AT344325B - PROCESS FOR THE PREPARATION OF NEW 6-SUBST.-AMINOPENICILLANIC ACID AND 7-SUBST.-AMINOCEPHALOSPORANIC ACID DERIVATIVES - Google Patents

Description

  

   <Desc / Clms Page number 1>
 



   The invention relates to a process for the preparation of new 6-subst. Aminopenicillanic acid and 7-subst. - Aminocephalosporanic acid derivatives.
 EMI1.1
 
 EMI1.2
 in which Q is a group of general formulas
 EMI1.3
 or
 EMI1.4
 represents in which
 EMI1.5
 

 <Desc / Clms Page number 2>

 means where EI is hydrogen or a salt-forming cation, an ester group such as a lower alkyl group, optionally substituted with a lower alkanoyloxy group, which can also be substituted, a
Silyl, phenacyl, benzyl, benzhydryl, trichloroethyl or tert.

   Butyl group, X represents hydrogen, a hydroxy group, a lower alkanoyloxy group, preferably acetoxy group, or the residue of a nucleophilic agent such as a halogen, an azido group, a cyano group, a
Carbamoyloxy group, an optionally substituted, mononuclear, heterocyclic group which contains a sulfur or nitrogen atom, such as a pyridinyl group, or a group - SQ 'in which Q' is a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl -, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxyzolyl, triazolopyridinyl or purinyl group, or X is an amino group if Q is a group of the formula (IV),
R1 is a lower alkyl group, such as methyl, ethyl, propyl, isopropyl, butyl, sec. Butyl, isobutyl, tert.

   Butyl group, optionally substituted in the primary or secondary position by a fluorine atom, a chlorine atom, a hydroxyl group or a lower alkoxy group, such as a fluoromethyl, 2-chloroethyl, methoxymethyl or 1-hydroxyethyl group, or a cycloalkyl group, optionally substituted with one or more lower alkyl groups, hydroxyl groups or lower alkoxy groups, or
R1 represents an adamantyl group or a phenyl group, optionally substituted by at most three of the aforementioned substituents, or
 EMI2.1
 
R1 is oxazolyl, isothiazolyl, oxadiazolyl group, optionally substituted by lower alkyl groups, or
R1 is an aralkyl group, for example a benzyl group, optionally substituted in the phenyl nuclei as mentioned above, or a carboxymethyl group,

   and Z1 is hydrogen, a lower alkyl group optionally substituted with a chlorine atom or a
Fluorine atom, a lower alkoxy group, a cycloalkyl group, a phenyl group, which itself may optionally be substituted by at most three of the aforementioned substituents, or Z1 is a carboxy group esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl radical, where the phenyl groups can optionally be substituted by at most one of the aforementioned substituents, or
Z is a carbamoyl group, optionally substituted on the N by one or two lower alkyl groups, a phenyl, a mononuclear, 5-membered, heterocyclic group, a cycloalkyl group, one or two aryl-lower alkyl or cycloalkyl-lower alkyl groups,

   where the phenyl and cycloalkyl groups can optionally be substituted with at most one of the aforementioned substituents, or Z stands for a carbamoyl group whose nitrogen atom is a member of a heterocyclic ring, such as morpholino, and Z1 is hydrogen when pure is acetic acid radical, and R2 for a group of the formula
 EMI2.2
 in which n is 0, 1, 2 or 3, R is hydrogen or a lower alkyl group,
R4 is hydrogen, a lower alkyl, cycloalkyl, phenyl or aralkyl group, or
 EMI2.3
 

 <Desc / Clms Page number 3>

 
4E hydrogen (if n:::

   1) or a lower alkyl, benzyl or phenyl ester group, or in which
R4 is a carbamoyl group, optionally N-substituted by one or two lower alkyl or alkenyl groups, a phenyl group, a cycloalkyl group, one or two aryl-lower alkyl or
Cycloalkyl-lower alkyl groups, where the phenyl and cycloalkyl groups can optionally be substituted by at most one of the aforementioned substituents, or in
 EMI3.1
 
R3 Z4 represents hydrogen or an optionally substituted aryl group.



   The salt-forming cation E 'in the group OE' comes e.g. B. an alkali metal, alkaline earth metal or amine cation into consideration, and in the group - S-Q 'the groups listed for Q' can optionally be substituted.



   The term "lower" used in connection with alkyl, alkoxy and alkanoyloxy groups means that the group concerned contains at most 6 carbon atoms. The term "cycloalkyl" refers to a carbocyclic ring having from 5 to 8 carbon atoms.



   A preferred group of compounds obtainable according to the invention are compounds of the general formula (I) in which R1 is a lower alkyl, hydroxymethyl, carboxymethyl or lower alkoxymethyl group; more preferred are compounds in which R is a methyl, ethyl, methoxymethyl or carboxymethyl group, Z1 is hydrogen or a lower alkyl group, and their alkali metal, alkaline earth metal and amine salts.
 EMI3.2
   Nosubstituted carbamoyl group or an unsaturated heterocyclic group and Z is as defined above, and the alkali metal, alkaline earth metal and amine salts thereof.



   The essence of the process according to the invention consists in that a salt, an ester or an amide of a 6-amino-penicillanic acid or 7-amino-cephalosporanic acid compound of the formulas
 EMI3.3
 or

 <Desc / Clms Page number 4>

 
 EMI4.1
 in which the substituent X is as defined above and is preferably protected, if it is a hydroxy or an amino group, with an active ester, acid halide, acid anhydride including the mixed anhydrides prepared from stronger acids, an acid azide, an active thioester or an azolide, which are derived from an acid of the general formula:

   
 EMI4.2
 
 EMI4.3
 
 EMI4.4
 
 EMI4.5
 as such in the presence of, for example, a carbodiimide reagent or similar reagents, optionally subjecting the compound obtained to a customary oxidation process, then separating and / or isolating the compound obtained and removing any protective groups present in order to produce the corresponding penicillanic or cephalosporanic acids , and optionally the acids obtained are converted into their salts or esters.



   In the compounds of the formulas (VIII), (IX), (K), (XI) and (XII), the carboxyl group, and in the compounds of the formulas (tex) and (XII), the hydroxyl or amino group which may be present in the Implementation preferably protected. Preferably, the protecting group of the carboxyl group or the hydroxyl group, if present, in the 6-aminopenicillanic acid or 7-aminocephalosporanic acid reactant is a di- or trialkylsilyl group which can easily be removed from the corresponding product by hydrolysis.



   As esters of the acids of the general formulas (UNI) and (XIV), for. B. the 2, 4-dinitrophenyl, p- -nitrophenyl or N-hydroxysuccinimido esters, as acid halides, carboxylic acid chlorides and bromides can be used. The useful acid anhydrides include mixed anhydrides made from stronger acids such as the lower aliphatic monoesters of carbonic acid, of alkyl and aryl sulfonic acids, and of more hindered acids such as diphenylacetic acid. One can also use an acid azide or an active thioester, for example with thiophenol or thioacetic acid, of the acids.

   Alternatively, the free acids of the general formulas (XIII) and (XIV) can be coupled with the 6-amino-penicillanic acid or 7-aminocephalosporanic acid compound using a carbodiimide reagent. A corresponding azolide can be used in place of the active ester; H. an amine of the corresponding acid, whose amide nitrogen is part of a quasi-aromatic 5-membered ring which contains at least 2 nitrogen atoms, such as imidazole, pyrazole, the thiazoles, benzimidazole, benzotriazole and their substituted derivatives.

   The methods of carrying out these reactions to make a penicillin or a cephalosporin, and the methods used to make the so-

 <Desc / Clms Page number 5>

 compounds are well known for similar compounds (see GB-PS No. 932, 644, No. 957, 570, No. 959, 054, No. 952, 519, No. 932, 530, No. 967 , 108 and no. 967, 890).



