PROCEDURE FOR the PRODUCTION OF 6-AMINOPENICILLANSAUREDERIVATEN

The invention concerns a procedure for the production of derivatives of 6-Aminopenici] lansäure and of them pharmaceutical acceptable, non-toxic salts. The connections received with proceeding in accordance with the invention have the general formula \ C] I I \ O C N CH CH3 COOH (I) in that g 1, pH and R3 directly or differently are and in each case a unsuhstituieße or substituted aliphatic group of hydrocarbons, a more monooder bicyclische carbocyclische Arylgrnppe, a Aralkyl, Cycloalkyl, Cycloalky! - alkyl, to represent and R3 furthermore hydrogen mean, zusarnmen g 1 and R2 know hetero-cyclic group or a hetero-cyclic substituted alkyl group with the nitrogen atom in ring system to form to be able and pH and R3 as well as the numerical control flavours a ring system to represent be able. In particular represent g 1, R2 and R3 the following groups. an aliphatic Kohlenwasserstoffgrnppe, in which the carbon chain straight branches out or, satisfied or insatiated to be can, like a methyl, ethyl, Propyl, Isopropyl, Butyl, sek.BuLyI, tert. Butyl, l entyl, Hexyl, Dodecyl, A] lyl, ButenyI, Pentenyl or Propargylgruppe; one mono or bicyclische group of aryls, e.g. one PhenyI or Naphthylgruppe; a Aralkylgruppe, like a more mcaooder bioyolisohe Aralk ylgrnppe, for example a benzyle, a Phenäthyl, 1oder 2-Naphthylmethylgrnppe; a CycloalkyIoder Cycloalkyl alkylgrnppe, in which the Cycloalkylgruppe 3 to 10 ring members or or two double bonds have can be exhibited and satisfied, like a Cyclopentyl, a cyclohexyl, a 1-AdamantyI, a 1-Bicyclo (2nd 2nd 2) octyl, Cyclopentyl undCyclohexenylgruppe, a CycIopentylmethyl, cyclohexyl methyl, cyclohexyl ethyl, Cyclopentyläthyl, Cyclohexenylmethylgruppe etc.; a hetero-cyclic group or a hetero-cyclic substituted alkyl group, in which the hetero-cyclic part can exhibit completely or partly hydrogenated its kùnn, in the ring 5 to 10 atoms and contain oxygen, Schwefeloder of nitrogen atoms, like e.g. a Pyridyl, Pyrazinyl, Pyrimidyl, Pyrrolidyl, PiperidyI, Morpholinyl, Thiazinyl, Furyl, Thienyloder Chinolylgruppe, whereby in all these groups the Heteroatome can be arranged in any of the available positions; G 1 and R2 as well as the nitrogen atom, and g 1 and R3 as well as the numerical control flavours hetero-cyclic groups with 5 to 10 flavours and gewünschtenfalls still different Heteroatomen in the ring, like S, O or N, and vo] lständig or partly Pängsysteme, like a Piperidyl, e.g. hydrogenated Morpholinyl, Hexahydro1H-azepin-l-yl, Hexahydro l (2H) - more azocinyloder Octahydro LH azonin l ylgruppe. Furthermore the substituents Ri, R2 and R3 can be substitaiert by halogen atoms, an alkyl, hydraulic XY, Alkoxy, carbocyclische Aryloxy, A1kylthiooder carbocyclische Arylthiogruppe, an ecyl, Carboxy, Carbalkoxy, CarbamyI, Carbamid, Cyauoder group of sulphonyls, a Azido, Aminooder substituted A, m nogrnppe. The connections of the general formula (I) can in form of their zwitterions or salts, e.g. .derA1kalimetall, Ammoniumoder of amine salts or the salts with strong acids, like hydrochloric acid, phosphoric acid, qalpetersäure, p-Toluolsulfosäure, tartaric acid or maleic acid, be isolated. Furthermore can also with other antibiotics, which have sour or basic characteristics, and in particular with antibiotics, with which available the according to invention connections form synergistic mixtures, drink as with Penicillinen, salts to be manufactured. It is particularly appropriate to use acids which form salts, which have desirable self-work regarding the absorption and the use in clinical practice with the gegenständlichen connections. Examples of such salts are the Pamoat and Naphsylat or salts, which contain Probenecid, whereby the connection mentioned last results in the elimination erfändungsgemäß of the available connections retarded and from it increased Blutspiegel. With muddled in accordance with the invention received connections are used appropriately for a parenteral treatment. Therefore the connections are given favourably