NO762440L - - Google Patents

Description

Heterocyclic compounds.

The present invention relates to new 1,2,4-oxadiazolylacetic acid derivatives and new compounds derived therefrom, especially new therapeutically useful 1,2,4-oxadiazolylacetamidopenicillan and -cephalooporanic acid derivatives and phanaasbytic compositions containing these as well as methods for their preparation.

The new 1,2,4-oxadiazolylacetic acid derivatives according to the invention are represented by general formulas I, II and III<1> below:

where R^denotes a lower alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, isobutyl, t-butyl), optionally substituted in a primary or secondary position in relation to the carbon atom in the ring r.ed a fluorine atom, a chlorine atom, a hydroxy group or a lower alkoxy group (e.g. fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl), or a cycloalkyl group optionally substituted with one or more lower alkyl groups, hydroxy groups or lower alkoxy groups, or where R-^means an adamantyl group or a phenyl group, optionally substituted with up to three substituents selected from a fluorine atom, a chlorine atom, a hydroxy, a lower alkyl or lower alkoxy group, or where K± means a mononuclecsr heterocyclic five-membered group (e.g. furyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl) optionally substituted with lower alkyl groups, or where means an aralkyl group (e.g. benzyl) optionally substituted in the phenyl nucleus as mentioned above, and where Z^means a hydrogen natom, a lower alkyl, an arelkyl, a cycloalkyl or a phenyl group, where the cycloalkyl or phenyl group is optionally substituted with substituents as mentioned above, or means a lower alkyl group substituted with a mononucletor five-membered heterocyclic group as mentioned above.

Preferably represents a lower alkyl group (e.g. methyl or ethyl), optionally substituted with a fluorine atom, a chlorine atom, a hydroxy group or a lower alkoxy group, or a substituted phenyl group or a benzyl group, and Z represents a hydrogen atom, a lower alkyl group or a phenyl group.

(b)

where Z« represents a hydrogen atom, a lower alkyl, phenyl, cycloalkyl-aryl-lower alkyl group, a carboxy group esterified with a lower alkyl-y phenyl, cycloalkyl or aralkyl residue or an N-disubstituted carbamoyl or N-monosubstituted carbamoyl group and Z^means a hydrogen atom or a phenyl group, optionally substituted with up to three of the substituents mentioned above, or an N-disubstituted carbamoyl or carboxyl group esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl residue. Preferably is

Z2 and/or Z^ a hydrogen atom, a lower alkoxycarbonyl group,

an optionally substituted phenyl group or an N,N-di-lower-alkyl-carbamoyl group, while Z 2 can also be a lower alkyl group.

wherein Rg represents a group

wherein n means 0, 1, 2 or 3" and means a hydrogen atom, a lower alkyl group, and R^ means a hydrogen atom, a lower alkyl, cycloalkyl, phenyl or aralkyl group, or R^ means a -C00E group, where £ means a hydrogen atom or a salt-forming residue (when >.1), or one lower alkyl, benzyl or phenyl ester residue, or R^+ means a Icarbaraoyl group, optionally N-substituted with 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 are optionally substituted with hSyst one of the substituents as mentioned above, or where R^ and IU together with the carbon atom to which they are bound represents an optionally substituted cycloalkyl group, and Z represents a hydrogen atom or an optionally substituted aryl group. Preferably, R2 represents a lower alkyl group, a benzyl group optionally substituted in the phenyl ring, a lower alkyl acetate group or a K,II di-lower alkylacetamide group and Z represents a hydrogen atom or an optionally substituted phenyl group.

The term "lower" as used herein for alkyl and alkoxy groups means that the group in question contains up to six carbon atoms. As used in the present description, the term "cycloalkyl" means a carbocyclic ring with 5-3 carbon atoms.

The compounds with the general formulas I, II and III can be prepared using several methods known per se by starting from the substituted oxydiazole molecule. Be substituted 1,2,4-oxadiazole derivatives can be prepared using a large number of preparation methods, as described e.g.

of F, Eloy in Fortschr. Cheo. Forsch., volume 4v pages 807 - 876

(1965), by P. Rajagopalan, in Tetrahedron Letters, No. 5, pp. 311'r 312 (1969) and by F. Eloy and R. IJSwmaers in Bull Soc. Chim. Belg., 72, pages 719-724 (1963). The substituted 1,2,4-oxadiazolyl acetic acids are preferably prepared according to the methods indicated below.