   The corresponding R-sulfoxides can, for example, be produced selectively from penicillins or cephalosporins by using singlet oxygen produced in situ.



   The ester, the salt or the amide of the product obtained in accordance with the process described above can be converted into the corresponding penicinic acid or cephalosporanic acid derivatives by methods known per se. If z. For example, when a silyl (e.g. trialkylsilyl) ester of the starting materials of formulas (VIII) to (XII) is used as a reactant, the ester group can be easily hydrolyzed to give the corresponding acid compound of general formulas (I) and (EI).



   The acids of the general formulas (XIII) and (XIV) used as starting materials can be obtained by
A) a stable, reactive nitrile oxide with an imidate of a suitable nitrile according to the equation
 EMI5.1
 reacted, then the methylene group of the resulting compound (XVIII) (1, 2, 4-oxadiazole) metallized and the metal atom or

   the metal component is replaced by a carboxyl group by reaction with carbon dioxide (carbonization) under anhydrous conditions by mixing the reaction components with cooling, or a nitrile of the general formula
 EMI5.2
 into a corresponding amidoxime of the general formula
 EMI5.3
 transferred and thereupon this amidoxime 0-acylated with an acid anhydride and causes a ring closure of the intermediate compound (XVIII) formed and then metallized and carbonized, B) a nitrile converted into the corresponding amidoxime, then the amidoxime 0-acylated with an acid anhydride and in the intermediate compound obtained closes the ring, where a compound of the general formula
 EMI5.4
 is obtained, and then this connection is double metallized and then double carbonized, C) with the help of the A) and B)

   methods described a 1, 2, 4-oxadiazole derivative of the general
formula
 EMI5.5
 produces, this double carbonized and the 5-substituent of the correspondingly substituted 1, 2, 4-oxadiazol-3, 5- (di) yl-acetic acid derivative selectively monodecarboxylated.

 <Desc / Clms Page number 6>

 



   The compounds of the general formulas (XIII) and (XIV) can accordingly be prepared by various processes known per se, the substituted oxadiazole core being used. The substituted 1, 2, 4-oxadiazole basic derivatives can be prepared with the aid of a large number of processes, which are described, for example, in the following literature references:
 EMI6.1
 F. Eloy and R. Lenaers, Bull. Soc. Chim. Belg, 72, pp. 719-724 (1963).



  The following can be stated in detail with regard to these procedures:
 EMI6.2
   like a tert. Butyl or adamantyl group, and Z'einwasserstoffatom or a lower alkyl group, a cycloalkyl, aralkyl (for example a benzyl) or aryl group can be obtained by cycloaddition of stable and reactive nitrile oxides of the formula (XVI) with imidates of the various nitriles ( Formula (XVII) are reacted, whereby 1, 2, 4-oxadiazoles of the formula (XVIII) are obtained in accordance with the reaction scheme given above.



   This reaction is described, for example, by P. Rajagopalan in Tetrahedron Letters, No. 5, pp. 311-312 (where R 'and Z' are defined as mentioned above). The methylene group, i.e. the -CH group, of the compound of the formula (XVIII) is then metallized and the metal atom or the metal component is then replaced by a carboxyl group, for example by the action of carbon dioxide. For the sake of simplicity, such a replacement is referred to below as "carbonization".

   The reaction between the imidates and the nitrile oxides is preferably carried out under anhydrous conditions by mixing the two components with one another while cooling, stirring the reaction mixture for about 1 hour at room temperature, then removing the excess imidate by evaporation in vacuo. A few recrystallizations of the product give the desired pure 1,2,4-oxadiazole compound.



  The imidates used as starting material can be prepared by processes known per se, as described, for example, in Organic Synthesis, Coll. Volume 1, pp. 5-6, and S.A. Glickmann et al, J.A.C.S. (1945), 67, p. 1020.



    The group of the 3-substituted 1, 2, 4-oxadiazol-5-yl-acetic acids, in which, for example, R 'is a lower alkyl, cycloalkyl and phenyl group substituted by chlorine, fluorine, hydroxy, lower alkyl or lower alkoxy, or a heterocyclic group such as a 2- or 3-thienyl, 4- or 5-isoxazolyl or 4-isothiazolyl group, and where Z 'is as defined above, can be obtained by converting nitriles of the above-mentioned general formula (XIX ), in which RI has the meaning given above, into the corresponding amidoximes of the general formula (XX) using methods known per se and subsequent 0-acylation with z.

   B. acid anhydrides, ring closure of the intermediates to compounds of the general formula (XVIII) and subsequent metallization and carbonization. This production process for the compounds of the general formula (XVIII) is known per se, cf. z. B. F. Eloy, Progr. Chem. Forsch., Volume 4, p. 814. For example, the compounds can be prepared by heating the corresponding O-acylated amidoxime until temperatures between 120 and 170 ° C., preferably about 150 ° C., are reached. It can then be distilled, a mixture of water and the desired 1, 2, 4-oxadiazole compound being obtained.

   The distillate is saturated by adding potassium carbonate, a two-layer system being obtained. The top layer is removed, dried over calcium chloride, washed with small amounts of ether and redistilled.



  The metallization of the methylene group and the subsequent carbonization can be carried out by methods known per se, such as those described in e.g. B. in Houben-Weyl, Methods of Organic Chemistry, 4th Edition (1970), Volume 13/1, pp. 93 to 114, 173 to 174 and 296 to 350, are described. The introduction of, for example, a lithium atom or a sodium atom can be carried out by e.g. B.

   Butyl-lithium / TMEDA, butyl-lithium / DABCO, lithium-diisopropylamine, lithium-isopropyl-cyclohexylamine, lithium-N, N-dimethylacetamide, lithium-bis-trimethylsilylacetamide, 2-lithium-1, 3-dithiane and 2- Lithium 1, 3, 5-trithiane, sodium hydride, sodium amide, sodium methoxide, naphthyl sodium or phenyl sodium in inert solvents such as pentane, hexane, toluene, diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, at very low temperatures, e.g. . B. used at -600C and lower.



  The replacement of the metal atom or the metal component by a carboxyl group can thereby be effected, for example. that one adds a solution of the organometallic compound to fresh, solid carbon dioxide, on which a layer of dry diethyl ether or tetrahydrofuran is optionally present, or by gaseous carbon dioxide over or through a

 <Desc / Clms Page number 7>

 
Solution of the organometallic compound conducts.



   The amidoxime used as starting material can be prepared by processes known per se, such as those described e.g. B. by R. Lenaers, C. Moussebois and F. Eloy in Helv. Chim. Acta, Volume 45 (1962),
Pp. 441-446 (and the references cited therein), and by C. D. Hurd, Inorganic Synthesis,
Volume 1, p. 89.



  B) Substituted 1, 2, 4-oxadiazol-3, 5-yl-diacetic acids can be prepared from compounds of the general formula (XXI), in which Z 'and Z' are defined as above, by double metallization and subsequent double carbonization.



   The compounds of the formula (XXI) can be obtained, for example, by converting nitriles into the corresponding amidoximes and subsequent O-acylation with acid anhydrides and ring closure of the intermediates.



  C) The 5-subst. -1, 2, 4-oxadiazol-3-yl-acetic acid compounds in which R2 is a straight-chain lower alkyl (preferably a methyl) group, optionally substituted with a branched alkyl group, or a cycloalkyl, phenyl or an unsaturated heteroeyelic group
 EMI7.1
   R has the meaning given above. Then a double carbonization and a
Monodecarboxylation of the substituent at the 5-position of the oxadiazole nucleus is carried out.



   The compounds of the formula (XXII) can be obtained analogously, for example in accordance with the two preferred reaction routes for the formation of the oxadiazole ring as indicated above under A).



