DD106044B3 - PROCESS FOR PRODUCING NEW PENICILLINE - Google Patents

Abstract

1392849 Penicillins BAYER AG 23 Oct 1972 [23 Oct 1971 22 Nov 1971 25 March 1972 25 July 1972] 48699/72 Heading C2C [Also in Division C3] Penicillins of the general formula or their salts in which C* is a carbon atom constituting a centre of chirality; A is a radical of one of the general formulµ (in which general formulµ X is Y is Q 1 is or a radical of formula and Q 2 is or a radical of formula wherein R is a straight-chain or branched alkyl radical with up to 5 carbon atoms; R 1 is a hydrogen atom or an alkyl, cycloalkyl, alkenyl or cycloalkenyl radical with up to 10 carbon atoms, or a vinyl, arylvinyl, mono-, di- or trihalo C 1-6 alkyl radical, or an H 2 N-, R-NH-, (R) 2 =N-, aryl -NH-, or aryl C 1-6 alkylamino radical or an alkoxy*, or aralkoxy* radical with up to 8 carbon atoms, or a cycloalkoxy* radical with up to 7 carbon atoms, or an aryloxy*, R-O-V-, R-S-V-, (R) 2 =N-CO-V- or a radical of formulµ V is a divalent organic radical with 1 to 3 carbon atoms; n is 0, 1, or 2; R 2 and R 3 which may be the same or different are each a hydrogen atom or an alkyl or alkenyl radical having up to 8 carbon atoms or a vinyl, allyl or propenyl radical, or a cycloalkyl or cycloalkenyl radical having up to 6 carbon atoms; or a mono di-, or tri-halogeno C 1-6 alkyl or aryl radical; R 4 , R 5 and R 6 which may be the same or different are each a hydrogen, nitro, nitrile, (R) 2 =N-, (R) 2 = N-CO-, R-CO-NH-, R-O-CO-, R-CO-O-, R, R-O, H 2 N-SO 2 -, chlorine, bromine, iodine, fluorine or trifluoromethyl radical; and G is a hydrogen atom or a radical R; with the proviso that the meanings marked* are only available if X is not an -SO 2 - radical); Z is a -CO- or -SO- radical; and B is a radical of the general formula in which R 7 , R 8 and R 9 are identical or different radicals selected from hydrogen, halogen, R-, R-O-, R-S-, R-SO-, R-SO 2 -, nitro(R 2 )=N-, R-CO-NH-, OH, and radicals and R is as above defined; and in which above general formulµ the arrow in the divalent linkage member ##Q 2 means that the linkage of two atoms by the two free valencies of this linking member is not free to take place in either direction but only in the manner indicated by the arrow are prepared by reacting a 6-amino-penicillanic acid derivative of the general formula or a product of the condensation of such a derivative with a carbonyl compound 'of formula or a silyl or disilyl derivative of the derivative of the general formulµ respectively is reacted with a compound of the general formula A-Z-W, in an anhydrous or aqueous solvent in the presence of a base, when a compound of general Formulae XIV and XV is reacted, and in an anhydrous solvent free of hydroxyl groups, with or without a base, when a compound of the general Formulµ XVI and XVII is reacted, at a temperature of - 50‹ to + 50‹ C. (wherein A, C*, G, Q 1 , Q 2 , R 1 , R 2 , X, Y, Z and B are as above defined and R 10 , R 11 and R 12 , which can be the same or different are C 1-6 alkyl and W is halogen, azide or Compounds of the above general formula wherein B is phenyl, cyclohexadienyl or hydroxyphenyl are stated to be novel. Compounds of the formula A-Z-W, and Formulµ XVIII and XIX are prepared by conventional methods. Pharmaceutical compositions having antibacterial activity useful in human and veterinary medicine comprise the above penicillins and a carrier. The compositions may be administered orally, parenterally, rectally or topically in conventional pharmaceutical forms. The following starting materials are also prepared: 3 - acetyl - 3 - (N - methylaminocarbonyl}-, 3 - methoxy - carbonyl, 3 - methylsulphonyl-, 3 - aminocarbonyl-, 3 - dimethylaminocarbonyl-, 3 - isopropoxycarbonyl-, 3 - pyrrolidyl - N- carbonyl-, 3 - piperidyl - N - carbonyl-, 3- phenylaminocarbonyl-, 3 - phenoxycarbonyl-, 3- benzoyl-, 3-furoyl-, 3-butyryl-, -, 3-formyl- 3 - pivaloyl-, 3 - cyclohexyloxycarbonyl-, 3- ethane - sulphonyl-, 3 - propionyl-, 3 - benzenesulphonyl-, 3 - methane - sulphonyl - aminocarbonyl- and 3 - thienyl - 2 - sulphonyl - imidazolidine - 1 - carbonyl chloride and the corresponding N - substituted - imidazolidin - 2- ones; 2 - chlorosulphonylthiophene; 1 - methanesulphonyl - 3 - chlorocarbonyl - 4 or -5 - methylimidazolidine - 2 - one and 1 - methanesulphonyl- 4- or 5 - methylimidazolid - 2 - one; 4 - methylimidazolidin - 2 - one; 1 - chlorocarbonyl - 2- methylsulphonylamino- and 2 - tosylamino - 4,5- dihydroimidazoles; 1 - (methylaminocarbonyl)- 3 - ethoxycarbonyl - guanidine and its N- nitroso derivative, N (1,1 -dioxo-isothiazolidin-2- yl] - carbonyl] - N - methyl - carbamic acid chloride; N - mesyl - N<SP>1</SP> - chlorocarbonylurea; 3- acetyl-, 3 - formyl-, 3 - mesyl-, and 3 - phenyl sulphonyl-, 1 - chlorocarbonyl - 2 - oxo - 1,3- diazacyclohexanes and their 1 -unsubstituted derivatives.

Description

-N-lower alkyl NO

means compounds of the general formulas II and III in anhydrous or aqueous solvents in the presence of a base in the case of using the compounds of general formulas IV and V in anhydrous and hydroxyl-free solvents, with or without addition of a base at a temperature in the range of about 50 to +50 ⁰ C brings to implementation

 2. The method according to claim 1, characterized in that W means chlorine.

Field of application of the invention

The present invention relates to processes for the preparation of novel penicillins which are useful as medicaments in human medicine, as therapeutic agents in poultry and mammals, in feed additives and as growth promoting agents in animals

are usable.

The novel synthetic compounds are useful as therapeutic agents in poultry and mammals as well as humans in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, and more particularly by bacteria from the enterobacteria and pseudomonads group. They are oral and parenteral

applicable.

Antibacterial agents such as ampicillin (U.S. Pat. No. 2,985,548) have been shown to be very effective in the therapy of Gram-positive and Gram-negative bacterial infections. However, they are not capable of infections, e.g. are caused by bacteria of the group Klebesiella aerobacter or by indole-positive Proteus strains.

Carbenicillin (U.S. Pat. Nos. 3,142,673 and 3,228,226) is effective in humans for bacterial infections of the Klebsiella aerobacter group only when given in sustained high dosage, as achieved only by infusion

The present invention relates to methylpenicillins which are substituted in the methyl group by a radical B and an acyl-biureido radical whose carbonyl function in the acyl group may be replaced by an-SCV group:

Acyl-N-C-N-C-N- (= E is: = 0, = S, = N-)

E 0 (S)

6- (a-Biureido) -acetamido-penicillanic acids are described in US Pat. No. 3,483,188 and German Offenlegungsschrift No. 1959920, however, all 6- (a-biureido) acetamidopenicillanic acids described and claimed in these patents have no acyl moiety the 5-position nitrogen atom of the Biureidorestes.

The present invention also relates to a process for the preparation of such compounds which are useful in the treatment of infections by Gram-positive and Gram-negative bacteria, in particular by bacteria from the group of enterobacteria,

can provide valuable help at low dosage. The present invention relates to compounds of general formula I.

AZ-NH-CH-CONH - ^ ^ ^Η '

COOH

where A is a group

N = C-N-Y-N

R ₁ -X-KK ST-. -Ri -XNYN-

^R * R ₃

R ₁ -XN-C N-X NYN-

A ₂ N ^ Q ₁ ^ q ^

R _{1 represents} -CNYN-, GG

S X is a group -S- or -C- or -C-,

Y is a group -C-, -C-, -C-,

NR N-Aryl N-SO ₂ -R N-SO ₂ -aryl

QS Z is a group -C- or -C-,

Q _{1 is} a group

OO C

-C-O-C-,

or 5, -C-CO-O

GOG

2 J U. Qi

GG G GG

_{0 o 1} or

GRG ^

Q _a a group

<f

RG

or 4 '"SO- (J-> ^C , -I GG Gi

0 or

represents,

wherein R is a straight-chain or branched alkyl radical having up to 5 C atoms,

Ri ^ alkyl of up to 10 carbon atoms, cycloalkyl of up to 10 carbon atoms, alkenyl of up to 10 carbon atoms and cycloalkenyl of up to 10 carbon atoms, vinyl, arylvinyl, mono-, di- and trihalogeno-lower alkyl, HfeN-, R-NH -, (R ^ N-, aryl-NH-, aryl-lower alkylamino, alkoxy * having up to 8 carbon atoms, cycloalkoxy * having up to 7 carbon atoms, aryloxy *, a group ROV, RSV, N = CV, RO-CO -V- H ₂ N-CO-V-, R-NH-CO-V-,

(R) ₈ ^ N-CO-V-

V is a bivalent organic radical having 1 to 3 carbon atoms, ri is an integer from 0 to 2 inclusive,

R ₂ and R _{3 are} each hydrogen, alkyl and alkenyl each having up to 8 carbon atoms, vinyl, allyl, propenyl, cycloalkyl and cycloalkenyl having up to 6 carbon atoms each, mono-, di- and trihalogeno-lower alkyl or aryl,

R ₁ , R ₅ and R _{2 are} each hydrogen, nitro, nitrile, (R) p = N-, (R) ₂ = N-CO-, R-CO-NH-, RO-CO-, R-CO-O -, R-, RO-,

H ₂ N-SO ₂ -, chlorine, bromine, iodine, fluorine or trifluoromethyl, and

G is hydrogen or R, the arrow in the divalent spacer

should express that the

linking of two atoms caused by the two free valences of this intermediate piece is not arbitrary, but should take place in the manner indicated by the arrow,

only if X ₂ is non-SO ₂ at the same time.

B is a group of the formula R ₇

ro

R ₂ , R ₂ and R 9 are hydrogen, halogen, R, RO, RS, R-SO, R-SO y, nitro,

-, R-CO-NH-, HO, R-CO-O-

wherein R is as defined above and their non-toxic, pharmaceutically acceptable salts.

The penicillins of the general formula I and their non-toxic, pharmaceutically acceptable salts can with respect to the chiral center CJ ^ in the two possible R and S configurations and as mixtures of the resulting

Diastereomers are present.

According to the invention, a process for the preparation of the compounds of general formula I has now been created by

that compounds of the general formula II

COOH

B-CH

CH ₃ CH ₃ ο I

COOH

or compounds of general formula IV or V

B-CH-CONH NH ₂

IV

COO-Si ^ -R _{1 ΛR 1} 2

wherein B and G have the abovementioned meaning, and R ₁₀ , Rn and R _{12 is} alkyl having up to 6 carbon atoms, with compounds of the general formulas Vl, VII, VIII, IX or X.

AZW, N = CNYN = Z, R ₁ -XNYN = Z, R ₂ R ₂

VI VII VIII

X U-Y-N = Z,

ϊχ χ, \

wherein A, Q ₁ , Q ₂ , R ₁ , R ₂ , X, Y and Z have the abovementioned meaning and W is halogen, azide or a group -N-lower alkyl, in the case of using the compounds of the general formulas II and III in anhydrous or

aqueous solvents in the presence of a base, in the case of using the compounds of general formulas IV and V in anhydrous and hydroxyl-free solvents with or without Zufz a base at a temperature in the range of about -50 ⁰ C to + 5O ⁰ C to implement.

The non-toxic pharmaceutically acceptable salts mentioned above include acidic carboxyl group salts such as sodium, potassium, magnesium, calcium, aluminum and ammonium salts and non-toxic substituted ammonium salts with amines such as di- and tri-lower alkylamines, procaine, dibenzylamine, Ν, Ν'-dibenzylethylenediamine, N Benzyl-β-phenylethylamine, N-methyl- and N-ethylmorpholine, I-ephenamine, dehydroabiethylamine, Ν, Ν'-bis-dehydroabietylethylenediamine, N-lower alkylpiperidine and other amines which have been used to form salts of penicillins. By the term "lower alkyl" in the present invention is meant both a straight-chain and a branched alkyl group of up to 6 carbon atoms In connection with other groups, as in "lower alkylamino", the term "-lower alkyl" refers only to the alkyl moiety the group concerned.

If compounds of the general formula II or III are used as starting material for the synthesis of the penicillins according to the invention and reacted with compounds of the general formula VI, VII, VIII, IX or X, this reaction can be carried out, for example, in mixtures of water with such organic solvents, which are miscible with water, such as acetone, 'tetrahydrofuran, dioxane, acetonitrile, dimethylformamide, dimethyl sulfoxide or isopropanol perform. The pH of the reaction mixture is kept between 2.0 and 9.0 by adding bases or using buffer solutions. However, the reaction of the present invention is preferably carried out in the pH ranges between 4.5 and 9.0 or 2.0-3.0. Furthermore, it is possible to react in water-immiscible solvents, for example chloroform or.

Methylene chloride with the addition of preferably triethylamine, diethylamine or N-ethylpiperidine perform. Furthermore, the reaction can be carried out in a mixture of water and a water-immiscible solvent, e.g. Run ether, chloroform, methylene chloride, carbon disulfide, isobutyl methyl ketone, ethyl acetate, benzene, it being appropriate to stir vigorously, and the pH by addition of base or use of buffer solutions between 4.5 and 9.0 or z. B. 2.0 and 3.0. If compounds of the general formulas IV or V are used as starting material for the synthesis and if this substance is reacted with compounds of the general formulas VI, VII, VIII, IX or X, it is necessary to use water-free and hydroxyl-free solvents, for example methylene chloride, chloroform, Benzene, tetrahydrofuran, acetone or dimethylformamide work. The addition of bases is not necessary in this case, but "in some cases, the yield and purity of the products improve.The reverse effect is also possible.The optionally added bases either tertiary amines, such as pyridine or triethylamine or by steric hindrance difficult to be acylated secondary amines such as dicyclohexylamine, the number of useful bases is therefore scarcely limited.

As with most chemical reactions, higher or lower temperatures than those used in the examples given may be used. However, if one goes considerably beyond the values given therein, side reactions will increasingly take place which reduce the yield or adversely affect the purity of the products. On the other hand, excessively lowered reaction temperatures reduce the reaction rate so much that yield reductions may occur. It is therefore preferred reaction temperatures in the range of -20 ⁰ C to + 50 ⁰ C, with a temperature of about 0 ⁰ C to + 20 ⁰ C is particularly preferred.

The reactants can be reacted with each other in equimolar amounts. However, it may be desirable to use one of the two reactants in excess to facilitate the purification or purification of the desired penicillin and to increase the yield. For example, one can use the reactants of the general formulas II or III with an excess of 0.1 to 0.3 molar equivalents and thereby achieve a lower decomposition of the reactants of the general formulas VI, VII, VIII, IX or X in the aqueous solvent mixture. The excess of the reactants of the general formulas II or III can be easily removed because of the good solubility in aqueous mineral acid when working up the reaction mixture. On the other hand, it is also possible with advantage to use the reactants of the general formulas VI, VII, VIII, IX or X with an excess of, for example, 0.1 to 1.0 molar equivalents. As a result, the reactants, for example, of the general formulas II or III are better utilized and the decomposition of the reactants of the general formulas VI, VII, VIII, IX or X, which takes place as side reaction in aqueous solvents, is compensated. Since the excessively added compounds of the general formulas Vl, VII, VIII, IX or X are rapidly converted into neutral compounds in water, which can be easily removed, the purity of the penicillins is hardly affected thereby.

The amount of bases used is e.g. determined by the desired maintenance of a certain pH. Where a pH measurement and adjustment is not made or is not possible or useful because of the lack of sufficient amounts of water in the diluent, in the case of using the compounds of general formulas H or IM preferably 2 molar equivalents of base, in the case of using the compounds of general formulas IV or V either no base or preferably 1 mol equivalent of base added.

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

The compounds of the general formula II used as starting material in the present invention may have the configuration at the asymmetric center in the side chain (: C *) in the D = R-form or L = S-form. They are described in German Patent No. 1156078, U.S. Patent Nos. 3,334,277, 3,175,740,298, 5648, 3,140,282, South African Patent No. 68 / P290, and (anhydrous form) in U.S. Patent No. 3,144,445. All crystal forms and configurations of the compounds of general formula II are suitable as starting material for the reaction according to the invention. The compounds of the general formulas III, IV or V used as starting material in the present invention can also have the configuration in the asymmetric center in the side chain (: C *) in the D = R-form or L = S-form. The configuration of the asymmetric centers of the 6-aminopenicillanic acid nucleus in the compounds of general formulas II, III, IV and V are said to be with the corresponding asymmetric centers of 6-aminopenicillanic acid, e.g. B. from penicillin G was obtained by fermentative processes, be identical.

The preparation of the compounds of general formulas IV and V used as starting material is described in Dutch Patent No. 68/18057.

The preparation of the compounds of the general formulas Vf, VII, VIII, IX or X used as starting material in the present invention is described in more detail in the examples.

The chemotherapeutic efficacy of the new penicillins was tested in vivo and in vitro. In the following Tables 1 and 2, the in vitro inhibitory values (MIC) in E / ml * nutrient medium are given. The determination was carried out in liquid medium in the tube serial dilution test, the reading after 24 hours of incubation at 37 ⁰ C. The MIC is given by the turbidity-free tube in the dilution series. The growth medium used was a complete medium of the following composition:

Lab Lemco (OXOID) 10g Peptone (DIFCO) 10g NaCl 3g D (+) Dextrose (MERCK) 10g Buffer pH 7.4 1000ml

The numbers assigned here to the penicillins correspond to the numbers of the examples in which the presentation of the respective penicillin is described.

The spectrum of action includes both Gram-negtive and Gram-positive bacteria. The particular advantage of the penicillins according to the invention is that they are resistant to both ampicillin and carbenicillin-resistant bacteria from the group Klebsiella aerobacter, to ampicillin and carbenicillin-resistant indole-positive Proteus and Provodencia bacteria, to ampicillin and carbenicillin both in vitro and in animal experiments. resistant Escherichia coli strains and to ampicillin and carbenicillin resistant Pseudomonas aeruginosa and Serratia marcescens bacteria.

The concentrations necessary for the killing are reached in the serum after paranteraler administration. The animal test results for some of the penicillins according to the invention are summarized in Table 3.

The generally excellent effect is achieved both with single and repeated administration. The penicillins according to the invention are stable to gastric acid. Some of the new penicillins are excellently tolerated, which is made particularly clear by the extremely high dose, which is tolerated without complications in the mouse when administered intravenously into the tail vein (Table 4).

Table 1 gives a number of minimal inhibitory concentrations of penicillin # 4 (see Example 4a) as compared to carbenicillin.