Type I

The group of 3-substituted 1,2,4-oxadiazol-5-yl diacids' where e.g. means a 2,6-dichlorophenyl-, 2,4,6-trimethylphenyl- or :{'* 2-kiloiv6-fluorophenyl group, a t-alkyl group such as t-butyl or adamantyl, and where Z^ means a hydrogen atom or a lower alkyl group, a cycloalkyl, aralkyl (e.g. benzyl) or aryl group, can be prepared by cycloaddition of stable and reactive nitrile oxides with imidates of various nitriles to 1,2,4-oxadiazoles according to the reaction scheme:

as described, e.g., by P. Rajagopalan in Tetrahedron Letters, No. 5, pages 3U-312 (wherein R^ and Z^ are as defined above), followed by metallation of the methylene (e.g. -CH2-) group in the connection with group VI, and replacement of the metal atom or component with a carboxyl group, e.g. by the action of carbon dioxide (hereafter such a replacement is called "carbonation" for the sake of simplicity). The reaction between the imidates and the nitrile oxides is preferably carried out under anhydrous conditions by mixing the two reagents together under cooling, stirring the reaction mixture 1 for about 1 hour at room temperature, followed by removal of excess imidate by evaporation in vacuo. Some oracrystallizations of the product give the desired pure 1,2,4-oxadiazole compound.

The output initial data can be produced in ways known per se. e.g. as described in Organic Synthesis, Coll. volumes. 1, pages 5 - 6, and by S.A. Glickmann et al. in J.A.C.S. (1943), 67» page 1020.

The group of 3-substituted 1,2,4-oxadiazol-5-yl diacids where e.g. R 2 represents a lower alkyl group, a cycloalkyl group and

a phenyl group substituted by chlorine, fluorine, hydroxy* lower alkyl or lower alkoxy, or a heterocyclic group, such as 2-,

or 3-thienyl, 4- or 5-isoxazolyl or 4-isothiazolyl, and where Zn is as indicated above, can be prepared by converting the nitriles with the formula:

(where R^ has the meaning given above) to the corresponding amidoximes with the general formula:

in ways known per se, followed by O-acylation e.g. with acid anhydrides, alkylation of the intermediates to compounds of the general formula VI, followed by metalation and carbonation. This method for the compounds of the general formula VI is known per se, e.g. from F. Eloy, Cont. Chera. Forsch., volume 4, page 814. Faeks. the compounds are prepared by heating the corresponding o-acylated amidoxime until temperatures between 120 and 170°C are reached, preferably around 150°C, followed by distillation, which gives a mixture consisting of water and the desired 1,2,4- oxadiazole dye mixture. The distillate is saturated by adding potassium carbonate and a two-layer system is obtained. The solid layer is removed, dried over potassium chloride, washed with small amounts of ether and distilled again.

In fact, none of the methylene group and the subsequent carbonation can be carried out by methods which are known per se, and which are described e.g. in Houben-Weyl, Methoden der Organischen Chemle, 4th edition (1970), volume 13/1, page 93 r 114,

173 - 174, 296 - 350. The introduction of e.g. an lltium atom or

sodium atora can be furrowed through f .ules. using butyl-lithium/TMSDA, butyl-lithium/DABC$, lithium-dlisopropylamine, lithiumisopropyl-cyclohexylamine, lithium-N,N-dimethylacetamide, lithium-bltrimethyl-silylacetamide, 2-lithium-1,3-dlthiane and 2- lithium-1,3,5-trithiane,

sodium hydride, sodium aiide, sodium nxethanolate, sodium naphthyl, phenyl sodium, in inert solvents (eg* penteny.^hexane,

toluene, diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane) and at very low temperatures, e.g. -60°C or lower.

