ imlidazolidin-2 -on-1-yl) carbcmylamlin] -4-methylthiiophenylacetic acid, 80 parts by volume of dichloromethane and 2.7 parts by weight of l-methyl-2-chloro-Al-pyrrolindium chloride and 2.0 parts by volume of tetraethylamine mixtures A, and 4.0 parts by weight of 6-aminopenicillic 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. P-lactam content: 36%. The NMR signals are given in Table 7. Example Uli; [Alpha] - [(Imidazolidin-2-[alpha] -l-yl) carbonylamino] -4-methylthiobenzyleneylin sodium salt. According to Example XLVIII, this penilline is prepared from 1.9 parts by weight of a - [(imidazolidin--2-one-1-yl) carbonylamdno] -4-imethylthiophenylacetic acid, 40 parts by volume of dichloromethane, 1.2 parts by weight of tetramethylchlorophoramidinium chloride and 0.98 parts by weight of triethylamine of Mixture A, and 1.73 parts by weight of 6-aminopenicillanic acid, 40 parts by volume of dichloromethane, 1.9 parts by volume of triethylamine and 1.5 parts by weight of sulfur Of sodium nitrate, mixture B. Yield: 2.6 parts by weight of sodium salt. P- -Jactam content: 61%. Penicillin has an infrared spectrum corresponding to its structure. The NMR signals are listed in Table 7. Example LIII. 1,3-Dimethyl-2-chloro-A-1-dmidazoline chloride. a) To obtain N, N, N'-dimethyl-N-bis-triethylsilylethylene diamine, a mixture consisting of 176 parts by weight of N, N'-dimethylethylene diamine, 1000 parts by volume of benzene and 552 parts by volume of triethylamine is mixed at temperature. 434 parts by weight of triethylchlorosilane, diluted with 500 parts by volume of benzene, are dripped in 3 hours. It is stirred for another 3.5 hours, left overnight, the sediment remaining is sludged and washed with benzene. The combined filtrates are evaporated on a rotary evaporator and the residue is distilled under reduced pressure. Cost: 364 parts by weight; Boiling point: 55—60 ° C / 0.15 Torr. The NMR spectrum (solvent CC14) shows signals at -160 (4H) and -148 H2 (6H), with the signal for the trimethylsilyl radical (9H) at OH2. Analysis. Calculated: 51.7% C, 12 ^ 1% H, 124% N; found: 51.1% C, 11.9% H, 12.1% N. b) In order to obtain N, N'-dimethyldimidazolidone (2) up to 800 parts by volume of dichloromethane is added dropwise within 4, 5 hours, stirring simultaneously and separately a solution of 363 parts by weight of N, N, N, N, N, B, trimethylsilyl, ethylenediamine, in 440 parts by volume of dichloromethane and a solution of 170 parts by weight of phosgene in 700 parts by volume of dichloromethane. The reaction mixture is then left to stand overnight, the unreacted phosgene is blown out with dry air, the solvent is removed in a rotary evaporator and the residue is distilled under reduced pressure. Yield: 119 parts by weight. Boiling point: 95 ° C 95.5 ° C / 10-10.5 Torr. c) In order to obtain ly3-dimethyl-2-chloro-A1-imidazoline chloride, a solution of 150 parts by weight of phosgene in 330 parts by volume of toluene is introduced into a solution of 150 parts by weight