1 mole of penicillin is known to have 5.9514 χ 10 ⁸ E

Table 1:

Minimal inhibitory effects Carbeni in E / ml cillin penicillin No. 4 200 bacteria 100 Pseudomonas Bonn 16-32 100 aeruginosa Walter 8th 100 F 41 25 100 E 27 500 12.5 50 V 10 818 25 100 V 10 797   12.5 50 V 10,887 12.5 25 V 10 900 12.5 100 A · '-. > 12.5 100 Klebsieila-60 <0.8 400 Aerobacter 62 1.6 > 400 63 4-16 400 69 .1,6 > 400 70 3 > 400 1852 > 400 400 K 10 4-16 > 400 1871 6 400 75 6 '. 1.6 aerogenous 418 3 400 Escherichia 14 <1 12.5 · coli A 261 32 - 64 .12,5 C 165 1-4 , - 183/58 1 - 4 1.6 · B <0.8 · · - B 94 <0.8 55 B 5 <0.8

Continuation: Tab. 1

Bacillus Protous Minimal inhibitory concentrations Carbeni rettgeri Sp. in E / ml cillin 1 050 penicillin 824 No. 4 > 400 bacteria mirabilis sp. > 400 Escherichia T 7 ' G. > 400 > 400 coil T 20/2 605 > 400 3 1465 1 235 > 400 6 6.26 morganii sp. <0.8 400 N 932 1.6 12.5 S 1 102 32 400 Serratia .2 vulgaris 1 017 1.6 12.5 marcescens 3 3 400 12.5 12.5 4 1.6 100 6 1.6 6 7 1.6 6 9 <0.8 6 13 <0.8 6 K <0.8 3 Providencia 930 <0.8 3 933 12.5 945 <0.8 1.6 > 400 , 0.8 > 400 > 400 1.6 > 400 1.6 1.6 400 <0.4 3 3 3 1.6 6 3 > 800 6 3 200 50 1.6 6

Continuation: Tab! 2 689 756 Minimal concentrations of heromas in E / ml Carbeni cillin -12- 106 044 2 718 133 Penicillin No. 4 bacteria 2,786 2,788 2,684 209 0.25 1.6 Haemophilus 8 709 511 0.1 0.8 inf luenzae 8,711 0.06 0.5 0.1 1.6 <0.4 8 698 12.5 200 Strepto BRL 1 3 50 coccus 1.6 100 faecalis P 200 200 Staph SG 1 coccus <0.8 <0.8 aureus <0.8 (0.8

Table 2 gives the minimum inhibitory concentrations (MICs) in E / ml of some penicillins of the present invention against a number of bacterial species:

CU H ι-Λ

I Ü ί I O U co  Η ιη O VO OJ OJ OJ νο CO CO CO VO OJ VO OJ φ ΡΛ 'H cn a> H S-! OJ Κ "\ I N "\ cn H OJ OJ OJ H ro H ro J® «Η CL ' CTi • P 00 'H • HS VO H H γΗ  Ρ CU H ln Ü H a CO VO φ O 13 H CO CO U U O O O* H H rh "* ο- ο- H H H H ro H VO rh , aur. rO O νο O O ιη νο VO ^ - CO CO νο νο Ο VO ω OO cn OJ O O OJ in in VO OJ OJ ιη νο ln OJ OJ a < OJ OJ OJ H H OJ OJ OJ H H co VO -r-j I ro in Sn fo ιη vo I O O> S H νο ι VO r ^ LTV OJ f ~ 'f H vo OJ ο- OJ ω CO ο- co CO O" CO * I. ι I m HI ro ta C-- VO a> VO HrH O O H OJ vo ο- CO ω ο · ο- O- • f-J M 3 o O ιη vo f O * η > H H H O O I rH ' O- 'JD UE0 O ιη H OJ OJ ω OJ OJ νο VO OJ νο OJ H H O ιη OJ ω. , Κ "! ΚΛ ιη H ro H ro Ü CM 0 CFJ crt νο * * * ü υ H ln O H OJ OJ OJ VO OJ Ο OJ OJ VO OJ • OJ ιη m rn m H νο νο ΓΟ ro H ro CU I 0] O VO a ' CO VO ω H rf VO ι-ϊ OJ ο- ο- Ο OJ ο- CO co H rh • P - VD νο νο ro "" "^ -ρ O U Sh Ρ * I CO VO • Η • VO νο VO νο OJ OJ CO VO O- O- O- Ph H H H ro H O a, MD Ο " - approx ro. γΗ O- ο- H ό- ο- ο- γΗ H H CQ ! [ VO r ~ i ο- ro rh ο- Ο ο- ο- ο- ο- Ο- O- O- O- νο I, t O O m νο νο νο νο νο VO νΟ O- CO co O O OJ ο- in m ιη m ιη ιη VO OJ OJ ο- H νο OJ -OJ OJ OJ oj OJ OJ H H I OJ CO CO r-i O* O* rh ο- γΗ ο- H γΗ rh H H rh ro rh rh OJ in νο CO ο H OJ ro O- H H rh H H

Continuation :

Escherichia coli 14 A 261 C 165 183/58 bacteria Prot. PSDM. aerug. Klebsiella 63 Staph. aur. Strept.faec. Peni cillin No. 4 > 256 8th 16 Prot. Vulg. 1017 932 Bonn V / old K 10 - 1756 E 133 ATCC 979.0 19 4 > 256 8th 64 16 32 - - - 64 - - - 20 <1 256 4 <1 16 8th 8th* 16 32 8th 128 <1 32 21 0.8 ) 400 6 200 4 4 32 * 32 8th 100-200 256 <1 64 Ampi cillin 1.6 400 12.5 12.5 400 200 200 100-200 400 (1 12.5 Carbeni cillin 3 6 200 100 > 400 200 1

= Psdm. aerug. F 41

Continuation Table II

Peni E. coli 14 A 261 C 165 183/58 bacteria Prot. PSDM. aerug. Klebsiella 63 Staph .aur. Strep cillin no. Prot. morg. 932 F 41 Walter K 10 1756E 133 toc.f. ATGC 4 > 256 8th . 8th vulgar. 1017 64 9790 <1 128 4 <1 128 16 - 32 32 8th 128 4 32 22 <1 512 2 <1 16 (1 16 32 8th 8th 64 <1 32 23 8th > 256 16 32 4 2 32 32 4 64 32 <1 16 24 4 > 256 4 4 2 4 64 32 64 16 64 <1 16 25 0.5 > 256 1 0.5 16 4 32 64 32 4 64 <1 8th 26 4 > 256 16 32 4 <1 32 32 4 64 64 <0.25 4 27 α ) 256 8th 64 1 128 16 16 64 63 256 <1 16 29 8th > 256 32 128 64 8th 32 32 128 256 256 4 128 30 4 > 256 8th 8th 4 64 256 256 > 256 16 64 <1 32 31 256 8th 256 128 32 64 U- 16 32 8th

Tables 1 and 2 show the superiority of the new penicillins in their in vitro activity compared to the commercial products ampicillin and carbenicillin.

Table 3 gives the effective dose (ED ₅₀ values) of intraperitoneal I with the indicated bacteria infected mice. This results in the superiority of the penicillins according to the invention in animal experiments with Gram-negative bacteria to carbenicillin, furthermore, Table 3 also shows the good action against Gram-positive bacteria.

Table 3:

Results of animal experiments with the white mouse for some of the penicillins according to the invention (ED ₅₀ in subcutaneous treatment in E / kg)

Penicillin no.

bacteria

Klebsieila 63 Klebsiella1871 Prot.vulg.1017 Prot. Morg. 932 Psdm. aerug. Walter Psdm.aerug.F41

carbenicillin

> 2 x 300,000 2x60000 2x40000 2x40000 > 1 χ 500 000 1x350000 2x50000 2x25000 2x25000 2 x 75,000 2x75000 4x150000 4x150000 4x100000 4x25000

Staph.aur. 133

Propicillin 2X2000

2x3000e

2X4000

2x2500

Table 4 shows the extremely good compatibility of some of the penicillins according to the invention.

Table 4:

Penicillin no.

DL ₅₀ in intravenous injection into the tail vein in the mouse in mg / kg

2 4

> 3000> 3000

The penicillins according to the invention can be formulated and administered alone or in combination with a pharmaceutically acceptable carrier according to the usual pharmaceutical procedure. For oral administration, they may be given in the form of tablets which, for example, may additionally contain starch, milk sugar, certain types of alumina, etc., or in the form of capsules, drops or granules, alone or together with the same or equivalent additives. They may also be given orally in the form of juices or suspensions, which may contain flavoring agents or colorings customary for such purposes.

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

apply.

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

The α-aminobenzylpenicillin used in the examples contained about 14% water, but it is also possible to use anhydrous α-aminobenzylpenicillin (see US Patent 3,144,445).

Unless otherwise stated, "ampicillin" is that α-aminobenzylpenicillin of the D (-) - = R configuration

meant in the side chain.

The β-lactam content was determined by iodometry. All the penicillins described here showed one of their constitution

corresponding IR spectrum.

The NMR spectra of the penicillins were recorded in CD ₃ OD solution, the signals given in the examples correspond to the respective structure; the position of the signals is given in τ values.

When calculating the analysis values, the water content is taken into account.

When referring to "efficacy in animal studies", "A" means that the mouse penicillin in question is more effective than carbenicillin in subcutaneous administration to Pseudomonas aeruginosa F41, "B" to be 63-more effective than carbenicillin against Klebsiella, "C "that it is more efficacious than cephalothin against Klebsiella 63 and" D "that it is more effective against Klebsiella 63

Cephalexin is.

The numbers given in efficacy against certain bacteria (U / ml) are minimal inhibitory concentrations in the tube serial dilution test after 24 hours of incubation.

example 1

A) D-ATO-acetyl-imidazolidine ^ -on-i-y-carbonylbenzene-benzylpenicillin sodium:

CH ₃ -CO-I ^ tf-CONH-CH-CONH

(R)

COONa

17,5Gew. parts. Ampicillin were suspended in 80% aqueous tetrahydrofuran (140VoL TeNe) and added dropwise with stirring at 20 ⁰ C with as much triethylamine (about 6.3 parts by volume) that just a clear solution was formed and the pH between 7.5 and 8.2 (glass electrode). It was cooled to 0 ° C and added gradually with stirring gradually 7.6 parts by weight of S-Aetyl-imidazolidin ^ -one-i-carbonyl chloride in the course of 30 min., By simultaneously adding triethylamine, the pH Value was kept between 7 and 8. It was stirred 10 * min. at 0 ⁰ C and then at room temperature until, to maintain a pH of 7-8 triethylamine was no longer required. Now 150Vol.-parts of water were added and the tetrahydrofuran was largely removed at room temperature in a rotary evaporator. The remaining aqueous solution was shaken once with ethyl acetate, then coated with 250 parts by volume of fresh ethyl acetate and acidified with ice cooling with dilute hydrochloric acid to pH 1.5-2.0. The organic phase was separated, washed twice with 50Vol.-parts of water, and dried for 1 hr. Anhydrous MgSO ₄ in a refrigerator. After filtration, the solution of penicillin was mixed with about 45 parts by volume of a 1 molar solution of sodium 2-ethyl-hexanoate in methanol-containing ether. The mixture was then concentrated on a rotary evaporator to an oily consistency, dissolved by vigorous shaking in the sufficient amount of methanol and rapidly added dropwise with vigorous stirring in 500 volts TeNe ether containing 10% methanol. The mixture was allowed to sit for 30 minutes, the solution was decanted from the precipitate, slurried again with ether, filtered off with suction and washed with anhydrous ether. After drying over P ₂ Og in a vacuum desiccator, the sodium salt of penicillin was obtained in the form of a white solid.

Yield: 95% β-lactam content: 84%

Calculated: C 48.3 H 4.9 N 12.8 S 5.8 Found: C 48.6 H (6.2) N 11.7 S 5.6

NMR signals at τ = 2.3-2.7 (5H), 4.3 (1H), 4.5 (2H), 5.8 (1H), 6.15 (4H), 7.5 (3H), 8.4 (3H) and 8.45ppm (3H) The product showed only one antibiotic spot in the electropherogram.

Efficacy in animal experiments: B and C Activity against E. coli 183/58: 3 Activity against Prot. Morg. 932: 6 Efficacy against Psdm. aerug. Bonn: 25 effectiveness against Klebs. 63: 25

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

CH ₃ -CO-N 1 N-COCl

20 parts by weight of N-acetyl-imidazolidone-2 were introduced in a mixture with 25 parts by weight of triethylamine and 150 parts by volume of dry benzene over 30 min. with stirring at room temperature with 27 parts by weight of trimethylchlorosilane in 40Vol.-parts of benzene added dropwise. Under exclusion of moisture, one then cooked 18 hours. at reflux, filtered after cooling from the precipitated triethylamine hydrochloride (22 parts by weight = 100%), which was washed thoroughly with dry benzene. The benzene solution thus obtained was treated at 5 ° C with the solution of 17Gew.-parts of phosgene in 50Vol.-parts of benzene and allowed to stand overnight at 5 ° C. Then the solvent was removed in vacuo and the residue was dried on the oil pump. It was recrystallized from acetone / pentane mixture.

Yield: 81%, mp = 104 ^° C.

Calculated: C 37.7 H 3.7 Cl 18.6 N 14.7 Found: C 39.3 H 4.3 Cl 17.7 N 14.7

IR bands at 1798, 1740, 1690 and 1660 cm ^-1

NMR signals at τ = 5.65-6.3 (4H) and 7.45ppm (3H). The product contained according to the NMR spectrum still 5-10% N-acetylimidazolone, but this does not interfere with the reaction with ampicillin (Example 1A).

C) N-acetyl-imidazolidone ^

0 CH ₃ CO-N- ^ NH

V_v.

To the suspension of 25.8 parts by weight imidazolidone-2 in 350VoI.-Parts of tokenem tetrahydrofuran was added dropwise in the course of 60 min. At O ⁰ C 23.6Gew.-parts of acetyl chloride in 10Vol.-parts of tetrahydrofuran. It was stirred at room temperature for 3 hours, then dry air was bubbled through the solution for a while, then the solvent was removed in vacuo and the residue was recrystallized from boiling nitromethane.

Yield: 52%, mp = 188 ° C

Calculated: C 46.9 H 6.9 N 21.9 Found: C 47.0 H 6.2 N 22.5

IR bands at 3230, 1730 and 1640 cm ^-1 NMR signals at τ = 6.2 (2H), 6.5 (2H) and 7.6 ppm (3H)

Example 2

A) D-a - [(3-Methylaminocarbonylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin sodium:

CH ₃ -NH-CO-N-N-CONH-CH-CONH-i- f- X ³

COONa

This penicillin was prepared in the manner described in Example 1A from 6.5 parts by weight of 1- (N-methyl-N-trimethylsilylaminocarbonyl-hmidazolidone-2 and 14 parts by weight of ampicillin.

Yield: 27% β-lactam content: 83%

Calculated: C 46.5 H 4.9 N 14.8 S 5.6 Found: C 46.0 H 5.6 N 14.0 S 5.2.

IR bands at 3330, 1765, 1722, 1662 and 1266 " ¹

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.55 {2 H), 5.85 {1 H), 6.25 (4H), 7, 15 (3H), 8.45 (3H) and 8.5ppm (3H)

Efficacy in animal experiments: B, C and D Activity against E. coli 183/58: 1,6 Activity against Prot. Morg. 932: 1,6 effectiveness against Psdm. aerug. Walter: 25 Efficacy against Klebsiella 63:12

B) 3- (N-Methyl-N-trimethylsilyl-aminocarbonyl) -imidazolidin-2-one-1-carbonyl chloride:

The suspension of 7.1 parts by weight of N-methylaminocarbonylimidazolidone-2 in 150 parts by volume of benzene and 12 parts by weight of triethylamine was treated dropwise with stirring and exclusion of moisture at room temperature with 13Gew.-parts of trimethylchlorosilane over 30 min., And then 24h. held at reflux. It was then cooled, sucked from the triethylamine hydrochloride, washed with benzene and added with 5Gew.-parts of phosgene in 20Vol.-parts of benzene. It was left to stand in the refrigerator overnight, the solvent was removed in vacuo and dried on the oil pump. The residue was slurried with a 1: 1 mixture of benzene and pentane and filtered with suction, the filtrate was evaporated to dryness, slurried with dry ether and sucked off again. The filtrate thus obtained was cooled in ice for about 1 h, again sucked from the precipitate and evaporated to dryness the resulting solution. The semi-solid mass was dried on the oil pump.

The substance thus obtained consisted, according to the NMR spectrum, of a 3: 1 mixture of 1-methylaminocarbonylimidazolidone-2

(NMR signals at 6,1,6,5 and 7,15τ) and S-fN-methyl-N-trimethylsilylamino-carbonyl-imidazolidine ^ -one-i-carbonyl chloride (NMR signals at 6.0, 7.0 and 9.7ppm), which could be reacted with ampicillin to the corresponding penicillin. (Example 2A).

C) N-f-methylaminocarbonyl-1-imidazolidine ^ -one:

CH ₃ NH-CO-N, JH

To dissolve 20Vol.-parts of a 50% aqueous methylamine solution in 50Vol.-parts of tetrahydrofuran, which had been adjusted with concentrated hydrochloric acid to a pH of 8.5, was added under ice cooling in portions 14.9Gew.-

N-Chlorocarbonylimidazolidon ^ while maintaining a pH of 8.5 by simultaneous addition of triethylamine upright.

The mixture was then stirred until the pH had not changed without addition of triethylamine for 15 minutes.

By adding HCl, a pH of 6.5 was set and the tetrahydrofuran was removed in vacuo. One sucked off, washed with

little ice water and crystallized from methanol.

Yield: 72%, mp = 198 ° C.

Calculated: C 41.9 H 6.3 N 29.4 Found: C 41.7 H 6.5 N 30.2

IR bands at 3220,1728 and 1645cm ~ ¹ . NMR signals at τ = 2.0 (1H), 2.5 (1H), 6.2 (2H), 6.6 (2H), and 7.2 ppm (3H).

Example 3

A) D-α-KS-methoxycarbonyl-imidazolidine ^ -one-i-y-carbonylaminol-benzylpenicillin sodium:

⁰ (R)

CH ₃ 0-CO-N- ^ n -Co-NH-CH-CONH ₁ - ( ^s \ _< ^ - ^{j: H3}

COONa

This penicillin was prepared in the manner described in Example 1 from 7.8 parts by weight of S-methoxycarbonyl-imidazolidine -on-icarbonyl chloride and 17.5 parts by weight of ampicillin.

Yield: 97% β-lactam content: 87%

Calculated: C48.8H 4.4 N 12.9S5.9 Found: C 48.6 H (6.7) N 11.0 S 5.5

IR bands at 3 300, 1775, 1740, 1667, 1 605 and 1 262 cm ^-1 *

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.15 (3H), 6 , 0-6.3 (4H), 8.4 (3H) and 8.5ppm (3H)

The product shows in the electropherogram only one antibiotic effective spot.

Efficacy in animal experiments: B and C Activity against E. coli 183/58: 4 Activity against Prot. Morg. 932: 8 Efficacy against Psdm. aerug. Walter: Efficacy against Klebsiella K10: 16

B) S-Methoxycarbonyl-imidazolidine ^ -one-i-carbonyl chloride

0 CH ₃ O-CO-N- ^ N-COCl

This carbamic acid chloride was prepared in the manner described in Example 1B from 8 parts by weight of N-methoxycarbonylimidazolidone-2.9.7 parts by weight of trimethylchlorosilane, 9 parts by weight of triethylamine and 6.2 parts by weight of phosgene.

Yield: 72%, mp = 129 ^° C.

Calculated: C 34.8 H 3.4 Cl 17.2 N 13.6 Found: C 34.8 H 3.4 Cl 17.1 N 13.6

IR bands at 1820, 1727, 1690 and 1 260 cm ^-1 NMR signals at τ = 5.7-6.3 (4H) and 6.1 ppm (3H)

C) N-methoxycarbonyl-imidazolidone-2

CH ₃ O-CO-Nr ^ NH

14.9 parts by weight of N-chlorocarbonyl-imidazolidone were added in 70 parts by volume of ice-cold methanol and 1 hr. At room temperature, then 1 h. at 40-50 ⁰ C stirred. After removal of the excess methanol was recrystallized from acetone. '

Yield: 55%, mp = 185 ° C

Calculated: C41.6 H 5.5 N 19.4 Found: C 41.8 H 4.8 N 19.2

IR bands at 3320, 1745 and 1670 cm " ¹

Example 4

A) D-a - [(3-Methylsulfonyl-imidazolidin-2-on-1-yl) carbonylamino] -benzylpenicillin sodium

CH ₃ -SO ₂ - ^^ - CONH-CH-CONH-pr ^ V ^

COONa

This penicillin was prepared in the manner described in Example 1A from 5.1 parts by weight of S-methylsulfonyl-imidazolidine -on-icarbonyl chloride and 9.3 parts by weight of ampicillin.