by injection of an aqueous, sterile solution or suspension of the zwitterion or one of its suitable salts alone or in combination with a Puffersubstanz. The connections in accordance with the general formula (I) are so far on in brit. Patent specifications No. 1.293.590 and No. 1.315.566 describe-wise by conversion of a reactive derivative of an amide or Thioamids of the general formula Ri 3 N-C=R 1% (II) in that g 1, R2 and R3 the meaning stated above have and R5 for O or S stand, e.g. a connection of the general formula N - C = (0 universe:)2 J (REAR ONES) in that g 1, R2 and R as above are defined and alkene for a Niederalkylgruppe stand, with a 6-Amiuopenicillansäurederivat of the general formula H H H2N - -- ] i I \ O -- -- C N--CH CH “COOR 4 in the R4 hydrogen or a unsubstituierte or substituted AlkyIoder Aralkylgruppe represents, or with a Silylestervon 6-Aminopeuicillansäure to be received. If - COOR4 for a group of esters stands, a splitting of the group of esters must follow for receipt of the gegenständlichen connections the conversion. It was now found that the connections in accordance with the general formula (I) in favourable way to be received can, if a reactive derivative of a connection of the general formula (IL) is preferably converted with a salt from 6-Amlnopenicillansäure (6-APA), a salt with a strong tertiary amine, in a suitable solvent and at a temperature close of the ambient temperature or under it and isolated in form of the free acid or a salt. Contrary to the mentioned well-known procedures with the procedure according to invention in all cases a salt is converted by 6-Aminopenicillansäure and in only one Verfahrensstufe, without ester splitting od. such, which desired Endprodakt receives. Beyond that the yields reached with proceeding in accordance with the invention are far better than the yields receiptable with these well-known procedures. For example it can be mentioned that with the procedures of this kind already described (see. österr. Patent specification No. 301,026) the production of 6 [(Hexahydro LH azepin l yl) - methylenamino] - penicillansäure only with a yield of 54% succeeds to be received, with the help of the erfindangsgemäßen procedure however substantially better results, as is too seen from the following examples I to 14 2S. Examples of reaktionsf'ähige derivatives of the connections of the general formula (H) are in particular acid amids acetal of the general formula (III), Di-niederalkylsulfatkemplexe with the connections of the general formula (H), or acid amide halides, which will receive by conversion of a connection of the general formula (IL) with a Halogenierungsmittel. These examples are to be understood restrictive however for the ErfindLmg in no way. It is surprising that with proceeding in accordance with the invention at pro bearing with high purity will receive distinguished exploiting, about 70 to 90%, because it admits is, since derivatives of amides react to real-time frequently with acids. Therefore acid amide halides with acids can form Säurehalogenide, against what Säureamidaeetale can form esters during such a conversion. Furthermore the procedure so far-well-known-proceeded in accordance with the invention more simply than. It is accomplished in a stage, against what with the earlier method the production took place zo B. of a Silylesters or a benzyle ester from 6-APA and afterwards a transfer into the Amidinopenieillansäureester and hieranf a splitting of the group of esters. The conversion becomes by release or suspending the functional components in an organic solvent, preferably in absence of water imHinblick on it that the reactive Derirate of the connections of the general formula (II) with presence of water to be hydrolyzed, accomplished in a stage. The material ion conditions depend on the components used with the procedure and become from there in the following in detail more near besehrieben. If during proceeding in accordance with the invention as Reak ion component an acid amid acetal is used, are the preferential material