of 1,2-dimethyl lithium-dimazolidone (2) in 200 parts. volume of toluene and the mixture is left overnight at room temperature. The crystallized product is then filtered off, washed with tetrachloromethane and dried in an desiccator with P4O10. Yield: 177 parts by weight. Melting point: about 95: -100 ° C (Kotfler block). The product is crystalline and very hygroscopic. The NMR spectrum (solvent: chloroform) shows signals at x = 5.6 (4H) and 6.65 ppm (6H). Example LIV. The procedure is as in Example XLII, * substituting the α - [/ imiidozolidin-2-one-1-yl] -carbonylamino] -β-methylphenylacetic acid in this example with the following acids in an amount of 0.02 mole: Da- [yU, 3-diazacyclohexan-2-one-1-yl) -car-4S bonylamino) -lphenylacetic acid, Da - [(II, 3-diazacytelohexan-2-one-l-) yl) -carbonylamino] -p-methylphenylacetic acid, α - [(1,3-diazaciflhexane-2-one-1-yl) -carbonylamino] -p-chlorophenylacetic acid, α - [/ 1,3- -d &quot; yuazacyMohexane &quot; -onrl-yl (4-carbonylamino] -p-non-ethylthiophenylacetic acid, α - [/ diazace: clo-hexan-2-one-1-yl) -caribonylamino] &quot; p-hydroxyphenylacetic acid,. a - [(ly3-, diazacyclohexain-2-one-1-yl) -carbonylamino] -thienyl- (2) -acetic acid, a - [(11, 3-diazacyclohexanH2-one-1-) yl) -carbonylamino] -thienyl- (3) -acetic acid, Da - [(benzimlidazolone-1-yl) -carbonylamino] - phenylacetic acid, a - [(benzimidazolone-1-yl) -, kai1bonylamino] -p-methylphenylacetic acid, a - [(i-benzimidazolone-1-yl) -carfbonylamino] - * p -chlorophenylacetic acid, t a - [(benzimidazolone-1-yl) -cairbonylamlin] -p- M-methylthiophenylacetic acid, 45 [alpha] - [[beta] benzimidazolone-1-yl) -caribonylamino] -p-hydroxyphenylacetic acid, [alpha] (bem-imidazo-1-yl) [beta] -catbonylamino] -thienyl- (2) -acetic acid, aH [(benziiniidazolone-1) acid -yl) -car, bonylolami, no] -thienyl- (3) -ootic acid, Da - [(5-methylimiidazolidin-2-one-1-yl) - 'carbonylamlin] -phenylacetic acid, a- [ (4-methylimidazolidin-2-one-1-yl) -cair (bonylamino] -p-methylfemylacetic acid, α - [(5-methylimidazilide; n-2-one-1-yl) -carbonylamino ] ip-clilo-phenylacetic acid, a - [(5-methylimidazólidy'n-2-one-1-yl) -ca.rbonylamino ] -p-methylthiophenylacetic acid, a-1 [(5-methylimiiidazolidin-2-one-1-yl) -carbonylamino] e.g. -hydroxyphenylacetic acid, a - [(5-Imethylimiiazolidin-2-oin-1-yl) Jcaribonylamino] -thie.nyl- (2) -acetic acid, α - [(5-methylolifmidazolidin-2-one-1-yl) -caribonylamino] -thienyl- (3) -acetic acid, Dai acid [/ 5,5-dw; umethyl-imidazolidin-2-one-1-. -ylZ-carbonylamino] -phenylacetic acid, α - [(5,5-dimethylimidazolidin-2-one-1-yl) - β aribonylamino-p-methylphenylacetic acid, α - [(5,5-dimethylaminosollylidin-2-one-) 1-yl) -carbonylamino] -p-chlorophenylacetic acid, a-XM, 5-dimethylimidazolidin-2-one-1-yl) - carbonylamino-p-methylthiophenylacetic acid, a - [(5,6-dimethyliiiiuidazolidin-2-one -1-ylq) - -carbonylaminol-p-hydroxyiphenylacetic acid, t (SjS-dimethylimidazolidin-1-one-1-yl) - caribonylamino] -thienyl »- (2) -acetic acid or α - [(4,4-) dimethylimidazolyrdyn-2-one-1-yl) -carfoonylamino] -thienyl- (3) -acetic. The following penicillins are obtained in the form of their sodium salts: Da - [/ 1,3-diaz (clohexan-2-oin-yl -yl / -carbonylamino] -benzyl pemicyline, α - [(1,3-diazocyclohexane-'2-one-1-yl) -carbonylamino] -amino] -β-hlo.robenzylpenicyline, α - [/ l , 3-Diazacyclohexan-2-oin-1-yl) -carbpnylamino] -p-meitythiobenzylpenicyline, a - [/ 1,3-diazatim! Moh6xain-2-one-1-yl / -carbonylmo] - p-hydrdxybenzylpenicyline, a - [/ l, 3- dVuazacyclohexan-2-oin-1-yl) -caribonylamino] -a-thienyl (2) -methylpenicyllne, a - [(1,3-diazacyclohexan-2-an-1-yl) - a amlino) - a thienyl- (3) -methylpenicillin, Da - [(benzimidazolone-1-yl) -canbonylamino] -benzylpenicillin, α- (benziimidazolone-1-yl), carbonylaminol-p-, methylphenzylpenicyline, α- [7lbeolon- dlmid 1-yl) -caiibonylamino] -p-chlorobenzyl-enicyline, a - [(beiizimiidazolone-1-yl) -lka-bonylamino] -p-methyltobenzylpenicyline, a - [beinzimidazolone-1-yl) -carbonylamino] - p-Hydroxybenzylpenaciline, 668 46 a - [(BenziTnidazolone-1-yl) -carbonylamino] -a-thienyl- (2) -methylpenicyline, a - [(5-methylimidazolidin-2-one-1-yl) -carbonylamino] -benzylpenicillin, α - [(4-imeityl-imlidazolium) (n-2-one-1-yl) -carbonylamino] -β-methylibenzylpenicyline, V α - [(5-methyl'iimidazolides! n-2-one-1-yl) -carbonylamino / i-p-chlorobenzylpenicyl! me, at (5-methylimidazolidin-2-OJi-1-yl) -carbonylamino] -p-methylthiobenzylpetoicyline, and - {/ 5-methylimidazo-2-one-1-yl) -car'bonylam i-no] -p-hydroxyphenzylpenicyline, a - [(5-methyliniildazplidy (n- "2-one-1-yl) -carbonylamino] -a-itienyl- (2) -methylpenicyline, a - [/ 5- methyl <) imidazolidin-2-one-1-yl) -carbonylamino] -a-thienyl- (3) -methylpenicillin, Da - [? 5,5-dimethylolimidazolidin-2-one-1-yl / carbonyl - bonylamino] -benzylpenicyline, α - [(5,5-dimethylimidazolidy, n-2-one-1-yl) Jcaribonylamino] -p-methylbenzylopeinicyline, α - [(5,5-dimethylimidazole) din-2-one -1-yl) -caribonylamino] -p-chloroibenzyiopenicillin, α - [(4,5-dimiethylimidazolidin-2-one-1-yl) -carbonylamino] -p-methylthiobenzylpenicyline, α - [/ 15 , 5-dimethyl-ylmidazolidin-2-one-1-yl) -carbonylamino] -p-'hydroixbenzy] o | peinicyline, α - [(5,5-dimethylimidazolidin) (n-2-one-1-yl) -lkaiibo - nylamino] -α-thienyl- (27-methylpenicillinolu-[(4,4-dimethylimidazolidin-2-one-1-yl) -carnylamino] -α-thienyl- (3) H-methylpenicilline, Example LV. according to Example XLII, replacing the α - [/ imidazolidin-2-oh-1-yl] -carbonylamino] -β-methylphenylacetic acid used in this example with the following acids in an amount of 0.02 moles: Da acid - [/ 5-Imidazolidin-2-one-ly! Lo / -carbonyl- amino] -p-methoxylphenylacetic acid, La - [(ilmlidazoladin-one-1-yl) -kalpha.bonylamino] -p-, methoxyphenylacetic acid, D, La - [(imidazolidin-2-oneHl-yl) -kaiflx) nylamino] -β-imethoxyphenylacetic acid, Da - [(imidazolidin-2-one-1-yl) -caiiibonylamino] -OjO- dichlorophenylacetic acid, La - [/ imidazolidyairS-one-1- yl (kaiibonylamino) -o, o'-dichlorophenylacetic acid, or