Yield:> 90% β-lactam content: 81%

Calculated: C 42.7 H 4.6 N 11.8 S 10.8 Found: C42.7 H5.4 N 11.6 S 11.4

IR bands at 3305, 1760, 1728, 1670, ¹ 605, 1360 and 1174 cm ^-1

NMR signals at τ = 2.3-2.7 (5H), 4.35 (1H), 4.5 (2H), 5.8 (1H), 5.8-6.2 (4H) , 6.65 (3H), 8.4 (3H) and 8.5 ppm (3H)

Efficacy in animal studies: A, B, C and D Activity against E. coli A 261: 32-64 Activity against E. coli 183/58: 1-4 Activity against Proteus 1017: 1,6 Activity against Psdm. aerug. Walter: 4-16

Efficacy against Klebsiella K10: 4-16 ·

B) 1-Chlorocarbonyl-3-methylsulfonyl-imidazolidone (2): 0

CH ₃ SO ₂ -N ^ N-COCl

16.4 parts by weight of 1-methylsulfonylimidazolidone (2) were boiled in dioxane 3day with 27 parts by weight of trimethylchlorosilane and 20 parts by weight of triethylamine. It was filtered from the precipitated triethylamine hydrochloride, added with 11 parts by weight of phosgene and allowed to stand overnight at room temperature. It was then evaporated to dryness and recrystallized from boiling acetone.

Yield: 70%, mp = 178 ° C

Calculated: C 26.5 H 3.1 Cl 15.7 N 12.4 S 14.1 Found: C 27.2 H 3.4 Cl 15.3 N 12, OS 14.1

NMR signals at τ = 5.6-6.2 (4H) and 6.6ppm (JH)

IR bands at 3010, 1807, 1721, 1360, 1654, 984 and 742 cm ^-1 .

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

C) N-Methylsulfonylimidazolidone-2:

CH ₃ -SO ₂ -N ^ NH

Regulation 1

63 parts by weight of methanesulfonyl chloride were added dropwise at room temperature to the suspension of 43 parts by weight of imidazolidone-2 in 400 parts by volume of dry tetrahydrofuran, stirred for 1 hour at 30-40 ° C. and then heated at reflux for 1 hour. Subsequently, the solvent was distilled i.V. off and held for 1 hr. At 60 ° C at the oil pump. The residue was recrystallized from warm acetone.

Yield: 25%, mp = 193 ° C

Calculated: C 29.3 H 4.9 N 17.1 S 19.5 Found: C 29.0 H 5.0 N 17.2 S 19.6

IR bands at 3250, 3115, 1715, 1350, and 1160 cm ^-1 NMR signals at τ = 2.4 (1H), 6.2 (2H), 6.5 (2H), and 6.8ppm (3H)

Regulation 2

To suspension of 43 parts by weight of imidazolidone-2 in 300 parts by volume of dry tetrahydrofuran was added dropwise over 30min. While stirring, 80 parts by weight of methanesulfonyl chloride and then 56 parts by weight of triethylamine, so that the internal temperature was 35-40 ° C. It was stirred for 2h. at 45 ° C, then the solvent was removed in vacuo, the remaining residue extracted twice with 150Vol.-parts of chloroform and crystallized the remaining crystals of methanol

Yield: 49%. The product is consistent with mp and IR spectrum with the N-methylsulfonylimidazolidone-2 described above.

Examples', ".

A) D-α-to-aminocarbonyl-imidazolidine-1-ylJ-carbonylamino-benzylpenicillin sodium:

^0A (R)

H ₂ N-CO-N 1 N-CONH-CH-CO-NH

16.2 parts by weight of ampicillin were stirred in 170 parts by volume of methylene chloride with 10 parts by weight of triethylamine and 20 parts by weight of anhydrous sodium sulfate for 90 min. At room temperature. The mixture was then filtered off with suction and the resulting solution was dissolved in OX with the suspension of 11 parts by weight of S-aminocarbonyl-imidazolidine ^ -one-i-carbonyl chloride in 30 parts by volume of methylene chloride. The mixture was stirred 1 hr. At 0 ⁰ C and 1 hr. At room temperature, poured into 200Vol. parts of water, provided a pH = 7 and fired from the methylene chloride IV. The aqueous solution thus obtained was extracted once with 10% by volume of ethyl acetate, layered with 300 parts by volume of fresh ethyl acetate and adjusted to pH = 1.5-2.0 with ice cooling with dilute hydrochloric acid. The precipitated, relatively poorly soluble in ethyl acetate precipitate, consisting of the somewhat contaminated free acid of penicillin was filtered off with suction and washed with water. The organic phase was then separated from the water, washed once with water, dried over MgSO ₄ and obtained as described in Example 1A after addition of sodium 2-ethylhexanoate penicillin in the form of its sodium salt.

Yield: 25% β-lactam content: 76%

Calculated: C 45.5 H 4.7 N 15.2 S 5.8 Found: C 45.6 H 6.0 N 13.7 S 5.6

IR bands at 3300, 1760, 1725, 1670 and 275 cm ^-1

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.2 (4H), 8, 4 (3H) and 8.5ppm (3H)

The free penicillin obtained in 37% yield showed a β-lactam content of 65% and had the correct structure after analysis and spectra.

Efficacy in animal experiments: B, C and D. Activity against E. coli 183/58: 4 Activity against Proteus 1017: 4 Efficacy against Psdm. aerug. Walter: Efficacy against Klebsiella 63:16

B) S-aminocarbonyl-imidazolidine ^ -one-i-carbonyl chloride:

H ₂ N-CO-N 1 N-COCl

The mixture of 7.7 parts by weight of N-aminocarbonyl-imidazolidone-2, lejSGew. Parts of trimethylchlorosilane. 15 parts by weight of triethylamine and 10 parts by volume of benzene was first converted into the silyl compound in the manner described in Example 2CB and then into the carbamic acid chloride with 6 parts by weight of phosgene.

Yield: 11.6 parts by weight of IR bands at 3400, 3300, 2950, 2895, 1795 and 1600 cm ^-1

C) N-aminocarbonyl-imidazolidone-2

o '·

H ₂ N-CO-N- ^ H

29.7 parts by weight of N-chlorocarbonyl-imidazolidone-2 were reacted at pH = 8.5 with 20 parts by volume of a 25% aqueous NH ₃ solution in 80% aqueous tetrahydrofuran at room temperature. After removal of the tetrahydrofuran in vacuo was filtered off with suction from the precipitated product and this with a little ice water, washed. Yield after drying over P ₂ Os in the desiccator: 62%, mp. = 200 ^° C.

Calculated: C 37.2 H 5.4 N 32.6 Found: C 37.7 H 5.3 N 33.2

IR bands at 3345,3260,3200,1740,1677 and 1590cm " ^1. $

From the evaporated to dryness filtrate of Hauptfällung could be by boiling with several portions of acetone

again 12% of the product win (mp = 199 ⁰ C, IR bands as in the main amount).

Examples

A) D-α-tis-dimethylaminocarbonyl-imidazolidine ^ -one-i-y-carbonylaminoJ-benzylpenicillin sodium:

COONa

This penicillin was prepared in the manner described in Example 1A from 7.1 parts by weight of 3-dimethylaminocarbonyl-imidazolidin-2-one-1-carbonyl chloride and 13 parts by weight of ampicillin.

Yield: 76% β-lactam content: 93%

calculated: C 47.9 H 5.1 N 14.6 S 5.5 found: C 48.1 H 5.7 N 14.0 S 6.1

IR bands at 3290,1760,1722,1662,1600 and 1260cm " ¹

NMR signals at τ = 2.4-2.75 (5H), 4.4 (1H), 4.53 (2H), 5.8 (1H), 6.2 (4H), 7.0 (6H), 8.43 (3H) and 8.5 ppm (3H)

Efficacy in animal studies: B, C and D. Activity against E. coli 183/58: 4 Activity against Proteus 1017: 16 Efficacy against Psdm. aerug. Walter: Efficacy against Klebsiella K10: 16

B) S-dimethylaminocarbonyl-imidazolidine ^ -one-i-carbonyl chloride:

CH;

CH ₃

This carbamic acid chloride was prepared in the manner described in Example 1B from 6 parts by weight of N-dimethylaminocarbonyl-imidazolidone-2. Crystalline substance.

Yield: 93%

Calculated: C 38.3 H 4.6 Cl 16.2 N 19.1 Found: C 3878 H 5.0 CM 6.4 N (17.3)

IR bands at 2 930, 1800, 1758, 1720 and 1675 cm ^-1

C) N-Dimethylaminocarbonylimidazolidone-2:

  CH °

The mixture of 50 parts by volume of a 50% aqueous Dimethylaminiösung and 70Vol.-parts of tetrahydrofuran was adjusted with 5 η hydrochloric acid to pH = 8. With stirring and ice-cooling, Mn parts by weight of N-chlorocarbonylimidazolidone-2 was added little by little, and the pH was maintained by the simultaneous addition of further dimethylamine solution. The mixture was stirred until the pH remained constant, then the tetrahydrofuran was stripped off, saturated with common salt and extracted several times with ethyl acetate. The organic solution was washed with saturated brine, dried over MgSO4, filtered and the solvent evaporated. The residue was recrystallized from acetone and dried over P2O ₅ in a vacuum dessicator.

Yield: 36%, mp = 135 ° C

Calculated: C 45.9 H 6.4 N 26.8 Found: C 45.9 H 6.8 N 27.1

IR bands at 3280, 1740, 1715 and 1660cm " ¹

Example?

A) D-aKS-i-propyloxycarbonyl-imidazolidine ^ -one-i-y-carbonylamino-benzylpenicillin sodium:

° (R) - ^ S _v ^ CH ₃

Ii (R) .Sv ^

CH-O-C O-N-Nj-C ONH-CH-C ONH-f-f V ^

\ L l \

COONa

This penicillin was prepared in the manner described in Example 1A from 6.3 parts by weight of 3- (i-propyloxycarbonyl) -imidazolidine-2-o-1-carbonyl chloride and 10.9 parts by weight of ampicillin.

Yield: 62%

β-lactam content: 85%

Calculated: C 49.1 H 5.1 N 11.9 S 5.5 Found: C 49.2 H 6.2 N 11.6 S 5.6

IR bands at 3300.1, 765.1, 665.1, 600 and 1 260cm ^-1

NMR signals at τ = 2.3-2.8 (5H), 4.3 (1H), 4.5 (2H), 4.5-5.1 (1H), 5.8 (1H) , 6.1 (4H), 8.4 (6H) and 8.6ppm (6H)

Efficacy in animal experiments: B, -C and D Activity against E. coli 183/58: <1 Activity against Proteus morg. 932: 4 Efficacy against Psdm. aerug. Walter: 8 Efficacy against KlebsieHa K10: 4

B) S-Fi-propyloxycarbonyl-himidazolidine ^ -one-i-carbonyl chloride:

CH3V. A

This carbamic acid chloride was prepared in the manner described in Example 1B from 11 parts by weight of N-i-propyloxycarbonylimidazolidone-2,13,5 parts by weight of trimethylchlorosilane and 7 parts by weight of phosgene. Recrystallization from acetone: pentane.

Yield: 6.8 parts by weight M.p. = 98-102 ° C

According to the NMR spectrum and the analysis, the substance consisted of 65% end product and 35% starting material, which, however, did not interfere with the reaction to penicillin.

calculated for 65% final product and 35% starting material:

C43.7H5.5CI 9.9N 13.5 found: C 44.3 H 5.5 Cl 10.1 N 14.5

IR bands at 3220, 1820, 1760, 1740, 1695 and 1685 cm ^-1 NMR signals at τ = 4.85.6.1 and 8.6 ppm (final product) and at τ = 4.9, 6, 4 and 8 , 7 ppm (starting material)

C) N- (i-propyloxycarbony!) - imidazolidone-2:

  0 '

14.9 parts by weight of N-chlorocarbonylimidazolidone were dissolved in 10 volumes of i-propanol and 10 volumes of dioxane 3h. heated to 50 ° C. After removal of the solvent was recrystallized from acetone.

Yield: 67%, mp = 86 ^° C.,

IR bands at 3320.1764 and 1670cirT ¹ NMR signals at τ = 5.05 (1H), 5.7-6.75 (5H) and 8.75ppm (6H)

Examples

A) D-α-KS-pyrrolidyl-N-carbonyl-imidazolidine ^ -on-1-yl-carbonylamino-benzylpenicillin sodium:

i-CO-N ^ U-CO-NH-CH-CONH-

COONa

This penicillin was prepared in the manner described in Example 1A from 8 parts by weight of S-pyrrolidyl-N-carbonyl-imidazolidine ^ -one-1-carbonyl chloride and 13.2 parts by weight of ampicillin.

Yield: 82% β-lactam content: 95%

Calculated: C 49.2 H 5.3 N 13.8 Found: C 49.3 H (7.1) N 13.4

IR bands at 3290,1760,1720,1655,1600 and 1 250cm " ¹

NMR signals at τ = 2.4-2.8 (5H), 4.4 (1H), 4.55 (2H), 5.8 (1H), 6.2 (4H), 6.3 -6.6 (4H), 7.9-8.3 (4H), 8.45 (3H) and 8.5ppm (3H)

Efficacy in animal experiments: A, B and C Activity against E. coli 183/58: 4

Efficacy against Proteus 1017: 32.

Efficacy against Psdm. aerug. Walter: 32 Efficacy against Klebsiella K10: 8

-25- 106 044 B) S-f-pyrrolidyl-N-carbonyl-imidazolidine ^ -one-i-carbonyl chloride:

Q-

CO-N ^ N-COCI

This carbamic acid chloride was prepared in the manner described in Example 1B from 9.2 parts by weight of N- (pyrrolidyl-N-carbonyl) -imidazolidone-2.13.6 parts by weight of trimethylchlorosilane and 5.6 parts by weight of phosgene. Primary crystallization from acetone / ether.

Yield: I.Fraction of mp. = 125 ° C: 71% 2nd fraction of mp = 120-122 ° C: 25%

T.Fraktion:

Calculated: C 44.0 H 4.9 Cl 14.5 N 17.1 Found: C 44.1 H 5.3 Cl 15.0 N 16.8

IR bands at 1795, 1755, 1725 and 1660 cm ^-1

C) N-f-pyrrolidyl-N-carbonyl-imidazolidone ^: .0

Ql-CO-N ^ -NH

This substance was prepared in the manner described in Example 6C from N-chlorocarbonyl-imidazollidori ^ and pyrrolidine.

Yield: 56%, mp = 155 ^° C.

Calculated: C 52.3 H 7.1 N 22.9 Found: C 51.5 H 7.0 N 22.6

IR bands at 3240, 1720, 1698, 1647 and 1620 cm ^-1 NMR signals at τ = 6.0-6.8 (8H) and 8.0-8.3 (4H)

Example 9

A) D-α-KS-piperidyl-N-carbonyl-imidazolidine ^ -one-i-yD-carbonylaminol-benzylpenicillin sodium:

-CO-N- ^ N-C ONH-CH-CQNH-

^^ . COONa._

This penicillin was prepared in the manner described in Example 1A from 5.0 parts by weight of 3- (piperidyl-N-carbonyl) -imidazolidin-2-one-1-carbonyl chloride and 7.6 parts by weight of ampicillin.

Yield: 92% β-lactam content: 94%

Calculated: C 51.0 H 5.4 N 13.7 S 5.2 Found: C 50.7 H (6.8) N 13.5 S 5.7

IR bands at 3295, 3050, 1765, 1725, 1 667, 1608 and 1 265 cm ^-1 NMR signals at τ = 2.3-2.7 (5H), 4.3 (1H), 4.65 ( 2H), 5.8 (1H), 6.2 (4H), 6.3-6.6 (4H) and 8.1-8.5ppm (12H)

Efficacy in animal experiments: B and C Activity against E. coli 183/58: 4 Activity against Proteus 1071: 32 Efficacy against Psdm. aerug. Walter: Efficacy against Klebsiella K10: 4

B) S-f-piperidyl-N-carbonyl-imidazolidine ^ -one-i-carbonyl chloride:

"Λ Jl

N-CO-N ^ Si-COCl

^J V

This carbamic acid chloride was prepared in the manner described in Example 1B from 15.7 parts by weight of N- (piperidyl-N-carbonyl) -imidazolidone-2.21.7 parts by weight of trimethylchlorosilane and 8.4 parts by weight of phosgene. Recrystallization from acetone / ether.

Yield: I.Fraction of mp. = 117 ° C: 27.5% 2nd fraction of mp. = 112 ° C: 49%

I.Fraktion:

Calculated: C 46.3 H 5.4 Cl 13.7 N 16.2 ',

Found: C 46.3 H 5.8 Cl 14.6 N 15.8

IR bands at 3060.1, 793, 1710.1, 659 and 1 234 cm ^-1 C) N- (piperidyl-N-carbonyl) -imidazolidone-2:

Nanh

This substance was prepared in the manner described in Example 6 C from N-chlorocarbonyl-imidazolidone-2 and piperidine. Recrystallization from nitromethane.

Yield: 85%, mp = 187X

Calculated: C 54.8 H 7.6 N 21.3 -

found: C 55.2 H 7.8 N 20.3

IR bands at 3 240.1710, 1675 and 1640 cm ^-1 NMR signals at τ = 6.0-7.0 (8H) and 8.0-8.6 ppm (6H)

Example 10

A) D-α-IO-Phenylaminocarbonyl-imidazolidine ^ -one-i-yD-carbonylaminoJ-benzylpenicillin sodium:

ο (R)

/ "Vnh-co-n ^ n-conh-ch-conh-i-r ^s \ ^ ^CH3

CH ₃ COONa.

This penicillin was prepared in the manner described in Example 1A from 2.4 parts by weight of 3- (phenylaminocarbonyl) -imidazolidin-2-one-1-carbonyl chloride and 4.4 parts by weight of ampicillin.

Yield: 54% β-lactam content: 86%

Calculated: C 50.9 H 4.9 N 13.2 S 5.0 Found: C 51.3 H 5.5 N 12.2 S 5.2

IR bands at 3390.3290.1 782.1720.1 678 and 1598 cm ^-1 NMR signals at τ = 2.3-3.0 (10H), 4.4 (1H), 4.5 (2H ), 5.8 (1H), 6.1 (4H), 8.4 (3H), and 8.5 ppm (3H)

Efficacy in animal experiments: BundC. Efficacy against E. coli 183/58: 4 Activity against Proteus morg. 932:

Efficacy against Klebsiella K10: 8.

B) S-f-phenylaminocarbonyl-himidazolidine ^ -one-i-carbonyl chloride:

"Vnh-co-n ^ n-coci.

This carbamic acid chloride was prepared in the manner described in Example 1B from 15.0 parts by weight of N- (phenylaminocarbonyl-imidazolidone-2.15.8 parts by weight of trimethylchlorosilane and 7.2 parts by weight of phosgene.) Recrystallization from acetone / pentane ,

Yield: 12%, mp = 198-200 ⁰ C..

A refill of 8.3 parts by weight was significantly more impure.

IR bands at 3, 240, 1785, 1715, 1690 and 1598 cm ^-1

C) N-phenylaminocarbonyl-imidazolidone ^:

10.2Gew.-parts of aniline were charged in 120 parts by volume of 80% aqueous tetrahydrofuran at pH = 8 and treated at room temperature with stirring under stirring with 14.9 parts by weight of N-chlorocarbonyl-imidazolidone-2, wherein the pH Value by simultaneous triethylamine addition at 7-8. The mixture was stirred until the pH remained constant, 80 parts by volume of water were added, the tetrahydrofuran was stripped off in vacuo, adjusted to pH = 2.5 and filtered after standing for one hour in an ice bath, the precipitated product. It was washed with ice water and dried over P ₂ O ₅ in a vacuum desiccator.

Yield: 91%, mp = 164 ^° C.

Recrystallization from acetone gave in a yield of 78%, a product which also melted at 164 ⁰ C.

Calculated: C 58.5 H 5.4 N 20.5 Found: C 59.0 H 5.4 N 20.7

IR bands at 3275, 3090.1, 735-1, 715.1, 658.1, 616 and 1600 cm ^-1

Example 11

A) D-a - [(3-Phenoxycarbonylimidazolidin-2-on-1-yl) carbonylamino] benzylpenicillin sodium:

COONa

This penicillin was prepared in the manner described in Example 1A from 5 parts by weight of S-phenoxycarbonyl-imidazolidine -on-icarbonyl chloride and 8.1 parts by weight of ampicillin;

Yield: 42%

β-lactam content: 88% (determined from analytical Craig distribution chromatogram): C 53.7 H 4.3 N 11.6 S 5.3

found: C 53.5 H (5.8) N 11.1 S 5.4 IR bands at 3300, 3050, 1775, 1740 (shoulder), 1670, 1600 and 1198 cm ^-1

NMR signals at τ = 2.3-2.9 (10H), 4.3 (1H), 4.5 (2H), 5.8 (1H), 6.05 (4H), 8.4 (3H) and 8.5ppm (3H) Efficacy in animal experiments: B and C

Efficacy against E. coli 183/58: <1

Efficacy against Prot. Morg. 932: 8.

