PROCEDURE FOR THE PRODUCTION OF NEW OF PENICILLIN DERIVATIVES.

The subject of available invention is a procedure for the production of a connection of the formula I 630,922 R.C " H. CO. h H I I C02R.

OCH_ CH -: .9: - 1 3 = S (z) c°, in which R is the Phenyloder 2oder 3-Thienylgruppe, R2 for a hydrogen atom, for a pharmakologisch compatible salt supplying ion or for one in vivo hydrolyzable ester remainder stands and for RI a pharmakologisch compatible ester remainder meant, which is characterized by the fact that one a connection of the formula III -- CO.O. -- CH --Z' I I X' -- C = Y' in and Z' group of ethylens or a 1,2-Phenylengruppe are meant the X' and Y' Sauerstoffoder of sulfur atoms, if necessary the Alkoxyreste low by halogen atoms or Nitrooder substituted ist.

Preferential ester remainders are the Phthalidund lo the 5,6-Dimethoxyphthalid-Ester.

Furthermore the remainder of g 1 can be alkyl, Cycloalkyl, alkenyl, Alkinyl, aryl, Aralkyloder a hetero-cyclic remainder, whereby the remainders can be substituted. Suitable remainders are:

a) Alkyl residues, in particular low alkyl residues, like methyl, ethyl, nund ISO Propyl, n, sec. - tert, isound. - Butyloder the Pentylgruppe; °çH3 s cz3 (zzr.) c°2 - O or their N-Silyloder N-phosphoryliertes derivative of the 6-Aminogruppe with one N-acylierenden derivative of an acid of the general formula IV R -- CH.CO2 H I C02W b) substituted low alkyl residues with at least one • the following substituents: a chlorine, Bromoder fluorine atom, a Nitro, nitrile, l-Indanyl, 2-Indanyl, Furyl, Pyridyl, 4-Imidazolyl, Phthalimido, Azetidino, Aziridino, Pyrrolidino, Piperidino, Morpholino, Thio2s morpholino, Pyrrolo, Imidazolo, Imidazolo, 2-Imidazolino, 2,5-Dimethylpyrrolidino, 1,4,5,6-Tetrahydropyrimidino, 4-Methylpiperidinooder of a 2,6-Dimethylpiperidino-Gruppe or a Carbo (niederalkoxy) -, Niederalkanoyl, Niederalkoxy, Niederalkylmercapto, Niederalkylsulfinyl, Niederalkylsulfonyl, n (Niederalkyl) - piperazino, Alkylamino, Dialkylamino, Alkanoylaminooder a Alkylanilino remainder, what latter by a Chloroder bromine atom or by a low Alkyloder AlkoxyRest to be substituted can; , a aUfällig existing Silyloder PhosphorylGruppe converts a received free acid off by hydrolysis or Alkoholyse splits and if necessary into its salt überführt.

Suitable ones, a salt supplying ions for the remainder of R2 are metal ions, e.g. Ions of aluminum, the alkali metals, like sodium or potassium, the alkaline earth metals, like the Cal4s ciums or magnesium, as well as ions of the ammonium or the substituted ammonium, e.g. such of low alkyl amines, like tri ethyl amine, of low-molecular hydroxyalkyl amines, like 2-Hydroxy-äthylamin, until (2hydroxyäthyl) - amine or trichloroethylene (2-hydroxyäthyl) - amine, of Cycloalkylaminen, like Bicyclohexylamin, or ions of Procain, Dibenzylamin, N, N-Dibenzyläthylendiamin, l-Ephenamin, N-ethyl-piperidin, N-benzyle - phenäthylamin, Dihydro abietylamin, N, N' until dehydro--abietylãthylendiamin or ions used by bases of the Pyridintyps, like Pyridin, Collidin, or Chinolin, or ions of other amines, those for the formation of salts with Benzylpenicillinen sind.

Into vivo hydrolyzable and/or pharmakologisch compatible ester remainders for the remainders Rl and R2 are such, those in the human body under formation of the master acid hydrolisieren.

Suitable examples cover Acyloxyalkyl remainders, like the Acetoxymethyl, Trimethylacetoxymethyl, “- Acetoxyäthyl, A-Acetoxybenzylund the ct-TrimethylacetoxyäthylGruppen, furthermore Alkoxycarbonyl oxyalkyl remainder, like the 6s Äthoxycarbonyloxymethylund a-Äthoxy-carbonyloxyäthyl-group, furthermore Lactone, Thiolactone and Dithiolactono, i.e. groups of esters of the general formula c) Cycloalkyloder by low alkyl residues substituted cycloalkyl residues with 3 to 7 carbon atoms in the Cycloalkylhälfte or [2,2-Di (down alkyl) - 1,3-dioxolon-4-yl] - methyl remainders; d) Alkenyl residues with up to 8 carbon atoms; e) Alkinyl remainders with up to 8 carbon atoms; f) Aryl residues, as Phenyloder substituted Phenylgrupe, with which at least one substituent a chlorine, a Bromoder fluorine atom, which Nitrogruppe, a low alkyl, low Alkoxy, low Alkanoyl, Carbo (low alkoxy) - or a Di (low alkyl) - amino remainder or a group of the general formula into the y2 one of the following groupings means - CH = CH-O - CH = CH-S - CH2-CH2-S - CH = N-CH = CH - CH = CH-CH = CH - CO-CH = CH-CO-or - CO-CO-CH = CHoder a group of the general formula 630,922 is, in the Z2 a low alkyl remainder, like the Trimethylenoder the Tetramethylen group and of them is substituted derivatives, whereby the substituent is group of methyls or a Chlorz0 or a bromine atom; g) Aralkylreste, like the Benzyloder substituted benzyle .

group, whereby as Sabstituenten chlorine, Bromund of fluorine atoms, Nitrogruppen, low alkyl, low Alkoxy, low Alkanoyl, Carbo (low alkoxy) - or Di (low alkyl) - amino remainders are possible; h) Chinolyl, Chinolyl, Phenazinyl, 1,3-Benzodioxolyl, 3 (2-Methyl-4-pyronyl) -, 3 (4-Pyronyl) - or the n (Methylpyridyl) methyl-substituted hetero-cyclic remainders, like the Furyl, - group; j) other hydrocarbon remainders, like alicyclische lndanylreste or of them by Chloroder of bromine atoms or by Mêthylgruppen substituted derivatives, furthermore derivatives, as well as the Benzohydroyl, Trityl, Cholesteryloder the Bicyclo [4.4.0] substituted alicyclische Tetrahydronaphthylreste or of them by Chloroder of bromine atoms or by groups of methyls decyl Gruppe.

61] - (D, L-2-Isobutoxycarbonyl-2-phenyl-acetamido) - 6ctmethoxy-penicillansäure.

If preferential remainders for RI are low alkyl, benzyle, Phtalidyl, Indanyl, phenyl, mono, diund trichloroethylene (low alkyl) - substituted Phenyl groups, like the o, decay p-Methylphenyl, Äthylphenyl, noder ISO Propylphenyl, n, sec. -, isooder test Butylphenyl Gruppe.

Special connections in accordance with the procedure according to invention are:

Used the expression “N-Silyl-derivative” of a connection of of the general formula III the here means a product of the conversion of the 6-Aminogruppe of the connection of of the general formula III with a Silylierungsmittel with a halogenosilane or a Silazan of of the following of the general formulas 6ct-Methoxy-613 (D, L-2-phenoxycarbonyl-thien-2' yl-acetamido-penicillansäure, 6t - Methoxy-613 (2 ' - phenoxycarbonyl-thien-3-yl-acetamido) - penicillansäure, 6 D, L-2 (lsobutyloxycarbonyl) - thien-3-yl-acetamido] - 6ctmethoxy-penicillansäure, 61 - [D, L-2 (Indan-5-yloxycarbonyl) - thien-3-yl-acetamido-6u-methoxy-penicillansäure, 6ct-Methoxy-6lS [D, L-2 (4-methylphenoxycarbonyl) - thien-3yl-acetamido] - penicillansäure, 6ct-Methoxy-13 [D, L-2 (phtalid-3-yloxycarbonyl) - thien-3' ylacetamido] - penicillansäure, 61 - [D, L-2 (2-sek. - Butylphenoxycarbonyl) - thien-3' yl-acetamido] - 6ct-methoxy-penicillansäure, 61] - [D, L-2 (2-Äthylphenoxycarbonyl) - thien-3' yl-acetamido] - 6cz-methoxy-penicilansäure, 6ct-Methoxy-613 [D, L-2 (4-isopropylphenoxycarbonyl) - thien-3' yl-acetamido] - penicillansäure, 6 [3 [D, L-2 (3,4-Dimethylphenoxycarbonyl) - phenyl-acetamido-6ct-methoxy-penicillansäure, 6 z-Methoxy-613 [D, L-2 (4-methylphenoxycarbonyl) - phenylacetamido] - penicillansäure, 6cc-Methoxy-613 (D, L-2-phenoxycarbonyl-phenyl-acetamido-penicillansäure, 6ct-Methoxy-6 [3 [D, L-2 (3-methylphenoxycarbonyl) - 2phenyl-acetamido] - penicillansäure, 6 - [D, L-2 (5-lndanyloxycarbonyl) - 2-phenyl-acetamido] - 6ctmethoxy-penicillansäure and 1_, 3 SI U; L2 SI U2; L3 SI NL2; L3 SI NH SI L3; L3 Si.NH.COL; L3Si.NH.CO.NH.Si L3; L NH.CO.NH.Si L3; LC.OSi L3 I NSiL in those U a halogen atom is and the different remainders of L, which can be same or different, hydrogen atoms or alkyl, Alkoxy, Aryloder Aralkylreste sind.