D, La - [(imidazolidin-H 2 -one-yl) -carbonylamino) -o, o'-dichlorophenylacetic acid, to give stepwise penicillins in the form of sodium salts: Da - [(imidazolidin-2-one-l-: yl) -ka'rbO'nylamino] -p-50-methoxylbenzylpenicilline, La- [Amidazolidin-2-one-i-yl) caribonylamino] -p-methoxybenzylpenicyline, D, La - [(imidazolidin-2-one-) ly, lo (-kaHbonyla.mino] - -p-Tnetoxylbenzylpenicyline, 55 Da - [/ Umadaiz &lt;) lidin-2-one-yl-yl) - (caribonylamino] - -o, o'-dichlorobenzylpenicyline, Lat (imidazolidin-2-one-l-yl) -carbonylamino] - -OjO &lt; 2 &gt; dichlorolbenzylpenicyline and D11-at / imidazolidin- N-OH-1-yl (-kaiflxnylamino) -60-OjO-dichloiribenzylpenicillin.47 89 668 Table 7 48 NMR data for some penicillins of general formula 1. The position of the signals is given in the t-scale (ppm) Solvent: CDgOD Example 1 1 XLII XLIII XLIV XLV A XLV B acetone d6 as a solvent XLV C acetone d6 as a solvent XLVI XLVII XLVIII XLIX LI LII N1MR signals {signal intensity after taking into account precursor acid signals 1 2 2,4-3,0 &Lt; 4H), 4.3-4.6 (3H), 5.8 (1H), 5.9- -h6.4 (2H), 6.4- <6.9 (2fH), 7.7 (3H) and 8.4 µ (6H) as in Example XLII 2.6 (4H), 4.3 ^ 1.6 (3H), 5.8 (1H), 5.9-6.8 (4H) and 8.3-8.6 C6H) as in Example XLIV and 0.9 (lii), 2.6 (2H), 2.8 (3H), 4.5 (1H), 6.2 (2H), 6.6 (2H) and 7 , 7 (3H) 0.9 (1H), 2.55 (4H), 4.5 (1H), 6.2 (2H) and 6.5 (2H) 2.4 ^ 2.75 (5H), 4.45 ^ 4.6 &Lt; 1H), &quot; 6.0-6.85 (4H) 2.5: 5-2.8 (4H), 4.55 &gt; 1.7 (IH), 5.95-6.8 (4H), 7.5 (5 (3H) 2.35-2.75, 4.35-4.55, 75-5.95, 8.8-8.55 (free acid) 2.4-2.7 (5H ), 4.3-4.6 (3H), 15. <1H), 5.9-6.7 (4H), 8.25-fl; 5 (6H), (Na salt) 2.45 ^ 2.45 (5H), 4.3-4.6 (3H ), 5.8 (1H), 5.95-6.75 (4H), 8.3-8.6 (6H) 2.45-2.9, 4.35-4.6, 5.8, 5.9-6.85, 8.3-8.55 8.4-2.9, 4.35-6.65, 5.8, 5.95 ^ 6.8, 7.6, 8.3 - —8.6 Impurity in the spectrum 1 3% by weight of α- (imidazolidin--2-one-1-yl-carphbonylamino) -p-methyl- acid | phenylacetic acid 60% by weight of α- (imidazolidin-2-o-i-yl-cairbon, ylamino) -β-methylphe | % by weight of α-imidazolidin- [-2-one-, 1-yl] -carbonylamino / -p-chloro-1-phenylacetic acid% by weight of α-imidazolidin--2-one-1-yl-carbonylamino (p-chlorophenylacetic acid) - - - - 58 wt.% of Da- (dmiidazolidin-2-one-l-yl) -carbonylamino) -phenyl-acetic acid - 60 wt.% of α- (imidazolidin--2- acid) on-1 -ylO'-kaffbonylam, ino (p-methylthio-phenylacetic acid) 40% by weight of α- (imidazoyilidin--2-one-1-yl-carbonylamino) -p-methyl-Itlphenylacetic acid PL

Claims (1)

Claims 1. Process for the preparation of penicillins of the general formula I, in which A is a group of formula 13, 14, X is a hydrogen atom, an alkyl radical of up to 10 carbon atoms, an alkenyl radical of up to 10 carbon atoms , vinyl, cycloalkyl and cycloalkenyl with up to 10 carbon atoms, airylvinyl, lower mono-, di- or trihaloalkyl radical, lower 65 monoalkylamino group, lower dialkylamino, monarylamino, lower alkyl to 8alkylamino group in the arylalkyl group , digital alkoxy of up to 7 carbon atoms, arylalkoxy of up to 8 carbon