iensmedien Methylenehlorid, chloroform, Aeeton with a small quantity form amide, methanol and Msthylformiat, in the case of use of the first three mentioned reaction media is the presence of a strong tertiary amine require CH, in order the desired yields at the connections of the general formula to receive (I) with high purity, against what e.g. in methanol the conversion can be accomplished due to the circumstance that weakly basic acid can form the r idacetal in this medium with 6-APA a salt, without additive of a tertiary amine. As examples of strong tertiary Ambone, which can be used on the way stated above, TriäthylAmiu and N, N-Diisopropyläthylamin can be called, against what Pyridin, N-Methylmorpholin or Triäthanolam u fiir this purpose are too weak e.g. The evenly mentioned Umsstzung lmnn using equivalent quantities of the setting right ion components takes place, but it is preferred to use a small surplus of acid amid acetal and tertiary A 4u (in both cases about 20 to 30). It is naturally possible to use as raw material a salt of 6-APA and the tertiary amine by using either a before manufactured salt or partly with the tertiary Amen lets 6-APA before the additive of the acid amid acetal react. The conversion is durchgefiihrt for instance at ambient temperature or at a temperature under the ambient temperature, preferably at a temperature from 0 to 5°C, nn however also still at lower temperatures, z, B.bei about -25oc, to take place. The Reaktienszeit depends on the temperature and the used Reak iensmedium and furthermore on it whether a tertiary amine is added or not, amounts to however usually 1 to 6 h. If during proceeding in accordance with the invention as reaction component Di-niederalkylsulfatkomplex one uses, is the preferential reaction medium dichloromethane or methanol. In this case it is necessary to use at least an equivalent of a strong tertiary amine to protect in order - the I ctamring in the final connection of the general formula (I) and in the 6-APAgegendenDi-niederalkylsulfatkomplex, which an opening of the erwähnten/3-Lactamringes ansonst would cause. Preferably about 1, 5 to 3 equivalents of the tertiary amine and a surplus to Di-niederalkylsulfatkomplex (about 20 to 30%) is used. When using of Methylenehlorid as reaction medium it is appropriate, before the additive of the Di - the down-alkyl-sulfate-complex largest part of the 6-APA in form of a tertiary amine salt to solve. The preferential reaction temperature is appropriate with approximately 0 to 5°C, but can also higher (about ambient temperature) and lower temperatures (about - 10oc) just as well to be used. The response time h ugt from the temperature, the material - ion medium and the reaction components off, amount to however usually 1 to 6 h. If during proceeding in accordance with the invention an acid amide halide is used as Reaktionskemponente, can be used due to the circumstance that the acid amide halides are very reactive, only dichloromethane, chloroform and similar inert Renktiensmedien. In this case it is appropriate to use 2 to 3 equivalents of a tertiary amine in order - lactam ring in the Endproduk and in the 6-APA to protect. It is favorable to solve before the additive the acid amide halides the majority of the 6-APA in form of a tertiary Zinnsalzes. The conversion is to be accomplished at low temperatures, beginning with approximately - 50oc. The reaction temperature is left to for instance 0oC to rise and the conversion to approximately 3/4 h is terminated. The formed material ion mixture, which the stable tertiary rnln “alz one of the connections of the general formula (I) or in some cases the Zwitterien contains, is filtered, to remove around a possibly existing remainder from not converted 6-APA and the clear solution of D nù in the vacuum is evaporated. That is solved in a suitable solvent, from that the acid of the general. Formula (I) by additive of another Lösnngsmittels, in which it is only weakly soluble, one precipitates; preferably the Zwitterien is set free by additive of a auorganischen