Preferably Silyl chloride, in particular tri methyl chlorosilane, becomes verwendet.

as Silylierungsmittel The expression “N-phosphoryliertes derivative” of a connection of the general formula III is used for the Veranschauli2s chung by connections, with which the 6-Aminogruppe of the connection of the general formula III is substituted with a group of the general formula ùP.RaRb in R an alkyl, a halogen alkyl, an aryl, a Aralkyl, Alkoxy, Halogenalkoxy, Aryloxy, or Dialkylamino remainder is and Rb has the same meaning as RA or a halogen atom means, whereby also RA and Rb form together a ring können.

Suitable ester remainders of the formula - CO2R2 are:

i) - COOCRcRaRe, whereby at least one of the remainders of RH, RA or RH is a Elektroncndonator, e.g. the p-Methoxyphenyl, 2,4,6-Trimethylphenyl, 9-Anthryl, Methoxy, Acetoxy, Methoxymethyl, Benzyloder the Fur-2-yl-Gruppe.

The remaining remainders of RH, RD or RH can be hydrogen atoms or organic remainders. Suitable ester remainders of this type are the p-Methoxybenzyloxycarbonyl, 2,4,6-Trimethylben4s zyloxycarbonyl, until (p-methoxyphenyl) - methoxycarbonyl, 3,5-Di-tera-butyl-4-hydroxybenzyloxycarbonyl, Methoxymethoxycarbonylund the Benzyloxycarbonyl group; ii) - COOCRçR “RH, whereby at least one of the remainders of RH, approx. Rà or R electrons an attractive group, e.g. the Benzoyl, p-Nitrophenyl, 4-Pyridyl, tri chlorine methyl, tri bromine methyl, iodine methyl, Cyanomethyl, Äthoxycarbonylmethyl, aryl sulphonyl methyl, 2-Dimethyl-snlfoniumäthyl, o-Nitrophenyloder the Nitril-Gruppe is. The remaining remainders of RH, ss Rà or RH can be hydrogen atoms or organic remainders. Suitable esters of this type are the Benzoylmethoxycarbonyl, p-Nitrobenzylcarbonyl, 4-Pyridylmethoxycarbonyl, 2,2,2-Trichloräthoxycarbonylund the 2,2,2-Tribromäthoxyearbonyl-Ester; iii) - COOCReRaRe, whereby at least two of the remainders are R RA or RH Kohlenwasscrstoffreste, like alkyl residues, e.g.

the Methyloder group of ethyls, aryl residues, e.g. the Phenylgruppe, during which remaining remainder of RH, RA or RH - so available - is a hydrogen atom. Suitable esters of this type are tert the test Butyloxycarbonyl. - Amyloxycarbonyl, Diphenylmethoxycarbonylund of the Triphenylmethoxyearbonyl esters; 630,922 iv) - COORf, whereby Rf is the Damantyl, 2-Benzyloxyphenyl, 4-Methylthiophenyl, Tetrahydrofur-2-yl, Tetrahydropyran2-yl or the Pentachlerphenyl group; v) Silyloxycarbonyl Réste, which are available by conversion of a Silylierungsmittels, as it was managing described, with a group of carboxyls; '5 vi) - CO2P.RaRb, whereby RA and Rb possess those managing indicated meanings; or vil) described in vivo hydrolyzable ester remainder, as it managing ist.

From that managing specified esters the Carbo13 xylgruppe can be repaired in usual procedures, e.g. by means of one with acid and base catalyzed hydrolysis or by means of an enzymatically catalyzed hydrolysis. The moreover the following procedures for splitting can be used: Conversion with Lewis Säaren, like tri fluorine acetic acid, formic acid, hydrochloric acid in acetic acid, zinc bromide in benzene and aqueous Lõsungen or suspensions of mercury (II) - connections. The reaction with an Lewis acid can by additive of a nukleophilen connection, as anisole, erleich2s are tert; Reduction with systems, like zinc/acetic acid, zinc formic acid, zinc/low-molecular alcohol, zinc Pyñdin, charcoal with palladium and hydrogen as well as sodium and liquid ammonia; Angriffsmittei of nucleophiler connections, as such, which contain nukleophile Sauerstoffoder of sulfur atoms, e.g. Alcohol, Mercaptane and water, furthermore oxidative procedures, e.g. such, hydrogen peroxide and acetic acid use; as well as attack by Strahlung.

With the aforementioned procedures a N-acylierendes derivative of the acid of the general formula IV is used. The appropriate choice of a reactive derivative becomes naturally from the chemical nature of the substituents of the acid beeinflusst.

Suitable ones N-acylierende derivatives are Säurehalogenide, preferably the Säurechloride or - bromide. The acylation with a Säurehalogenid can in presence of a acid-binding means, e.g. a tertiary amine, like tri ethyl amine or Dimethylanilin, an inorganic base. like 43 calcium carbonate or Natriumbiearbonat, or a Oxifans to be caused, with the acylation the set free hydrogen halide-bind. With the Oxiranen it preferably acts around 1,2-Alkylenoxide with 2 to 6 carbon atoms, like ethylene oxide or propylene oxide. The acylation using a Säurehalogenids can at a temperature from -50 to + 50°C. preferably accomplished from -20 to +30 " C, in an aqueous or non-aqueous medium, as aqueous acetone, ethyl acetate, Dimethylacetamid, dimethylformamide, acetonitrile, Dichlormethan, 1,2-Dichloräthan or their mixtures werden.

If necessary one knows the reaction also still in an unstable emulsion of a solvent would drive through, in particular an aliphatic ester or Ketons not mixable with water, like Methylisobutylketon or Butylacetat.

The Säurehalogenid can by shifting of the acid of the general formula IV or their salt with a Halogenierungsmittel, e.g. a Chlorierungsoder Bromierungsmittel, like phosphorus pentachloride, Thionylchlorid or Oxa63 lylchlorid, manufactured werden.

The moreover the N-acylierende derivative of the acid of the general formula IV can be a symmetrical or mixed anhydride. Suitable ones mixed anhydrides are Alkoxyameisensäureanhydride or anhydrides with e.g.

Carbonic acid mono esters, tri methyl acetic acid, Thioessigsäure, Diphenylessigsäure, benzoic acid, phosphoric acids, as more phosphorous or phosphoric acid, sulfuric acid or or aromatic sulfone acids aliphatisehen, like p-ToIuolsulfonsäure. The mixed or symmetrical anhydrides can be produced in situ. E.G. a mixed anhydride can be manufactured using N-Äthoxy-carbonyl-2äthoxy-l, 2-dihydrochinolin. If a symmterisches anhydride is to be used, the reaction can accomplished in presence of 2,4-Lutidin as catalyst werden.

Further N-acylierende derivatives of the acid of the general formula IV were manufactured acid azides or activated esters, like esters with Cyanomethanol, p-Nitrophenol, 2,4-Dinitrophenol, Thiophenol, halogen phenol, including Pentachiorphenol, Monomethoxyphenol or 8-Hydroxychinolin, or amides, like N-Acylsaccharine or N-Acylphthalimide, furthermore Alkyliden more iminoester, those by shifting of an acid of the general formula IV with a Oxim sind.

Some activated esters, e.g. the esters formed with 1-Hydroxybenztriazol or N-Hydroxysuceinimid, can in situ by shifting the acid with an appropriate Hydroxyverbindung in presence of a Carbodiimids, preferably manufactured by Dicyclohexylcarbodiimid, werden.

Other reactive N-acylierende derivatives of the acid of the general formula IV are reactive intermediate products, which are manufactured with a condensing means by shifting in situ, like a Carbodiimid, e.g.

N, N-Diäthyl, Dipropyloder Diisopropylcarbodiimid, N, N' Dicyclohexylcarbodiimid or N-Äthyl-N'-7-dimethylaminopropylcarbodiimid or with a suitable Carbonylverbindung, e.g. N, N' Carbonyldiimidazol or N, N' Carbonylditriazol, or with a Isoxaliniumsalz, e.g. N-Äthyl-5-phenyl-isoxazolinium-3-sulfonat or N-tert. - Butyl-5-methylisoxazolinium-perchlorat, or with a N-Alkoxy-carbonyl-2-alkoxy-1,2-dihydrochinolin, like N-Äthoxycarbonyl-2-äthoxy1,2-dihydrochinolin.

Other condensation means are Lewis acids, e.g. BBr3/C6H6, or condensation means on basis of phosphorous acids, like Diäthylphosphorylcyanid. The condensation is preferably accomplished in an organic reaction medium, e.g. Dichloromethane, dimethylformamide, acetonitrile, alcohol, benzene, Dioxan or Tetrahydrofuran.

The connections of the general formula III can e.g. after of Jen et al. in J. Org. Chem. 38 (1973), page 2857 descriptive procedures of an ester a connection of the formula 3s H2 N ç B' N 'CH3 0 C02 H to be made, whereby this connection is made first from the appropriate 6-Isocyano-Verbindung, those in the DT-OS 2,407,000 described ist.