atoms, aryloxy, lower alkyl-O-V-, lower grulpe alkali S-V, group N = CV, lower alkyl-O-CO-V, lower binaryamino-CO-V- group, group of formula 16, 17, 18, 19, 20, 21, 25, 23, 24, 25 or 26, V is divalent-49 (organic radical containing 1 to 3 carbon atoms) , n is an integer from 0-2 and R1 · R2 and R3 oz They include hydrogen atoms, nitro groups, cyano groups, lower diallkylamino groups, lower dialkylamino-carbonyl groups, lower alkanoylamino groups, lower alkanoyloxy groups, lower alkanoyloxy groups, lower alkyl radicals, lower chloro, fluoro, or iodo groups trifluoromethyl groups, Y is an alkyl radical of up to 10 carbon atoms, alkenyl of up to 10 carbon atoms, vinyl, propenyl, cycloalkyl and cycloalkenyl of up to 10 carbon atoms, the lower group is mono-, di- and tri - (haloalkyl, arylalkyl radical of up to 8 carbon atoms, aryl or heterocyclic group) - * - Z - denotes a divalent group of the formula WGH2 (n-, 27, S-OH2), ^ S- (CH2) / m-1 /, 28, 89 WCH = CH2 /, m stands for integer m-1, 3–5, where the arrow in the bivalent group - <- Z— means that the binding of both free values of this the N-atom gruip and the aito- "meim C" in the Formula 14 grulp is not any, but it runs as marked by the arrow, Q means a bivalent group of formula 30, 31 or 32, where pg = 0, 1, 2 or b3, p + g = 1,2 or 3, formula 33, formula 34 , 35 or 36, in which pg = 0 or 1, and p + g = 0 or 1, or formulas 37, 38, 39, wherein in these formulas E is oxygen or grain, G is oxygen or lower alkyl , Rt and R2 are hydrogen atoms, nitro groups, cyano groups, lower dialkylamino groups, lower alkylaminocarfoonyl groups, lower alkanoylamino groups, lower alkoxy carboinyl groups, lower alkanoyloxy groups, lower alkyl radicals, lower alkyloxy groups, lower alkoxy groups chlorine, bromine, iodine, fluorine or trifluoromethyl groups, the arrow in the bivalent group of formula 40 means that the bonds between the two free values are not arbitrary, but take place as marked, the arrow M denotes a group of Formula 41 or Formula 42, where Pg = '0, 1 or 2, and p + g = 2 or 3, or Formula 43, where E and G are as defined above, S is a group of formula 44, 45, 46 or 47, where in formula 44 R4, R5 and R6 are hydrogen atoms, halogen atoms, lower alkyl radicals, lower alkoxy groups, lower alkylthio groups , lower alkylthionyl groups, lower alkylsulfonyl groups, nitro groups, lower dialkylamino groups, lower alkanoylamino, hydroxyl groups, lower alkanoyloxy groups, whereby the compounds of formula I with regard to the C asymmetry center may have the configuration of one of the two possible diastereoisomers of the R or S configuration or being a mixture of diastereoisomers and their non-toxic pharmaceutical salts, in particular the compounds of formula I in which A is gffupe of formula 50, 51, 52, 53 and 54, Iab in which B is phenyl, p-methylthiophenyl, p-methylphenyl, p-methoxyphenyl or thienyl (2), or compounds of formula I wherein C has the R-configuration, characterized in that the 6-amino-penicillanic acid of formula 2 9 