or organic acid. In particular with the production of larger quantities it is vorzuziehon, possible remainders of the Reak of ion medium thereby that one zussrnmen a high-simmering solvent, like methylethylketone, gewünschtenfalls with the acid, which is used for the release of the zwitterion adds, to remove and to on that evaporate the Lösungsmittelmisohung in the vacuum. The combination of tertiary Arnin, solvents and acid can be selected zweekmäßigimHinbliek on it that the zwitterion is to be held to be precipitated and with the Nentralisation formed amine salt in the solvent in solution. For the release of the zwitterion p-Toluolsulfosäure can solved in acetone or methylethylketone be used, but can also different acids and solvent, as a function of the assigned reaction components, be used. The expenditure August materials used with the conversions eye-led above are connections, which are behannt or will receive with the help of usual methods for the production of similar connections can. With proceeding in accordance with the invention a sewing product will receive from high purity (, determines 97 to 98% by jodometrische titration). For reasons of stability is it of importance that the final product contains as few impurities as possible, because even small impurities decrease the durability considerably. I0 for this reason can be further cleaned the sewing product by Umkrietallisieren from a suitable solvent or a Lösungsmi telmisehung. In some cases it can be appropriate to transfer the raw product in its Hyclrat then from a suitable solvent or a mixture of Lösungsmittelu, e.g. Form amide acetone, for the education of the desired water-free connection of the general formula (I) one umkrietallisiert. The connections of the formula (I) can as such or in form of a salt, e.g. a Alhalimetall, Ammoniumoder Arnlnsalzes or a same with pharmaceutical acceptable, strong acids, as hydrochloric acid, phosphoric acid, nitric acid, pToluolsulfosäure, tartaric acid and maleic acid, be isolated. With proceeding in accordance with the invention all possible isomers forms of the connections of the general formula as a function of the different substituents (I) become received, while the 6-Aminopenicillunsäureteil has the configuration of the part received with the fermentation procedure. The connections of the formula (I) a valuable antibacterial effectiveness and its toxicity have are extraordinarily low, how this brit in. Patent specifications No. 1.293.590 and No. 1.315.566 is descriptive. The invention is described now on the basis the following examples, which are not to be understood restrictive however for the invention, more near. B e i s p i e 1 1: 6 - [(Hexahyclro-lH-azepin-1-yl) - methylenamino] - penicillansäure: 2.48 g 6-Aminopenicillansäure, 1.62 ml tri methyl amine and 2, 98 g 1 - Hexamethylenimincarboxaldehyd - dimethylacetal were long agitated in 40 ml dichloromethane at a temperature of 0 to 5°C 2.5 h. After filtering the filtrate in the Val was evaporated tum and the arrears were taken up to 50 ml acetone. The received solution by additive of 1, 9 g p-Toluolsulfosäure-Monohydrat in 25 ml acetone under l ühren neutralized and at ambient temperature angeimpft. The mixture was then held and filtered 1.5 h to 0 to 5°C. Yield 82%, purity 97%. B e i s pi e 1 2:6 - [(Hexahydro LH azepin I yl) - methylenamino] - 'penicillansäure: A suspension of 2, 48 g 6-Aminopenicillansäure in 40 ml chloroform was agitated 4, 5 h long with 0 to 5°C with I, 62 ml tri ethyl rnlu and 2, 25 g 1-Hexamethylenimincarboxaldehyd-dimethylacetal. The formed weakly gloomy solution was filtered with an F terhilfsmitteI. The filtrate was evaporated in the vacuum, whereby an oil became to receive, which was taken up to 50 ml acetone. The pure connection by additive of a solution of 1, 9 g p-Toluolsul£osäure-Monohydrat in 25 ml Aceten under l ühren at ambient temperature during 1/2 h and-following-agitate over I h with 0 to 5°C precipitated. The crystalline connection was filtered off, washed with acetone and dried in a Exsikkator. Yield 