The connections working as antibiotics can be prepared for administration in arbitrary way for use in the Humanoder veterinary medicine, as this admits with other antibiotics is, i.e. contain together with 630922 pharmakologiseh compatible substrates and/or after the administration form. If the ArzneiVerdünuungsmitteln. 'means from single dosages exist, contain each unit the drugs can for administration aufbelievorzugsweise 50 to 500 mg active ingredient. The Dosierungsbigem of ways to be formulated, although an oral Verabreimenge, which is preferred with a treatment by adults angechung. The drugs know 3000 mg, e.g. with daily 1500 mg, in the form of s, turn become, preferably lie within the range of daily 100 tablets, caps, propellants, granulates, Pastillen or flüsbis depending upon the frequency sigen preparations, like oral or sterile parenteral and the way of the Verabreichung.

Solutions or suspensions, are present. It is evident that the Seitenkette of the Penieiline of the all tablets and caps can be present za oral administration in common formula I an effective asymmetrical coal single dosage forms and, o material atom exhibit usual Excipientien. The invention covers from there sãmtliche like bonding agents, e.g. Syrup, acacia rubber, gel, Sorbit, Tragant or Polyvinylpyrrolidon, fillers, e.g.

Lactose, sugar, corn strength, calcium phosphate, Sorbit or Glycerin, lubricant, e.g. Magnesium stearate, talcum powder, PL glycol or silicon dioxide, decay aid, e.g. is of potato strength, or compatible wetting agents, like Natriumlaurylsulfat, contain. The tablets can be coated according to the methods well-known in usual pharmaceutical practice. Oral liquid preparations can be present in the form of for example aqueous or oily suspensions, solutions, emulsions, syrups or Elixieren, or they can be handed as drying product for a redissolution with water or other suitable vehicles before a Inbenutzungnahme. Such liquid preparations know usual additives, like Suspensions2s aid, e.g. Sorbit, syrup, methyl cellulose, glucose syrup, gel, Hydroxyäthylcellulose, CarboxymethylceIlulose, Aluminiumstereat gel or hydñerte Speisefette, emulsifying means, e.g. Lecithin, Sorbitan monooleat or acacia rubber, furthermore not aqueous vehicles, which include food oils, e.g. Almond oil, fractionated coconut oil, oily esters, like Glycerin, propylene glycol, or ÄthylaIkohol, as well as preservative, e.g. the Methyloder Propylester of the p-Hydroxybenzoesäure or the Sorbinsäure, and if necessary usual Geschmacksund Farb3s of materials, enthalten.

Suppositorien contain usually a Suppositoriengrundmasse, e.g. Cocoa butter or other Glyceñde.

For a parenteral administration liquid single dosage forms are manufactured using the connection and a sterile vehicle, whereby water is preferred. The connection can be present depending upon the used vehicle and the applied concentration either in the vehicle suspended or solved. During the production of solutions the connection in water to Injek4s can tionszwecken to be solved and under sterile conditions filtered, before the solution is filled up and sealed in suitable Gefäse or ampuls. Preferentially auxiliary materials, like local anaesthetics, can be solved in the vehicle preservatives and Puffersubstanzen. For increase the staff ISO lität can be frozen the drugs after the racking into containers and be released from the water under decreased pressure. The gefriergetroeknete powder is then melted in the glass container and a Fläschchen with water for injection purposes is added, in order to rekonstituieren the liquid ss before use. Parenteral suspensions can be manufactured essentially in the same way, however with the measure that the connection in the vehicle suspends instead of in it is solved and that sterilization does not need to be accomplished together with a filtration. The connection can be sterilized by the fact that one exposes it before suspending in the steñlen vehicle to ethylene oxide. Favourable way can be worked one grênzflächênaktivê connection or a wetting agent into the drug, around a 6s gleichmässigê distribution of the connection too erleichtern.

The Arznêimittel can do 0, I to 99 Gêwichtsprozent, vorzugswêise 10 to 60 weight percentage Aktivverbindungje possible Epimeren of the connections of the general formula I as well as their Gemische.

The examples describe the Erfindung.

Example on behalf) 6oE-Methoxy-6 [3-amino-penicillinsäureSbenzylester in the procedure of Jen et al. in J. Org. Cheto. 38 (1973), page 1857, the appropriate 6ct-MethylthioDeñvat (see DT-OS 2,407,000) becomes into the connection specified in the heading überführt.

b) 6oE-Methoxy-613 (2 ' - phenoxycarbonyI-thien-3-yl-acetamido-penicillansäure-benzylester a solution of 1,6 mMol 6ct-Methoxy-6 [3-amino-penicillansäure-benzylester in 15 ml alcohol-free dichloromethane and 0.2 valley Pyridin with 0 to 5°C with a solution of the Säurechlodds in 4, made of 2 mMoI Thien-3-yI-malonsäure-monophenylester, ml dichloromethane is treated. After 2,5 hours the solution is washed, dried to diluted hydrochloric acid, water and diluted Natriumbicarbonatlösung with water, and evaporated then. The chromatography at Silicagel shows the desired Diester in a yield of 52,2%.

NMR spectrum (CDC13): 8 = 1.35 (6H, s, in accordance with Dimethylgruppen); 3,55 (3H, s, OCH3); 4,52 (1H, s, C3-Proton); 5,09 (1 H, s, 2 ' - proton); 5,27 (2H, s, OCH2Ph); 5,69 (1 H, s, CsProton); 7,09-7,88 (13H, m, PhenyIund Thienylprotonen).

c) 6 - Methoxy-6 - (2 ' - phenoxycarbonyl-thien-3-yl-acetamido) - a penicillansäure Lõsung of 150 mg of the Diesters from example 1 (B) in valley water-free ethanol, 3 valley water and a Æquivalent n-Natriumbiearbonat is treated 2.5 hours with a pressure by 3,5 kg/cm2 with 200 g 10prozentiger Palladíumkohle. After the freezingdry one receives the connection specified in the heading as Natñumsalz in 62prozentiger Ausbeute.

NMR spectrum (I) 20): Æ = 1.4 and 1.6 (6H, 2s, in accordance with Dimethylgruppen); 3,45 and 3.60 (3H, 2s, OCH3); 4,35 (1 H, s, C3-Proton); 5,1 (1 H, s, 2 ' - proton); 5,6 (1 H, s, Cs-proton); 7-7,7 (8H, m, Phenylund Thienylprotonen).

Beispiel2 a) 6 - [D, L-2 (Isobutyloxycarbonyl) - thien-3-yl-acetamido] - 6oE-methoxypenicillansäure-benzylester 1.21 g 3-Thienyl-malonsäure-monoisobutylester are weakly warmed up in ml Methylendichlorid, which is free from water and alcohol and dimethylformamide contains 2 drops, under return flow. Afterwards one gives in the process of minutes a solution of 0,5 ml Thionylchlorid in 10 to valley Methylendichlorid in addition, which is free of water uñd alcohol. Then one continues a heating up under return flow further minutes, cools the Lõsung and evaporates her under decreased pressure. After the addition of 5 valley toluol one steams the solution again under decreased pressure ein.

Then further 5 is admitted ml toluol and evaporation wiederholt.

Then one vibrates 1.57 g of the p-Toluolsulfonats of the 613-amino-6ct-methylthiopenicillansäure-benzylesters with 110 ml to ice-cooled ethyl acetate and 75 valley 2n-Natriumbicars bonatlösung. Then one separates the layers and washes the organic phase twice with ever 75 ml to ice-cooled water, troeknet her and evaporates her under decreased pressure. The arrears are solved in 27 valley freshly distilled water-free methanol and freshly shifted with 12 ml J0 distilled water-free dimethylformamide. Then the solution auf10°C is cooled and treated with 0,57 valley Pyridin. After further cooling auf-20°C 0.813 g mercury (II) - chloride are admitted, and the mixture becomes minutes - 10°C agitated. After the addition of 110 ml is water-free ether the solution is filtered by a filter from Dicalciumsilicat and Dicalciumaluminat. The solution is washed, dried to water-free ether with 450 ml diluted, then six times with ever 75 ml water again and evaporated under decreased pressure. The received 613-Amino-6 - dichloromethane in 40 ml, which is free from water and alcohol, becomes methoxy penicillansäure more benzylester, and 0.45 valley Pyridin solved and then with a solution of the Säurechlorids managing specified in 10 ml dichloromethane, which is free from water and alcohol, shifts. The mixture becomes 2 hours with 0 to 5°C gerührt.

Then one adds 20 valley water and evaporates the Methylendichlorid under decreased pressure. The arrears are vibrated to water with 75 ml ethyl acetate and 55 ml. After dividing in two layers the organic layer is washed to each of 40 successively with 40 ml 10prozentiger Citronensäure, ml water, 40 mi n-Natriumbicarbonatlõsung and three times with 40 mi water, dried then and evaporated under decreased pressure. One receives 1.44 g to yellow-brown rubber antigen of a substance. The raw product is chromatographiert at AC Silicagel using ethyl acetate and rising quantities of petroleum ethers by the boiling range 60 to 80°C (10% - 15% - 20%). One receives the pure ester as Sehaum in a yield from 9 I0 mg.

Dünnschichtchromatographie and SiO2 with a mixture from ethyl acetate and petroleum ether from the boiling range to 80°C in the relationship 1:3 as run means: Rf = 0,16; with a mixture from chloroform, acetone and acetic acid in the relationship 50:50: 7 as run means: Rr - 0,91.

IR spectrum vmax (CCh): 3310, 1780, 1753, 1710, 1498, 4s 1325, 1264, 1199, 1173, 1108, 1018 and 696 cm " l.