Efficacy against Psdm. aerug. Walter:

Efficacy against Klebsiella K10: 4

B) S-phenoxycarbonyl-imidazolidine ^ -one-i-carbonyl chloride:

/ "" VOCO N ^ N-COCI

This carbamic acid chloride was prepared in the manner described in Example 1B from 11 parts by weight of N-phenoxycarbonyl-imidazolidone-2,11,7 parts by weight of trimethylchlorosilane and 5.3 parts by weight of phosgene. Recrystallization from acetone / pentane.

Yield: 21%, mp. About 130 ° C IR bands at 1780, 1758, 1682 and 1594 cm ^-1

C) N-phenoxycarbonyl-imidazolidone-2:

12.7 parts by weight of sodium phenolate were dissolved in 120 parts by volume of 80% tetrahydrofuran and the solution was adjusted to pH = 8. 14.9 parts by weight of N-chlorocarbonyl-imidazolidone-2 were now introduced with stirring, the pH was kept constant by the simultaneous addition of triethylamine to 8. The mixture was stirred until the pH remained constant even without the addition of triethylamine. Then 100 parts by volume of water were added, the tetrahydrofuran was stripped off in vacuo, adjusted to pH = 10 with sodium hydroxide solution and the solution extracted with ethyl acetate. The organic solution was washed with water, dried over MgSO ₄ , evaporated, on the oil pump at 60 ° C for 1 h. dried and the residue recrystallized from acetone.

Yield: 56%, mp = 182 ^° C.

Calculated: C 58.3 H 4.9 N 13.6 Found: C 58.5 H 5.1 N 13.6

IR bands at 3260, 3110, 3050, 1780, 1760, 1695, 684, 1597 and 1182 cm ^-1

Example 12

A) D-α-HS-benzoyl-imidazolidine ^ -on-1-yl-carbonylamino-benzylpenicillin sodium:

COONa

This penicillin was prepared in the manner described in Example 1A from 5.5 parts by weight of S-benzoyl-imidazolidine -on-icarbonyl chloride and 10.1 parts by weight of ampicillin.

Yield: 92%

β-lactam content: 89% calculated: C 49.2 H 5.2 N 10.8 S 4.9

found: C49.2 H 5.3 N 10.8 S 5.2 IR bands at 3220, 3050, 1755, 1725 and 1667 cm ^-1

NMR signals at τ = 2.2-2.8 (10H), 4.4 (1H), 4.55 (2H), 5.85 (1H), 6.05 (4H), 8.4 (3H) and 8.5ppm (3H)

B) S-Benzoylimidazolidine ^ -one-i-carbonyl chloride:

NN

This carbamic acid chloride was prepared in the manner described in Example 1B from 4.8 parts by weight of N-benzoyl-imidazolidone-2, 4.4 parts by weight of trimethylchlorosilane and 2.8 parts by weight of phosgene.

Yield: 100%, mp = 153-154 ° C

Calculated: C 52.2 H 3.6 Cl 14.0 N 11.1 Found: C 51.2 H 4.4 Cl 13.2 N 11.1

IR bands at 3060, 1768, 1725 and 1672 cm ^-1 NMR signals at τ = 2.5 (5H) and 6.0 ppm (4H)

C) N-Benzoylimidazolidone-2:

8.6 parts by weight of imidazolidone-2 in 100 parts by volume of dry tetrahydrofuran were added over 15 minutes. at 5-1O ⁰ C with 15.5Gew.-parts of benzoyl chloride in 30Vol.-parts tetrahydrofuran and then 3 hr. stirred at 10 ⁰ C. The solvent was removed, the residue was shaken with a mixture of chloroform and aqueous NaHCO 3 solution for 15 min, the chloroform separated, the water extracted once more with chloroform, the combined organic phases washed with water, dried over MgSO ₄ and evaporated. The residue was recrystallized from ethyl acetate / ether.

Yield: 30%, mp = 169-170 ° C

Calculated: C 63.2 H 5.3 N 14.8 · Found: C 63.0 H 5.3 N 14.8

IR bands at 3190, 3110, 1742, 1718 and 1655 cm ^-1 NMR signals at τ = 2.2-2.9 (5H), 3.9 (1H), 6.0 (2H) and 6.6 ppm (2H)

Example 13

A) D-a - [(3-Furoyl (2) -imidazolidin-2-one-1-yl) carbonylamino] benzylpenicillin sodium:

Il

COONa

This penicillin was prepared in the manner described in Example 1A from 6.0 parts by weight of 3-furoyl (2) -imidazolidin-2-one-1-carbonyl chloride and 12.1 parts by weight of ampicillin.

Yield: 90% β-lactam content: 97% '

Calculated: C 50.0 H 4.4 N 11.6 S 5.3 Found: C 49.9 H 4.9 N 11.1 S 6.1

IR bands at 3300.1770 (shoulder), 1740.1, 670.1, 605 and 1 260cm ^-1

NMR signals at τ = 2.2 (1H), 2.3-2.8 (6H), 3.4 (1H), 4.35 (1H), 4.55 (2H), 5 , 8 (1H), 6.1 (4H), 8.45 (3H) and 8.5ppm (3H)

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

CO-N ^ N-COCI

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

Yield: 55%, mp = 119 ° C

Calculated: C 44.5 H 2.9 Cl 14.6 N 11.5 Found: C 45.0 H 3.6 Cl 13.4 N 11.5

IR bands at 3150, 31100, 1800, 1745, 1715, ^1, 650, 1620 and 1255 cm ^-1 NMR signals at τ = 2.3 (1H), 2.5 (1H), 3.4 (1H ) and 5.9ppm (4H)

C) N-furoyl (2) -imidazolidone-2: O

This substance was prepared in the manner described in Example 12C from imidazolone-2 and furan-a-carboxylic acid chloride. Instead of 10 ⁰ C was 3h. stirred at 30-40 ⁰ C. Recrystallization from nitromethane.

Yield: 53% m.p. = 144-146 ° C

Calculated: C 53.2 H 4.5 N 15.6 Found: C 51.2 H 4.5 N 15.3

IR bands at 3245, 3120, 1740, 1622, 560, 125, and 1240 cm ^-1 . NMR signals at τ = 2.25 (1H), 2.6 (1H), 3.35 (1H), 6.0 (2H) and 6.4ppm (2H).

Example 14

A) D-a-IfS-n-butyryl-imidazolidine ^ -one-i-yD-carbonylaminol-benzylpenicillin sodium:

CH, -CH ₂ -CH ₂ -CO-W ^ N-CONH-CH-CONH-i-f \ / ^Clis

^ Y ^ CH ₃ COONa

This penicillin was prepared in the manner described in Example 1A from 6.0 parts by weight of S-n-butyryl-imidazolidine -on-icarbonyl chloride and 11.3 parts by weight of ampicillin.

Yield: 100% β-lactam content: 93.5%

Calculated: C 50.5 H 5.3 N 12.2 S 5.6 Found: C 50.1 H 6.0 N 11.8 S 6.7

IR bands at 3310, 3055, 1760, 1730, 1680, 1663, 265 and 1230 cm ^-1 .

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.25 (4H), 7.1 (2H), 8.2 (2H), 8.4 (3H), 8.5 (3H) and 9.0ppm (3H).

B) S-n-butyryl-imidazolidine ^ -one-i-carbonyl chloride:

0

CH ₃ -Ch ₂ -CH ₂ -CON ^ -COCl

This carbamic acid chloride was prepared in the manner described in Example 1B from 10.0 parts by weight of N-n-butyryl-imidazolidone-2,11.4 parts by weight of trimethylchlorosilane and 7.0 parts by weight of phosgene. Recrystallized twice from acetone / pentane.

Yield: 65% m.p. = 103 ^° C.

Calculated: C 40.2 H 4.4 CM 4.9 N 11.8 Found: C 40.2 H 4.8 Cl 14.7 N 11.7

IR bands at 3060, 1792, 1722, 1686, and 1220 cm ^-1 . NMR signals at τ = 6.0 (4H), 7.1 (2H), 8.4 (2H), and 9.0 ppm (3 H).

C) N-n-butyryl-imidazolidone-2:

CH ₃ CH ₂ CH ₂ COl ·

This substance was prepared in the manner described in Example 12 C from imidazolidone-2 and n-butyryl chloride. Instead of 10 ⁰ C was stirred for 1 hr. At room temperature and 1 hr. At 5O ⁰ C. Twice recrystallization from methanol.

Yield: 36% m.p. = 96 ° C

Calculated: C 53.9 H 7.7 N 18.0 Found: C 53.5 H 7.6 N 18.3

IR bands at 3200, 3120, 1740, 1662 and 1262 cm ^-1 .

NMR signals at τ = 6.15 (2H), 6.5 (2H), 7.2 (2H), 8.4 (2H), and 9.1 ppm (3H).

Example 15

If, in the manner described in Example 1A, 0.05 mol!

S-acetylimidazolidine ^ -one-1-carbonyl chloride,

S-methylaminocarbonyl-imidazolidine ^ -one-i-carbonyl chloride, 3-methoxycarbonyl-imidazolidin-2-one-1-carbonyl chloride, 3-methylsulfonyl-imidazolidin-2-one-1-carbonyl chloride,

3-aminocarbonyl-imidazolidon-2-one-1-carbonyl chloride, 3-phenoxycarbonyl-imidazolidin-2-one-1-carbonyl chloride, 3-furoyl (2) -imidazolidin-2-one-1-carbonyl chloride or

3-ethylsulfonyl-imidazolidin-2-one-1-carbonyl chloride, each containing 0.05 mol of α-amino-p-methylbenzylpenicillin α-amino-p-methoxy-benzylpenicillin,

a-amino-p-methylthio-benzylpenicillin,

a-amino-p-hydroxy-benzylpenicillin,

a-amino-p-chloro-benzyl penicillin,

a-amino-p-nitro-benzylpenicillin,

a-amino-a-thienyl (2) -methylpenicillin or

a-amino-a-thienyl (3) -methylpenicillin, the following penicillins are obtained in the form of their sodium salts:

α-IO-acetyl-imidazolidine ^ -one-i-yl-carbonyl-aminol-p-methylbenzylpenicillin, α-KS-acetyl-imidazolidine-1-yn-1-yl-carbonyl-amino-p-methoxybenzyl-penicillin, a - [(3-acetyl) imidazolidin-2-one-1-yl) carbonylamino] -p-methylthiobenzylpenicillin, a - [(3-acetylimidazolidin-2-one-1-yl) carbonylamino] -p-hydroxybenzylpenicillin, a - [(3 Acetylimidazolidin-2-one-1-yl) carbonylamino] -p-chlorobenzylpenicillin, a - [(3-acetylimidazolidin-2-one-1-yl) carbonylamino] -p-nitrobenzylpenicillin, a - [( 3-acetyl-imidazolidin-2-one-1-yl) -carbonylamino] -a-thienyl (2) -methylpenicillin, a-io-acetyl-imidazolidine ^ -on-1-yl-carbonyl-aminol-a-thienyl) -l-methylpenicillin, α-IO-methoxycarbonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p-methoxybenzylpenicillin, α-KS-methoxycarbonyl-imidazolidine ^ -one-i-ylJ-carbonylaminoI-p-methylthiobenzylpenicillin, α-fO-methoxycarbonyl-imidazolidine ^ -on-i-y-carbonylaminol-p-hydroxybenzylpenicillin, a - [(3-methoxycarbonyl-imidazolidin-2-one-1-yl) carbonylamino] -p-chlorobenzylpenicillin, α-IO-methoxycarbonyl-imi dazolidin-1-yl-carbonylamino-p-nitrobenzylpenicillin, a - [(3-methoxycarbonyl-imidazolidin-2-one-1-yl) carbonylamino] -a-thienyl (2) -methylpenicillin, a - [( 3-methoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylamino] -a-thienyl (3) -methylpenicillin, α-fO-methylsulfonyl-imidazolidine ^ -one-i-ylJ-carbonylamino-p-methylbenzylpenicillin, a- IO-methylsulfonyl-imidazolidine ^ -one-i-ylJ-carbonylaminol-p-methoxybenzylpenicillin, α-IO-methylsulfonyl-imidazolidine ^ -one-i-yl-carbonyl-aminol-p-methylthiobenzylpenicillin, α-tfS-methylsulfonyl-imidazolidine ^ -one -i-y-carbonylaminol-p-hydroxybenzylpenicillin, α-IO-methylsulfonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p-chlorobenzylpenicillin, α-IO-methylsulfonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p -nitrobenzylpenicillin, a - [(3-methylsulfonyl-imidazolidin-2-on-1-yl) -carbonylamino] -a-thienyl (2) -methylpenicillin, a-fO-methylsulfonyl-imidazolidine ^ -one-i-ylJ-carbonylamino -a-thienyl-O-methylpenicillin, a-IfS-aminocarbonyl-imidazolidine ^ -one-i-ylJ-carbonylaminol-p-methylbenzy lpenicillin, α-KS-methylaminocarbonyl-imidazolidine ^ -one-i-y-carbonylaminol-p-methylbenzylpenicillin, α-IO-methylaminocarbonyl-imidazolidine ^ -on-i-y-carbonylaminol-p-methoxybenzylpenicillin, α-fO-methylaminocarbonyl- imidazolidine ^ -one-i-y-carbonylaminol-p-methylthiobenzylpenicillin, α-IO-methylaminocarbonyl-imidazolidine ^ -on-T-ylJ-carbonylaminol-p-hydroxybenzylpenicillin, α-ffS-methylaminocarbonyl-imidazolidine ^ -one-i-yD carbonylaminoJ-p-chlorobenzylpenicillin, α-IO-methylaminocarbonylimidazolidine ^ -one-i-ylJ-carbonylaminoJ-p-nitrobenzylpenicillin, a - [(3-methylaminocarbonylimidazolidin-2-on-1-yl) carbonylamino] - α-thienyl (2) -methylpenicillin, α-KS-methylaminocarbonyl-imidazolidine ^ -on-i-y-carbonylamino-1-thienyl-β-methylpenicillin, α-to-methoxycarbonyl-imidazolidine-1-y-y-carbonyl-aminol-p -methylbenzylpenicillin, α-IO-aminocarbonyl-imidazolidine ^ -one-i-y-carbonylaminol-p-methoxybenzylpenicillin, α-KS-aminocarbonyl-imidazolidine ^ -on-1-yl-carbonylaminol-p-methylthiobenzylpenicillin, a - [(3 -Ami nocarbonyl-imidazolidin-2-one-1-yl) carbonylamino] -p-hydroxybenzylpenicillin _/ a-tO-aminocarbonyl-imidazolidine ^ -one-i-y-carbonylaminoJ-p-chlorobenzylpenicillin, a-fO-aminocarbonyl-imidazolidine ^ - on-i-ylJ-carbonylaminol-p-nitrobenzylpenicillin, a - [(3-aminocarbonyl-imidazolidin-2-on-1-yl) -carbonylamino] -a-thienyl (2) -methylpenicillin, a - [(3-aminocarbonyl -imidazolidin-2-on-1-yl) carbonylamino] -a-thienyl (3) -methylpenicillin, α-to-phenoxycarbonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p-methylbenzylpenicillin, α-IO-phenoxycarbonyl -imidazolidine ^ -one-i-ylJ-carbonylaminol-p-methoxybenzylpenicillin, α-IO-phenoxycarbonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p-methylthiobenzylpenicillin, α-IO-phenoxycarbonyl-imidazolidine ^ -one-i- yl-carbonylaminol-p-hydroxybenzylpenicillin, a - [(3-phenoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylamino] -p-chlorobenzylpenicillin, α-IO-phenoxycarbonyl-imidazolidine ^ -one-i-yD-carbonylaminol -p-nitrobenzylpenicillin,

a - [(3-phenoxycarbonyl-imidazolidin-2-on-1-yl) -carbonylamino] -thienyl {2) -methylpenicillin, α-IO-phenoxycarbonyl-imidazolidine ^ -one-i-yD-carbonyl-amino-α- thienyl OJ-methylpenicillin, a - [(3-furoyl (2) -imidazolidin-2-one-1-yl) carbonylamino] -p-methylbenzylpenicillin, a - [(3-furoyl (2) -imidazolidin-2-one 1-yl) carbonylamino] -p-methoxybenzylpenicillin, a - [(3-furoyl (2) -imidazolidin-2-one-1-yl) carbonylamino] -p-methylthiobenzylpenicillin, a * [(3-furoyl (2 ) -imidazolidin-2-on-1-yl) -carbonylamino] -p-hydroxybenzylpenicillin, a - [(3-furoyl (2) -imidazolidin-2-on-1-yl) carbonylamino] -p-chlorobenzyl ! penicillin, a - [(3-furoyl (2) -imidazolidin-2-one-1-yl) carbonylamino] -p-nitrobenzylpenicillin, a - [(3-furoyl (2) -imidazolidine-2-pn-1 -yl) carbonylamino] -a-thienyl (2) -methylpenicillin, a - [(3-furoyl (2) -imidazolidin-2-on-1-yl) carbonylamino] -a-thienyl (3) -methylpenicillin, a-toO-ethylsulfonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p-methylbenzylpenicillin, a-IO-ethylsulfonyl-imidazolidine ^ -one-i-ylJ-carbonylaminoJ-p-methoxybenzylpe nicillin, α-KS-ethylsulfonyl-imidazolidine ^ -on-1-yl-carbonylaminol-p-methylthiobenzylpenicillin, α-fO-ethylsulfonyl-imidazolidine ^ -one-i-yD-carbonylaminol-p-hydroxybenzylpenicillin, α-IO-ethylsulfonyl- imidazolidine ^ -on-i-yD-carbonylaminoJ-p-chlorobenzylpenicillin, a - [(3-ethylsulfonyimidazolidin-2 <> n-1-yl) carbonylamino] -p-nitrobenzylpenicillin, a - [(3-ethylsulfonyl) imidazolidin-2-on-1-yl) carbonylamino] -a-thienyl (2) -methylpenicillinbzw. a-IO-ethylsulfonyl-imidazoIidin ^ -one-i-YLJ carbonylaminoJ-a-thienylOl-methyl penicillin.

Example 16

If in each case 0.05 mol of i-chlorocarbonyl-1-dimethyl-S-acetyl-urea are added in the manner described in Example 1A,

i-chlorocarbonyl-i ^ dimethyl-S-methylsulfonyl-urea,

i-Chlorocarbonyl-1-dimethyl-S-methoxycarbonylurea,

N- (isothiazolidine-1,1-dioxide-2-ylcarbonyl) -N-methyl-carbamic acid chloride, ' 1-chlorocarbonyl-3-p-methoxybenzoyl-imidazolidone (2), 1-chlorocarbonyl-3-methylsulfonyl-4 methyl-imidazolidone (2), 1-chlorocarbonyl-3-methylsulfonyl-5-methyl-imidazolidone (2), i-chlorocarbonyl-1-methyl-S-methylsulfonylurea, i-chlorocarbonyl-1'-diaza- thia- cyclohexane-mono- ^ -dioxide or i-chlorocarbonyl-thia-imidazolidine ^ -on-M-dioxide with 0.05 mol of ampicillin in each case, the following penicillins are obtained, in the form of their sodium salts:

Da-iS-acetyl-β-dimethyl-biureidoJ-benzylpenicillin, Da-tos-methylsulfonyl-Sjö-dimethyl-biureidoJ-benzylpenicillin, Da-fo-methoxycarbonyl-S-dimethyl-biureidol-benzylpenicillin, Da- [3] (isothiazolidine-1,1-dioxide-2-yl-carbonyl) -3-methyl-ureidoj-benzylpenicillin, Da-IS-fp-methoxybenzoyl-imidazolidine ^ -one-i-yl-1-carbonylaminoJ-benzylpenicillin, Da-tO -Methylsulfonyl-methyl-imidazolidine ^ -one-i-y-carbonylaminol-benzylpenicillin, Da-IO-methylsulfonyl-6-methyl-imidazolidine ^ -one-i-y-carbonylaminol-benzylpenicillin, DaO-methyl-6-methylsulfonyl- biureidol benzylpenicillin, Da-fi-diaza-thia-cyclohexane -on-1-dioxide-i-yl-carbonylaminoJ-benzylpenicillin; D-a-I ^ thia-imidazolidin ^ -one - ^ - i-yl-dioxide-carbonylaminol-benzylpenicillin.