70%, purity 98.5%. B e i s p i e 1 3: 6 - [(Hexahydro-1H-azepin-1-yl) - methylenamino] - penicillansäure: 2.48 g 6-Amiuopenioillansäure were suspended in a mixture of 0,5 mi form amide and 25 mlAceton (lVlerok per annum). Then 1, 62 was added ml tri ethyl amine and 2, 37 ml 1-Hexamethylenimincarboxaldehyd-dimethylaeetal. The mixture was agitated 5 h long with 0oc and filtered then with a filter aid. At a temperature from 0 to 5oc under agitating and Animpfen a solution was added of 1, 9 g p-Toluolsulfosäure-l Ionohydrat in 25 mi acetone. The formed precipitation was filtered off and washed with acetone. Yield 67%, purity 98%. B e i s p i e 1 4: 6 [(Hexahydro LH AZEPIN L yl) - methylenamino] - penicillansäure: 2, 48 g 6-Aminopenicillansäure, i, 95 ml N, N-Diisopropyläthylamin and 2, 37 ml 1-Hexamethylenimincarboxaldehyd-dimethylacetal were agitated 3, 5 h long with one temperature of 0 to 5oc in 40 ml Methylenehlorid. After filtering with a filter aid and an evaporation of the filtrate the received oily arrears in 50 became ml peat. ButanoI solved. Under agitating became at ambient temperature hydrogen chloride in isopropanol (Sn, 1.44 valley) and afterwards further 20 ml text. Butanol added. The formed precipitation was filtered off, tert with. Butauol and ether washed and dried. Yield 69%, leerheit 97 B e i s p i e 1 5: 6 - [(Hexahydro-1H-azepin-1-yl) - methylenamino] - penicillansäure: 2.48 g 6-Aminopenicillansäure, 1, 62 ml tri ethyl amine and 2, 37 ml 1-Hexamethylenimincarboxyldehyd - dimethylaoetal 3 h long with 0 to 5°C in 40 ml dichloromethane were agitated. After filtering with a filter auxiliary with valley the filtrate in the Valmum was evaporated. Ml acetone under agitating 0, 66 was added to the arrears in 60 ml glacial acetic acid. The formed precipitation was sucked off and dried. Yield 57%, purity 98%. B e i s p i e I 6: 6 - [(Hexahydro LH azepin l yl) - zaethylenamino] - penicillansäure: With application of the function, whereby however in place by acetic acid 1.4 g benzoic acid were used, described in example 5, the desired connection in good yield was received. Yield 70%, purity 97%. B e i s pi e 1 7: 6 [(Hexahydro LH azepin l yl) - methylenamlno] - peniefllansäure: 2, 48 g 6-Aminopenicillansäure, 1.62 ml tri methyl amine and 2, 37 ml 1-Hexamethylenimincarboxaldehyd - dimethylacetal in 40mll Iethylenchlorid with 0 to 5oc 3, 5 h were long agitated. After filtering with a Fflterhilfsmittel the filtrate in the vacuum was evaporated. The arrears were taken up in15 ml acetone and under agitating at ambient temperature with 60 m! Ether shifts. The mixture was then held and filtered 1, for 5 h on a temperature from 0 to 5oc, whereby the desired crystalline connection became to receive. Yield 70%, purity 97.5%. Example 8:6 - [(Hexahydro LH azepin l yl) - methylenamino] - penicillansäure: 10, 0 g 6-Aminopenieillansäure, 7, 0 ml tri ethyl amine and 10, 9 ml 1-Hexamethylenimincarboxaldehyd - dimethylaeetal in 50 mi] Viethanol 1, 5 were agitated h long with 0 to 5oc. After Ffltration the filtrate in the vacuum was restricted and the arrears in 45 ml Methylä'thylkston with a content of 8,0 g p-Toluolsulfosäure-Monohydrat aufgenoroTnen. The solvent was abdestilliert in the vacuum and the arrears with 50 were shifted ml methylethylketone. The apparent pH value was stopped by addition by tri ethyl amine to 7,2. After agitating at a temperature from 0 to 5oc during one period of 1 h the crystals were filtered off and washed with methylethylketone. Yield 83%, purity 99%. B e i s p i e 1 9: 6 - [(Hexahydro LH azepin l yl) - methylenamino] - penicillansäure: 10, 0 g 6-Am nopenieillansäure and 10, 9tal 1-Hexamethyleniminearboxaldehyd-dimethylaeetal were long agitated in 50 ml methanol with 20 to 25oc 5 h. After the Ffltrat imVakuum were evaporated and the arrears in 45 ml Mefiayläthylketon suspendieß. The solvent was removed in the vacuum and the received arrears with 50 were shifted ml methylethylketone. The apparent pH value was stopped by additive of p-Toluolsulfosäure-Monohydrat to 7,5. After agitating with 