NMR spectrum (CC14): ì = 0.92 [6H, D, (J= 17Hz), BH3 --]; -- CH cH3 1.28 (6H, s, in accordance with. Dimethylgruppen); 1,94 (1H, m, - CH2CHMe2); 3,42 (3H, s, 6 - Methoxygruppe); 4,01 (2H, D, [J = 17Hz], - OCH2CI-I); 4,40 (I H, s, C3-Proton); 4,78 (1H, s, - CHe); 5,25 (2H, s, - OCH2Ph); 5,56 (1 H, s, Cs-proton); 7,29 and 7.42 (7H, m, - OCH2Ph, Thienyl-4-Proton, - CONH); 8,06 (2H, D, Thienyl-2 and 5-Protonen).

630922 destillientem ethanol becomes with 11,5 ml water and 1.6 mi freshly prepared n-Natriumbicarbonatlösung behandelt.

Then one gives 0.29 g 10prozentige to palladium coal in addition and hydrogenates the mixture I hour. After filtering the mixture by a filter from Dicalciumsilicat and Diealciumaluminat the filter arrears are washed to aqueous ethanol with 10 ml 50prozentigem. Then one gives further 0.29 g to catalyst in addition and continues the hydrogenation, until no more benzyle ester is to be determined, like with the Dünnschichtchromatographie at silicon dioxide with a mixture from chloroform, acetone and acetic acid in the relationship the 50:50: 7 as Laufmittel shows. The mixture is filtered again by a Dicalciumsilicat and a DicalciumaluminatFilter and evaporated then for removing ethanol under decreased pressure, washed and freezingdried afterwards with 20 ml ethers. One receives 0.5 g of the connection as sodium salt. Dünnschichtchromatographie at SiO2 with a mixture from chloroform, acetone and Essigsãure in the relationship 50:50: 7 as Laufmitel: Rf = 0,68.

IR spectrum of Vmax (KBr): 1757, 1606, 1505, 1335, 1102, 1012 and 775 cm NMR spectrum (DzO): Æ = 0.91 [6H, D, (J = 17Hz)], BH, 2s _ CHICHE3; 1,40 (6H, m, in accordance with. Dimethylgruppen); 1,92 (1H, m, - CH2CHMe); 3,45 (3H, D, - OCH); 4,07 [2H, D, (J = 17Hz), - OCH2CH; 4,33 (1 H, D, C3-Proton); 5,20 (< 1H, s, rapidly reducing, CHe; b) 613 [D, L-2 (Isobutyloxycarbonyl) - thien-3-yl-acetamido] - 6s '6ct-methoxy-penicillansäure 0.9 g 61 - [D, L-2 (I sobutyloxycarbonyl) - thien-3 - yl-acetamido] - 6ct-methoxy-penicillansäure-benzylester in 48 mi 5.63 (1 H, D, Cs-proton); 7,32 and 7.58 (3H, m, Thienyl protons).

Example 3 a) 61 - [D, L-2 (Indan-5-yloxycarbonyl) - thien-3-yl-acet - amido-6oE-methoxy-penicillansäure-benzylester in the same way as in example 2 (a) 613-Amino6ct-methoxy-penicillansäure-benzylester with the Säurechlorid from 3-Thienyl-malonsäure-monoindan-5-yl-ester is acylient. One receives the connection in 23prozentiger yield, specified in the heading, after cleaning by chromatography at Silieagel. Dünnschichtchromatographie at SiO with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship 1:3 as Laufmittel: Rf = 0,15; with a mixture from chloroform, acetone and acetic acid in the relationship 50:50: 7 as run means: Rr = 0,82.

IR spectrum vmax (CC14): 3310, 1779, 1750, 1702, 1483, 1216, 1262, 1230, 1202, 1180, 1157, 1139, 1011 and 699 cm-1.

NMR spectrum (CC14): Æ 1.23 (6H, s, gladly. Dimethylgruppen); 2,11 (2H, m, Indan-2-methylengruppe); 2,90 (4H, t, [J= 8Hz], Indan-1und -3-methylengruppen); 3,42 (3H, D, 6-Methoxygruppe); 4,40 (1 H, s, C3-Proton); 5,06 (1H, D, 5.18 (2H, s, - OCH2Ph); 5,60 (1 H, s, Cs-proton); 7,39 (5H, s, - OCH2Ph); 6,7-7,6 and 8.14 (7H, m, aromatic Thienylund Indan protons, - CONH).

b) 613 [D, L-2 (Indan-5-yloxycarbonyl) - thien-3-yl-acetamido] - 6 “- methoxy penicillansäure of the 61 - [D, L-2 (Indan-5-yloxycarbonyl) - thien-3-yl-acetamido] - 6 - as in 630,922 example becomes methoxy penicillansäure more benzylester 2 (b) indicated hydrogenated. One receives the aforementioned connection as Natdumsalz.

Dünnschichtchromatographie at SiO2 with a mixture to the chloroform, acetone and acetic acid in the relationship 50:50: 7 as Lanfmittel: Rf -- 0,62.

Example 4 a) 6 “- Methoxy-6 [3 [D, L-2-O-methyl-phenoxycarbonyl) - thien-3-yl-acetamido] - penicillansäure benzylester in the gleidlen way as in example 2 (a) 613-Aminoz0 6ct-methoxy-penicillansäure-benzylester with the Säurechlorid from Thien-3-yl-malonsäure-mono-4-methylphenylester is acyliert. One receives the aforementioned connection in a yield from 67,4% to cleaning by chromatography at Silicagel. is Dünnschiehtehromatographie at SiO2 with a mixture from petroleum ether of the boiling range 60 to 80°C and ethyl acetate in the relationship 3:1 as Laufmittel: Rf = 0,11; with a mixture from chloroform, acetone and acetic acid in the relationship 50:50: 7: R = 0,88.

IR spectrum of Vmax (CCl4): 1778, 1752, 1701, 1501, 1315, 1194, 1162, 1019 and 701 cm-l.

NMR spectrum (CC14): 6 = 1.24 (6H, s, gladly. Dimethylgruppen); 2,34 (3H, s, TolyI-CH3); 3,42 (3H, D, - OCH3); 4,39 (IH, s, C3-Proton); 5,02 (1H, s, “5.21 (2H, s, - OCH2Ph); 5,58 (1H, s, Cs-proton); 7,0-8,1 (13 H, m, aromatic Phenylund Thienyl protons, - CONH).

b) 6c - Methoxy-613 [D, L-2 (4-methylphenoxycarbonyl) - as thien-3-yl-acetamido] - penicillansãure 1.2 g 6 - Methoxy-613 [D, L-2 (4-methylphenoxyearbonyl) - thien-3-yl-acetamido] - penicillansäure more benzylester in mi freshly distilled ethanol are solved and treated with 6 valley water. Then one sets 0.40 g I of per cent palladium coal in addition and hydrogenates the mixture 1 hour. Then the mixture is filtered by a filter from Dicalciumsilicat and Dicalciumaluminat. The arrears are washed to freshly distilled ethanol with 5 ml. Then one gives further 0.40 g to catalyst in addition and continues the hydrogenation, to 4s no more benzyle ester by Dünnschichtchromatographie at Silicagel in a mixture from chloroform, acetone and acetic acid in the relationship of 50:50: 7 as Lanfmittel to be determined can do. One adds 25 ml water and distills ethanol under decreased pressure off. Then so one places the mixture by addition of Natriumbicarbonatlösung alkalinely, washes it with ether and acidifies it with 5n-Salzsäure. Sew twice extracting with ever 25 ml ethers washes one the excerpts twice with ever 10 ml to water, it dries and evaporates it under decreased pressure. ss one receives the aforementioned free Säure.

Dünnschiehtchromatographie at SiO2 with a mixture from chloroform, Aeeton and acetic acid in the relationship 50:50: 7 as Laufmittel: Rf = 0,65.

NMR spectrum (CDCh): Æ= 1.40 (6H, m, in accordance with Dimethylgruppen); 2,38 (3H, s, TolyI CH); 3,52 (3H, s, - OCH); 4,51 (1 H, s, C3-Proton); 5,71 (1 H, s, Cs-proton); 7,0-7,75 (5H, m, aromatic Tolylund Thienyl-4-Protonen); 8,18 (3 H, m, Thienyl-2und -5-Protonen, - CONH).

The received connection is solved in water-free ether and treated with 1 equivalent Natrium-2-äthylhexoat (when for instance 2-molare solution in 4-Methylpentan-2-on), which was diluted with water-free ether. The solid is filtered off, washed and dried with ether. One receives the desired connection in form of sodium salt in a yield from 16%.

IR spectrum of Vmax (KBr): 3410 (broadly), 2962, 1758, 1684, 1602, 1504, 1402, 1335, 1196, 1167, 1130, 848 and 779 cm-l.

Example a) 61 - [D, L-2 (3,4-Dimethylphenoxycarbonyl) - phenyl-acetamido-6c - methoxy penicillansäure more benzylester after in example 2 (a) indicated procedures using 1,42 g von Phenyl-malonsäure-mono3,4-dimethylphenylester the aforementioned connection will receive. After chromatography one receives the pure ester in a yield from 64%. IR spectrum of max (CHCI3):

2880, 1770, 1730, 1690, 1490, 1150 cm-l.