Example 17

If in each case 0.05 mol of N-benzoyl-N-methyl-carbamoyl isocyanate are added in the manner described in Example 1A,

N-benzoyl-N-methyl-carbamoylisothiocyanat,

N-acetyl-N-methyl-carbamoylisocyanat,

N-acetyl-N-methyl-carbamoylisothiocyanat,

lmidazolidon (2) -1-yl-carbonylisocyanat,

lmidazolidon (2) -1-yl-carbonylisothiocyanat,

Pyrrolidone (2) -1-yl-carbonyl isocyanate,

Pyrrolidone (2) -1-yl-carbonylisothiocyanat,

i ^^ - trimethyl-ureido-i carbonylisocyanat,

lAS-trimethyl-ureido-i-carbonylisothiocyanat,

N-methylsulfonyl-N-methyl-carbamoylisocyanat,

N-methylsulfonyl-N-methyl-carbamoylisothiocyanate,!, S-dimethylureido-i-carbonyl isocyanate,

!, S-Dimethyl-i carbonylisothiocyanat,

N-furoyl (2) -N-methylcarbamoylisocvanat,

N-furoyl (2) -N-methylcarbamoylisothiocyanat,

Isothiazolidine-iji-dioxide ^ yl-carbonyiisocyanatbzw. Isothiazolidine-i ^ -dioxid ^ -yl-carbonylisothiocyanat with in each case 0.05 mol of ampicillin in order to obtain the following penicillins in the form of their sodium salts:

D-α- (5-Benzoyl-5-methyl-biureido) -benzylpenicillin, D-α-O-benzoyl-S-methyl-thio-biureido-1-benzylpenicillin, D-α-F-acetyl-S-methyl-biureidol-benzylpenicillin,

D-a-fB-acetyl-B-methyl-thio-biureido J-benzylpenicillin, D-α-is-dmidazolidine ^ -on-i-yl-carbonyl-ureidol-benzylpenicillin,

DaP-dmidazolidine ^ -one-i-yl-carbonyl-thioureidoJ-benzylpenicillin, DaP-f-pyrrolidine ^ -one-i-yl-carbonyl-ureidol-benzylpenicillin, DaP-t-pyrrolidine ^ -one-i-yl-carbonyl-D-thioureidol-benzylpenicillin , Da-IB-dimethylaminocarbonyl-o-methyl-biureidol-benzylpenicillin, Da-IB-dimethylaminocarbonyl-B-methyl-thio-biureidol-benzylpenicillin, Da-fb-methylsulfonyl-S-methyl-biureidol-benzylpenicillin, Da- (5 -Methylsulfonyl-5-methyl-2-thio-biureido) -benzylpenicillin, Da-fB-methylaminocarbonyl-S-methyl-biureidol-benzylpenicillin, Da-fB-methylaminocarbonyl-S-methyl-thio-biureidol-benzylpenicillin, Da ( 5-furoyl (2) -5-methyl-biureido) -benzylpenicillin, Da (5-furoyl (2) -5-methyl-2-thio-biureido) -benzylpenicillin, Da-isothiazolidine-U-dioxide ^ -yl carbonyl-J-ureidol-benzylpenicillin or Da-Ilsothiazolidin-II-dioxide ^ -yl-carbonyl-J-thioureidol-benzylpenicillin.

Example 18

If 0.05 mol of 1-chlorocarbonyl-3-propionyl-imidazolidone (2), 1-chlorocarbonyl-3-acetyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3 are added in the manner described in Example 1A. acetyl-5-methyl-imidazolidone (2), 1-chlorocarbonyl-3-acetyl-1,3-diaza-cyclohexanone (2), 1-chlorocarbonyl-3-n-propylsulfonyl-imidazolidone (2), 1-chlorocarbonyl-3 ethylsulfonyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-ethylsulfonyl-5-methyl-imidazolidone (2), 1-chlorocarbonyl-3-ethylsulfonyl-1,3-diaza-cyclohexanone (2), 1- Chlorocarbonyl-3-methylsulfonyl-1,3-diaza-cyclohexanone (2), 1-chlorocarbonyl-3-n-propylsulfonyl-1,3-diaza-cyclohexanone (2), 1-chlorocarbonyl-3-i-propylsulfonyl-1, 3-diaza-cyclohexanone (2), 1-chlorocarbonyl-3-i-propylsulfonyl-imidazolidone (2), 1-chlorocarbonyl-3-i-propylsulfonyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-i -propylsulfonyl-5-methyl-imidazolidone (2), 1-chlorocarbonyl-3-n-propylsulfonyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-n-propylsulfonyl-5-methyl-imidazolidone (2), l-chlorocarbonyl-3-phenylsu imonazolidone (2), 1-chlorocarbonyl-3-p-methylphenylsulfonylimidazolidone (2), 1-chlorocarbonyl-3-cyclohexylsulfonylimidazolidone (2), 1-chlorocarbonyl-3-thienyl (2) sulfonylimidazolidone ( 2), 1-chlorocarbonyl-3-formyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-formyl-5-methyl-imidazolidone (2), T-chlorocarbonyl-3-formyl-1,3-diazacyclohexanone (2), 1-Chlorocarbonyl-3-methylaminocarbonyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-methylaminocarbonyl-5-methyl-imidazolidone (2), 1-chlorocarbonyl-3-methylaminocarbonyl-1,3- diaza-cyclohexanone (2), 1-chlorocarbonyl-3-methoxy-carboxyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-methoxycarbonyl-5-methyl-imidazolidone (2), 1-chlorocarbonyl-3-methoxycarbonyl-1 , 3-diazacyclohexanone (2), 1-chlorocarbonyl-3-i-propyloxycarbonyl-4-methyl-imidazolidone (2), 1-chlorocarbonyl-3-i-propyloxycarbonyl-5-methyl-imidazolidone (2), 1-chlorocarbonyl- 3-i-propyloxycarbonyl-1,3-diazacyclohexanone (2), 1-chlorocarbonyl-3-methylsulfonyl-4,5-dimethyl-imidazolidone (2), 1-chlorocarbonyl-3-methylsulf Onyl-4,4-dimethyl-imidazolidone (2) or 1-chlorocarbonyl-3-methylsulfonyl-5,5-dimethyl-imidazolidone (2) with 0.05 mol each ampicillin in order to obtain the following penicillins in the form of their sodium salts:

Da-IP-propionyl-imidazolidine ^ -one-i-ylJ-carbonylaminol-benzylpenicillin, Da-KS-acetyl-methyl-imidazolidine ^ -on-i-yD-carbonylaminol-benzylpenicillin, Da-IO-acetyl-B-methyl- imidazolidine ^ -one-i-y-carbonylaminolbenzylpenicillin, Da - [(3-acetyl-1,3-diaza-cyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin, Da-IfS-n-propylsulfonyl -imidazolidine ^ -on-i-yD-carbonylaminoI-benzylpenicillin, Da-KS-ethylsulfonyl-methyl-imidazolidine ^ -one-i-yD-carbonylaminol-benzylpenicillin, Da - [(3-ethylsulfonyl-5-methyl-imidazolidine 2-on-1-yl) carbonylamino] benzylpenicillin, Da-KS-ethylsulfonyl-i-diaza-cyclohexane ^ -on-i-y-yl-carbonylamino-1-benzylpenicillin, Da - [(3-methylsulfonyl-1,3- diaza-cyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin, Da - [(3-n-propylsulfonyl-1,3-diaza-cyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin, Da-t-O-i-propylsulfonyl-IS-diaza-cyclohexane ^ -one-i-yD-carbonylamino-benzyl-penicillin, Da-t-i-propylsulfonyl-imidazolidine ^ -one-i-yD-carbonylamino-benzylpenicillin, Da-KS -ip ropylsulfonyW-methylimidazolidine ^ -one-i-yD-carbonylaminolbenzylpenicillin, Da-l-propylsulfonyl-S-methylimidazolidine ^ -on-1-ylcarbonylaminolbenzylpenicillin, Da-tts-n-propylsulfonyl ^ -methyl-imidazolidine ^ -one-i-y-carbonylaminol-benzylpenicillin, Da-KS-n-propylsulfonyl-B-methyl-imidazolidine-Z-on-i-yD-carbonylaminol-benzylpenicillin, Da-tfS-phenylsulfonyl-imidazolidine ^ -on-i-y D-carbonylaminoI-benzylpenicillin,

Da-IO-p-Methylphenylsulfonylimidazolidine ^ -one-i-yD-carbonylaminolbenzylpenicillin, Da-tO-cyclohexylsulfonylimidazolidine ^ -one-i-yD-carbonylaminolbenzylpenicillin, Da - [(3-Thienyl (2) -sulfonyl-imidazolidin-2-one-1-yl) carbonylamino] benzylpenicillin, "Da-IO-formyl-methyl-imidazolidine ^ -one-i-y-carbonylaminol-benzylpenicillin, Da-IO-formyl-B- methylimidazolidine ^ -one-i-yD-carbonylaminolbenzylpenicillin, Da - [(3-Formyl-1,3-diazacyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin, Da-forMethylaminocarbonylM-methylimidazolidine ^ -on-i-yD-carbonylaminolbenzylpenicillin, Da-IO-methylaminocarbonyl-B-methylimidazolidine ^ -on-i-yD-carbonylaminolbenzylpenicillin, Da - [(3-methylaminocarbonyl-1,3-diaza-cyclohexane -2-on-1-yl) -carbonylamino] -benzylpenicillin, Da-10-methoxycarbonyl-methyl-imidazolidine ^ -one-i-yD-carbonylaminol-benzylpenicillin, Da-fO-methoxycarbonyl-B-methyl-imidazolidine ^ - on-i-y-carbonylaminolbenzylpenicillin, Da - [(3-methoxycarbonyl-1,3-diaza-cyclohexan-2-one-1-yl) carbonylamine o] -benzylpenicillin, Da-t-PropyloxycarbonyM-methyl-imidazolidine ^ -one-i-yD-carbonylaminol-benzylpenicillin, Da-KS-i-propyloxycarbonyl-B-methyl-imidazolidine ^ -one-i-yD-carbonylaminoJ-benzylpenicillin , Da - [{3-i-propyloxycarbonyl-1,3-diazacyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin, Da-tO-methylsulfonyl-B-dimethyl-imidazolidine ^ -on-i-yD- carbonylaminolbenzylpenicillin, Da-IO-methylsulfonyl ^^ -dimethyl-imidazolidinegon-i-y-yl-carbonylaminolbenzylpenicillin and Da-IO-methylsulfonyl-B 1 -dimethylimidazolidine ^ -on-i-yD-carbonylamino benzylpenicillin.

Example 19

A) D-a - [(2-Methylsulfonylamino) imidazolidine (2) -1-yl) carbonylamino] benzylpenicillin sodium:

CH ₅ -SO ₂ -NH

Kan-CONH-ch-CONH

COONa

This penicillin was prepared in the manner described in Example 1A from 4.8 parts by weight of i-chlorocarbonyl-2-methylsulfonylamino-4,5-dihydroimidazole and 9 parts by weight of ampicillin.

Yield: 38% β-lactam content: 96%

IR bands at 3060,1764,1670,1605 and 1130cm " ¹ .

NMR signals at τ = 2.3-2.9 (5H), 4.45 (1H), 4.55 (2H), 5.8 (1H), 5.9-6.5 (4H) , 6.95 (3H), 8.4 (3H) and 8.5ppm (3H).

Efficacy against E. coli C 165: 8 activity against Prot.vulg. 1017: 16

B) i-chlorocarbonyl ^ -methylsulphonylamino ^ S-dihydro-imidazole: CH ₃ -S0 _Ä -NH

8,2Gew. parts 2- (N-methylsulphonyl-imino) imidazoline were placed with 8,0Gew. parts phosgene in anhydrous dioxane at 60-70 ⁰ C for reaction. However, the crude product obtained when reacted with ampicillin gave the penicillin with the expected structure.

Example 20

D-a - [(3-formyl-imidazolidin-2-on-1-yl) carbonylamino] -benzylpenicillin sodium:

Da-Aminobenzylpenicillin (5.7 parts by weight) was suspended in 80% aqueous tetrahydrofuran (60VoL TeNe) and then added dropwise with stirring at 2O ⁰ C with as much triethylamine that just a clear solution was formed and the pH the mixture was between 7.5 and 8.2 (glass electrode). Then was cooled to 0 ⁰ C, and added dropwise the solution of 3-Formylimidazolidin-2-on-1 -carbonyl chloride (2.2 parts by weight) in tetrahydrofuran (20Vol. parts). The pH of the mixture was kept at 7.5 to 8.0 by appropriate addition of triethylamine. The mixture was stirred at 0 ⁰ C for 30 minutes. Then no addition of triethylamine to maintain the pH of 7.5 to 8.0 more was required. After addition of water (60 parts by volume), the pH was adjusted to 6.5 with dilute hydrochloric acid and the tetrahydrofuran in

Rotary evaporator largely removed. The remaining aqueous solution was shaken out once with ether (the ethereal extract was discarded), then covered with a 1: 1 mixture (VoLVoI.) Of ether and ethyl acetate and adjusted with stirring and ice cooling, the pH of 1-2 using dilute hydrochloric acid. The organic phase was then separated, washed with water, dried over magnesium sulfate at 0 ° C for about one hour, and diluted after filtration with about half the volume of ether. By adding a slightly 1 molar solution of sodium 2-ethylhexanoate in methanol-containing ether then the sodium salt was precipitated. The precipitate was initially oily, but could be transferred after decantation of the supernatant solution and trituration with ether in an amorphous solid.

Yield: 0.9 parts by weight (crude product) β-lactam content: 77%

According to the NMR spectrum, the substance contains 3.5 mol of H ₂ O per mole and 0.3 mol of sodium 2-ethylhexanoate. This was taken into account in the calculated values of the analysis data:

calculated: C45 / I H5.4N 11.2S5.1 found: C 45.2 H 5.3 N 11, OS 5.3

NMR signals at τ = 1.0 (1H), 2.4-2.8 (5H), 4.3-4.6 (3H), 5.8 (1H), 6.1-6, 3 (4H) and 8.3-8.5 ppm (6H).

Activity against E. coli C165: 8 Activity against Prot. Morg. 932: 8 Efficacy against Psdm. F 41: 8 Efficacy against Klebs. K10: 32

The 3-formyl-imidazolidin-2-one-1-carbonyl chloride used in the preparation of this penicillin was obtained by the following route:

! N-formyl-imidazo idin-2-one:

Imidazolidin-2-one (8.6 parts by weight) was suspended in tetrahydrofuran (10Vol parts), added with stirring at room temperature formic acid-acetic anhydride (10 parts by weight) and then after 3 ¹ A hours in the stirred at the same temperature. The precipitate was filtered off with suction, washed with tetrahydrofuran and dried.

Yield: 6.4 parts by weight. Melting point: 156-158 ° C

Calculated: C 42.1 H 5.3 N 24.6 Found: C 42.2 H 5.4 N 25.3

NMR signals at τ = 1.2 (1 H) and 5.9 to 6.5 ppm (4H)

 3-Formyl-imidazolidin-2-one-1-carbonyl chloride:

The mixture of N-formyl-imidazolidin-2-one (6.0 parts by weight) benzene (40 parts by volume) and triethylamine (11.8 parts by volume) was refluxed to give the solution of trimethylchlorosilane (8, 5 parts by weight) in benzene (20VoL TeNe) was added dropwise. Then it was still 5h. boiled, then allowed to stand overnight at room temperature, the precipitate sucked off and washed with benzene. The combined benzene solutions separated on standing overnight further amounts of precipitate, which were filtered off with suction. To the filtrate was then added dropwise a solution of phosgene (15.6 parts by weight) in dichloromethane (30 parts by volume), and then the mixture was allowed to stand overnight in the refrigerator. Then the mixture was completely evaporated to dryness in a rotary evaporator. The residue, a non-solidified mass, was thus used for the reaction with amplicillin.

Example 21

D-a-KS-pivaloyl-imidazolidine ^ -one-i y D-carbonylaminol-benzylpenicillin sodium:

(CH ₃ ) 3 ^ -CO-N ^ ^Uv NC 0 -NH-QH-C 0 -NH-

COONa

This penicillin was prepared in the manner described in Example 20 from ampicillin (9.8 parts by weight) and 3-pivaloylimidazolidin-2-one-1-carbonyl chloride (4.9 parts by weight). ,

Yield: 8.6 parts by weight of β-lactam content: 97.8%

calculated: C 50.3 H 5.6 N 12.2 S 5.6 · ·

found: C 50.6 H 5.9 N 11.6 S 5.6

NMR signals at τ = 2.4-2.8 (5H), 4.3-4.7 (3H), 5.8 (1H), 6.0-6.4 (4H) and 8.3 -8.9 ppm (15H).

Activity against E. coli C165: 4 Activity against Prot. Morg. 932: <1 Efficacy against Psdm. F 41: 4 Efficacy against Klebs. K10: 8

N-Pivaloyl-imidazolidin-2-one: (CHj) ₃ = C-CC

To the cooled to 0 ⁰ C suspension of imidazolidin-2-one (17.2 parts by weight) in tetrahydrofuran (200 parts by volume) was added dropwise over the course of one hour at the same temperature pivaloyl chloride (24.2Gew.-parts). The mixture was then stirred for 3 hours at 0 ⁰ C, then added dropwise triethylamine (27.8VoL TeNe), which was cooled with ice water and then allowed to stand overnight at room temperature. Then, the precipitated triethylamine hydrochloride was filtered off with suction, the filtrate using a rotary evaporator under vacuum completely evaporated and the residue further 1 h. Heated in vacuo in a bath at 60 ⁰ C. The oily product (crude yield: 32.8 parts by weight) was further processed. In an attempt to distill the substance in vacuo, strong decomposition occurred.

3-pivaloyl-imidazolidin-2-on-1-carbonyl chloride:

Concentrated mixture of N-pivaloyl-imidazolidin-2-one (17.5 parts by weight), benzene (100 parts by volume) and triethylamine (23 parts by volume) became the solution of trimethylchlorosilane (16.65 parts by weight) in benzene (15VOL TeNe) added dropwise over an hour, then further boiled for 6 hours and then filtered with suction, the precipitated triethylamine hydrochloride. The filtrate was combined with a solution of phosgene (13 wt. Parts) in benzene (20 vol. TeNe) and the mixture was allowed to stand at room temperature overnight. Then the reaction mixture was completely evaporated in vacuo and the oily residue dried in a desiccator over NaOH. Crude yield 22.2 parts by weight. The product was reacted with ampicillin in this form.

Example 22

D-a-ILS fAethoxy-carbonyl-amino-sulfonylJ-imidazolidine ^ -on-i-yll-carbonylaminoj-benzylpenicillin sodium:

C ₂ H ₅ O-CO-NH-SO ₂ -N ^^^ N-CO-NH-CH-CO-NH-J-K

CH ₂ -CH ₂

This penicillin was prepared in the manner described in Example 20 from ampicillin (9.8 parts by weight) and 3- (ethoxycarbonyltrimethylsilylaminoH-imidazolidine ^ -one-i-carbonyl chloride, FS.ew parts).

Yield: 2.8 parts by weight of β-lactam content: 76.8%

NMR signals at τ = 2.4-2.7 (5H), 6.3-6.7 (3H), 5.8 (1H), 5.85-6.4 (6H), 8.3 -8.6 (6H) and 8.6-8.95 ppm (3H).