0 until seconds during one period of I h the crystals were filtered off and washed with methylethylketone. Yield 78%, purity 99, 5%. Example 10:6 - [(- Hexahydro LH azepin l yl) - methylenamino] - penicillansäure: 2! , 6 g 6-Aminopenieillansäure, 23, 6 ml tri ethyl amine and 32, 9 g N-Formylhexamethylenimln-dimethylsulfatkomplex were long agitated in 85 ml methanol with 0 to 5oC 2 h. After filtering the filtrate in the vacuum was evaporated and the arrears were taken up to 110 mlMethyläthylketon with a content by 14, 3 g p-Toluolsulfosäure-Monohydrat. The solvent was abdestilliert in the vacuum and the arrears with 110 ml MethyIäthylketon were shifted. The apparent pH value was stopped by additive of tri methyl amine to 7,3. It was agitated i h long at a temperature from 0 to 5oc, then the crystals were washed abfiltrieß and with methylethylketone. Yield 74%, purity 98%. B e i s p i e 1 11: 6 [(ttexahydro LH azepin l yl) - methylenam o] - penicillansäure: 21, 6 g 6-Aminopenicfllansäure and 17, 8 ml tri ethyl amine were agitated in 85 ml Methylenehlorid 2 h long with 0 to 5°C. After additive of 22, 4g 1-Hexamethyleniminearboxaldehyd-dimethylacetal was continued agitating 2 h long at a temperature from 0 to seconds. Then the material ion mixture was filtered and the filtrate in the vacuum evaporated the arrears was taken up to 110 mI methylethylketone, which contained 19, 0 g p-Toluolsulfosäure-Monohydrat. The solvent was abdestilliert in the vacuum and the arrears with 110 were shifted ml methylethylketone. The apparent pH value was stopped dareh additive of TriäthyIamiauf 7, 3. After 1 h had been agitated with 0 to 5oc, the crystals were abfiltrieft and washed with lViethyläthylketen. Yield 84%, purity 99%. B e i s p i e 1 1 2:6 - [(Hexahydro LH azepin l yl) - methylenamlno] - penicillansäure: 21, 6 g 6-Aminopenicillansäure and 31, 4tal tri ethyl amine were long agitated in 85 ml dichloromethane with 0 to 5oc 2 h. After additive of 32, 9 g N-Formylhexamethylenimin-dünethylsulfatkomplex the Rfihren 2 h was continued with 0 to 5oc. Then the Reaktionsmisehung was filtered and the filtrate was evaporated imYakuum. The arrears were taken up to 110 times methylethylketone with a content by 19, 0 g p-ToluolsulfosäureMonohydrnt. The solvent was removed in the vacuum and the arrears with 110 were shifted ml methylethylketone. The apparent pH value was stopped by additive of tri ethyl min to 7,2. After agitating during one period of 1 h with 0 to 5oc the crystals were filtered off and washed with methylethylketone. Yield 68%, purity 97.5%. B e i s p i e 1 1 3: 6 - [(Hexahydro LH azepin l yl) - methylenamlno] - penicillansäure: 2, 2 g 6-Amlnopehicillansäure, 0.81 ml l yridin and 6, 5 ml 1-Hexamethylenimincarboxaldehyd-dimethylacetal were long agitated in 30tal methanol with 0 to 5oc 1, 5 h. The received weakly gloomy solution was filtered with a filter aid. The filtrate was evaporated in the vacuum and the arrears were solved in 50 mI acetone. The solution was neutralized by additive of 1, 9 g p-Toluolsulfosäure-Monohydrat under agitating and Animpfeu at a temperature from 0 to ö°C. The formed crystals were filtered off and washed with 10 ml acetone and 20 ml ethers. Yield 65%, purity 97%. B e i s p i e 1 1 4:6 - [(Hexahydro LH azepin l yl) - methylenamino] - peuicillansäure: 2, 2 g 6-A nopenicillansäure and 4, 2 ml tri ethyl amine were agitated in 25 ml dry chloroform 1 h at ambient temperature. The formed solution was cooled down on a temperature of -45oc. Then 1.82 g of the SäursamidchlorJds, which had been manufactured by conversion by N-Formylhexamethylenimin and Oxalylchlorid, in 15 ml was slowly added to dry chloroform, whereby the temperature rose to -25°C. In the process of 3/4 h the temperature was increased to 0oc and then the solution in the vacuum sing-confined. The arrears warde with 25 ml Aoeton agitated and filter. The filtrate was evaporated in the vacuum and the arrears were taken up to methylethylketone. With additive of 1,7 g p-Toluolsulfosäure was precipitated the zwitterion. Yield 62%, purity 97%. B