668 50 is subjected to the reaction with pr the reaction product of a compound r of the general formula 5 with a compound of the general formula [T-W] + W ~, in which T is a group of the formula 6, 7, 8 or 9; in which the formulas R ma has the meaning given above, R10 has the meaning Rg or is a phenyl radical, Rn is a bivalent radical - / CH2 / 4-, - / CH2 / 5 or 2 - / CH2 / 2 -O- (CH2 / 2-) and W is a halogen atom or an azide group in anhydrous or water-containing solvents in the presence of a base. 2; The method for the preparation of penicillins of the general formula 1, in which A represents the group of formula 15, X represents a hydrogen atom, an alkyl radical containing up to 10 carbon atoms, an alkyl radical containing up to 10 carbon atoms, vinyl, cycloalkyl and cycloalkenyl with up to 10 atoms of carbon, arylvinyl, lower group of one-, di- or trihaloalkyl, lower group of one-allkylamino, lower group dialkylamino, monarylamino, lower group (alkyle) amine up to 8 carbon atoms, cycloalkoxy up to 7 carbon atoms, arylalkoxy up to 8 carbon atoms, aryloxy, lower alkyl-O-V-, lower alkyl-SV, six alkyl-O-CO- group V, lower dialkylamino-CO-V-, group of formula 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26, V is a divalent organic radical containing 1-3 carbon atoms, 30 n is an integer from ^ 0-2 and Ri, R2 and R8 are hydrogen, groups n yttrium, cyano, lower dialkylamino groups, lower dialkylaminocarbonyl groups, lower alkanoylamino groups, lower alkoxycarfoonyl groups, lower alkanoyloxy groups, lower alkyl radicals, lower alkoxy groups, sulfamoyl groups, alkanoyl groups, fluorine or trifluoromethyl groups, Y is an alkyl radical of up to 10 carbon atoms, an alkenyl radical of - 40-1 ° carbon atoms, a vinyl, pro-penyl, cycloalkyl and cycloalkenyl radical of up to 10 carbon atoms, a mono-lower group , di- and tri-haloalkyl, aralkyl radical of up to 8 carbon atoms, aryl or heterocyclic group, - * - Z - denotes a divalent group of the formula (CH2), 27, "-S" CH2), "S" (m-1 (CH2), 28.29 "(OH = OH2), m is number-1 and an integer of 3-5, the arrow in the bivalent" -Z "group means that the binding of both free values of this group with the N atom and the C atom in the group of formula 14 is not arbitrary, but the course and as marked by the arrow, Q stands for a bivalent group of formula 30, 31 or 32, where pig = 0, 1, 2 or 3, p + fg = 1,2 or 3, formula 33, formula 34, 35 or 36, in which pg = 0 or 1, and p + g = 0 or 1, or formulas 37, 38, 39, wherein in these formulas E is oxygen or grain, G is oxygen or lower alkyl radical, R2 and Rg denote hydrogen atoms, nitro groups, cyano groups, lower dialkylamino groups, lower alMloaminocarfoonyl groups, lower alkanoylamino groups, lower alkoxycarfoonyl groups, lower alkanoyloxy groups, , lower alkyl radicals, lower alkoxy, sulfamyl, chlorine, bromine, iodine, fluorine or trifluoromethyl groups, whereby an arrow in the bivalent group of formula 40 means that the binding of both free values of this group to two nitrogen