The 3- {ethoxy-carbonyl-trimethylsilylamino) -imidazolidin-2-one-1-carbonyl chloride used in the preparation of this penicillin was obtained by the following procedure: 3- (ethoxycarbonyl-trimethylsilylamino) -imidazolidin-2-one-1-carbonyl chloride

c ₂ H ₅ O-CO-N-So ₂ -rr ^^^

V ^{7 C1}

A mixture of the internal salt of ethyl (carboxysulfamoyl) triethylammonium hydroxide (GM Atkins, Jr., EM Burgers) (12.5 parts by weight) and imidazolidin-2-one (4.0 parts by weight) was bathed for 2 hours heated from 100 ⁰ C, dissolved the thick oil obtained in dichloromethane (80Vol. parts), triethylamine (10,9Vol. parts) added, then this solution is heated to boiling and thereby the solution vonTrimethylchlorsilan (15,8Gew.-parts) in benzene (30VOL TeNe) added dropwise. Subsequently, 3h. continue to boil under reflux. Then an additional 80 parts by volume of benzene were added and refluxed again for 3 hours. To

Standing overnight at 2O ⁰ C solvent was distilled off under normal pressure to a boiling point of 7O-75 ° C, then the hot triethylamine hydrochloride was filtered off with suction and the filtrate after cooling with the solution of phosgene (5.3 parts by weight) in benzene (20 parts by weight) combined. This mixture was allowed 24 hours. Well sealed at 20 ⁰ C stand. It was then filtered off with suction from the undissolved material and the filtrate was completely evaporated in a rotary evaporator. It left an oil which has a double band in the IR spectrum in the carbonyl region with peaks at 1790 and 1730 cm ^-1 (in dichloromethane) The substance was used without further purification for the reaction with ampicillin.

Example 23

D-a - [(3-cyclohexyloxycarbonyl-imidazolidin-2-on-1-yl) carbonyl-amino] -benzylpenicillin sodium:

° ^0Na

This penicillin was prepared in the manner described in Example 20 from ampicillin (6.6 parts by weight) and 3-cyclohexyloxycarbonylimidazolidin-2-one-i-carbonyl chloride (4.0 parts by weight).

Yield: 1.6 parts by weight of β-lactam content: 63.7%

Calculated: C 48.3 H 5.8 N 10.5 S 4.8 Found: C 47.5 H 7.0 N 10.5 S 5.1

NMR signals at τ = 2.5-2.7 (5H), 4.3-4.7 (3H), 5.8 (1H), 6.0-6.3 (5H), and 8.1 -9.2ppm (16H). 3-cyclohexyloxycarbonyl-imidazolidin-2-one-i-carbonyl chloride:

-CO-N " ^COv N-CC

To the mixture of imidazolidin-2-one-i-carbonyl chloride (7.4 parts by weight), tetrahydrofuran (50Vol-TeNe) and cyclohexanol (5.5 parts by weight) was added with stirring and cooling with ice triethylamine (5.8 wt Added dropwise, then stirred slowly overnight at room temperature, then boiled under reflux for a further T hour and sucked hot from Triäthylaminhydrochlorid. The filtrate was totally evaporated in vacuo, the residue was triturated with cyclohexane, the solid product was filtered off with suction and dried for 3 days in a desiccator. Yield: 5.0 parts by weight. This substance (5.0 parts by weight) was then suspended in tetrahydrofuran, triethylamine (5.2 parts by volume) added, the mixture was refluxed, and the solution of trimethylchlorosilane (3.8 parts by weight) in tetrahydrofuran (10 vol .) Parts dripped. The mixture was then refluxed overnight, and then sucked hot from the insoluble. To the filtrate, the solution of phosgene (2.6 parts by weight) in tetrahydrofuran (10 parts by volume) was added slowly at room temperature and the mixture was left for 24 h. be well closed at room temperature. Then an existing precipitate (mostly triethylamine hydrochloride) was filtered off with suction and the filtrate was completely evaporated in vacuo. The crystalline residue was dried in a desiccator. The substance has a broad absorption between 1 680 and 1820cm ~ ¹ in the carbonyl region of the IR spectrum (Nujol). It was reacted with ampicillin in this form.

Example 24

D-a-IO Aethansulfonyl-imidazolidin ^ -one-i-YLJ-carbonylaminol-benzylpenicillin sodium:

/ CO. ^(R)

C ₂ H ₅ -SO ₂ -N ^{/ OU} N-CO-NH-CH-CO-NH-

COONa

This penicillin was prepared in the manner described in Example 20 from ampicillin (9.4 parts by weight) and 3-ethanesulfonylimidazolidin-2-one-i-carbonyl chloride (5.0 parts by weight).

Yield: 5.7 parts by weight of β-lactam content: 89.1%

The penicillin contains about 3.3% sodium 2-ethylhexanoate and 6.7% water. This was taken into account in the calculated values of the analysis data.

Calculated: C 43.2 H 5.1 N 11.0 S 10.0 Found: C 43.3 H 5.8 N 10.8 S 9.9

S-Aethanesulfonyl-imidazolidine ^ -one-i-carbonyl chloride: C ₂ H ₅ -SO ₂ -

N-Aethansulfonyl-imidazolidine-2-one:

The mixture of imidazolidin-2-one (21.5 parts by weight) and ethanesulfonyl chloride (32.5 parts by weight) were allowed to stand for 4h. heated in a bath 150 ° C to 180 ⁰ C. Then the HCI development was largely completed. The reaction product was then boiled out successively twice each time with benzene, acetone and ethyl acetate on the water bath and the extracts were poured off. The combined extracts were completely evaporated in vacuo and the residue once from ethyl acetate and once out

Reconstituted acetone (here with the addition of carbon powder).

Yield: 8.1 parts by weight

Melting point: 114 ° C.

The N-Aethansulfonyl-imidazolidin-2-one was then suspended in dichloromethane, a large excess of phosgene at 0 ⁰ C, a little pyridine and the mixture was allowed to stand overnight. Then, the excess was largely removed by introducing dry air and the product slurried in dichloromethane and filtered with suction.

Melting point: 174 ° C

Calculated: C 30.0 H 3.8 Cl 14.8 N 11.6 S 13.3 Found: C 30.1 H 3.8 Cl 14.7 N 11.8 S 13.3

Example 25

A) D-a - [(2-tosylamino-imidazoline (2) -1-yl) -carbonylamino] -benzylpenicillin sodium:

CH ₃ - / ^ -SO _a -NR ^ NjONH-CH-CONH

COONa

This penicillin was prepared in the manner described in Example 1A from 7.5 parts by weight of i-chlorocarbonyl ^ -tosylamino ^ dihydroimidazole and 11 parts by weight of ampicillin:

Yield: 77% β-lactam content: 90%

calculated (water content of 6.1% was taken into account: C 47.9 H 5.0 N 12.4 S 9.5 found: C 48.3 H 4.8 N 10.8 S 9.1 '

IR bands at 3360-3200, 1775, 1725, 1675, 608, 1538, 1290 and 1146 cm ^-1 (in Nujol).

NMR signals at τ = 2.2 (2H), 2.4-2.9 (7H), 4.5 (3H), 5.8 (1H), 6.25 (4H), 7.6 ( 3H), 8.4 (3H) and 8.5ppm (3H).

B) i-Chlorocarbonyl-tosylamino-6-dihydro-imidazole:

CH ₃ - / "VsO ₂ -NiT ^X COC1

By boiling for 10 minutes in 150 parts by volume of absolute tetrahydrofuran, 12 parts by weight of 2-tosylimino-imidazolidine (prepared according to Gompper and Hagele, Ber.99, 2892 [1966]) were dissolved and then quickly brought to 0 ° C. by swirling in an ice bath cooled. 6Gew.-parts of phosgene were added with stirring to the suspension, stirred for 30 minutes at 0 ° C, then added dropwise 5Gew.-parts of triethylamine and then stirred after 3h. at room temperature. With a dry air stream, the excess phosgene was blown out, the tetrahydrofuran solution was filtered off with suction from the precipitated triethylamine hydrochloride, which was washed well with absolute tetrahydrofuran. The combined solutions were evaporated to dryness in vacuo and the residual oil crystallized by trituration with methylene chloride and ether, filtered off with suction and dried in vacuo. Melting point = 101 ° C (decomposition)

 Yield: 59%.

Calculated: C 43.8 H 4.0 Cl 11.8 N 13.9 S 10.6

found: C 43.0 H 4.3 CM 3.5 N 12.4 S 10.0 IR bands at 3340, 3050, 176, 1765, 628, 126, 145, 877 and 905 cm ^-1 (in Nujol) ,

Example 26

A) D-a - [(2-Oxo-3-propionyl-1-imidazolidinyl) carbonylamino] -benzylpenicillin sodium:

CH ₃ CH ₂ CO-> rHT-CONH-CH-CONH

CH ₃ CH ₃

COONa

This penicillin was prepared in the manner described in Example 1A from 9 parts by weight of i-chlorocarbonyl-oxo-S-propionyl-imidazolidine and 17.5 parts by weight of ampicillin.

Yield: 38% β-lactam content: 89%

calculated: (water content of 2% was taken into account):

C 50.1 H 5.0 N 12.7 S 5.8 Found: 49.8 H 6.3 N 12.7 S 5.6

IR bands at 3290.1, 760.1, 732.1, 670.1, 603.1, 525 and 1 250 cm ^-1 (in nujol).

NMR signals at τ = 2.3-2.8 (5H), 4.35 (1H), 4.5 (2H), 5.8 (1H), 6.0-6.3 (4H) , 7.1 (2H), 8.4 (3H), 8.5 (3H) and 8.8ppm (3H).

B) i-Chlorocarbonyl ^ -oxo-S-propionyl-imidazolidine:

CH ₃ CH ₂ '

12 parts by weight of 1-propionyl-2-oxo-imidazolidine, IS ^ parts by weight of trimethylchlorosilane, 15.1 parts by weight of triethylamine and 80 parts by volume of toluene were refluxed together with stirring overnight and after cooling from the precipitate filtered off, which was washed with toluene. The combined solutions were mixed with 9 parts by weight of phosgene, allowed to stand overnight at room temperature, then evaporated in vacuo and the residue was dried on the oil pump. The product was reacted in this form with ampicillin (Example 26A).

IR bands at 1822, 1770-1680, 1 385 and 1 280-1210 cm " ¹ .

C) t-Propionyl-2-oxo-imidazolidine:

CH ₃ CH ₂ COI

This substance was prepared in the manner described in Example C from 17.2 parts by weight of 2-oxo-imidazolidine and 20.4 parts by weight of propionic acid chloride. Mp = 147 ^° C. (from chloroform).

Yield: 45%

Calculated: C 50.7 H 7.0 N 19.7 'Found: C 49.2 H 7.1 N 20.2

[R bands at 3240,1760-1736,1 678 and 1280cm " ¹ .

NMR signals at τ (in CDCl ₃ ) = 3.8 (1H), 6.1 (2H), 6.4 (2H), 7.1 (2H) and 8.8ppm (3H)

Example 27

D-a - [(2-oxo-3-benzenesulfonyl-1-imidazolidinyl) -carbonylamido] -benzylpenicillin sodium:

0 - ^ N-CONH-CH-CONH

This penicillin was prepared in the manner described in Example 1A from 5 parts by weight of i-chlorocarbonyl-oxo-S-benzenesulfonyl-imidazolidine and 7.5 parts by weight of ampicillin.

Yield: 94% β-lactam content: 95%

calculated (the water content of 3.5% was taken into account):

C48,0H4,4N10,8S9,9 found: C48,1H4,6N10,9S10,5

IR bands at 3300, 1770, 1740, 1680, ¹ 610, 1530, ^1, 260, 1184 and 1136 cm ^-1 .

NMR signals at τ = 1.8-2.1 (2H), 2.2-2.8 (8H), 4.4 (1H), 4.5 (2H), 5.8 (1H) , 6.15 (4H), 8.45 (3H) and 8.5 ppm (3H).

B) i-chlorocarbonyl-oxo-S-benzenesulfonyl-imidazolidine:

COCI

The mixture at 0 ⁰ C of 80 parts by weight of i-benzenesulfonyl-2-oxo-imidazolidine, 69 parts by weight of phosgene, 31.6 parts by weight of pyridine and 350 parts by volume of dichloromethane was stirred overnight at room temperature and then evaporated to dryness. It was then slurried in 500 parts by volume of ice water, filtered off with suction, the residue was taken up in 500 parts by volume of dichloromethane, dried over MgSci, filtered, the solution was evaporated again to dryness and recrystallized from acetone / petroleum ether. Mp = 161 ⁰ C.

Yield: 64%

Calculated: C41.6 H3.5 CM 2.3 N 9.7 S 11.1 Found: C41.6 H3.0 Cl12.2 N9.7 S10.7

IR bands at 1802,1732,1318 and 1,200cm " ¹ , (in Nujol)

 NMR signals at τ = 1.8-2.1 (2H), 2.1-2.5 (3H), and 5.7-6.1 ppm (4H).

C) i-benzenesulfonyl-2-oxo-imidazolidine:

86 parts by weight of 2-oxo-imidazolidine, 194 parts by weight of benzenesulfonyl chloride, 800 parts by volume of tetrahydrofuran, 500 parts by volume of chloroform and 101 parts by weight of triethylamine were stirred overnight at 5O ⁰ C and then evaporated to dryness in vacuo , The residue was added gradually with stirring to 1000 parts by volume of ice water, filtered off with suction and the residue was recrystallized from ethanol. = 155 ° C

 Yield: 35%.

Calculated: C47.7H4.4N'12.4S14.2 Found: C47.8 H4.5 N 12.2 S 14.3

IR bands at 3280,1740,1700,1 280,1178,1095 and 1060CnT ¹ (in Nujol).

NMR signals at T = 1.8-2.6 (6H), 6.1 (2H) and 6.7ppm (2H) (in DMSO-d ₆ ). ,

Example 28

D-a- (4-imino-5-ethoxycarbonyl-biureido) -benzylpenicillin sodium:

CH, CH ₂ OCQNH-C-NH-CO-NH-Ah-CONH

COONa

To the stirred solution of 16.3 parts by weight of ampicillin and 5.7 parts by weight of triethylamine in 100 parts by volume of water, 8 parts by weight of i-fN-nitroso-N-methyl-aminocarbonyD were added in portions over 15 minutes -S-äthoxycarbonylguanidinzu. The initially foaming mixture was 4h. Stirred at room temperature, filtered with suction from undissolved overcoated with 200 parts by volume of ethyl acetate and acidified to pH = 2 with ice cooling with dilute hydrochloric acid. From the ethyl acetate solution of penicillin, as described in Example 1A, the penicillin was isolated by precipitation with sodium 2-ethylhexanoatiösung as the sodium salt.

Yield: 15%

β-lactam content: 66% IR bands at 3250, 1760 and 1665 cm ^-1 .

NMR signals at τ = 2.4-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (3H), 8.4 (3H), 8.5 ( 3H) and 8,8ppm

B)! - (N-nitroso-N-methyl-aminocarbony O-S-ethoxycarbonylguanidine:

CH ₃ CH ₂ OCONH-C-NH-CO-N-NQ

CH ₃

The solution of 7.3 parts by weight of sodium nitrite in 13 parts by volume of water was added dropwise over 20 minutes to the ice-cooled solution of 11 parts by weight of .alpha.-methylaminocarbonyO-S-ethoxycarbonyl-guanidine in 58 parts by volume of 5 to. One stirred one

Hour at 0 ⁰ C after, sucked off the precipitated yellow precipitate and washed with a little ice water.

Yield: 8.4 parts by weight. The product was reacted in moist form to give penicillin according to Example 28A. A small

Sample was dried in vacuo over P ₂ Os.

Mp = 116 ° C (dec.).

calculated (the calculation took into account a content of 15% NaCl):

C 28.1 H 4.3 N 27.4 found: C 27.0 H 4.3 N 28.2

IR bands at 3400-2400, 1790, 1762 and 1725 cm ^-1 C) - (methylaminocarbonyl-S-ethoxycarbonyl-guanidine:

CH ₃ CH ₂ OCONH-C-NK-CO-NH-Ch ₃

For the suspension of 10 parts by weight of ethoxycarbonylguanidine (prepared according to Isr. J. Chem. 8,651 [1970]) in 60 parts by volume of anhydrous dioxane, 5.1 parts by weight of methyl isocyanate were added, with the temperature rising to 45 ° C. and the precipitate went into solution. After a short time a crystalline precipitate separated again, which was sucked off after cooling and washed with ether. It was dried in vacuo over P ^ O ₅ and paraffin chips. Mp = 150 ^° C.

Yield: 80%. *. _ -

Calculated: C38.2 H6.4 N 29.8 Found: C38.8 H6.4 N 29.1

IR bands at 3380.3300.1 730.1 700-1600.1 580-1 520, .1300.1 260 and 1155cm ~ ¹ (in Nujol).

NMR signals at τ = 1.0 (3H), 2.8 (1H), 5.95 (2H), 7.3 (3H) and 8.8ppm (3H). (in DMSO-d ₆ )

Example 29

A) D-a-iS-tN-fi.i-dioxo-isothiazolidine ^ -d-carbonyl-S-methyl-ureido-benzylpenicillin sodium:

(R) -CO-N-CO-NH-QH-CO-NH

CH ₃

This penicillin was prepared in the manner described in Example 20 from 12.0 parts by weight of ampicillin and 6.3 parts by weight of N - [(1,1-dioxo-isothiazolidine) -diD-carbonyl-N-methyl-carbamic acid chloride acidification of the penicillin salt solution was acidified to pH 2.0, however, the solution kept at ⁰ ° C, and dried the solution of the free penicillin acid in an ether-Essigester mixture 15 minutes at 0 ⁰ C over MgSO _4.

Yield: 11.2 parts by weight.

β-lactam content: about 100% ^:

The electrophoresis of penicillin showed that only one antibiotic active substance was present. Specific rotation: [a] ₆₈₉ + 141 ° (methanol / water)

NMR signals at τ = 2.4-2.8 (5H), 4.3-4.6 (3H), 5.8 (1H), 5.9-6.3 (2H), 6.4 -6.8 (2H), 6.6 (3H), 7.3-7.7 (2H) and 8.3-8.5ppm (6H).

B) N-Id ^ -dioxo-isothiazolidine ^ -d-carbonyl-N-methylcarbamic acid chloride:

CH ₃

To dissolve 10.0 parts by weight of bis-chlorocarbonyl-methylamine (Farbenfabriken Bayer: German Offenlegungsschrift No. 1932830) in tetrahydrofuran (100 vol-TeNe) was added dropwise at room temperature, the solution of 7.7 parts by weight, 1,1-Dioxoisothiazolidin and 8.8 parts by volume of triethylamine in 30 parts by volume of tetrahydrofuran. The mixture was stirred for 1 hour at room temperature, the resulting triethylamine hydrochloride was filtered off with suction and washed with tetrahydrofuran. The combined filtrates were completely evaporated in vacuo and the residue recrystallized from hot tetrahydrofuran with the addition of some pentane.

Yield: 13.1 parts by weight, mp = 102-103 °

Calculated: C30.0 H3.8 Cl 14.7 N11.6 S 13.3 Found: C30.1 H3.9 CI14.3 N11.6 S13.3

NMR signals at τ = 6.15 (triplic) (2H), 6.65 (triplic) (2H), 6.8 (3H), and 7.3-7.9 ppm (multipl) (2H). IR spectrum: 1700 and 1740cm " ¹ (C = O).

Example 30

A) D-a {[3- (Methylsulfonyl-amino-carbonyl) -imidazolidinon-2-yl-1] -carbonylamino} -benzylpenicillin sodium:

CH ₃ -SO ₂ -NH-CO-N ^^ N-CO-NH-CH-CO-

This penicillin was prepared from 10.0 parts by weight of ampicillin and 5.9 parts by weight of S-t-methylsulfonyl-amino-carbonyl-O-i-chlorocarbonyl-imidazolidinone- (2) in the manner described in Example 20. · _;

Yield: 9.8 parts by weight of β-lactam content: 82%

NMR signals at τ = 2.4-2.8 (5H), 4.3- ^, 65 (3H), 5.8 (1H), 6.05-6.45 (4H), 6.95 (3H) and 8.35-8.75ppm (6H).

calculated *: C40.1H5.2N11.7S8.9 found: C40.4H5.2N11.7S8.8

* (Content of 5.8% sodium 2-ethylhexanoate and 10% water taken into account.)