e i s p i e 1 1 5:6 - [(Hexahydro-1H-azepin-1-yl) - methylenamino] - penicillans äure Trihydrat: 27 g in accordance with the examples 1 to 14 received of the product were acetone-suspended in 50 ml and solved by additive of 32 ml water. With addition of 200 ml acetone was precipitated pure tri hydrate. It was filtered off, washed with acetone and getroclmet at air. B e i s p i e 1 1 6: 6 [(Hexahydro-lH-azepin-1-yl) - methylenamino] - penicillans äure p Toluolsulfonat: A solution of 9, 5 g p-Toluolsulfosäure-Monohydrat in 50 ml isopropanol became under agitating at ambient temperature one suspension of 19 g 6 [(Hexahydro-2H-azepin-1-yl) - methylenamino] - isopropanol penicillansäureTrihydrat added in 100 ml. The received solution was filtered and the salt by additive of 100 ml Isopropyläther, anschließendesAnimpfen and further additive of 50 ml Isopropyläther precipitated. The crystals were sucked off and washed with Isopropyläther. Yield 78%, purity 100%. [A: + 182° (C =1, 0,1nHC1). B e i s p i e 1 17: 6 [(Hexahydro LH azepin l yl) - methylenamino] - penicillansäure Beuzolsulfonat: 19 g 6 [(Hexahydro LH azepin l yl) - methyleuamino] - peuicillansäure Trihydrat in 125 ml acetone were solved by slow addition from 8 g Benzolsulfosäure in 125 ml acetone under agitating with 0 to 5°C, on which presently/immediately the Benzolsulfonat failed. Was sucked off, washed with 25 ml acetone and 25 ml ethers and recrystallized from methanol ether (100 to 200 valley). Yield 80%, purity 100%. [A: + 192° (C = 1, 0,1nHC1). B e i s p [e 1 18: 6 [(Hexahydro LH azepin l yI) - methylenamino] - penicillansäure Maleatmonohydrat: A suspension of 19 g 6 [(Hexahydro-1H-azepin-l-yl) - methylenamino] - penicil] acidifying tri hydrate in 125 mI acetone was added under agitating at ambient temperature a solution of 6 g maleic acid in 125 ml Acetan. The formed solution was filtered and the salt by addition was precipitated of 100 ml cyclohexane. The solubility of the Maleats in water (5%) is lower than those of the p-Toluolsulfonats and the Benzolsulfonats. Yield 87.5%, purity 100%. [A: +200° (C = 1, 0,1nHCI). B e i s p i e 1 19: 6 - [(Hexahydr 1H azepin 1 y) methy enamin] penici acidify 2 naphtha insu f nat: A filtered solution of 3,8 g 6 - [(Hexahydro-lH-azepin1-yl) - methylenamino] - penieillans äure Trihydrat and 2, 6 g 2-Naphthalinsulfosäure-Trihydrat in 50 ml acetone were evaporated in the vacuum. The arrears crystallized with 75 ml ethers rubbed and darchVerreiben with 25 ml Äthylaoetat. The received salt is weakly soluble in water. Yield 60%, purity 100%. [A: +169° (C = 1, 0,1nHC1). B e i s p i e 1 2 0: Natrium-6 [(hexahydro LH azepin l yl) - methylenamino] - penicillanat: 11.4 g 6 - [(Hexahydro LH azepin l yl) - methylenamino] - penicillansäure - tri hydrate in 50 ml Isopropyläther by additive of a solution of 5,1 g Natrium-2-äthylhexanoat in 45 mlAceton under agitating at ambient temperature it was solved on which the salt failed presently/immediately. Then 75 ml Isopropyläther were added and the precipitation was filtered off. The salt was recrystallized from 95% n-Propanol-ether. Yield 81%, purity 98%. Example 21:6 - (N, n-Dimethylformamidino-N')-peuicillansäure: A Suspeusion of 2, 48 g 6-Aminopenicillansäure in 40 ml Msthylenehlorid was agitated 2 h long at a temperature from 0 to 5°C with 1, 62 ml tri ethyl amine and 1, 55 g 1,1-Dimethoxytrimethylamin. The received weakly gloomy solution was filtered with a filter aid and the filtrate in the vacuum was evaporated. The oily arrears were solved in 50 ml acetone, and under agitating with 0 to 5oc 2.14 g p-Toholsulfosäure-Monohydrat were added to the solution. The formed precipitation was filtered off, washed with acetone and recrystallized from Aeeton, water and acetone (10.8 and 30 ml). The up-this-wise won analytically pure product had a Fp. 173 to 174°C (Zers. }. Yield 90%. : + 18o (o = 1, H2 0). B e i s p i e I 2 2:6 - (N, N-Dipropylformamidino-n,) - penicillansäure: A suspension ven 5, 0 g 6-Am nopenicillansäure in 80 ml dichloromethane 3, 75 h with 0 b s 5oc with 3, 24 ml