Replacement of the metal atom or of the metaT T component with a carboxyl group can be carried out, e.g. by adding a solution of the organometallic compound to fresh phase carbon dioxide on which a layer of dry diethyl ether or tetrahydrofuran is optionally present, or by introducing gaseous carbon dioxide over or through a solution of the organometallic compound.

The starting amidoxime can be prepared by methods that are known per se and as described, e.g. by fULenaers, C. Moussebois and F. Eloy in "Heiv. Chia. Acta,, vol. 45 (1962), pp. 441 - 446 (including references therein) and by CD. Hurd in In-organic Synthesis, vol. 1, p 39.

Type II

The substituted 1,2,4-^dioxadiazol-3,5-yl-diacetic acids according to formula II can be prepared from compounds of the general formula:

. where Z2 and Z- are as stated above for double metallization* and subsequent double carbonation"

The compounds of formula IX can be prepared, e.g. by conversion of nitriles to the corresponding amidoxime followed by 0-acylation with f .eies. acid anhydrides and cyclization of the intermediates.

Type III

The 5-substituted 1,2,4-oxadiazol-3-ylacetic acid compounds where R2 denotes a straight-chain lower alkyl (preferably methyl) group, optionally substituted with a branched alkyl group, cycloalkyl, phenyl, or an unsaturated lower alkyl group ( e.g. according to the formula -CH^-R^), and Z^ denotes a hydrogen atom, can be prepared by double thiaetallation of compounds, e.g. with the general formal

(where R 1 is as indicated above), followed by double carbonation and monodecarboxylation of the substituents in the 5-position of the 1 oxadiazulfene.

The compounds of formula X can be prepared f.efes. according to the preferred reaction schemes for the oxadiazole ring formation, as indicated under type I.

In several cases, 5-substituents can be introduced, e.g. by selective reaction of the 5-acetic acid group 1 the corresponding biacetic acids with isocyanates, resulting in Rg substituents of the type

where R means the residue originating from the isocyanate.

The compounds of the general formulas I, II and III

as well as the intermediate organo-metallic precursors can thus be used as starting materials for the production of other products, which are new and which constitute another feature of the invention.

As starting materials, acids with the formulas I, II and III can be used as such, or active derivatives of these acids, such as various types of anhydrides (including mixed anhydrides), acid chlorides and active esters.

As final derivatives, the following can be produced:

(A) Esters of the general formula:

where FU and Z* have the same meaning as indicated above in connection with formula I, and 1^ means a lower alkyl, cycloalkyl, benzyl, benzhydryl or phonacyl residue;

or

where Z 2 and Z are as stated above and E 2 means lower alkyl, cycloalkyl, ar alkyl, phenyl, phenacyl or benzhydryl, where the phenyl residue . is optionally substituted with halogen, optionally esterified carboxy, lower alkoxy, lower alkylthio, lower alkyl-lower-alkyloxy and lower-alkyl-lower-alkylcarbonyl;

or

where R" and Z" have the same meaning as stated above in connection with formula III, and E" means a lower alkyl, cycloalkyl, araUcyl, phenyl, phenacyl, or benzhydryl group, where the phenyl residues are optionally substituted with halogen, optionally esterified carboxy, lower alkoxy, lower alkylthio, lower-alkyl-lower-alkyl, lower-alkyl-lower-alkylcarbonyl.

Transformation of compounds of formulas I, II and III

to the corresponding esters lean is carried out in a manner known per se, in the case of the less stable acids I pg II the reaction conditions are adapted to the sensitivity of the rather reactive acetic acid groups involved.

The esters according to the formulas XII and XIV can also be prepared by reacting the intermediate organometallic precursors (such are used for the production of the acids) and preferably the lithium-containing precursors, with chloroformate esters with the corresponding ester residues.

(B) Amides

Precise, secondary and tertiary amides can be prepared from reactive intermediates (e.g. acid chlorides and anhydrides) derived from the acids of the general formulas I, II and III using known methods or by reaction of these

acids with phosphazo intermediates, prepared in situ from amines and the phosphoric acid chloride. A wide spectrum of secondary amides can also be prepared by two methods with great applicability, both of which include a wide range of isocyanates as reactive agents.