5,17 (1H, s, b) 61 - [D, L-2 (3,4-Dimethylphenoxycarbonyl) - phenyl-acetamido-6-a-methoxy-penicillansäare of the benzyle esters becomes as in example 2 (b) indicated hydrogenated. One erhãlt in a yield of 32,8% the aforementioned connection as Natriumsalz.

IR spectrum of Vm x (KBr): 3410, 2970, 1755, 1675, 1600, 1495, 1240, 1150, 700 cm-I.

NMR spectrum (D20): õ= 1.47 (6H, m, gladly. Dimethylgruppen); 1,82 (6H, s, CH3); CH3 3.54 (3H, D, - OCH); 4,31 (1 H, s, C3-Proton); 5,75 (1H, s, CsProton); 6,6-7,7 (8H, m, aromatic protons). Dünnschichtchromatographie at SiO2 with a mixture to the chloroform, acetone and acetic acid in the relationship 50:50: 7 as Laufmittel: Rf = 0,66.

Example 6 a) 6ct-Methoxy-6p [D, L-2 (4-methylphenoxycarbonyl) - phenylacetamido] - peniciUansäure benzylester in the same way as in example 2 (a) acyliert one 613-Amino-6a-methoxy-penieillansäure-benzylester with the Säurechlorid from the Phenyl-malonsäure-mono-4-methylphenylester and receives the aforementioned connection in a yield from 70% to cleaning by chromatography at Silicagel.

Dünnsehichtchromatographie at SiO2 with a mixture from petroleum ether of the boiling range 60 to 80°C and ethyl acetate in the relationship 3:1 as Laufmittel: R = 0,18.

IR spectrum of Vm x (CHCI3): 2910, 1775, 1738, 1690, 1498, 1367, 1330, 1180 and 1010 cm-1.

NMR spectrum (CDCI3): 6 = 1.32 (6H, s, in accordance with Dimethylgruppen); 2,37 (3H, s, TolyI-CH3); 3,50 (3H, s, - OCH3); 4,54 (1H, s, C3-Proton); 4,99 (1H, s, PhCH); 5,29 (2H, s, - OCH2Ph); 5,71 (1H, s, Cs-proton); 6,9 - 8.15 (15H, m, aroes matsche protons, - CONI-I).

b) 6c - Methoxy-613 [D, L-2 (4-methylphenoxycarbonyl) - phenylacetamido] - penicillansäure benzylester the 6ct-Methoxy-61 - [D, L-2 (4-methylphenoxycarbonyl) - phenylacetamido] - becomes penicillansäure more benzylester after in example 4 (b) indicated procedures hydrogenated. One receives the aforementioned Verbindung.

NMR spectrum (CDCI3): 8= 1.38 (6H, D, in accordance with Dimethylgruppen); 2,35 (3H, s, Tolyl-CH3); 3,49 (3H, s, - OCH3); 4,37 (1 H, s, C3-Proton); 5,00 (IH, s, PhCH); 5,68 (1 H, s, Cs-proton); 6,86 - 7.84 (9H, m, aromatic protons); 8,16 (1 H, D, - NHCO); 9,00 (1H, s, - CO2H).

How in example 5 (b) described the free acid is transferred into sodium salt. Exploit 59,4%.

Dünnschichtehromatographie at SiO2 with a mixture from chloroform, acetone and acetic acid in the relationship 50:50: 7 as Laufmittel: Rf = 0,69.

IR spectrum of Vmax (KBr): 3400, 2962, 1755, 1685, 1605, 1505, 1345, 1195 and 700 cm-l.

Example 7 a) 6ct-Methoxy-6p (D, L-2-phenoxycarbonyl-phenyl-acetamido-penicillansäure-benzylester 1.28 g Phenyl malonic acid more monophenylester 90 minutes with 5 valley Thionylchlodd under Rüekfluss and J Rûhren one heats up. The solution is cooled and evaporated under decreased pressure. Then one sets 5 mi toluol in addition and evaporates the solution again under decreased pressure. One sets again 5 valley toluol in addition and repeats evaporation. One receives the Säurechlorid, which for the acylation of 61 - Amino-6 - methoxy penidllansåure more benzylester as in example 3 (a) described one uses. One receives the cleaned connection in a yield from 22,5%.

Dünnschichtchromatographie at SiO2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 3 “80 " C in the relationship 1:3 as Laufmitel: Rr = 0,16; with a mixture from chloroform, acetone and acetic acid in the Verhãltnis 50:50: 7 as Laufmittel: Ri = 0,91.

IR spectrum of Vmax (CHCI3): 3250, 2920, 1775, 1740, 1690, 1594, 1497, 1460, 1379, 1319, 1190, 1169, 1030, 699 cm-I.

NMR spectrum (CDCb): õ= 1.34 (6H, m, gladly. Dimethylgruppen); 3,50 (3H, D, OCH3); 4,51 (1 H, D, C3-Proton); 4,95 (1 H, s, PhCHç); 5,28 (2H, s, - CH2Ph); 5,69 (1 H, s, Cs-proton); 7,52 (15H, m, 3x pH). 4s b) 6c - Methoxy-6 [3 (D, L-2-phenoxycarbonyl-phenyl-acetamido-penicillansäure 620 mg 6c - Methoxy-61) - (D, L-2-phenoxycarbonyI-phenylacetamido) - penicillansäure more benzylester in 20 mi destilso liertem ethanol with 4,5 valley water and 0.92 valley freshly prepared n-Natriumbicarbonatlösung are freshly treated. Then one fûgt 620 mg 10prozentige palladium coal in nitrogen atmosphere in addition and hydrogenates the mixture 1 hour. Then one filters the mixture by a filter from Dicalciumsiss licat and Dicalciumaluminat and washes the arrears with valley 50prozentigem to aqueous ethanol. Then one sets far 0.7 g catalyst in addition and continues the hydrogenation, until no more benzyle ester can be proven, like this by Dünnschichtchromatographie at Silicagel in a mixture from chloroform, acetone and acetic acid in the en 'hältnis 50:50: is evident to 7 as Laufmittel. The mixture is evaporated by a filter from Dicalciumsilicat and Dicalcium aluminate filtered, under decreased pressure, in order to remove ÄthanoI, and freezingdried. One receives the 6s desired connection as Natriumsalz.

Dünnschichtchromatographie at SiO2 with a mixture from chloroform, acetone and acetic acid in the relationship 630922 50:50: 7 as Laufmitel: Rf = 5,69.

1 R-spectrum of Vmax (KBr): 3420 (broadly), 2967, 1710, 1680, 1597, 1490, 1190, 690 cm-I.

s NMR spectrum shows that no more benzyle ester available ist.

Example 8 a) 6 - Methoxy-6 - [D, L-2 (3-methylphenoxycarbonyl) - 2l0 phenylaeetamido] - penicillansäure benzylester as in example 7 (a) described, one receives the aforementioned connection in a yield when using Phenyl-malonsäure-mono-3-methylphenylester after cleaning from 76,0%. Dünnschiehtchromatographie at SiO2 with s a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship 1:3 as Laufmittel: Rr = 0,11.

IR spectrum of Vmax (CC14): 3310, 1779, 1746, 1700, 1490 cm-1.

'NMR spectrum (CCh): 8 = 1.20 (6H, s, in accordance with Dimethylgruppen); 2,35 (3H, s, Tolyl-CH3); 3,40 and 3.44 (3H, 2 x s, - OCH); 4,37 (1H, s, C3-Proton); 4,87 (1H, s, PhCH); 5,20 (2H, s, - CO2CH2Ph); 5,58 (1 H, s, Cs-proton); 6,8-7,7 (14H, m, aromatic protons); 8,0-8,2 (1 H, m, - NICO).

b) 6oE-Methoxy-6Ç [D, L-2 (3-methylphenoxycarbonyl) - 2phenylacetamido] - the penicillansäure 6e - Methoxy-6 [3 [D, L-2 (3-methylphenoxycarbonyl) - 2phenylacetamido] - becomes penicillansäure more benzylester as in example 4 (b) indicated hydrogenated. One receives the free Säure.

NMR spectrum [CCh + (CD3) 2SO]: -- 1,0 - 1.7 (6H, m, in accordance with Dimethylgruppen); 2,43 (3H, s, TolyI-CH3); 3,29 and 3.57 (3H, 2 x s, - OCH3); 4,2 - 4.4 (1 H, m, C3-Proton); 5,22 (IH, s, PhCH (); 5,45. , 6 (IH, m, C5-Proton); 6,9 -7.8 (9H, m, aromatic protons); 9,8 - 10.1 (1H, m, - CONH).

The acid becomes into sodium salt as in example 5 (b) described transferred. Exploit 73,5%.

Dünnschichtchromatographie at SiO2 with a mixture from chloroform, acetone and acetic acid in the relationship 7:7: 1 as Laufmittel: Rr = 0,66.

IR spectrum of Vmax (hot Nujol): 3310, 1760, 1685, 1608 cm-k Beiseid 9 a) 61 - [D, L-2 (5-lndanyloxycarbonyl) - 2-phenyl-acetamido-6c - methoxy penicillansäure more benzylester as in example 7 (a) one describes using Phenylmalonsäure-mono-5-indanylester the aforementioned connection in a yield of 31,4% (after cleaning) hergestellt.

Dünnschiehtchromatographie at SiO2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship 1:3 as Laufmitel: Rf -- 0,145.