   In various cases, 5-substituents can e.g. B. be prepared by selective conversion of the 5-acetic acid group of the corresponding bis-acetic acids with isocyanates, where R 'substituents of the formula
 EMI7.2
 obtained where R is the group derived from the isocyanate.
 EMI7.3
 (XIV) the reaction conditions must be chosen according to the sensitivity of the very reactive acetic acid groups.



   Esters of acids (uni) and (XIV) can also be obtained by mixing the organometallic compounds that occur as intermediates in the above-mentioned processes for preparing the acids, and preferably the lithium-containing intermediates, with chloroformic acid esters, which have the corresponding ester group included, implements.



   The new penicillanic acid and cephalosporanic acid derivatives of the general formulas (t) and (11), in which Q denotes the groups of the formulas (II), (TV), (VI) and (VII), have antibiotic properties which have an effect that they are valuable as medicines to humans and animals alone or mixed with other known antibiotics. Some of these new compounds of the general formulas (I) and (I) have activities which are comparable to those of the known β-lactam-containing antibiotics.

   They specifically develop an action against gram-positive microorganisms (for example Bacillus subtilis, Staphylococcus aureus, Streptococcus haemolyticus and faecalis and Diplococcus pneumoniae), and furthermore they show good activity against penicillin-resistant staphylococci; This applies in particular to compounds in which R1 and R2 are methyl, ethyl, methoxymethyl, mesityl, benzyl and 2,6-dichlorophenyl groups, Q is a group of the formulas (III) and (EV) and Z1 and Z are hydrogen atoms or Are methyl groups, and for the salts of these compounds.

   They are also active against gram-negative microorganisms, for example against Brucella melitensis, Pasteurella multocida, Proteus rettgeri and Salmonella dublin.



   The mentioned antibiotic compounds obtained according to the invention are preferably used for therapeutic purposes in the form of the non-toxic salts, such as the sodium, potassium or calcium salts. Other salts which can be used include the non-toxic, suitably crystalline salts with organic bases such as with amines, for example trialkyl amines, procaine and dibenzyl amine.



   In the treatment of bacterial infections, the antibiotic compounds obtainable according to the invention can be used topically, orally or parenterally according to known methods for the administration of

 <Desc / Clms Page number 8>

 Antibiotics are administered. They are administered in unit doses containing an effective amount of the active ingredient together with suitable physiologically acceptable carriers or diluents or excipients. The dosage units can be in the form of liquid preparations, such as solutions, suspensions, dispersions or emulsions, or in solid form, such as powders, tablets and capsules.
 EMI8.1
 dung also contain one or more therapeutically active ingredients.

   The term "effective amount" means, based on the compounds described, an amount which is sufficient to destroy or inhibit the growth of the sensitive microorganisms, if it is administered in the usual manner, in other words, an amount which is sufficient to control the growth of bacteria. The value or size of the effective amount can be readily determined by those skilled in the art by standard methods for determining the relative activity of an antibacterial agent against susceptible microorganisms using the various routes of administration available.



   Suitable carriers and diluents are any of the known physiologically acceptable materials which serve to facilitate the administration of the therapeutically active compound. Carriers can also have certain auxiliary functions, i. H. act as diluents, flavor or odor masking agents, binders, retarders or stabilizers. Examples of carriers are water, which may contain gelatin, gum arabic, alginate, dextran, polyvinylpyrrolidine or sodium carboxymethyl cellulose, aqueous ethanol, syrup, isotonic saline solutions, isotonic glucose, starch, lactose or other such materials commonly found in pharmaceutical and veterinary antibacterial agents used.



   The compounds obtainable according to the invention can, for. B. can be used to treat bacterial infections in animals by administering an effective amount of the antibacterial compound to the host.



   In order that the penicillanic acid or cephalosporanic acid derivatives of the formulas (t) and (H) are more suitable for absorption in the body while maintaining their antibiotic activity, the conversion of compounds of the formulas (t) and (il), wherein U -OH means to be required in special esters.



  Preferred ester groups are, for example, those of the type
 EMI8.2
    CH-O-CO-Wworin Weine denotes unsubstituted or substituted straight-chain or branched alkyl group with 1 to 8 carbon atoms, with lower alkoxy, lower alkylthio, halo (lower) alkyl, phenyl, cycloalkyl, nitro, amino as substituents -, guanidino, carboxy, carbalkoxy, hydroxyl groups or halogen atoms occur.



   The new penicillanic acid and cephalosporanic acid derivatives of formulas (E) and (I) can also be used as growth activators for ruminants such as cows. They are also very useful in in vitro applications such as in disinfectants (e.g. dairy stalls) at concentrations of about 0.1 to 1 gel% of these agents dissolved or suspended in a suitable inert carrier for use in washing or spraying.



   The invention is explained in more detail with the aid of the following examples, which, however, are by no means to be interpreted as restrictive. Before the examples, instructions for the preparation of starting compounds of the general formulas (XIII) and (XIV) are given.



   Regulation 1: Preparation of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid:
 EMI8.3
 
Ethylenediamine (TMEDA) in 100 ml of dry toluene is prepared in a 250 ml three-necked glass flask equipped with a thermometer, a gas inlet tube through which dry nitrogen is continuously introduced, and a dropping funnel with pressure compensation. The magnetically stirred solution is cooled to -750C with an acetone-carbon dioxide bath. A solution of about 40 mmol of n-butyllithium in 20 ml of n-hexane is slowly added through the dropping funnel in order to keep the reaction mixture below -650C. The reaction mixture is then stirred for a further 60 minutes at -55 to -600C.

   The reaction mixture is then introduced into a second vessel with a curved, ground glass tube, which contains powdered carbon dioxide and is covered with a layer of dry diethyl ether. After standing for a few hours, the carbon dioxide has practically disappeared from the mixture. 100 ml of water are then added, followed by 1N hydrochloric acid with stirring until a pH of 8 is reached. The layers are separated, the organic layer is discarded and the aqueous layer is extracted twice with 25 ml of dietary ethyl ether. The pH of the aqueous solution is adjusted to 2.0 with in hydrochloric acid.

   Seven extractions with approximately 25 ml parts of ethyl

 <Desc / Clms Page number 9>

 acetate at a pH of 2.0 result in an almost complete removal of the desired product from the aqueous layer. The extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo to a small volume until a crystalline, colorless precipitate appears. Thin-layer chromatography shows that the supernatant liquid still contains a considerable amount of the desired product and no by-products. The solvent is completely removed in vacuo. The practically colorless residue is dried to constant weight.



   Yield: 4.2 g (72%).



   Purity: at least 96in as determined by TLC and PMR spectrum.



   Recrystallization of the product by dissolving it in a small volume of chloroform and then slowly adding petroleum ether (boiling point 80 to 110 ° C.) until it becomes cloudy.
 EMI9.1
 
2,4-oxadiazol-5-yl-acetic acid Found: 42.24% 4.28% 19.60% (33.88%)
Partial analysis of the IR spectrum (KBr pellet, values in cm-1)::! : 3450, 1740, 1720, 1590, 1360, 1220.



    Thin layer chromatography:
Silica plate, eluent a 10: 2: 1: 0.2 mixture (expressed by volume) of diethyl ether, ethanol, water and formic acid. Drying was done by blowing warm air over the plate. Yellow-colored spots (Rf value approximately 0.7) after 5 min in a cylinder containing iodine
 EMI9.2
 
Since the compound decarboxylates easily, its molecular weight is indicated by a rather weak molecular ion peak at (M / e = 142). The decarboxylation product, namely 3,5-dimethyl-1,2,4-oxadiazole, is represented by M / e = 98. M / e 85, 59 and 57 probably mean the fragments N = CH2COOH, CH COOH and CH CNO and are further evidence for the assumed structure.



   The PMR spectrum of a solution of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in CDCl3 (60) Ce, # values in TpM, tetramethylsilane as internal comparison) showed signals at 2.43 (p , 3H), 4.06 (S, 2H), 9, 2 (S, about 1H).