In the first of these two methods, α-metalated 1,2,4-oxadiazoles, such as those used for the preparation of oleadiazolylacetic acids with the formulas I and II, are reacted according to the general formula

or

where R£, Z<*>, ZAnd Z^ are as stated above for R^, Z^, Z2 and Zy or mean groups which can easily be converted into these groups within the definition of 11^, % lf Zzog Z^ and which can be influenced or react under the reaction conditions, and where B means a metal atom

T TT

Me or a group He -Hal, where the Roman numeral indicates the net valence and where Hal means a halogen, preferably chlorine or bromine, with isocyanates under suitable conditions. Suitable substituting metal atoms or metal-containing groups are lithium, sodium and magnesium

sium chloride or magnesium bromide, and lithium is preferred.

According to a preferred method, a lithium atom is introduced by means of H-Li exchange using reagents such as n-butyllithium. In general, moderate to very good yields are obtained when starting from low-level (e.g. lithium- or sodium-containing) compounds in which at least two substituents (such

such as phenyl. cross-linked heterocyclic radicals or other groups, such as carboalkoxy) are present, which are capable of stabilizing the formed carbanion at low temperatures, and which are bound directly to the metalated carbon atom. -

According to the second method for the production of secondary amides, the 1,2,4-oxadiazolylacetic acids are reacted with various isocyanates in suitable, selected solvents (e.g. 3,5-dimethyl-1,2,4-oxadiazole), and preferably in the presence of particulate catalysts. This method offers further possibilities

than the first method in that in this case one from -

compounds of the general formulas I, II and III also achieve moderate to very good yields of amide, so that compounds

with the formula XVII C:

where R means the residue originating from the isocyanate, can also be obtained in addition to the amide derivatives with the formulas

In compounds with the general formula II, the acetic acid group in the 5-position of the oxadiazole ring appears to be much more reactive than the acetic acid group in the 3-position, which often allows for a so-called selective reaction of the acetic acid group in the 5-position when Z2 and Z is properly chosen, with an isocyanate in a suitable solvent under vapor-free conditions, under an inert gas atmosphere and in the presence of small amounts of a suitable non-strongly basic catalyst.

The conditions for the use of various types of suitable catalysts are known from South African Patent No. 71/7432.

(C) A large spectrum of salts can be prepared from the 1,2,4-oxadiazolylacetic acids according to the invention in ways known per se

manner.

It will be clear that in the esters and amides as they are prepared from the starting acids and organometallic compounds of the general formulas I, II, III, XV yXVI ZS^røC according to the ways indicated and described above, the substituents present in these compounds can be converted to other groups (e.g. by removing the protecting groups) or that other substituents,

which do not affect the structure, of these manufactured compounds, can be introduced later in and of themselves. known way.

A special feature of the invention is constituted by new penicillin and cephalosporanic acid derivatives, by methods for their production and by pharmaceutical compositions containing them.

These new penicillanic acid and cephalosporanic acid derivatives according to the present invention are compounds with the general formulas:

where Q denotes the group,

where U means an amido group (e.g. saccharyl, succininido or, phthalimido) or a group OE<*>where E<*>means hydrogen, a salt-forming cation (e.g. alkali metal, alkaline earth metal and amine cation), an ester- residue such as a lower alkyl group, optionally substituted with a free alkanoyloxy group which may also be substituted, a silyl, a phenacyl, a benzyl, a benzhydryl, a trichloroethyl or tert-butyl group, X means a hydrogen atom,

a hydroxy group, a lower alkanoyloxy group (preferably acetoxy) or the residue of a nucleophilic agent, such as a halogen atom,

an agido group, a cyano group, a carbamoyloxy group,.., an optionally substituted mononuclear heterocyclic group containing a sulfur or nitrogen atom (e.g. pyridinyl), a group -S-Q<*>

(where Q<1>meansST diazolyl-, triazolyl-, tetrazolyl-., t&azolyl-, thiadiazolyl-, thiatriazolyl-, oxazolyl-, oxadiazolyl-, (ben^Lmidazolyl-, benzoxazolyl-, triazolo-pyridinyl- or pjfcjrinyl group) or X means an amino group when Q means a group of the formula XX, R^ is as indicated above with respect to formula I, but also