NMR spectrum (CDCh): 8 = 1.2 - 1.7 (6H, m, in accordance with Dimethylgruppen); 1,9 - 2.6 (2H, m, lndanyl-2-CH2-Gruppe); 2,93 [4H, t (J = 7Hz), Indanyl lund -3-CH2-Gruppen]; 3,50 and 3.53 (3H, 2 x s, - OCH3); 4,50 (1 H, m, C3-Proton); 4,95 (1 H, s, PhCH (); 5,68 (1H, s, Cs-proton); 6,8 - 7.8 (13H, m, aromatic protons); 7,9 - 8.1 (1 H, m, - CONH).

b) 613 [D, L-2 (5-lndanyloxycarbonyl) - 2-phenyl-acetamido-6o - the methoxy penicillansäure after example 9 (a) received connection becomes after in example the 4 (b) described method hydriert.

NMR spectrum (CDCI3): õ = 1.48 (6H, s, gladly. Dimethyl630 922 groups); 1,8 - 2.4 (2H, m, Indanyl-2-CH2-Gruppe); 2.95 i4H, t, (J = 7Hz), Indanyl-1-und -3-CH2-Gruppen]; 3,52 (3H, s, - OCH); 4,50 (1 H, m, C3-Proton); 4,98 (1 H, s, PhCH); 5,65 (1 H, s, Cs-proton); 6,8 - 7.8 (8H, m, aromatic protons).

After the description in example 5 (b) sodium salt in a yield is made of 21%, like through Dünnschichtchromatographie at SiO2 with a mixture of chloroform, acetone and acetic acid in the relationship 7:7: 1 as Laufmittel to be determined konnte.

Example a) 6 [3 (D, L-Isobutoxycarbonyl-2-phenyl-aeetamido) - 6 “- methoxy peniciIIansäure more benzylester with application of the procedure in accordance with example 2 (a) one keeps the aforementioned ester in a yield with Phenylmalonsäure more monoisobutylester after is cleaning from 35,9%.

Dünnschichtchromatographie at SiO2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship 1:3 as Laufmittel: Rf - 0.22. za IR spectrum of Vmax (CHCh): 3300, 1780, 1740, 1720 cm-1.

NMR spectrum (CDCIa): 8 = 0.90 [6H, D, 0 = 7Hz), - CH (CHa) 2]; 1,32 (6H, s, gladly. Dimethylgruppen); 2,0 (1 H, m, - CH2CH (CH3) 2); 3,45 (3H, 2 x s, - OCH); 4,09 [2H, D, zs (J =7Hz), - CO2 CH2 CH (]; 4,55 (1H, s, C3-Proton); 4,82 (IH, s, PhCH); 5,30 (2H, s, - CO2CH2Ph); 5,73 (1 H, s, Cs-proton); 7,5 (10H, m, 2 x pH); 8,27 - 8.42 (1H, 2 x s, - CONH).

b) 613 (D, L-2-Isobutoxycarbonyl-2-phenyl-acetamido) - 6aaa the methoxy penicillansäure benzyle ester becomes as in example 4 (b) indicated hydrogenated. One receives the aforementioned Verbindung.

NMR spectrum (CDCla): 8 = 0.6 - 2.3 (13H, m, - CH (CH3) 2 and gladly. Dimethylgruppen); 3,52 (3H, s, - OCH); 4,07 [2H, D, (J = 7Hz), - CO2CH2CH]; 4,46 (1H, m, C3-Proton); 4,80 (1 H, s, PhCI I<); 5,62 (1 H, s, Cs-proton); 7,51 (5H, s, pH); 8,2 - 8.7 (1H, m, - CONH).

As in example 5 (b) beschñehen is, the acid into sodium salt is transferred. Yield: 54,1%.

Dünnschichtchromatographíe at SíO2 with a mixture from chloroform, acetone and acetic acid in the relationship 7:7: 1 as Laufmittel: Rf = 0,60.

IR spectrum of Vmax (hot Nujol): 3300, 1760, 1690, 1605 cm-I.

4 {I example 11 a) 6oE-Methylthio-6 - (D, L-2-phenoxycarbonyl-2-phenylaeetamido) - penicillansäure benzylester 1.57 g (3.0 mMol) of the Toluol-4-sulfonats the 61 - Amino6a-methylthio-penicillansäure-benzylesters are vibrated of a 0,5n-Bicarbonatlösung with 100 valley Äthylaeetat and 75 ml with 0 to 5°C, until everything separated. Then one separates the ethyl acetate layer, extracts the wässñge layer twice with ever 25 ml ethyl acetate, combines the excerpts, dries her over water-free Magnesíumsulfat and evaporates her. One receives 6fl-Amino-6a-methylthiopenicillansäure-benzylester. This ester is loosened in 60 mi Dichlormethan, which contains 0.67 ml Pyridin, cooled in the ice bath and treated with 1,28 g (5.0 mMol) 2-Phenoxyearbonyl-2-phenylacetylchlorid (made is of Phenyl malonic acid more monophenylester) in 20 mi Dichlormethan, as this in example 7 (a) is descriptive. The solution is agitated 2 hours and evaporated then. One receives an oil, which is loosened in ethyl acetate. The solution is washed to water, n-Natriumbicarbonatlösung and satisfied saline solution successively with water, 10prozentiger Citronensäurelösung, dried then and eingedampft.

One receives an oil. After chromatography at Silicagel one receives 1.32 g (= 74.5% the Theoñe) to the aforementioned connection as pale-yellow Sehaum.

Dünnschichtchromatographie at SiO2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship 1:3 as Laufmittel: Pf= 0.16, IR spectrum of Vmax (hot Nujol): 3300, 1780, 1740 and 1690 cm-l.

NMR spectrum (CDC13): õ = 7.90 (1 H, s, - NICO); 7,0 - 7.8 (15H, m, 3 x pH); 5,67 and 5.63 (1H, 2 x s, Cs-proton); 5,23 (2H, s, - CO2CH2Ph); 4,95 (1 H, s, PhCH); 4,50 and 4.47 (IH, 2 x s, C3-Proton); 2,25 and 2.22 (3H, 2 x s, - SCH3); 1,35 and 1.30 (6H, 2 x s, in accordance with Dimethylgruppen).

b) 6oE-Methoxy-6 [3 (D, L-2-phenoxycarbonyl-2-phenyl-acetamido-penicillansäure-benzylester 0.523 g (0.91 mMol) 6oE-Methylthio-613 (D, L-2-phenoxycarbonyle-2-phenyl-acetamido) - penicillansãnre benzylester and 0.29 g mercury (II) - in 4 ml methanol become aeetat under nitrogen 90 minutes at ambient temperature gerührt.

Then methanol under decreased pressure is vibrated removed, the arrears with ether, filtered by a filter from Dicalciumsilicat and Dicalciumaluminat and evaporated the filtrate to a strohfarbenen foam. The chromatography at Silicagel supplies 0.270 g (=52.7% of the theory) to the aforementioned Verbindung.

Dünnschichtchromatographie at SiO2 with a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 80°C in the relationship 1:3 as Laufmittel: Rf = 0,14.

NMR spectrum (CDCI3): õ = 8.12 and 8.02 (1 H, 2 x s, - NICO); 7,9 - 7.0 (12H, m, 3 x pH); 5,70 (1 H, s, Cs-proton); 5,25 (2H, s, - CO2CH2Ph); 5,00 (1 H, s, PhCH (); 4,49 (1 H, s, C3-Proton); 3,50 and 3.47 (3H, 2 x s, - OCH3); 1,33 (6H, s, gladly. Dimethylgruppen).

c) 6oE-Methoxy-613 (D, L-phenoxycarbonyl-phenyl-acetamido-penicillansäure with soaps of the benzyle ester in accordance with example 7 (b) receives one the aforementioned Verbindung.

Example 12 a) 6oE-Methoxy-6 [3 (D, L-2-phenoxycarbonyl-2-thien-2' yl4s acetamido) - penieillansäure benzylester Thien-2-yl-malonsäure-monophenylester is solved in 75 ml Dichlormethan, to which one added 3 drop dimethylformamide. This solution is shifted with 0,6 mi Oxalylchlorid and 1 hour at ambient temperature gerührt.

so then the solution under decreased pressure is evaporated. One receives the Säurechlorid, which as in example 5 (a) indicated for the acylation of 61 - Amino-6 “- methoxy penicillansäure more benzylester one uses. One receives the aforementioned cleaned ester in a yield from 44%.

ss Dünnschichtchromatographie at SiO2mit a mixture from ethyl acetate and petroleum ether of the boiling range 60 to 800C in the relationship 1:2 as Laufmittel: Rf = 0,26.

6S NMR spectrum (CriC13): 8 = 1.29 (6H, s, in accordance with Dimethylgruppen); 3,49 (3H, D, - OCH); 4,50 (1 H, s, C3-Proton); 3,25 (2H, s, Ph-CH2-O); 5,34 (IH, s, CHCONH); 5,70 (1H, s, Cs-proton); 7,50 (13H, m, aromatic Phenylund ThienylProtonen); 8,11 (1 H, D, - CONH). I R-spectrum of Vmax (hot Nujol): 3300, 1775, 1650, 1700, 1200, 770 cm-1.

b) 6c - Methoxy-613 (D, L-2-phenoxycarbonyl-2-thien-2' ylacetamido) - the penicillansäure 6oE-Methoxy-613 (D, L-2-phenoxycarbonyl-2-thien-2' 'yl-aeetamido) - becomes penicillansäure more benzylester as in example 4 (b) indicated hydrogenated. One receives the free acid in a yield from 67%. NMR spectrum (CDCh): 5 = 1.40 (6H, D, in accordance with Dimethylgruppen); 3,42 (3H, s, - OCH); 4,40 (IH, s, C3-Proton); 5,15 (1 H, s, CHCONH); 5,57 (1 H, s, Cs-proton); 7,24 (9H, m, aromatic Thienylund PhenylProtonen, - CO2H); 7,67 (1 H, D, - CONH).