   Regulation 2: Preparation of 3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl-acetic acid:
A solution is added dropwise to a solution of 10 g of 3- (2,6-dichlorophenyl) -5-methyl-1,2,4-oxadiazole (melting point 83 to 85 ° C.) and 6.4 ml of TMEDA in 140 ml of dry toluene of about the equivalent amount of n-butyllithium in 22.2 ml of n-hexane in the course of about 30 minutes (the process is analogous to the process described in instruction 1). The reaction temperature is -55 to -60oC. After stirring the reaction mixture for a further hour at about -60.degree. C., the mixture is added to powdered carbon dioxide which is covered with dry diethyl ether.

   After standing for a few hours, water and dilute hydrochloric acid are added until a pH of 8.0 is reached; the layers are separated and the organic layer is extracted with 50 ml of water. The organic layer is discarded and the combined aqueous layers (about 300 ml) are washed twice with 100 ml of diethyl ether. The aqueous layer is then extracted three times with 100 ml parts of diethyl ether at pH 2.0. The extracts are combined, washed twice with a small amount of ice water and completely evaporated in vacuo. The solid residue is stirred first with n-heptane and then with a small volume of toluene. After drying well in the desiccator, the end product weighs 7.6 g (63%).



   Mp. 124.5 to 125.5 C.
 EMI9.3
 material. The 3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid is prepared according to the method described in instruction 2. A powerful mechanical stirrer is used in the reaction using n-butyllithium.



   Yield 55.7%.



   M.p. 106 to 108oC,

 <Desc / Clms Page number 10>

   IR (KBR pellet, values in cm-1):: I: 3450, 1740, 1720, 1608.1590 and shoulder 1580, 1365 and 1240.



   PMR (60 Mc, CDCl3, tetramethylsilane as internal standard, o-values in tpm):
2, 13 (S, 6H), 2, 30 (S, 3H), 4, 07 (S, 2H), 6, 92 (S, 2H).



   Regulation 4: Preparation of 50-methyl-1,2,4-oxadiazol-3-yl-acetic acid:
80 g (0.816 mol) 3, 5-dimethyl-1, 2, 4-oxadiazole and 240 ml (1.6 mol) TMEDA are dissolved in 2050 ml dry toluene. The solution is cooled to -70 ° C., after which an approximately 20% strength solution (800 ml) of n-butyllithium in n-hexane (approximately 1.6 to 1.9 mol) is gradually added. The rate of addition is adjusted so that the reaction temperature varies between -60 and -65 ° C. The addition time of approximately 70 minutes is mainly consumed by the addition of the first equivalent of n-butyllithium. The reaction mixture is stirred for a further 60 min at -70 ° C. It is then slowly poured into a mixture of finely powdered carbon dioxide and dry diethyl ether.

   After standing for about 3 hours, 1 liter of water is added to the mixture of solid and liquid. The contents of the reaction vessel are transferred to a separating funnel. The aqueous layer is collected and since the solid is only partially dissolved, 250 ml of water are added to the mixture of salt and organic solvent. The mixture is shaken again and the aqueous layer is added to the first extract. This is repeated until all of the solid is dissolved in water. The organic layer is discarded and the alkaline aqueous layer
 EMI10.1
 a pH of 2.0 is reached and then the solution is concentrated in water at 60 ° C. in vacuo to a volume of approximately 21.

   During these steps the mixture of 3-methyl-1, 2, 4-oxadiazol- - 5-yl-acetic acid and 1,2,4-oxadiazol-3,5-diacetic acid (was contaminated with much smaller amounts of two or three identified by-products) already partially to 3, 5-Dimetb; yl-oxadiazole and 5-methyl-1, 2, 4-oxadiazol-3-yl-acylic acid decarboxylated. Decarboxylation was completed by heating the acidic solution for 1 hour on a water bath. The greater part of the desired product was extracted with three 300 ml portions of ethyl acetate. The residue was extracted continuously with diethyl ether (16 h). The collected organic layers were completely evaporated.

   The residue was dissolved in about 600 ml of diethyl ether, treated with activated charcoal, filtered and evaporated completely. The partially solid residue (54.6 g) was subjected to column chromatography (length 38 cm, diameter 5.7 cm) over silica, using diethyl ether mainly to remove the valeric acid. A fraction (1.6 g) with a product with a purity of over 90% and a fraction in an amount of 37.4 g with a purity of over 95% were obtained. The last-mentioned fraction was recrystallized from toluene / n-heptane.
 EMI10.2
 (calculated by TLC and PMR).



   Mp. 101 to 1030 ° C. (final melting point), above 70 ° C. sublimation, melting and resolidification. pKa value (determined in water): about 3.4.



   Thin layer chromatography: same system as in regulation 1.



   Rf value about 0.25.



   Oxadiazol-3-yl-acetic acid is much less sensitive to the labeling system than its isomer.
 EMI10.3
 



   In an analogous manner - of course adapted to the individual case - other 1, 2, 4-oxadiazol-3-yl-acetic acids were prepared, e.g. B.



   5-Benzyl-1,24-oxadiazol-3-yl-acetic acid, m.p. 109 to 111, 5 C.



   If 13 g of 3-methyl-5benzyl-1,2,4-oxadiazole are used, 5.8 g (34%) of pure compound are obtained.



  During the reaction, 2 equivalents of n-butyllithium, dissolved in n-hexane, are slowly added to the solution of the oxadiazole and 2 equivalents of TMEDA in toluene at -75 to -80 ° C. The resulting reaction mixture is additionally stirred for 6 h at -78 ° C. and then poured onto finely powdered carbon dioxide. The reaction product is poured into about 600 ml of water, then the pH is adjusted to about 7.0, the layers are separated, and the organic layer is washed once with water.



  The solution in water is purified by continuous extraction with diethyl ether at pH 8.0 for 5 h, acidified to pH 5.2 and then concentrated in vacuo at about 450C until a volume of about 300 ml is reached. The pH is adjusted to 7.0, then filtered using a pump. The pH is adjusted to 1.8, then extraction is carried out continuously with dichloromethane for 16 hours. The solvent is removed and the residue is dissolved in a small amount of water, then

 <Desc / Clms Page number 11>

 ssend extracted with a 1: 1 mixture of diethyl ether and ethyl acetate at pH 1.8. The finished extract is evaporated in vacuo and the residue is crystallized from diethyl ether.

   As will be explained later, the primary product [0! - (5) -Phenyl-l, 2,4-oxadiazole-3, 5-diyl-bis-acetic acid] subjected to selective decarboxylation under relatively mild conditions. However, it was found that it can also be obtained by extraction at room temperature and subsequent purification by column chromatography.



   IR (KBr pellet, values in cm-1):
 EMI11.1
 



   89.6 g of 3-methyl-5-ethyl-1,2,4-oxadiazole are used and 28 g (21%) of pure product are obtained after incomplete in situ decarboxylation of the primary product. 0! - (5) -Methyl-l, 2,4-oxadiazole-3, 5-diyl- - bis-acetic acid is a relatively stable compound. The reaction conditions were analogous to that described above, but the addition of the solution of n-butyllithium was extended to a period of 8 hours. The reaction vessel was then closed and kept at −78 ° C. overnight. After the reaction with solid carbon dioxide, the reaction mixture was neutralized as usual. After separation of the layers, the organic layer was discarded, the water layer acidified to pH 2.0 and warmed on a water bath for 3.5 h.

   The pH was adjusted to 8.0 with the solution concentrated in water to about half its volume in vacuo. The precipitated salts were separated off by filtration and the filtrate (pH 8.0) was extracted continuously with diethyl ether for 5 hours.