H

means a carboxymethyl group and means, combined with the above definition for R-^, a hydrogen atom, a lower alkyl group optionally substituted with a chlorine or fluorine atom, a lower alkoxy group, a cycloalkyl group, a phenyl group, which itself is optionally substituted with at most three of the substituents mentioned above, or ZJ represents a carboxy group which is esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl residue, where said phenyl radicals are optionally substituted with at least one of the substituents mentioned above, or Z£

means a carbamoyl group, optionally K-substituted with one or two lower alkyl groups, a phenyl, a mononuclear five-membered heterocyclic group, a cycloalkyl group, one or two aryl-lower-alkyl or cycloalkyl-lower-alkyl groups, where the phenyl and cycloalkyl groups optionally is substituted with at most one of the substituents as stated above, or Z£ represents a carbamoyl group with the nitrogen atom as a member of a heterocyclic ring (e.g. morpholino), and where ZJ means hydrogen in combination with R-^ representing an acetic acid residue.

The expression "lower" as used herein for alkanoyloxy group r indicates that the group contains at most 6 carbon atoms.

where O is as defined above, and R 2 and Z are as defined above for formula III.

A preferred group of compounds according to the invention

they are against the general formula XVIII, where the symbol R^ denotes a lower alkyl group, an adamantyl group, halomethyl, hydroxymethyl, carboxymethyl, lower alkoxyethyl, benzyl or phenyl, optionally bearing one, two or three substituents selected from chlorine and lower alkyl groups, or a single nitro group, and more particularly R^ means a methyl, ethyl, methoxymethyl, 2,6-dichlorophenyl, 2,4,6-trimethylphenyl or a lcarboxymethyl group, Z£ means a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, with substituents as indicated above, an esterified carboxy group or a carbamoyl group, and alkali metal, alkaline earth metal and

amii salts thereof.

Another preferred group of compounds is that of the general formula XXIV, where R 2 means a methyl or ethyl group or a group -CH 2 -R 2 where R 2 means lower alkyl, cycloalkyl, phenyl, lower alkoxycarbonyl, a N -monosubstituted carbamoyl group or an unsaturated heterocyclic group, and where Z has the same meaning as stated above, and alkali metal, earth Tlf al ime numbers and amine salts thereof.

The therapeutically useful compounds according to the invention can be prepared in several different ways, each of which is an application of a method known in itself for the preparation of penicillins and cephalosporins. According to a feature of the invention, compounds with the general formulas XVIII and XXIV are prepared by reacting a salt, an ester or an amide of a 6-aminopenicillanic or 7-aminocephalosporanic acid compound with the formula

(where X is as defined above), with the substituent X when it is a hydroxy or amino group preferably protected, with an active ester (e.g. 2,4-dinitrophenyl ester, p-nitrophenyl ester or N-hydroxysuccinimido ester) of a acid of the general formula: where R^ and Z£ are as indicated above for R^ and Z£ or represent groups which can be easily converted into those within the definition for R^ and Z£ and which can also be affected or reacted under the reaction conditions used (e.g. protected amino*hydroxy and carboxy groups), or

where R<*> and zj are as indicated above for R 2 and Z^ or denote groups which can easily be converted into these within the definition of R 2 and Z^ and which can also. are affected or react under the reaction conditions, optionally followed by further substitution of the compounds obtained in this way or conversion of the substituents present into others'. in and of itself known manner.

Instead of active esters, derived from the acids with the general formulas XXX and XXXI, other functional derivatives of these acids which are suitable as acylating agents for a primary amino group can be used. Such derivatives include e.g. the corresponding carboxylic chlorides, bromides, acid anhydrides Including mixed anhydrides prepared from stronger acids, such as lower aliphatic monoesters of carboxylic acids, of alkyl and aryl sulfonic acids and of more sterically hindered acids such as diphenylacetic acid.