The acid becomes as in example 7 (b) described transferred into sodium salt. Yield: 77,9%.

Dünnschiehtchromatographie at SiO2 with a mixture from chloroform, acetone and acetic acid in the relationship 50:50: 7 as Laufmitel: R-S -- 0,60.

Example 13 a) 6c - Methoxy-6 [3 [D, L-2 (phthalid-3-yloxycarbonyl) - thien Y YL acetamido] - penicillansäure more benzylester 1.59 g Thien-3-yl-malonsäure-monophthalid-3-ylester at ambient temperature into 35 mi water-free Methylendichlorid and shifted with 2,1 valley Oxalylchlorid and 1 drop dimethylformamide are stirred. After 90 minutes the solution under decreased pressure is evaporated. One uses the connection to the acylation of the 615-Amino-6oEmethoxy-penicillansäure-benzylester as in example 2 (a) indicated. After the chromatography one receives the connection in a yield from 22%.

IR spectrum of Vmax (CH2Ch): 1782, 1750, 1708, 1218, 1133 cm-1.

NMR spectrum (CDCI3: 8 = 1.37 (6H, in accordance with Dimethylgruppen); 3,44 (3 H, m, - degrees ha); 4,28 (1 H, s, C3-Proton); 5,00 (1 H, s CH); 5,30 (2H, s, - OCH2 F); 5,67 (1H, s, Cs-proton); 7,0 - 8.2 (14H, m, - ÇONH, 11 630922 .ri A crt, - o “_a ù. 0 tt - OCH2Ph).

Dünnschichtehromatographie at SiO2 with a mixture from Athylaeetat and petroleum ethers of the boiling range 60 to '80°C in the relationship 1:2 as Laufmittel: R-S = 0,12.

4,55 (1 H, s, C3-Proton); 5,15 (1 H, s CHCONH); 5,29 (2H, s, - CH2Ph); 5,73 (1 H, s, Cs-proton); 6,9 - 8.2 (13H, m, aromatic and Thienyl protons, - CONH).

s b) 613 [D, L-2 (2-sek. - Butylphenoxycarbonyl) - thien-3' ylacetamido] - 6 - methoxy penieillansäure of the 61] - [D, L-2 (2-sek. - Butylphenoxyearbonyl) - thien-3-ylacetamido] - 6ct-methoxy-penieillansänre-benzylester becomes as in example 4 (b) indicated hydrogenated. One receives vorgelO called connection in a yield of 46%. This acid is transferred using Natrium-2-äthylhexoat into sodium salt. Yield: 19% the Theorie.

Dünnschichtchromatographie at SiOz with a mixture from chloroform, Aeeton and acetic acid in the relationship 50:50: 7 as Laufmittel: R-S = 0,65.

IR spectrum of Vmax (KBr): 3410, 1965, 1755, 1600, 1175 and 758 cm-I.

Example 61 - [D, L-2 (2-Äthylphenoxycarbonyl) - thien-3' yl-acetamido] - 6cxmethoxy-penicillansäure-benzylester the production takes place as in example 2 (a) angegeben.

One receives the aforementioned after connection the Chromato2s graphie in a yield from 23,5%.

Dünnschichtchromatographie at SiOz with a mixture from ethyl acetate and petroleum ether of the Siedebereic 60 to 80°C in the relationship 1:2 as Laufmittel: Rf = 0,29.

IR spectrum of Vmax (CHCh): 2950, 1778, 1741, 1490, 1320, 1165 cm-1.

NMR spectrum (CDCI3): -- 1,25 (9H, m, in accordance with Dimethylgruppen, - CH2CH3); 2,5 (2H, q, - CH2CH3); 3,51 (3H, s, - OCH); 4,52 (1 H, s, C3-Proton); 5,18 (1 H, s, CHCONH); 3s 5.28 (2H, s, - CH2Ph); 5,75 (1 H, s, Cs-proton); 7,4 (12H, m, Thienylund aromatic protons); 8,07 (1 H, D, - CONH).

The hydrogenation as in example 4 (b) indicated supplies 61 - [D, L-2 (2-Äthylphenoxyearbonyl) - thien-3, - yl-acet. - amido-6 - methoxypenicillansäure.

b) The hydrogenation as in example 4 (b) supplies the 6 “- Methoxy-6 [3 [D, L-2 (phthalid-3, - yl-oxycarbonyl) _2.thien_3, _yl_ acetamido] - penicillansäure, ss example 14 a) 61 - [D, L-2 (2-sek. - Butylphenoxycarbonyl) - thien-3, - ylacetamido] - 6a-methoxy-penicillansäure-benzylester the production of the connection takes place as in example 2 (a) o indicated. One receives the connection in a yield after the chromatography from 29,4%.

NMR spectrum (CDCh): õ = 1.1 (14H, m, in accordance with Dimethylgruppen, --CHCH2CH3); 2,65 (1H, m, --CHCG2--); H= I CH3 example 16 a) 6 - Methoxy [D, L-2 (4-isopropylphen oxycarbonyl) - thien-3' yl-acetamido] - penicillansäure more benzylester the production takes place as in example 2 (a). One receives the connection in a yield after the chromatography from 47,2%. Dünnschichtchromatographie at SiO2 with a mixture from ethyl acetate and Petrolãther from the boiling range to 80°C in the relationship 1:2 as Laufmittel: R-S = 0,41.

IR spectrum of Vmax (CHCI3): 2950, 1780, 1740, 1700, 1500, 1140 cm-l.

NMR spectrum (CDCh): Æ = 1.22 (12H, m, in accordance with Dimethylgruppen, - CH (CH3) 2); 2,95 (1 H, m, - CH (CH3) z); 3,5 (3 H, s, - OCH3); 4,51 (IH, s, C3-Proton); 5,11 (IH, s, ì, CHCONH); 5,30 (2H, s, CH2Ph); 5,70 (1H, s, Cs-proton); 7,5 (12H, m, Thienylund aromatic protons, - CONH).

b) 6cx-Methoxy-6 [3 [D, L-2 (4-isopropylphenoxycarbonyl) - thien-3' yl-acetamido] - peniõUansäure 6 - Methoxy-6 [3 [D, L-2 (4-isopropylphenoxycarbonyl) - thien-3' yl-acetamido] - becomes penicillansäure more benzylester as in example 4 (b) indicated hydrogenated. One erhãlt the aforementioned connection, which is transferred using Natrium-2äthyl-hexoat in 4-Methylpentan-2-on into sodium salt. Yield: 37.2% the Theorie.

Dünnschichtchromatographie at SiO2 with a mixture from chloroform, acetone and acetic acid in the relationship 50:50: 7 as Laufmittel: R-S = 0,66.

630,922 IR spectrum vmax (KBr): 3400, 2960, 1765, 1600, 1200, 847 cm-I.

NMR spectrum (CDC13): õ = 1.4 (12H, m, gladly. Dimethylgruppen, - CH (CH3) 2); 3,0 (1 H, m, - CH (CH3) 2); 3,54 (3H, s, - OCH3); 4,5 (I H, s, C3-Proton); 5,15 (1 H, s CHCONH); 5,71 (1 H, s, C - proton); 7,4 (7H, m, Thienylund aromatic protons); 8,00 (1 H, s, - CONH).

Biological data Ith antibacterial effect the antibacterial effectiveness of a number of connections after available invention is into the nächste12 henden tables 1, 2 and 3 in the form of minimum inhibiting concentrations angegeben.

The table I refers to C - esters of the 6-Methoxy-carbenicillins of the general formula I, in the R of the Phenylrest s and R2 a hydrogen atom ist.

The table 2 refers up - esters of the 6-Methoxy-ticarcillins of the general formula I, in R the 3-Thienylgruppe and R2 a hydrogen atom ist.

The table 3 refers to Phenylester of the 6 - Methoxyto 6l - (2-carboxy-2-thien-2' yi-acetamido) - penicillansäure of the general formula I, in R die2-Thienylgruppe, R2 a hydrogen atom and a Rl the Phenylgruppe ist.

Table I - Ester of the 6-Methoxy-carbenicillins example 5 6 8 11 9 OCH - CH k. CH_COI.IH A-- -- “Nì--ßtl3 --%=1 I 1 'g 1 = g 1 = g 1 = g 1 = Rl = OH3.