   The pH was then adjusted to 5.0, followed by continuous extraction with n-heptane for 30 h. The solution in water was acidified to pH 2.5, saturated with sodium chloride and extracted five times with equal volumes of acetone. These extracts were combined and mixed with activated charcoal and concentrated to half the volume by distillation at atmospheric pressure. After filtration, the filtrate was evaporated and the residue was subjected to column chromatography over silica over n-hexane / chloroform. The pure fractions were combined and evaporated in vacuo. The remaining oil was dissolved in a small volume of ether, the solution filtered and evaporated to dryness. The colorless oil slowly solidified on standing.



   IR (ibidem): 3500 and 2600, 300, 2960, 1730.1580, 1465.1425, 1380.1360, 1300,
1210-1230, 1190,900, 825,805, 725.



   PMR (CDCI3'60 Mc, TMS, ö values in TpM):
1.40 (T, J = 7.5 cP, 3H), 2.92 (Q, J = 7.5 cP, 2H),
3.84 (S, 2H), about 8.6 (S, 1H).



   Procedure 5: Preparation of methyl 3-methyl-1,2,4-oxadiazol-5-yl acetate:
A solution with an excess of diazomethane in diethyl ether is added to a stirred, cold (approx. 20 ° C.) solution of 14 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in 500 ml of diethyl ether.



  After the initial vigorous evolution of nitrogen has ceased, the solution is concentrated to about 250 ml on the steam bath. The solution is washed three times with 100 ml of water. The wash solutions are combined, the pH is adjusted to 9.0 and then they are extracted with diethyl ether to obtain a portion of the product which dissolved in water during the wash. The combined ether extracts were filtered through a water-retaining paper filter and then evaporated in vacuo. The residue was kept at 8 mm for 1 hour; 14.8 g of oil were obtained. The yellow oil was distilled at 0.4-0.5 mm.

   The collected fraction with a boiling point of 70 to 71 C contained methyl 3-methyl-1,2,4-oxadiazol-5-yl acetate,
Weight 12.3 g,
 EMI11.2
    1, 4472.2, 38 (S, 3H), 3, 76 (S, 3H), 3.99 (S, 2H).



   IR (NaCl window, values in cm-i):
3020,2985, 2870,1760 and 1600.



   Regulation 6:
The following substituted 1, 2,4-oxadiazol-5-yl-acetic acids were prepared by processes which were identical to or analogous to the processes described in instructions 1 and 2, by first adding a slight excess of 3, 5-di -subst. -1, 2, 4-0xadiazole with the 1:

   I-complex of n-butyllithium with TMEDA in a toluene / n-hexane mixture (or alternatively with n-butyllithium in a tetrahydrofuran

 <Desc / Clms Page number 12>

   drofuran / n-hexane mixture) and then reacted the intermediate product with solid carbon dioxide.
 EMI12.1
 
For each product, the following are the first 1, 2, 4-oxadiazole, the method of how it is reacted with lithium, the solvent mixture, the reaction temperature and the approximate reaction time lithium
 EMI12.2
 



  Crude yield 4.3 g.



  After crystallization from toluene (dissolved at 60 ° C.) 3.6 g (41%).



  M.p. 106 to 1090 ° C. (with slow decarboxylation).



  Purity over 96%.



  IR::! : 3430, 1730,1585, 1600 sh, 1498,1420, 1390,1365, 1300,1248, 1230,
1215, 1165, 720 and 705.



  PMR: 3.87 (S, 2H), 4.06 (S, 2H), 7, 27 (S, 5H), # 9.8 (S, about 1H).
 EMI12.3
 
Yield 16g (50%).



   Purity over 96%.



   M.p. 86 to 900 ° C (with slow decarboxylation).



   Crystallization (not required) possible by dissolving in a small amount of a 2: 1-
Mixture of carbon tetrachloride and chloroform at about 450C and then slowly add hexane.



     In: 3440, 1730, 1715 and 1580.



   PMR: 1.35 (T, J = 7.5 cP, 3H), 2.8 (Q, J = 7.5 cP, 2H),
4.04 (S, 2H), -10.4 (about 1H).



  C) 3-methyl-5-ethyl-1,2,4-oxadiazole (22.4 g), n-butyllithium, TMEDA / toluene-hexane, -70 to -80 C, 1.5 h.



   Yield 7g (22%).



   Purity over 96%.



   Mp. 64.5 to 650C (slow decarboxylation begins at 570C).



   IR: 3450, 1730, 1600.



   PMR: 1.70 (D, J = 7, 5cP, 3H),
2, 41 (S, 3H), 4, 16 (Q, J = 7.5 cP, 1H), # 9.6 (S, about 1H).
 EMI12.4
 Yield 18.1 g (about 53%), purity about 95% (contains a small amount of valeric acid), m.p. 30 to 32 C.



  IR: ¯3500, ¯2600, ¯1740, 1580.



  PMR: 1.35 (T, J = 7.5 cP, 3H), 1.70 (D, J = 7.5 cP, 3H), 2.75 (Q, J = 7.5 cP, 2H), 4 , 6 (Q, J = 7.5 cP, 1H), and "'9, 4 (S, about 1H).

 <Desc / Clms Page number 13>

 
 EMI13.1
 Yield 31.5 g (approx 58%), purity over 96%.



  Melting point: melting and excessive decarboxylation between about 50 and 75 C.
 EMI13.2
 
Yield 50%.



    Purity over 96%.



   M.p. 70 C.



   Regulation 7: Preparation of 3-hydroxymethyl-1, 2, 4-oxadiazol-5-yl-acetic acid:
Under anhydrous conditions, a solution of approximately 1.2 moles of n-butyllithium in n-hexane is added dropwise within 3 hours to an effectively cooled solution of 66 g (0.58 moles) of 3-hydroxymethyl-5-methyl- - 1, 2, 4-oxadiazole and 87 ml of N, N, N ', N'-tetramethylethylene diamine in 1200 ml of tetrahydrofuran.



  During the addition, the reaction temperature cannot rise above about -700C. The reaction mixture is additionally stirred at -70 ° C. for 1 h. Dry, gaseous carbon dioxide is passed over the surface of the stirred reaction mixture for 10 hours at -70 ° C. while cooling well. The temperature can then gradually rise to -5oC. The precipitate formed is separated off by filtration with a pump, washed with dry ethyl acetate and n-hexane and then slowly dissolved by adding small amounts to an ice-cold mixture of 500 ml of water and 500 ml of diethyl ether with stirring.



  Then conc. Phosphoric acid was added to a pH of 4.0. The layers are separated and the organic layer is discarded. The water layer is acidified to pH 2.0 and then evaporated in vacuo. Remains of the water in the residue are removed in vacuo with the aid of benzene. The residue is dried in vacuo over phosphorus pentoxide for 16 hours. The syrupy product is stirred with 500 ml of acetone at about 350C. The acetone is discarded. This is done several times, the residue becoming a solid mass. The solid mass is placed on a filter and stirred several times with 500 ml of acetone each time until, after thin-layer chromatography, the filtrate contains no further desired compound.

   All filtrates are combined, a total of about 4000 ml, and concentrated in vacuo to a volume of about 300 ml. 600 ml of ethyl acetate are added and the resulting solution is again concentrated in vacuo to a final volume of 250 ml. The resulting crystalline precipitate is filtered in the pump and washed with dry ethyl acetate and with carbon tetrachloride. After drying in vacuo, 41 g are obtained. Melting and decomposition take place between 96 and 98 C. The filtrate is evaporated in vacuo. The oily residue is repeatedly stirred with small volumes of dichloromethane. The resulting solid is transferred to a filter and washed with ethyl acetate and carbon tetrachloride. After drying, the second batch weighs 14.1 g.

   It melts with strong decomposition at 92 to 96 ° C. According to the thin-layer chromatograms, IR and PMR spectra, the two batches are essentially identical.



   Overall yield 45.1 g (about 55%) with a purity of about 96%.