The penicillin shows in electrophoresis (microbiological evaluation with subtilis) only one spot. B) 1- (Methylsulfonyl-amino-carbonyl) -3-chlorocarbonyl-imidazolidone- (2): CH ₃ -SO ₂ -NH-CO-W ⁰⁰ ^ N-CO-Cl

7.0 parts by weight of 1-chlorocarbonylimidazolidinone- (2) were dissolved or suspended in 50 parts by volume of tetrahydrofuran, 5.7 parts by weight of methanesulfonyl isocyanate were added and the mixture was initially heated for 26 hours. stirred at room temperature. Since virtually no reaction had occurred, 5 drops of pyridine were added and stirred for a further 65 hours at room temperature. Then, a crystalline precipitate was sucked off.

Yield: 10.5 parts by weight

Mp = 218-22O ⁰ C ·

Calculated: C26.7H3.0CI13.1 N15.6S11.9 Found: C27.2H3.2 Cl 12.8N 15.5 S11.9

NMR signals at τ = 5.8-6.2 (multiply) (4H) and 6.7ppm (3H). IR spectrum: 1 800 and 1 730 cm ^-1 (C = O).

Example 31

A) D-α-tS-f-methylsulfonylamino-carbonyl-ureido-benzylpenicillin sodium:

CH ₃ -SO ₂ -NH-CO-NH-CO-NH-CH-CO-NH ^

(R)

CO-NH _n -r ^ ~ V ^ ^c H

CH ₃

H'COONa

This penicillin was prepared in the manner described in Example 20 from 11.2 parts by weight of ampicillin and 6.4 parts by weight of N-mesyl-N'-chlorocarbonylurea.

Yield: 3.4 parts by weight of β-lactam content: 66.5%

* (Content of 6.6% sodium 2-ethyl-hexanoate and 9% water taken into account.)

Calculated: C39.3 H5.1 N 10.9 S 10.0 Found: C39.6 H6.1 N10.2 S10.0

A microbiological (Bact. Subtilis) developed electropherogram showed a second, but very small, inhibition zone in addition to a large inhibition zone.

B) N-mesyl-N'-chlorocarbonylurea: <,

CH ₃ -SO ₂ -NH-CO-NH-Co-CI

To the mixture of 10.5 parts by weight of N-mesylurea, 60 parts by volume of dichloromethane and 15.0 parts by weight of phosgene, 6.1 parts by volume of pyridine were added dropwise with cooling, after a few hours at 0 ° C. removed the excess of the phosgene, the precipitate sucked off and the filtrate was completely concentrated in vacuo. There remained behind a viscous oil, which had a absorption at 1800cm ^"1 in the carbonyl of the IR spectrum. The substance was used without further purification for the preparation of penicillin.

Example 32

A) D-a - [(3-Methylsulfonyl-4- or 5-methyl-imidazolidinone- (2) -yl-1) -carbonylamino] -benzylpenicillin sodium:

H COONa

This penicillin was prepared from 12.0 parts by weight of ampicillin and 7.7 parts by weight of 1-methylsulfonyl-S-chlorocarbonyl ^ - or -5-methylimidazolidinon- (2) in the Be! 20 described manner.

Yield: 9.3 parts by weight of β-lactam content: 94%

Calculated: (with 1.33 moles of H ₂ O):

C44,0H4,8N11,7S10,7 found: C44,0H5,0N11,4S10,6

Specific rotation: [a] ₅₈ 9 + 135.9 ° (methanol-water)

NMR signals at T = 2.3-2.65 (5H), 4.25-4.6 (3H), 5.75 (1H), 5.8-6.4 (3H), 6.6 (3H), 8.3-8.5 (6H) and 8.6-8.8ppm (3H).

B) i-Methanesulfonyl-S-chlorocarbonyl- or -5-methylimidazolidinone- (2):

CH ₃

1 part by weight of methanesulphonic W- or 5-imidazolidinone- (2) were added to the solution of 15 parts by weight of phosgene in 60 parts by volume of dichloromethane, and at 0 ° C., 6.1 parts by volume of pyridine were added dropwise , It was then allowed to stand at room temperature overnight, remaining phosgene was removed by means of a dry stream of air and then the solution was completely concentrated in vacuo. The residue, an oil, was dried in a desiccator over P ₂ Os.

Yield: 27 parts by weight

IR bands in the carbonyl range: 1800, 1760 and 1720 cm ^-1 .

C) i-methanesulfonyl-4-resp. -5-methyl-imidazolidinone (2)

CH ₃ ·.

The mixture of 53.8 parts by weight of 4-methylimidazolidinone- (2) and 64.6 parts by weight of methanesulfonyl chloride was heated in a bath of 9O ⁰ C until completion of HCl evolution (about 7 hours). The crude product obtained (yield 34.2 parts by weight) melted at 131-133 ° C. Recrystallization from water on a water bath gives a product with a melting point of 135 ° C.

calculated: C33.7H5.7N15.7S18.0

Found: C33.5 H5.5 N 15.3 S 18.2

NMR signals at τ = 5.9-6.7 (multiply) (3H), 6.75 (3H) and 8.65 u. 8,75ppm (3H) (Dubl.). D) 4-Methylimidazolidinone- (2):

This substance was dissolved by lOstdg. Heating a mixture of 383 parts by weight of 1,2-diaminopropane and 611 parts by weight of diethyl carbonate in an autoclave to 180 ° C and recrystallization from isopropanol and methanol.

Yield: 109 parts by weight of Mp = 130 ⁰ C.

Example 33

A) D-α- [3- (Thienyl (2) sulfonyl) -imidazolidin-2-one-1-ylcarbonylamino] benzylpenicillin sodium:

This penicillin was prepared in the manner described in Example 1A from 3.3 parts by weight of 1-chlorocarbonyl-2-oxo-3- (thienyl) (2) sulfonyl-imidazolidine and 5.0 parts by weight of ampicillin.

Yield: 89% β-lactam content: 83%

Calculated: * C43.4H4.4 N 10.2 S 14.1 Found: C43.7H4.2 N 10.2 S14.1

* (Calculation of analytical data considered the water content of 6.4% and the sodium 2-ethylhexanoate content of 2.1%.) IR bands at 3320,1170,1742,1680,1 610,1 530, 1 258 and 1188cm ' ¹

NMR signals at τ = 2.0-2.2 (2H), 2.4-2.9 (6H), 4.4 (1H), 4.5 (2H), 5.8 (1H) , 6.2 (4H), 8.45 (3H), and 8.5ppm (3H).

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

This carbamic acid chloride was prepared in the manner described in Example 27B from 2.4 parts by weight of 1- (thienyl (2) sulfonyl) -2-oxo-imidazolinine and 2.7 parts by weight phosgene.

Yield: 80%. Mp = 166X.

IR bands at 3080,1800,1.728,1300 and 1178cm " ¹ (in Nujol).

C) 1- (thienyl (2) sulfonyl) -2-oxo-imidazolidine:

14Gew.-parts of 2-chlorosulfonyl-thiophene and 6,6Gew.-Teilelmidazolidon-2 to the end of the evolution of HCl was heated with stirring to 15O ⁰ C (about 4h.). It was then cooled, shaken with 150 parts by volume of chloroform / H ₂ O (2: 1), the chloroform layer separated, dried over MgSO ₄ , boiled with animal charcoal, filtered off with suction and evaporated to dryness. The residue was recrystallized from acetone.

Yield: 20.2%. . Mp = 174 ⁰ C. calculated found C31,1H3,5N12,0S27,5: C35,8H3,5 N11,9S27,5

[R bands at 3230, 3080, 1738, 1705, 1122 and 1062 cm " ¹ (in Nujol)."

NMR signals at τ = 2.1-2.4 (2H), 2.8-3.0 (1H), 4.0 (1H), 5.9-6.2 (2H) and 6, 3-6.7ppm (2H) (in CDCI ₃ ). D) 2-chlorosulfonyl-thiophene:

The compound was prepared according to the instructions for methylthiophenesulfochloride in J. org. Chem. 33, 1357 (1968) from thiophene, chlorosulfonic acid and PCI ₅ in 70% yield as a low-melting solid. Kp ₈ = 117 ⁰ C

Calculated: C26.3 H 1.6 Cl 19.4 S35.0 Found: C25.9 H2.6 Cl 19.4 S34.2 IR bands at 3110.1196, 1032 and 740 cm ^-1 NMR signals τ = 2.08 (2H) and 2.75 ppm (ΊH).

Example 34 A.) D-a - [(2-Oxo-3-acetyl-1,3-diaza-cyclohex-1-yl) carbonylamino] -benzylpenicillin sodium:

This penicillin was prepared in the manner described in Example 1A from 7.6 parts by weight of i-chlorocarbonyl ^ -oxo-S-acetyl-TiS-diazacyclohexane and 16.5 parts by weight of ampicillin.

Yield: 93%

β-lactam content: 94%. -

calculated: * C48.1 H5.2N12.2S5.5 found: C48.0 H 5.5 N 12.2 S6.2

* (The calculation took into account the water content of 6%.) IR bands at 3250, 1772, 1700, 6.115, 520, 1305 and 1180 cm " ¹ .

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H) 6.0-6.4 (4H), 7.5 (3H), 7.8-8.3 (2H), 8.4 (3H) and 8.5ppm (3H).

B) 1-chlorocarbonyl-2-oxo-3-acety! -1,3-diaza-cyclohexane:

- N ^ N-COCC

This carbamic acid chloride was prepared in the manner described in Example 27 B from 7.1 parts by weight of 1-acetyl-2-oxo-1,3-diazacyclohexane and 10 parts by weight of phosgene. Oil.

Yield: 89%

Calculated: C41 / I H4.4 Cl 17.4 N 13.7 Found: C41.1 H4.5 Cl 17.1 N 13.3 IR bands at 2950, 1800, 1730, 1706, 1400, 176, 16, 320, 1295 , 1,202,1178 and 1054cm- ¹ . NMR signals at τ = 5.9-6.3 (4H), 7.45 (3H) and 7.65-8.15ppm (2H). C) i-acetyl-oxo-ijS-diaza-cyclohexane:

CK COr-Λ / / VW

³ ] \ J

The mixture of 10 parts by weight of iso-diaza-cyclohexane ^ -one, 11.8 parts by weight of acetyl chloride, 8.7 parts by weight of pyridine, 50 parts by weight of tetrahydrofuran and 50 parts by volume of chloroform was heated for 24 hours. stirred at room temperature, filtered off with suction and washed with tetrahydrofuran / chloroform (1: 1). The combined solutions were evaporated to dryness, recrystallized from acetone / ethanol, added with 50 parts by volume of semi-saturated NaHCO ₃ solution and extracted 3 times with 50VoI.-parts of ethyl acetate. The extracts dried over MgSO ₄ were evaporated; the residue was crystallized from acetone / petyl ether.

Yield: 53%. Mp = 132 ^° C.

C50.7 H7.0 N 19.7 Found: C50.5 H7.1 N 20.1 IR bands at 3345.1708.1664.1320.1 281.1250.1175, 1130 and 1022 cm ^-1 (in Nujol) NMR signals at τ = 6.1-6.4 (2H), 6.6-6.85 (2H), 7.5 (3H) and 7.8-8.3ppm (2H) ( in CD ₃ OD).

Example 35

A) D-a [(3-Formyl-1,3-diaza-cyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin sodium:

H CO - / V ^ / V -CONH-CH-CONH

This penicillin was prepared in the manner described in Example 1A from 8.1 parts by weight of i-chlorocarbonyl-oxo-S-formyl-1S-diaza-cyclohexane and 18.9 parts by weight of ampicillin.

Yield: 41% β-lactam content: 94%

calculated *: C 48.7 H 4.8 N 12.9 S 5.9

found: C 48.4 H 5.4 N 11.3 S 6.5

* The calculation took into account the water content of 3%). IR bands at 3270, 1765, 1700, 1675, ¹ 603, 1310 and 1183 cm ^-1 .

NMR signals at τ = 0.6 (1H), 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.0-6.5 (4H), 7.75 (2H), 8.4 (3H), and 8.5 ppm (3H). B) i-Chlorocarbonyl-oxo-S-formyl-S-diaza-cyclohexane:

H-CO-NΝ-COCt

This carminic acid chloride was prepared in the manner described in Example 27 B. from 5 parts by weight of 1-formyl-2-oxo-1,3-diaza-

cyclohexane and 6 parts by weight of phosgene.

The resulting oil was reacted immediately, as described in Example 35 A, with ampicillin.

IR bands at 1790.1, 685.1, 300 and 1165 cm ^-1 .

C) i-Formyl ^ -oxo-1-S-diaza-cyclohexane:

The mixture of 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 49 parts by weight of trimethylchlorosilane, 25 parts by weight of triethylamine and 150 parts by volume of dioxane was boiled with stirring and exclusion of moisture for 3 days, then filtered, concentrated to 50 parts by volume in vacuo and stirred with 11.5 parts by weight of formic acid-acetic anhydride at room temperature overnight. The mixture was evaporated to dryness in vacuo and the residue recrystallized from ethanol / ether.

Yield: 40%, mp = 100 ^° C.

Calculated: C46.9H 6.9N 21.9 Found: C46.7H 6.3N 22.0

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

Example 36

A) D-a - [(3-Mesyl-1,3-diaza-cyclohexan-2-one-1-yl) carbonylamino] -benzylpenicillin sodium:

Oona,

This penicillin was prepared in the manner described in Example 1A from 5.6 parts by weight of i-chlorocarbony W-oxo-S-mesyl-1'-diaza-cyclohexane and 10 parts by weight of ampicillin.

Yield: 52% β-lactam content: 94%

calculated *: C44.8 H 4.8 N 11.4 S 10.4 Found: C 44.9 H 5.1 N 11.0 S 10.3

* (For the calculation of the analytical values, the water content was 2.9% and the sodium 2-ethylhexanoate content of

2.9% taken into account). · -.

[R bands at 3300, 1750, 1705-1 665.1, 605.1, 515, 1345 and 1164 cm " ¹ .

NMR signals at τ = 2.3-2.8 (5H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.0-6.4 (4H) , 6.6 (3H), 7.7-8.3 (2H), 8.4 (3H) and 8.5 ppm (3H).

B) 1-Chlorocarbonyl-2-oxo-3-mesyl-1,3-diaza-cyclohexane:

CM SO - / V N-

This carbamic acid chloride was prepared in the manner described in Example 4B from 4.5 parts by weight of 1-mesyl-2-oxo-1,3-diaza-

cyclohexane, 6.9 parts by weight of trimethylchlorosilane and 5.2 parts by weight of phosgene. The oily crude product was used as such for reaction with ampicillin (Example 36A).

Yield: 83%.

IR bands at 2980, 2950, 1790, 1760, 1680, 1452, 1355, 215, 1662, 982 and 855 cm ^-1 .

C) i-mesyl-oxo-LS-diazacyclohexane:

, ₃ SO-N

This compound was prepared in the manner described in Example 35C from 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 49 parts by weight of trimethylchlorosilane and 30 parts by weight of mesyl chloride. The product recrystallized at low temperature from acetone and then from acetone / ethanol was obtained in 34% yield. Mp = 172 ° C.

IR bands at 3210,3070,1692,1340 and 1170cm " ¹ (in nujol)

NMR signals at τ = 6.25 (2H), 6.5-6.8 (2H), 6.7 (3H) and 7.8-8.3ppm (2H) (in CD ₃ OD). * see the next page

Example 37

A) D-a - [(3-phenylsulfonyl-1,3-diaza-cyclohexan-2-one-1-yl) carbonylamino] benzylpenicillin sodium:

W ₁

r-, A / V ^ S

COOMu

This penicillin was prepared in the manner described in Example 1A from 2.6 parts by weight of 1-chlorocarbonyl-oxo-S-phenylsulfonyl-1,3-diaza-cyclohexane and 3.8 parts by weight of ampicillin.

Yield: 82%

 β-lactam content: 85%.

IR bands at 3300, 1770, 1695, 1610, 1520 and. 1180cm " ¹ .

NMR signals at τ = 1.9-2.1 (2H), 2.3-2.6 (3H), 2.6 (5H), 4.54 (1H), 4.6 (2H) , 5.85 (1H), 5.9-6.5 (4H), 7.8-8.25 (2H), 8.47 (3H) and 8.52ppm (3H).

B) 1-Chlorocarbonyl-2-oxo-3-phenylsulfonyl-1,3-diaza-cyclohexane:

λ.

N / A

This carbamic acid chloride was prepared in the manner described in Example 27 B from 6 parts by weight of 1-phenylsulfonyl-2-oxo-1,3-diaza-cyclohexane and 5 parts by weight of phosgene. The product recrystallized from acetone / petroleum ether, mp. = 123 ⁰ C was obtained in 35% yield

IR bands at 3350.1, 790.1, 692 and 1162cm " ¹ (in nujol)

C) i-Phenylsulfonyl-oxo-1'-diaza-cyclohexane:

To the stirred mixture of 10 parts by weight of 1,3-diaza-cyclohexan-2-one, 80 parts by volume of tetrahydrofuran and 80 parts by volume of chloroform were added dropwise over 15 min. at 10-15 ⁰ C 20.4 parts by weight of benzenesulfonyl chloride in 20VoI.-parts of tetrahydrofuran, then at the same temperature 10.1 parts by weight of triethylamine. The mixture was stirred for 30 minutes at 10-15 ⁰ C and then overnight at 5O ⁰ C. Then was evaporated to dryness, the residue stirred lOOVol. parts water, filtered with suction, again slurried with water, filtered off with suction and washed with ethanol.

Yield: 28%, mp = 207 ^° C.

Calculated: C 50.0 H 5.0 N 11.7 S 13.3 Found: C 49.0 H 5, ON 11.7 S 12.5

IR bands at 3320, 1665, 1348, 1300 and 1175 cm ^-1 (in Nujol).

NMR signals at τ = 1.8-2.2 (2H), 2.3-2.7 (3H), 6.0 (2H), 6.7 (2H) and 8.0 ppm (2H) (in CDCI ₃ ).

* calculated: C 33.7 H 5.6 N 15.8 S 18.0 found: C 33.4 H 5.7 N 15.6 S 17.3

Example 38

D-a - [(3-methylsulfonyi-imidazolidinone- (2) -yl-1-carbonylamino] -1,4-cyclohexadien-yl-1-methylpenicillin sodium:

_x co ^

CH, -SO ₂ -N N-CO-NH-CH-CO-I

"" "" "COONa

This penicillin was prepared from 2.5 parts by weight of Da-amino-1-cyclohexadienyl-1-methylpenicillin and 1.6 parts by weight of 1-methylsulfonyl-3-chlorocarbonyl-imidazolidinone- (2) in the manner described in Example 20 Made way.

Yield: 2.6 parts by weight of β-lactam content: 87%

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

Example 39

D-a - [(2-oxo-3-mesyl-imidazolidin-1-yl) carbonylamino] -benzylpenicillin sodium

JLY S/ CH

CH, S0 _o tf N CO NH - CH - CO NH - i f V 3

³ ^ '(R) / - ^N Y ^ ^H 3

^u COONa

A) Ampicillin trimethylsilyl ester

CH

/ - \ ^W

CH-CO NH NH ₂

COO-Si (CH ₃ ) ₃

20.2 parts by weight of ampicillin trihydrate, 11.1 parts by weight of triethylamine and 20 parts by weight of anhydrous sodium sulfate were stirred in 250 parts by volume of methylene chloride for two hours at room temperature; It was then filtered off with suction, washed with methylene chloride and the combined organic phases were added dropwise while cooling with cold water with 5.5 parts by weight of trimethylchlorosilanes in 50 parts by volume of methylene chloride. The solution was stirred for 30 minutes.