Rl CH3 CHCH2-- CHs minimum inhibiting concentration in Ixg/ml E. coli JT1 5.0,5.0,2.5,5.0 10 E. coli JT4 5.0 12.5 25 25 25 250 E. coli JT425 5.0,5.0,5.0 10 25 125 Salm typhi 5.0 12.5 5.0 10 10 Shig sonnei 5.0,2.5,2.5,2.5 10 HP. aeruginosa 10662 > 100,500,500 > 100 > 100 > 500 HP. aeruginosa 10662 (10-2) > 100,250,250 > 100 > 100 > 500 Serratia marcescens US32 25 25 12.5 25 25 250 Klebsiella of aero gene A 1.0,0.5,0.5,1.0,2.5 Enterobacter cloacae NI 5.0,5.0,2.5,5.0 10 P. mirabilis C977 5.0,2.5,2.5,2.5 10 P. mirabilis 889,5.0,5.0,2.5,5.0 10 P. morganii 5.0,2.5,2.5,2.5 10 P. rettgeri 2.5,2.5 1.25 2.5 10 B. subtilis > 100 > 500 > 500 > 100 > 100,250 Staph. aureus Oxford > 100,500,500 > 100 > 100 Staph. aureus Russell > 100,500 > 500 > 100 > 100 Staph. aureus 1517 > 100 > 500 > 500 > 100 > 100 > 500 Strep. faecalis 25 > 500 > 500 > 100 > 100 > 500 of B-haemolytisches Strep. C N 10 -- 125 > 500 50 > 100,0.5 standard dilution in 5prozentigem blood agar Q, table of 2 A-esters 6 A-Methoxy-ticarcillins 1.4,1.4 example 1 2 4 3 14 0CH3 -, oJ C02H RI= RI= Ri= RI= CH3-CH.

CH2CH3 E. coli JT1 E. coli JT4 E. coli JT425 Salto typhi Shig sonnei HP aeruginosa 10662 HP. aeruginosa 10662 (10 " 2) Serratia marcescens US32 Klebsiella of aero gene A Enterobacter cloacae N I P. mirabilis C977 P. mirabilis 889 P. morganii P. rettgeri B. subtilis Staph. aureus Oxford Staph. aureus Russell Staph. aureus 1517 Strep. Faecalis of B-haemolitisches Strep. CN standard dilution in 5prozentigem blood agar Mind¢sthemmkonzentration in lag/ml 2.5 25 5.0,5.0 12.5 50 5.0,5.0,6.2 25 5.0,5.0,6.2 50 2.5,5.0,125,5.0,2.5,2.5,125 > 500 > 100,250,125,500 > 100,125 > 500 10 12.5 1.25 50 1.0,2.5,6.2 50 5.0,5.0 1.25 50 2.5,5.0 25 2.5,5.0,2.5 25 2.5,5.0,2.5,5.0,2.5,2.5,125,125 > 100 > 500,125 25 > 100,500 > 250 50 > 100,500 > 250,250 > 100 > 500 > 250 > 500 > 100 > 500 1.25 50 125,2.5,5.0,2.5,2.5,0.5,250,250 12.5 0.5,2.5,2.5,2.5,2.5,0.5,250,250,500 > 500 > 500 12.5 16 Ri= C [- I3 CH3 0.5,2.5,2.5,2.5,0.5 5OO 250,5.0 0.25 1.25 1.25 1.25 0.5,0.5 > 500,250,500 > 500 > 500 7630 922 table 3 example 12 OCH3 “I/S R-CH-CONH j N IC02R10 C02 H RI= minimum inhibiting concentration in g/ml E. coli JT1 E. coli JT4 E. coli JT425 Salto typhi Shig sonnei HP. aeruginosa 10662 HP. aeruginosa 10662 (10-2) Serratia mareescens US32 Klebsiella of aero gene A Enterobacter cloacae NI P. mirabilis C977 P. mirabilis 889 P. morganii P. rettgeri B. subtilis Staph. aureus Oxford Staph. aureus Russell Staph. aureus 1517 Strep. feacalis B-haemolytisches Strep. CN 5.0 12.5 5.0 12.5 2.5,250,250 12.5 0.5,5.0,2.5,2.5,2.5,2.5,250,500 > 500 > 500 standard dilution in 5prozentigem blood agar 2nd oral absorption it is measured with Mäusert the Blutspiegel by 6-Methoxytiearcillin and 6-Methoxy-carbenieillin after an oral administration of the esters. With animals, the certain connections also the urine had received were collected and bioehromatographisch determined whether hydrolisierte esters are separated. The extent of the hydraulic: the lyse ester during the micro-biological attempt becomes in the mouse blood and in saline solution gemessen.

The following methods are used:

Speeies:

18 to 22 g heavy male albino mice CS 1 administration way:

orally dosage:

Each ester is given in a dose, the 100 mg/kg, related to the free Stammpenicillansäure enthält.

Attempt:

Samples examined in form of the Stammpenicilline using Neisseria catarrhalis as Versuehsorganismus.

Chromatography:

The urine is collected by mice, which the connections of the examples 2, 3, 4, 6 and 10 to have received. The samples are noted in the Bioehromatogramm. It becomes a butanol: Ethanol: Water system in the relationship 4:1: 5 applied, and the strips becomes visible on agar plates, which are inoculated with Neisseria catarrhalis, gemacht.

The results of the Blutspiegel with mice are in the tables 4 and 5 angegeben.

No Blutspiegel determined after a dosage of 6-Methoxy-carbenicillin with 100 mg/kg under the same Bedingungen.

63O 922 16 table 4 Blutspiegel of 6-Methoxy-ticarcillin with mice after oral doses of a set of A-Carboxyestem in a quantity of lO0 mg/kg ester example type mouse Nr.

Concentration (lxg/ml) of 6-Methoxy-tiearcUlin in minutes after the Verabreiehung 20 30 60 120,240 2 4 isobutyl 4-methylphenyl 5-indanyl 1 of,4.6,8.0 10.5 4.9,3.6 0.54 2 4.6,8.6 11.5 9.0,4.3 0.94 3 3.1,6.1 11.0 8.6,2.8 0.58 4 3.0,4.1 11.3 7.8,3.1 0.59 6.4,5.6,9.4,7.9,2.5,1.6 means 4.3,6.6 10.7 7.6,3.3 0.85 1 1.3,1.7,3.2 1.72 0.48 0.31 2 1.2,1.6,3.7,2.2 0.21 d0,10 of 3 0.99 1.95 3.0,2.1 0.50 0.27 4 1.25 1.95 1.7 1.85 0.52 0.51 1.1,3.5,2.0,1.4 - means 1.2 2.14 2.7 1.85 0.43 0.29 1 4.5,8.1,8.5,2.8 0.62 0.44 2 3.8,9.0,5.2,3.8 1.45 1.0 3 3.1,8.0,8,0 2,55 1.5 0.78 4 2.7,6.8,4.4,7.0,0.5 0.36 4.8,3.5,8.5,3.7 - - means 3.8,7.1,6.9,4.0,1.0 0.64 table Blutspiegel of 6-Methoxy-ticarcillin with mice after oral doses of a set of A-Carboxyestern in a quantity of 100 mg/kg.

Ester example type mouse Nr.

Concentration (p, g/ml) of 6-Methoxy-tiearcillin in minutes after the Verabreiehung 20 30 60 120,240 11 phenyl 3,4-dimethyl phenyl 4-methyl phenyl 3-methyl phenyl 1 of,3.4,5.4 10.5 3.9,3.0 0.85 2 5.0,7.0,6.4,4.3,2.9 0.53 3 3.9,6.1,7.4,5.6,2.0,1.4 4 3.8 15.9 8.4,2.1,1.4 0.80 2.9 - 5.8,3.5,1.7 0.78 means 3.8,6.1,7.7,3.9,2.2 0.87 1 9.2,7.4 19.0 15.0 7.8,1.8 2 13.0 9.2 17.5 11.0 7.7,4.9 3 12.0 11.5 14.5 8.5,7.5,3.7 4 7.8 13.0 20.0 4.4,5.3,3.1,8.0….

Means 10.0 10.3 17.8 9.7,7.1,3.4 1 of 6.5 10.0 9.4 11.5 3.8,1.8 2 6.5 10.5 11.5 15.0 3.1,1.1 3 3.8 10.2 9.6,7.4,4.9,2.0 4 2.1,6.5 12.0 9.5,3.2,2.6,2.4 10.5 9.6,8.9,3.1 0.62 means 4.3,9.5 10.4 10.5 3.6,1.6 1 1.4,5.4 12.0 9.4,4.3,3.5 2 4.6,8.8 11.9 6.5,4.9,2.4 3 2.7,9.3 12.0 5.3,4.0,1.8 4 3.1,8.4 13.5 9.0 - 0.7,2.6,5.1 13.5 6.8,5.4,1.2 Miel 2.9,7.4 12.6 7.4,4.7,1.9 17 630922 TabeHè5 (F0 setting) Blutspiegelvon 6-Methoxy-ticarcillin with mice after oral doses of one row of - Carboxyesternin one-mixes from 100mg/kg.

Ester example type mouse Nr.

Concentration (p.g/ml) of 6-Methoxy-ticarcillin in minutes after the administration 20 30 60 120,240 5-indanyl isobutyl 1 2 3 4 2.9 15.0 22.0 5.8,3.7,2.3,1.4 22.0 15.2 15.2 5.8,1.6,5.6 14.0 14.5 12.0 5.0,3.0,2.5 20.0 9.2,7.0,3.7,1.9,5.4 - - 8.8 - - 1 of,6.2,9.2,9.0,5.5,8.0,1.4 2 4.7,9.8 15.0 10.7 8.8,2.0 3 4.8 14.0 16.5 12.0 5.2,3.0 4 3.9 11.7 13.5 14.0 4.7,4.1,4.7 13.0 15.5 12.0 4.9,1.5 means of 4.9 11.5 13.9 10.8 6.3,2.4 means 3.6 17.8 15.2 9.8,4.6,2,2