   IR (KBr pellet, values in cm-1):
3440,1745, 1720,1600, 1430,1390, 1320,1240, 1220 sh, 1180,1070, 1040,
780,735, 650.
 EMI13.3
 : 1 mixture3, 95 (S, 2H),
4, 66 (S, 2H), about 7.5 (broadened S, about 2H).



   Example 1: a) Preparation of an acid chloride-like, reactive intermediate of 3- (2, 4, 6-trimethylphenyl) -1, 2, 4-oxadiazol-5-yl-acetic acid:
A solution of 250 mg (1 mmol) 3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid, 0.005 ml DMF and 0.11 ml pure thionyl chloride in 5 ml carbon tetrachloride is heated under reflux for 1 h under anhydrous conditions. Different samples were taken at different time intervals. Te-
 EMI13.4
 dissolved the residues in anhydrous chloroform and determined the IR spectra to check the progress of the reaction. It is evident that the reaction mixture should not be refluxed for more than 10 minutes (3 to 5 minutes is sufficient).

   The reactive intermediate produced is not the acid chloride as such, but a reactive intermediate.

 <Desc / Clms Page number 14>

 



   This reactive intermediate still gives the expected amides in moderate yields when reacted with amines. The empirically determined changes in the IR spectra are as follows:
The characteristic feature of a solution of the starting acid in chloroform is a monomeric OH at 3500, a dimeric OH at around 3000 to 3200, monomeric C = 0 (shoulder) at: 1760 and dimeric 0 = 0 at 1730 cm-1. After refluxing for 3 min, both the OH bands and the O = O bands at 1760 cm-1 disappear completely.

   There remains a sharp and intense absorption at 1740 cm -1, which is characteristic of the reactive compound. Reflux times of over 10 min result in a decrease in the absorption at 1740 and at least four further absorptions occur between 1660 and 1660
 EMI14.1
   -1 on; ransic acid:

     
967 mg (3.66 mol) of 7-aminocephalosporanic acid (7-ACA), suspended in 20 ml of ethyl acetate, are used as the starting material and a mixture is made with a majority of N, O-bis-trimethylsilyl- 7-ACA and a smaller amount of trimethylsilyl-7-aminocephalosporanate in the usual way by adding 1.02 ml (7.32 mmol) of triethylamine and 0.92 ml (7.32 mmol) of trimethylchlorosilane at 50C and then for a further 30 minutes at 30C stirs. One adds to the reaction mixture obtained
0.43 ml (3.66 mmol) quinoline.



   In the meantime, 900 mg (3.66 mmol) of 3- (2,4,6-0trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid are converted into the reactive intermediate according to the method described above, whereby 15 ml of dry carbon tetrachloride, 0.4 ml of thionyl chloride and about 0.02 ml of dimethylformamide were used. After refluxing for 5 min, the purple-colored solution is evaporated completely in vacuo and the residue is dissolved in 6 ml of dry ethyl acetate.



   The resulting solution is quickly added to the first solution after this solution has returned to room temperature (about 200C). When the "acid chloride" is added, the temperature rises by about 5 ° C. The reaction mixture is then stirred at 30 ° C. for 30 minutes.



   The reaction mixture is poured into 175 ml of ice-water and the pH is adjusted to 7.0. The layers are separated, the organic layer is discarded and the aqueous layer is washed twice with 50 ml of diethyl ether each time. The aqueous layer is adjusted to a pH of 3.7 and then extracted four times with 25 ml of ethyl acetate each time. The extracts obtained in this way are combined, washed with a small volume of ice-water, treated with activated charcoal, filtered, dried over anhydrous magnesium sulfate and filtered again using a water pump. Complete evaporation of the almost colorless filtrate and thorough drying of the residue in vacuo gives 650 mg of solid product.

   This product is not completely pure according to thin layer chromatography; the crude product is purified by column chromatography. However, the IR spectra of the raw and pure product hardly differ.



   IR (KBr pellet, values in cm-1): 3500 and 2600, 3280.1780, 1735.1700, 1660.1610, 1575.1540, 1380 and / or
1355 and 1230 (very intense).



   Example 2:
Preparation of sodium 6- [(5-methyl-1,2,4-oxadiazol-3-yl) acetamido] penicillanate: 1.42 g (10 mmol) of 5-methyl-1,2,4-oxadiazole 3-ylacetic acid is added to 20 ml of dry carbon tetrachloride. 1 ml of thionyl chloride and 2 drops of dimethylformamide are added to the suspension at room temperature. The mixture is heated moderately to the boil for 10 minutes, a clear solution being obtained and the substituted acetic acid being completely converted into its acid chloride.



   At the same time, a suspension of 2.15 g (10 mmol) of 6-amino-penicillanic acid in 30 ml of dry ethyl acetate is treated with 2.8 ml (20 mmol) of triethylamine and 2.5 ml (20 mmol) of trimethylchlorosilane and then treated for 30 min stirred at room temperature. First 1.2 ml (10 mmol) of quinoline and then the solution of the acid chloride in carbon tetrachloride are added to this mixture. The first addition of the dissolved acid chloride results in a temperature rise from about 100C to about 300C. The reaction mixture is then stirred for 30 min and then poured into 50 ml of ice-water. The pH is adjusted to 7.0 and the layers are separated, the organic layer is discarded and the aqueous layer is extracted once with 30 ml of diethyl ether.

   To obtain the desired penicillin, the aqueous layer is extracted 6 times at a pH of 3.0 with a 1: 1 mixture of diethyl ether and ethyl acetate. The organic layers are combined, washed twice with a small volume of ice-water, treated with activated charcoal, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of about 20 ml. Then 40 ml of diethyl ether and then a solution of sodium a-ethyl caproate in ethyl acetate are added until no further precipitation occurs. The solid precipitate is collected on a suction filter, repeated with a 2: 1 mixture
 EMI14.2
 

 <Desc / Clms Page number 15>

 



   The structure and the good degree of purity are confirmed by IR and PMR spectra. According to the PMR spectrum, the end product contains 1 mole of water / mole of penicillin.



   IR (KBr pellet, values in cm-1): 3400, 1775, 1685, 1610, 1590,:! ; 1540, 1390.



   PMR (60 Mc, d6-dimethyl sulfoxide, 2,2-dimethyl-silapentane-5-sulfonate, # values in ppm): 1, 51 and 1, 62 (2 singlets, 6H), 2, 58 (S, 3H) , 3, 78 (S, 2H),
4.02 (S, 1H),
5, 45 (center of a multiplet, 2H),
8.9 (D, J about 8.5 cP, 0.9 H).



   Example 3: Preparation of 7- [(5-methyl-1, 2, 4-oxadiazol-3-yl) acetamido] -3-azidomethyl-3-ceph-em-4-carboxylic acid:
A mixture of 0.71 g (5 mmol) of 5-methyl-1,2,4-oxadiazol-3-ylacetic acid, 0.5 ml of thionyl chloride, 1 drop of dimethylformamide and 10 ml of dry carbon tetrachloride was heated for a gentle 13 minutes under anhydrous conditions. The solvent was removed in vacuo and the colored residue was dissolved in 10 ml of dry ethyl acetate.



   In the meantime, 1.39 ml of triethylamine and 1.26 ml of trimethylchlorosilane were successively prepared from a suspension of 1. 225 g (4.8 mmol) of 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid [prepared according to D. Willner . The Journal of Antibiotics, Volume 25 (No. 1), 64 (January 1976)] in 12, 5 ml of ethyl acetate added. The mixture was stirred for 45 min at room temperature, then cooled to OOC, and then 0.66 ml of quinoline and the prepared solution of the acid chloride in ethyl acetate were added in succession. After 5 minutes the ice bath was removed and the reaction mixture was stirred for a further 60 minutes at room temperature. The reaction mixture was poured into a well-stirred, ice-cold mixture of 50 ml of water and 40 ml of ethyl acetate at pH 2.