atoms of the group Formula 115 is not arbitrary, but is the arrow as indicated, M represents Formula 41 or Formula 42, where p and g = 0, 1 or 2, and p + g = 2 or 3 or of formula 43, in which E and G - the meaning given above, S is a group of formula 44, 45, 46 or 47, where in formula 44 R4, R5 and R6 represent hydrogen atoms, halogen atoms, lower alkyl radicals, lower alkoxy groups, lower alkylphthio groups, lower alkylthionyl groups, lower alkylsulfomyl groups, nitro groups, lower di-alkylamino groups, lower alkanoylamino groups, lower hydroxyl groups alkanoyloxy compounds, whereby the compounds of formula I with respect to the asymmetry center C may have the configuration of one of the two possible diastereoisomers of the R or S configuration or be a mixture of both diastereoisomers and their non-toxic pharmaceutical salts, in particular compounds of the formula I, wherein A is 50, 51, 52, 53 or 54, or wherein B is phenyl, p-methylthiophenyl, p-methylfemyl, p-methoxyphenyl or thienyl (2), or compounds of formula The compound of claim 1 wherein C has the R-configuration, characterized in that the acid 6 A -aminopenicylic acid of formula II is reacted with the reaction product of a compound of general formula 5 with a compound of general formula [TW] + W, in which T is a group of formula 6, 7, 8 or 9, wherein Rg * has the meaning given above, R10 is R9 or is a phenyl radical, Rn is a bivalent radical - / CH2 / 4-, - / CH2 / 5-, or - / CH2 / 2- -O- / CH2 / 2- and W is halogen or azide in anhydrous or water-containing solvents in the presence of a base. ./* CH, A — CO— NH-CH-CO-NH-CH — CH Z "N \ CH ^ XCH3 / I COOH FORMULA 1 f ^ —Sl-nh-ch — ar CT XCH 'XH5 XCH3 Formula A R9 CH , * CH 'AND COOH FORMULA 2 CH, / 1-C0-NH-CH-C00H IB (R9) c- Formula 5 Ex 6 ./ H2N — CH / ^ CHX <OI, CH3 CH3 co-o-si ^ - Ri MODEL 3 Formula 7 P9 CH2— N CH2 — ffl R9 C- Wzfird89 668 A- CH2 1 CH2 -CO- - CH2 Rio Formula 9 nh-ch-c; B • 0-NC U Formula 10 / U * HO-N = C; H2H-CH-COOH B Formula 11 Wztfr (289 668 X — CO-N- (CO- ^ r Y KZJ MODEL 13 W2CJR 14 o II MM '\ _ J <, / ^^ DESIGN 15 MODEL 16 KJ MODEL 17 W2 (5R 1S, '^ - (CBl) "- PATTERN 19 CO 2 2089 668 PATTERN 21" HO "PATTERN 22 * f2: PATTERN 23 CH, - 0 XH, PATTERN 24 CT XHS PATTERN 25 TT PATTERN 26 lower alkyl PATTERN 27 CH- MODEL 2889 668 -CH. MODEL 29 ^ kr, | '1,2,3 or 4 G MODEL 30 ii T, ^' Óluul ° ^ i 'i or 2 GG MODEL 31 <- {fV MODEL 32 «C3 G <(C) - O likes and GO or 1 GG MODEL 3389 668 GG —c == c -— (c) - VM ^ G MODEL 34 MODEL 38 SJ MODEL 39 <-i? K IGG 1, U = c— ( cV G ^ M- ^ Pattern 35 Pattern 40 • ly2,3,4 or 5 G Pattern 41 (93 = t = -; c ^ -c— (c} ^ - Pattern 42 GGGG Pattern 43 Pattern 36 .CH2 CH. \ CH2 CH2 ^ PATTERN 37 PATTERN 44 U- PATTERN 4589 668 DESIGN 46 o II HN NH MODEL 48 MODEL 47 MODEL 49 / \ —O — CO — N ist. CH, FORMULA 50 CL— (CH2) 3 — CO — N ist. CH, MODEL 51 I ^^ JI-CO — N ist. CH, MODEL 52 O ^ co- ^ CO — N • iit. CH, PATTERN 53 co • / \ H — N N— ist. \ / CH, —CH3 MODEL 54 Bltk 1211/77 r. 110 copies A4 Price PLN 10 PL