BJD-α-Cia-oxo-S-mesyl-imidazolidin-1-ylJ-carbonylaminol-benzylpenicillin sodium from ampicillin trimethylsilyl ester The solution of the ampicillin trimethylsilyl ester in methylene chloride obtained according to a) was added in portions to the reaction vessel with exclusion of moisture and stirring within 15 minutes. 3 parts by weight of 1-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine in solid form, stirred for 1 hour at room temperature and then evaporated to dryness on a rotary evaporator. The solid residue was treated with 400 parts by volume of water, the mixture was adjusted to pH 7 and extracted with 200 parts by volume of ethyl acetate, which was discarded. The aqueous phase was again treated with 200 parts by volume of ethyl acetate, acidified with 2 η HCl pH = 2 , the ethyl acetate separated and the aqueous phase extracted once with 200 parts by volume of ethyl acetate. The combined ethyl acetate solutions were dried over MgSO ₄ , added after separating the MgSO ₄ with 50Vol.-parts of a Tmolaren solution of sodium 2-ethylhexanoat in methanol-containing ether, the solvent was removed to the oily consistency of the residue on a rotary evaporator and dissolved in the same amount methanol. The resulting solution was allowed to flow in a thin stream with vigorous stirring in an ice-cold mixture of 1 OOOVol.-parts ether and 100Vol.-parts of methanol, the precipitated product was filtered off with suction, washed with ether and dried over P ₂ O ₅ and Paraffinschnitzeln in vak. Desiccator. Yield of Da - [(2-oxo-3-mesyl-imidazolidin-1-yl) carbonylaminobenzylpenicillin sodium: 27 parts by weight of β-lactam content: 85%.

IR bands at 3305, 1760, 1728, 1670, ¹ 605, 1360 and 1174 cm ^-1 .

NMR signals at τ = 2.3-2.7 (5H), 4.35 (1H), 4.5 (2H), 5.8-6.2 (4H), 6.65 (3H), 8.4 (3H) and 8.5ppm (3H).

Example 40 D-a - ^ - Oxo-S-mesylimidazolidine-i-yD-carbonylaminol-benzylpenicillin sodium

CH _x SO ₀ N ^ N CO NH - CH - CO NH

A) N-trimethylsilyl-ampicillin trimethylsilyl ester

- CO NH

NH Si (CH 2).

  χ

CH,

»Y CH ₃

COO-Si (CH ₃ ) ₃

20.2 parts by weight of ampicillin trihydrate, 11.1 parts by weight of triethylamine and 20 parts by weight of anhydrous sodium sulfate were stirred in 250 parts by volume of methylene chloride for two hours at room temperature; then sucked off, washed with methylene chloride and the combined organic phases with 5.0 parts by weight of triethylamine and then added dropwise with cooling with cold water dropwise with 11 parts by weight of trimethylchlorosilane in 100VoI.-parts of methylene chloride. The solution was stirred for 30 minutes.

B) D-a - [(2-Oxo-3-mesylimidazolidin-1-yl) carbonylamino] -benzylpenicillin sodium from N-trimethylsilylampicillin trimethylsilyl ester

The obtained according to a) solution of N-trimethyl-silyl-ampicillin-trimethylsilyl ester in methylene chloride was under. Moisture exclusion and stirring in portions over 15 minutes with 11.3Gew. Parts of solid i-chlorocarbonyl-2-oxo-3-mesyl-imidazolidine, stirred for 1 hour at room temperature and then worked up as described in Example 58b, worked up. The D-a - [(2-oxo-3-mesylimidazolidin-1-yl) carbonylamino] benzylpenicillin sodium was isolated in an amount of 28 parts by weight.

ß-Lactamgehalt90%. -.

Example 41 D-a - [(2-Oxo-3-phenylsulfonylimidazolidin-1-yl) carbonylamino] benzylpenicillin sodium

NCO NH

Oona

A) Ampicillin trimethylsilyl ester

CH-CO NH

COO-Si (CH ₃

4.1 parts by weight of ampicillin trihydrate, 2.94 parts by volume of triethylamine and 6.0 parts by weight of anhydrous magnesium sulfate were stirred in 80 parts by volume of dichloromethane for 2 hours at 20 ⁰ C. It was then filtered off with suction, washed with dichloromethane and the combined organic solutions were added dropwise while cooling (with cold water) with 1.1 parts by weight of trimethylchlorosilane in 30 parts by volume of dichloromethane. The solution was stirred for 30 minutes.

B) Da-tia-oxo-S-phenylsulfonyl-imidazolidin-1-yd-carbonylaminol-benzylpenicillin sodium from ampicillin trimethylsilyl ester The solution of the ampicillin trimethylsilyl ester in dichloromethane obtained according to a) was hydrolyzed with 2.9 parts by weight of i-chlorocarbonyl ^ -oxo-S-phenylsulfonyl-imidazoline in solid form, stirred for 1 hour at 20 ⁰ C and evaporated on a rotary evaporator to dryness. The solid residue was suspended in water, with yerd. NaOH, the pH adjusted to 7.0-7.5 with stirring and the slightly cloudy solution once carefully extracted with ethyl acetate. After separating off the organic phase, the aqueous phase was covered with fresh ethyl acetate and acidified with stirring to pH 2 with dilute HCl. °

The organic phase was then separated, washed with saturated NaCl solution, diluted to twice its volume with ether and the sodium salt precipitated using a 1 molar sodium 2-ethylhexanoate solution in methanol-containing (about 5%) ether. The precipitate was initially oily. After stripping off all solvents and absolute ether, the precipitate became powdery. To

vacuuming and washing with ether containing 10% methanol was dried over P ₄ O _{10 in a} desiccator.

Yield: 5.9 parts by weight of D-α-i (2-oxo-3-phenylsulfonyl-imidazolidin-1-yl) carbonylamino] benzylpenicillin sodium. β-lactam content: 80%

IR bands at 3300, 1770, 1740, 1680, 1610, 1530, 1260, 1184, and 1136 cm ^-1 . NMR signals at? = 1.8-2.1 (2H), 2.2-2.8 (?). 8H), 4.4 (1H), 4.5 (2H), 5.8 (1H), 6.15 (4H), 8.45 (3H) and 8.5ppm (3H).

Example 42 D-a [(2-Oxo-3-phenylsulfonyl-imidazolidin-1-yl) -carbonyl-amino] -benzylpenicillin sodium

-S0 ~ K N CO NH - CH - CO NH η

² J

⁰ COONa

A) N-trimethylsilyl-ampicillin trimethylsilyl ester

CH-CO NH

Si (CHj) ₃

4.1 parts by weight of ampicillin trihydrate, 4.2 parts by weight of triethylamine and 6.0 parts by weight of anhydrous magnesium sulfate were stirred in 80 parts by volume of dichloromethane at 2O ⁰ C for 2 hours. It was then filtered off with suction, washed with dichloromethane and the combined organic solutions were added dropwise while cooling (with cold water) with 2.2 parts by weight of trimethylchlorosilane in 30 parts by volume of dichloromethane. The solution was stirred for 30 minutes.

B) D-a - [(2-Oxo-3-phenylsulfonyl-imidazolidin-1-yl) carbonylamino] -benzylpenicillin sodium of N-trimethylsilyl-ampicillin trimethylsilyl ester

The solution of N-trimethylsilyl-ampicillin trimethylsilyl ester obtained in A) in dichloromethane as solvent was added with exclusion of moisture and stirring with 2 $ parts by weight of i-chlorocarbonyl ^ -oxo-S-phenylsulfonyl-imidazolidine (in solid form), 1 hour at 2O ⁰ C and then worked up as described in Example 60 b, worked up. The Da - [(2-oxo-3-phenylsulfonyl-imidazolidine-i-yD-carbonylamino] -benzylpenicillin sodium was obtained in a yield of 5.7 parts by weight as a white powder.

β-lactam content: 71%

3

% OO ν

CL

Oi

ι cn

OJ cn

(U C / -3

£ · ρ

Ό H (/ J OO CU S

* υ O ι I O & O OVj Iu Qj VO H W O ro Ή ο-  Η • Η · H W I Ü , α Ι O α O ο H P U r-l • < P EGG to 0) O co "3 W H . "-) m U -μ O OO .ρ CU O CO ιη CU ιη CM .Ό CO • H ιη CM ♦ ιη VO  <3 " γ-ε ε VO W H O H • Η _) CM H O H H * V O Ü χθ m • r-l f CM • μ W CC • ιη OJ γ-Ι N VO * O ^- O .ic ο "J- ε ο VO ε / \ Η-ι VO H ιη G) * H H CC 1 ε O • Η O - C • Η H CM Σ H ro IN ro m O • o ro H r-l

O LO OJ O UO ro S VO O in 3.1 12.5 3.1 > 400 O CVJ r-l IO ω • ο O O Π? U H ω 14 037 13 033

r-l H t f0 V O OVj O ro H O CM O m CM O CM O fO CM O VO O H OJ O VO O H H O O r-l O UO IO H I O CJ I O O VO VO ro to ro ro O O IO r-l H

in CM from H 200 VO H 200 VO H O in CO in CM <r 12.5 O O o · in CM, · VO VO in CM O O O. a? U H V co m 13 033 m 14 037

Annex 2

₁ iCiIUn (example from I) T) - ^ p 9 / j Rp-CO-ampicillin (example from OD-ft

June 9, 1989

MHK i. U / ml

Ex

 Mr.

E.colj

Prot.

Ps GiTi.

Klebs.

| 4__26j.? _ I§5_ _ 1g3 / 58i ^{m <} 9% ^ 1OVJ I Walt. ^! K 10! 63

R ₁

in-

CH ₂ -CH ₅

13 R ₂ O-C0-N. ' ^C0 V

> 5o j

ι.

1-4-

i i J256

III

(CH ₃ ) JC-CO-N, ^U- N-

-M

20-100

'J, 6' 400 6.2. : '1.6

1.6 400 6.2. 50

512 25

4-16 32

1-6

<1 256 4 4 <1 4 <1 <1 • 5: 1 <i

1-8 ^ Ll

100

20-100

100

: 50 4-16

4-16

4 8th 8th 8th 4-16 4-8

Annex 3

Berlin, 4 August 1989 32 582/12 32 581/12

A-Z-NH-CH-CO APS | MIC | = better than Azlocillin B

Bsp.Nr.

14

A261

C165

183/58

Prot

 morg

 932

vulgar

 1017

PSDM. Walt.

F41

Klebs.

Loo

CH ₃ OCON N-0

CH ₃ SO ₂ NN

CH,

CH.

CO

<0.8

<0.8

400 3, 1 100 256 l 1. 6 U

<1

32-64

1-4

> 256

6.3 6 3 1.6 ⁶ F 3 | 8 8th ]

4-1δΙ

Γΐ. 6

64]

50

25

16

4-16

{32

16

Appendix 3 - continued

Bsp.Nr.

E. coli 14 A261

C165 183/58

Prot. Morg.

vulgar,

PSDM. Walt. F41

Adhesive. Loo

CH. CH.

C ^ N-

CH-OCO-N ^. -

CON N

V-NHCO

Ni ₁ N -

'VOCON,

<1

> 256

<1

> 256

> 256

> 256

> 256

<1

Π.

32

32

32

256

16

32

32

Appendix 3 - continued

Bsp.Nr.

E. coli 14 A261

C165

183/5

Prot. Morg

vulgar.

Ps dm. Walt.

F41

Klebs. KlO f

13

-CON ^ Ji

CH ₃ SO ₂ -N

H-CON

vN

| L2B

LI

> 256

> 256

<1

[256

> 256

16

l0,4

16

32

16

16

32

32

16 '

32

32

32

16

64

64

64

Appendix 3 - continued

Bsp.Nr

E.coli

14 1A261 I C165 183/58

Prot morg

vulgar.

PSDM

 Walt.

F41

Klebs. KlO ι 63

H VOCON H

CH, CH _o S0_N N-3 2 Z

CH, CH "CON N-3 2 \ _j

"VSO ₂ N.

NH

CH ₃ Ch ₂ OCONH-C-NH

<1

128

It Iff

518

> 256

> 256

> 256

16

<J.-B>

32

32

32

16 8 8

Lt

64 64 64

64

32

32 32 16

32-64 I 4-16 1 I 4-8

Appendix 3 - continued

Bsp.Nr

E. coli 14 A261

C165 183/58

Prot. Morg. vulgar

PSDM. Walt. F41

Klebs. Loo ,

N-CO-N-CH.

CH ₃ SO ₂ NH-CO

ν / -

CH ₃ SO ₂ NH-CO-NH-

^0Η 6 ⁵⁰ 2 ^Ν ψ ^Ν -CH ₃

^ SO _n -.

• -co

> 256

> 256

> 256

> 256

4-16

J64-256

> 256

16

32

4-16

32

64

128

64

16

16

64

JÜ

64j

32

256

128

32

256

256

128

> 256

32

Ud

(64-256

4-256

16-64

4-256

16-64

4-256

16-64

64

64

1-4

16-64

O) Xl

ro • ifiL

I K)

νθ

VO

CVJ K)

10

CVJ

VO

CVJ K)

U.

tn CVJ

VO IO

VO

in

CVJ

CM _sdL

VO

cm

K)

VO ICM K)

νθ

wl

CM

"*

VO

VO

in

CM I

CM

in

CM

K) CM

VO

in

CVI

1-1

* J O)

O U

t- O

Q.E

in

VO

CM K)

, - | VO νθ in in CM CM I ω CM VO  Η VD VO I Ti <* I ω

VO

in

CM I

CM

in

VD

in CM

CM H

Appendix 3 - continued

Bsp.Nr

E.coil.

14 A261 C165 183/58

Prot. Morg.

vulgar.

Ps dm. Walt. F41

Klebs. Loo

CH, CH "S0 _o N

AJ

CH ₃ NHSO ₂

H ₂ NSO ₂ -I

\ J

JL \ j

M N

CH ₃ NHSO ₂ ,

| l28-256

128-2561

CO

Ph

(l28-256

128-2561

| 128-256

132-64 y

32-64

32-64

32-64

[l 28-256

HO-PH

| l28-256

128-256

32-64

32-64

[32-641

8-16,

32-64

32-64

32-64

52-64

128-256 1

128-256

8-16

32-64

128-256

32-64

32-64

32-64

128-256

32-64

128-256

32-64

32-64

| 8-16

32-64

8-16

8-16

8-16 |

8-16

8-161

8-16

8-16

8-ie

Appendix 3 - continued

Bsp.Nr

E.coil 14 A261

C165 1183/58

Prot.

morg. vulgar.

Ps dm. Walt. F41

Klebs. Loo

EtNHSO ₂ N. N-

Λ / Y ⁰⁰ VA

Sn ''

ςτ

con: n-

Ph

HO-P

Ph

HO-Ph

> 256

154-128

128-256

52-6

[32-64]

J8-16

J32-64I

Ph

HO-Ph

J32-64

8-16J

32-64

8-16

32-64

32-64

64-128

8-16

32-64

64-128

32-64

J32-64 j

128-256

<LJ

32-64j

| 8-16

32-641

128-256

32-64

32-64 L28-256

32-64

32-64

64-128

8-16J

Appendix 3 - continued

Bsp.Nr.

E.coil 14 A261

C165 183/58

Prot. Morg.

vulgar

Ps dm. Walt. F41

Klebs. Loo

O £> -C0N N-

 CON N

HO-Ph

2-4

J32-64

2-4 |

32-64

128-256

8-16 |

16-32

32-64

128-256

32-64

64-128

8-16

HO-Ph

2-4

2-4

128-256

Z *

2-4

128-256

8-16 |

32-64

64-128

3-16]

I32-64j

32-64

4-128

<1

32-64

32-64

32-64

128-256

32-64

L28-256

> 256

128-256

> 256

32-64

32-64

2-4

Appendix 3 - continued

Bsp.Nr

E.coli

14 r A261 C165

183/58

P red. morg.

vulgar.

PSDM. Walt. F41

Klebs. KlO j

⁰⁰¹ W

N N

Ph

HO-Ph

8-16

132-64 y

2-4

8-16J

32-64]

> 256

2-4

HO-Ph

8-16 |

32-64,

2-4

8-16 |

32-64

32-64 32-64

32-64

32-64

32-64

32-64

32-64

32-64

128-256

128-256

128-256

16-32

16-32

32-64 32-64

32-64

32-64

128-256

64-128

32-64

Annex 3 - continued -

Bsp.Nr.

E. coli 14 A261

C165

183/58

Prot. Morg,

vu Ig,

PSDM. Walt.

F41

Klebs.

Loo

63

71 72

74 75

Azlozillin

^S0

HN. NCO

Ph

HO-Ph

Ph

HO-Ph

128-256

> 256 [

<1

32-64

32-64J

<1

32-64 |

1.6

400

6.2

[2.4

132-64

| 32-64

2-4

8-16

8-16

[32-641

32-64I

50

512

32-64

128-256 32-64

32-64

128-256

25

32-64

128-256

32-64

128-256

32-64

12.5

32-64

32-64

32-64

64-128

8-16 |

| 2-4

8-16

6.2

50

50

Claims (1)

A process for the preparation of novel penicillins of general formula I, wherein A is a group Y. NSC-N N-N = C-N-Y-N- v; ι ι ^QR 2 ^R 3 R ₁ -XN ^ N-R ₁ -XNYN- I ₁ R ₂ R ₃ C NYN-R ₁ -XN CN Ii ι i ¹ ι it ι NQ ₁ R ₃ Q ₁ -NR R ₁ -XNC N-X H YN- 'Il i\ / > R ^N QQ ^R R _{1 is} C-N-YN N C represents, Ό 0 S • Il Il Il X is a group -S- or -C- or -C- p S NH N-R Il H Il. H Y is a group -C-, -C-, -C-, -C- N-aryl N-SO ₀ -R N-S _{0 o} -aryl It Il ² Il ² -C, -C or -C- O S H ii; Z is a group -C- or -C-, CL is a group ? GG G - * - - * -. ' -Ή- co-c- - c - u- _L I 2 or 3 'T ^υυ ,', - ^u V G '· Il C - O - C - Il G G G G GG GGG I I I Il I I | 0 or 1 * I Ό or G R G G Eine «a group G G G G G I I I I C4, -C0-C-, -C-N-C - I 3 or 4 I | j, G G G GRG Cf- , f-N fC - ^ -, -C - CO- ΟΙ 2 I 12 IIG RG GG G I I ^ν ί Ό or 1 G G represents, wherein IR is a straight-chain or branched alkyl radical having up to 5 C atoms, Ri, H **, alkyl having up to 10 carbon atoms, cycloalkyl having up to 10 carbon atoms, alkenyl having BTs of 10 carbon atoms and cycloalkenyl having up to 10 carbon atoms, Vinyl, arylvinyl, mono-, di- and tri-halo-lower alkyl, H ₂ N-, R-NH-, (R) ₂ N-, aryl-NH-, aryl-lower alkylamino, alkoxy * having up to 8 carbon atoms, cycloalkoxy * having up to 7 Carbon atoms, aryloxy * is a group ROV, RSVN = CV, RO-CO-V, H ₂ N-CO-V, R-NH-CO-V-, only if χ at the same time non-SO ₂ - is only if χ is simultaneously -CO- (R) ₂ -N-CO-V-, (CH ₂ ) _n - means V is a bivalent organic radical having 1 to 3 carbon atoms, η is an integer from 0 to 2 inclusive, R ₁ and R _{3 are} each hydrogen, alkyl and alkenyl, each containing up to 8 carbon atoms, vinyl, allyl Propenyl, cycloalkyl and cycloalkenyl, each containing up to 6 carbon atoms, mono- and di- Trihalogeno-lower alkyl or aryl, a, R ₅ and Rg are each hydrogen, nitro, nitrile, (R) 2 ^ -N-, (R) £ z N-CO-, R-CO-NH-, RO-CO-, R-CO-O-, R-, RO-, H ₂ N-SO ₂ , Chlorine, bromine, iodine, fluorine or trifluoromethyl and G is hydrogen or R, the arrow in the divalent spacer is to express that the linking of two atoms caused by the two free valences of this intermediate piece should not be arbitrary, but should take place in the manner indicated by the arrow, B a group of the formula and R ₂ , Rg and Rg are hydrogen, halogen, R-, RO-, RS-, R-SO-, R-SO ₂ -, nitro, (R) ₂ > N-, R-CO-NH-HO, R- CO-O-, where R has the meaning given above and its non-toxic, pharmaceutically acceptable salts, wherein the penicillins of general formula I and their non-toxic, pharmaceutically acceptable salts with respect to the chiral center C ^ in the two possible R and S configurations and may be present as mixtures of the resulting diastereomers, characterized in that compounds of the general formulas II and III or compounds of the general formulas IV and V, in which Bund G has the abovementioned meaning, and R ₁₀ , Rn and R-, ₂ denotes alkyl having up to 6 carbon atoms with compounds of the general formulas Vi, VII, VIII , IX or X, wherein A, Q ₁ , Q ₂ , R ₁ , R ₂ , X, Y and Z are as defined above and W is halogen, azide, or a group