   The pH was raised to 7 and the layers were separated. The organic layer was discarded and the aqueous layer extracted once with 50 ml of ethyl acetate. The aqueous layer was purified once more by extraction with 50 ml of ethyl acetate at pH 6.0 and then six times with 50 ml of ethyl acetate each time at pH 5, 0, 4, 0 (twice), 3, 5 (twice) and 1, 0 extracted. The extracts were combined, centrifuged to remove some insoluble solid material, washed twice with a small volume of ice-water, treated with activated charcoal and dried over anhydrous magnesium sulfate, filtered and evaporated completely in vacuo.

   The residue was triturated with diethyl ether, filtered with a suction pump and washed with diethyl ether and dried in vacuo to constant weight.



   Yield 1.17 g (64%).



   The final product contained about 90% of the desired compound and about 10% of the corresponding hā - cephem derivative.



   IR (KBr pellet, values in cm-1):: 1: 3450 and: 2600, 3305, 2135, 1790, 1710, 1660, 1585 and 1540.



   PMR (d 6-dimethyl sulfoxide, 60 Me, 2, 2-dimethylsilapentane-5-sulfonate, 6 values in ppm):
2, 58 (S, 3H), 3, 3 to 3, 95 (Q, JAB about 18.3 cP), 3, 76 (S) and about 3, 8 to 4, 6 (Q, JAB = 13, 1 cP) together 6H,
 EMI15.1
 
1: 59.3 (D, J '= 8.3cP, 0.9H).



   Example 4:
Preparation of 7- (5-benzyl-1,2,4-oxadiazol-3-yl-acetamido) -cephalosporanic acid:
In the same way as described in Example 2, 1048 mg (4 mmol) of 5-benzyl-1,2,4-oxadiazol- - 3-yl-acetic acid were converted into the acid chloride, 12 ml of dry carbon tetrachloride and 0.4 ml of thionyl chloride and used 2 drops of dimethylformamide. The solution was heated moderately for 15 minutes, then the carbon tetrachloride was removed in vacuo and the discolored residue was dissolved in 5 ml of dry ethyl acetate.



   At the same time, a suspension of 1.088 g (4 mmol) of 7-aminocephalosporanic acid in 25 ml of dry ethyl acetate was treated with 1.14 ml (8 mmol) of triethylamine and 1.04 ml of trimethylchlorosilane (8 mmol). After stirring for 30 minutes at room temperature, 0.47 ml (4 mmol) of quinoline and (dropwise) the solution of the acid chloride were added. The reaction mixture was stirred for a further 30 min and then treated as usual. In the isolation procedure, the desired compound was obtained by extraction with

 <Desc / Clms Page number 16>

   Ethyl acetate obtained at decreasing pH values from 6.0 to 4.5.



   Yield 1.35 g (70%) of practically pure product.



   IR (KBr pellet, values in cm-1):
 EMI16.1
    and 2600,2,06 (S, 3H), 3, 4 (broadened S, 2H),
3, 79 (S, 2H),
4, 34 (S, 2H),
4.60 to 5.17 (ABq, J = 12, 4 cP) and
 EMI16.2
    1: 5, 1 (D, J = 4, 8 cP) together 3H, 7, 35 (5H),
9.2 (D, J 'about 8.2 cP, about 0.8H).



   Example 5:
Preparation of 7- (5-ethyl-1,2,4-oxadiazol-3-yl-acetamido) -cephalosporanic acid:
Under anhydrous conditions, a mixture of 3.1 g (20 mmol) of 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid, 2.2 ml of thionyl chloride, 2 microdrops of dimethylformamide and 60 ml of carbon tetrachloride moderately about 20 min heated. According to the IR spectrum, the carboxylic acid was then completely converted into the acid chloride. The resulting solution was evaporated in vacuo and the residue dissolved in 20 ml of ethyl acetate. In the meantime, 5.6 ml of triethylamine were added at 100 ° C. to a suspension of 5.44 g (20 mmol) of crude 7-aminocephalosporanic acid in 50 ml of ethyl acetate. Then 5.1 ml of trimethylchlorosilane were added.

   The mixture was stirred at room temperature for 60 minutes. Then 2.36 ml of quinoline and the solution of the acid chloride were added dropwise. The reaction mixture was stirred for an additional 30 minutes at room temperature. The contents of the flask were poured into 75 ml of ice water. The pH was adjusted to 7.0, the layers were separated and the organic layer was discarded. The desired compound was extracted from the water layer by a number of extractions each with 100 ml of ethyl acetate at pH values which were gradually lowered from pH 5.0 to 2.0. The combined extracts were washed twice with small volumes of ice water, once at pH 1.0 and once at pH 2.0.

   The extract was treated with activated charcoal, over anhydrous ma-
 EMI16.3
 the impact was filtered on the pump, washed with dry ethyl acetate and carbon tetrachloride and dried to constant weight.



   Yield 5.9 g (about 7cP10).



   This product was 90 to 95% pure.



   The combined filtrates were evaporated in vacuo to give 1.3 g of a pale yellow material which was purified by repeated trituration with diethyl ether to give 0.65 g of additional product. According to the thin layer chromatogram and the IR spectrum, this second batch had approximately the same purity.



   IR (KBr pellet, values in cm-1):
 EMI16.4
    and 2600.1, 30 (T, J = 7.5 cP, 3H),
2.05 (S, 3H),
2.95 (Q, J = 7.5 cP, 2H), 3.6 (broadened S, 2H),
3, 77 (S, 2H),
4.60 to about 5.25 (AB-Q, J = 12.8 cP) and about
5, 15 (D, J = 4, 8 cP) together 3H, about 5, 25 (Q, J = 4, 8 cP and J '= 8, 0 cP, 1H), 9, 2 (D, J' = 8.0 cP, about 0.8H).



   According to the usual procedure, a solution of 5.7 g of the first batch in 250 ml of acetone was treated with a solution of equivalent amounts of sodium α-ethyl caproate dissolved in 12.5 ml of ethyl acetate.



    5.3 g of the somewhat purer sodium salt of cephalosporin were obtained.

 <Desc / Clms Page number 17>

 



   Example 6:
Preparation of sodium 7- (5-ethyl-l, 2, 4-oxadiazol-3-yl-acetamido) -3- (5-methyl-1, 3, 4-thiadiazol-2-yl-mercaptomethyl) -3-cephem- 4-carboxlate:
 EMI17.1
 are described in Example 5, -1,3,4-thiadizol-2-yl-mercaptomethyl) -3-cephem-4-carboxylic acid with a purity of about 927o gave 2.58 g of the almost pure desired product.



   In the isolation procedure, the compound was removed from water by a number of extractions with ethyl acetate between pH 5.0 and pH 3.5. The combined extracts were washed with water at pH 1.0 and 2.5, decolorized with activated charcoal and completely evaporated in vacuo. The residue weighed 3.2 g (about 65%). It was dissolved in a mixture of 65 ml of acetone and 250 ml of ethanol. A concentrated solution of 6 mmol of sodium a-ethylcaproate in ethyl acetate was added and the resulting solution was concentrated in vacuo to a volume of 50 ml. 100 ml of dietary ethyl ether were slowly added to the well-stirred solution. The precipitate formed was collected by filtration, washed with ether and dried in vacuo.



   IR (KBr pellet, values in cm-1): Ä3450 (H2O), 3280, 3050, 2985, 2940, 1765, 1680, 1610, 1580, 1550, 1415 sh,
1390, 1370.



   PMR (d6-DMSO, 60 Me, DSS, # values in TpM):
1.28 (T, J = 7.5 cP, 3H),
2.69 (S) and 2.93 (Q, J = 7.5 cP) together 5H, about 3.6 (2H),
3.77 (S, 2H), from about 4.25 to 4.7 (AB-Q, J about 13 cP, 2H),
5.0 (D, J about 4, 9 eP, 1H),
 EMI17.2
 analogously 1.85 g (55%) of the almost pure cephalosporin was obtained. In this case, the ACA derivative was not dissolved by treatment with triethylamine and trimethylchlorosilane, but rather by adding 14 mmol of N, O-bistrimethylsilylacetamide.