Tiäthylamin and 5, 25 g N-tDimethoxymethyl) dipropylamin was agitated. After evaporation of the filtrate in the vacuum the received oily arrears were solved in 50 ml Aceten. With additive of 3,8 g p-Toluolsulfosäure-Menohydrat took place a precipitation of a solid material, that to the 96% ethanol ethyl acetal 150, 125 ml) was recrystallized, whereby the analytically pure connection with Fp. 154 to 156°C (Zers.) one received. Yield 64%. [0Z: + 3050 (C = 1, H2 0). B e i s p i e! 2 3:6 - (N-benzyle-N-methylform midino n,) - penici] lansäure: 4, 96g 6-Aminopenicil nsäure, 3, 24 ml Triäthylaznin and 5, 84 g n (Dimethoxymethyl) - N-methylbenzylam 2 h nwurden long in 80 ml dichloromethane with 0 to 5oC agitated. After filtering with a filter] iilfsmitBeI the filtrate was evaporated imVatmum. The oily arrears were taken up to 75 ml acetone and precipitated by additive of 3, 8 g p-Toluolsulfosäurc-Monohydrat the Zwitterien. 2, 8 g of the raw product were solved in 30 ml warm 60%igem ethanol. With additive of 60 zal acetone became the analytically pure connection with Fp. 165 to 167oc (Zers.) receive. Yield 83%. : +280° te=l, 0,1n HC1). B e i s p i e I 2 4:6 - tPYrrclid nforma nidino n,) - p6nicillansäure: A mixture of 4,96 g 6-Am nopenicillansäure, 3, 24 ml tri methyl amine and 3.78 g 1-Dimethoxymethyl-pyrrolidin in 80 ml Methylenehlorid was agitated 4.75 h with 0 to 5oc. After filtering the filtrate in the vacuum was evaporated, whereby an oil stayed, which was loosened in 100 ml acetone. With additive of 3,8 g p-Toluolsulfosäure at ambient temperature failed the connection stated above. After leaving untouched ü it one period of 1/2 h at a temperature from 0 to 5oc was filtered off the precipitation and recrystallized from water acetone and 90% isopropanol acetone, whereby the analytically pure connection with Fp. one received to 172, 5 to 173, 5°C (Zers.). Yield 76%. ICl]: + 3060 (C = 1, H2 0). B e i s p i e] 2 5: 6 [(Hexahydro-1 (2H) - azoeinyl)]- methylenarnino penicill nsäure: 7.44 g 6-Aminope icillansäure, 4.86 mI tri ethyl amine and 9, 7 g 1-PIeptamethylenimincarboxaldehyd - dimethylacetal 2, 5 h were agitated with 0 to 5oc in 120 ml Methylenchlerid. After filtering the filtrate in the vacuum was potted and the arrears were taken up to 150 ml Acetou. The solution by additive ven 5, 2 g p-Toluolsulfosäure-Menohydrat in 75 ml acetone under agitating with 0 to 5°C during 1, 5 h agitated. The precipitation was filtered off, washed with Aeeton and recrystallized from water acetone, whereby - the n lytiseh pure connection with Fp. 169 to 170°C (Zers.) one received. Yield 73, 5%. [“: + 309o Te = 1, H2 0). With s pi e 1 2 6:6 - (n-Morpholinformamidino-N')-penie 11 " nsäure: 2.48 g 6-Aminopenicillansäure, 1, 62 m! Tri methyl amine and 2.10 g 4-Morpholincarboxaldehyd-dimethylaceh were agitated 4 h with 0 to 5oc in 40 ml Methylenchlerid. The filtrate was evaporated in the vacuum and the arrears were taken up to 75 ml Aeeten. With addition of 2,14 g p-Toluolsulfosäure-Monohydrat was auagefällt a solid material, which was recrystallized from acetone, water and Aceten (5, 3.5 and 15 valley), whereby to, lyrically pure connection with Fp. 172, 5 to 174oc (Zers.) one received. Yield 69, 5%. [“: +275° Te = 1, IO) o B e i s p i e 1 2 7: 6 (N, n-Dimekhylbenzamidino-N')-penicfllansäure: Under application in example 7 of the described proceed ensweise and replacement of 1-Hexamethylenimincarboxaldehyd-dimethylacetal by N, N-Dimethylbenzamidimetäylacetal became the connection 6 (N, NDimethyltryptamin N') peniejll nsäure received in form of a white, amorphous powder, which is soluble in water. Yield 87%. It was darchgeführt a Dünnschichtchromatogrsmm (1Vferck silica-gel HF254) in the following solvent systems: N-butanol-ethanol-water (8: 2: 2), Rf = 0.10, and n-Propanol-water (7: 3), Rf = 0,24. N1ViR-Spek mml 110% thread iVol. D2 0): - 9. - No. 329178 C (2) (CHs) '{aHaH N (Ctts) 2 3It C (s) H IH C (“) H IH C () H IS f--% s s s s s D D with 1, 54 at 1,72 with 3,10 with 3, with 4, with 5, 01 with 5, 24 m with 7,4 - 7.9 (J = 4) (J = 4)