   IR (KBr pellet, values in cm "): 3400 (HO), 3200-3300, 1760, 1680, 1600, 1580, 1540, 1400 (sh), 1380, 1355.



   PMR (d6-DMSO, 60 Me, DSS, # values in tpm): 2. 58 (S, 3H), about 3.45 (2H), 3.75 (S, 2H),
3.95 (S, 3H), from about 4.15 to 4.65 (AB-q, J R! 13, 5 cP, 2H),
5, 0 (d, J 4, 8cP, 1H), 5, 55 (q, J 4, 8 cP, J '8, 2 cP, 1H), 9, 2 (d, J' # 8.2 cP, about 1H).

** WARNING ** End of DESC field may overlap beginning of CLMS **.

 

Claims (1)

PATENT CLAIMS: 1. Process for the production of new 6-subst. Aminopenicillanic acid and 7-substituted aminocephalosporanic acid derivatives of the general formulas EMI17.3 and <Desc / Clms Page number 18> EMI18.1 in which Q is a group of general formulas EMI18.2 or EMI18.3 represents in which U is an amido group, for example a saccharyl, succinimido or phthalimido group, or a group OE 'in which E'Hydrogen or a salt-forming cation, an ester group such as a lower alkyl group, optionally substituted with a lower alkanoyloxy group, which can also be substituted, a Silyl, phenacyl, benzyl, benzhydryl, trichloroethyl or tert. Represents butyl group, X is hydrogen, a hydroxy group, a lower alkanoyloxy group, preferably acetoxy group, or the residue of a nucleophilic agent such as a halogen, an azido group, a cyano group, a carbamoyloxy group, an optionally substituted, mononuclear, heterocyclic group which contains a sulfur or nitrogen atom , such as a pyridinyl group, or a Group - S-Q ' <Desc / Clms Page number 19> represents in which Q 'an optionally substituted diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, Thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazoJyl, benzoxazolyl, triazolopyridinyl or Purinyl group, or X is an amino group when Q is a group of the formula (IV) stands, Pure lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec. Butyl, isobutyl, tert. Butyl group, optionally substituted in the primary or secondary position by a fluorine atom, a chlorine atom, a hydroxyl group or a lower alkoxy group, such as a fluoromethyl, 2-chloroethyl, methoxymethyl or 1-hydroxyethyl group, or a cycloalkyl group, optionally substituted with one or more lower alkyl groups, hydroxyl groups or lower alkoxy groups, or Represents a pure adamantyl group or a phenyl group, optionally substituted by at most three of the aforementioned substituents, or a pure mononuclear, heterocyclic, 5-membered group, for example a furyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl group, optionally substituted with lower alkyl groups, or R1 is an aralkyl group, for example a benzyl group, optionally substituted in the phenyl nuclei as mentioned above, or a carboxymethyl group, and Z1 is hydrogen, a lower alkyl group, optionally substituted by a chlorine atom or a Fluorine atom, a lower alkoxy group, a cycloalkyl group, a phenyl group, which itself can optionally be substituted with at most three of the aforementioned substituents, or Z1 represents a carboxy group esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl radical, where the phenyl groups can optionally be substituted by at most one of the aforementioned substituents, or Z1 is a carbamoyl group, optionally substituted on N by one or two lower alkyl groups, a phenyl, a mononuelearic, 5-membered, heterocyclic group, a cycloalkyl group, one or two aryl-lower alkyl or cycloalkyl-lower alkyl groups, the phenyl and cycloalkyl groups optionally with can be substituted at most one of the aforementioned substituents, or Z1 represents a carbamoyl group, the nitrogen atom of which is a member of a heterocyclic ring, such as morpholino, and Z represents hydrogen when R represents acetic acid radical, and R represents a group of the formula EMI19.1 in which n is 0, 1, 2 or 3, R is hydrogen or a lower alkyl group, R4 is hydrogen, a lower alkyl, cycloalkyl, Is phenyl or aralkyl, or R is 4th EMI19.2 denotes in which E denotes hydrogen (if n1) or a lower alkyl, benzyl or phenyl ester group, or in which R4 denotes a carbamoyl group, optionally N-substituted by one or two lower alkyl or alkenyl groups, a phenyl group, a cycloalkyl group, one or two Aryl lower alkyl or EMI19.3 denoted cycloalkyl group, and wherein Z4 represents hydrogen or an optionally substituted aryl group, characterized in that a salt, an ester or an amide of a 6-amino-penicillanic acid or 7-amino-cephalosporanic acid compound of the formulas is used <Desc / Clms Page number 20> EMI20.1 or EMI20.2 in which the substituent X is as defined above and is preferably protected, when it represents a hydroxy or an amino group, with an active ester, acid halide, acid anhydride including the mixed anhydrides prepared from stronger acids, an acid azide, an active thioester or an azolide, which are derived from an acid of the general formula: EMI20.3 where R 'and Z' have the meanings given above for R1 and Z1 or are groups which are easily EMI20.4 EMI20.5 EMI20.6 as such in the presence of, for example, a carbodiimide reagent or similar reagents, optionally subjecting the compound obtained to a customary oxidation process, then <Desc / Clms Page number 21> separating and / or isolating the compound obtained and removing any protective groups present in order to prepare the corresponding penicillanic or cephalosporanic acids, and optionally converting the acids obtained into their salts or esters, 2. Process for the preparation of 7- [(3-methyl-1, 2, 4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid or its pharmacologically acceptable salts and esters according to claiml, characterized in that 7-aminocephalosporanic acid with trimethylchlorosilane and Triethylamine converts, the intermediate compound obtained with thionyl chloride and dimethylformamide freshly prepared acid chloride of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid, the protective group is removed from the compound obtained, the desired compound is isolated and purified and if appropriate, the free acid is converted into a salt or an ester. EMI21.1 The intermediate compound is reacted with the acid chloride of 5-methyl-1,2,4-oxadiazol-3-yl-esigsäre freshly prepared using thionyl chloride and dimethylformamide, the protective group present is removed from the compound obtained, the desired compound is isolated and purified, and optionally the free acid converted into a salt or an ester. EMI21.2 indicates that 7-amino-cephalosporanic acid is reacted with trimethylchlorosilane and triethylamine, the intermediate compound obtained with acid chloride of? freshly prepared using thionyl chloride and dimethylformamide. -Methyl-3-methyl-1,2,4-oxadiazol-5-yl-acetic acid is reacted, the protective group present is removed from the compound obtained, the desired compound is isolated and purified and, if appropriate, the free acid is converted into a salt or an ester. EMI21.3 The intermediate compound is reacted with the acid chloride of 3-ethyl-1,2,4-oxadiazol-3-ylacetic acid freshly prepared by means of thionyl chloride and dimethylformamide, the protective group present is removed from the compound obtained, the desired compound is isolated and purified and optionally the free acid converted into a salt or an ester. 6. Process for the preparation of 7- (3-methyl-1,2,4-oxadiazol-5-yl-acetamido) -3- (1-methyl-tetrazol--5-yl-mercaptomethyl) -3-cephem-4-carboxylic acid or their pharmacologically acceptable salts and esters according to claim 1, characterized in that 7-amino-3- (1-methyltetrazol-5-yl- - mercaptomethyl) -3-cephem-4-carboxylic acid is reacted with trimethylehlorsilane and triethylamine, the resulting Intermediate compound reacts with acid chloride of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid freshly prepared using thionyl chloride and dimethylformamide, the protective group present is removed from the compound obtained, the desired compound is isolated and purified and, if necessary, the free acid in a salt or an ester converted.