Furthermore, an acid azide or an active thioester (e.g. with thiophenol or thioacetic acid) of the acids can be used. Alternatively, you can

. the free acids with the general prefixes XXX and XXXI are coupled with the 6-aminopenicillan or 7-amlnocephalosporanic acid linker using a carbodilimide reagent. Instead of Qyii <teiifrtoe^<g>gȣ=*B05-pinitiiiiofLiijiluu Lill ~ a corresponding azolide, i.e. an amide of the corresponding acid whose anide nitrogen is a member of a qua&iaromatic

5-membered ring containing at least two hydrogen atoms, e.g. imidazole, pyrazole, thiazolenes, benzimidazole, bezotriazole and their substituted derivatives are used. The procedures for execution. of these reactions to obtain a penicillin or an e.cephalosporin and the methods used to isolate the compounds produced in this way are well known in the state of the art for corresponding compounds 5 see e.g. British patent heirfe&F. 932.644, 957.570, 959.054, 952.519, 932.530, 967.108 and 967.890).

The ester, salt or amide of the product obtained

by the method indicated above can be converted in a known manner into the corresponding penicillin or cephalosporanic acid derivatives, e.g. when a silyl (e.g. trialkylsilyl) ester of the starting material with the formulas XXV - XXIX is used as reactant, and the esterifying group can be easily hydrolyzed to obtain the corresponding acid compound with the general formulas XVIII and XXIV.

Another method according to the invention for the preparation of compounds with the general formulas XVIII and XXIV comprises the reaction of an acid with the general formulas XXX and XXXI

and with the general formula:

where and Z^ are as indicated above for Z^ and Z^ or represent groups which can easily be converted into these groups within the definition of Z2 and Z^, which can be affected or reacted under the reaction conditions, with a 6-isocyanate penicillanic acid or

-7-isocyanate cephalosporaxic acid compound of the formula 0=C=«N-Y, where

Y represents the radicals of formulas XIX and XX with atoms

or groups representing the carboxy group and possibly the hydroxy or amino group if these are present, i.e. when X in the formula XX is hydroxy or amino. Preferably, the group protecting the carboxy radical or hydroxy radical when present, in the 6-isocyanatopenicillan or 7-isocyanatocephalosporanic acid reactant is a di- or trialkylsilyl group which can be easily removed from the resulting product by hydrolysis.

The reaction between a carboxylic acid with the formula XXX, XXXI and XXXII and an isocyanate with the formula 0=C=H-Y is preferably carried out in an inert organic solvent such as toluene, dichloromethane, benzonitrile or 3'5-dimethyl-1,2,4-oxadiaz& . A small amount of an organic base, e.g. a substituted imidazole such as N-vinylimidazole, N-methylbenzimidazole or N-isopropyl-benzimidazole can serve as catalyst. These and other conditions for the use of various types of suitable catalysts are described in South African patent no. 71/7432. The reaction takes place according to the reaction nucleus indicated below for e.g. penicillanic acid derivatives.

der-E" represents a group which protects the carboxyl group during the reaction and which is removed after the reaction, for example by hydrolysis, hydrogenation or a substitution reaction with basic or nucleophilic agents.

In another method for preparing the penicillin and cephalosporanic acid derivatives with the general formulas XVIII and XXIV, a 6-isocyanatopenicillan or 7-isocyanatocephalosporanic acid compound 0=C=N-Y (where Y is as stated above) is reacted with the carboxyl group and hydroxy or amino the group, if these are to--'.

present, suitably protected, with an organometallic compound of the formula A-Me1, A-MeII-Hal or A-HeI3:-A (where A means a group

with the general formal

(where z5 and 2^ are as indicated above), Me denotes a metal atom, e.g. lithium, sodium or magnesium, and the numbers I and II indicate the valency, and Kal means a halogen, preferably a chlorine or

br$9trtom)> followed by hydrolysis of the intermediate which is obtained for

to remove the metal ion, and any hydrolyzable group protecting the carboxy (or hydroxy) group. The reaction is carried out in a denatured organic solvent under conditions that favor a reaction of the Grignard type, the formate cloud type or an analogous type. A similar reaction procedure is known from British patent no. 1,268,536 and South African patent, no. 70/8521.

The isocyanate starting materials of the general formula 0=C=N-Y (where Y is as indicated above) can be prepared by reacting phosgene with a penicillan or cephalosporanic acid derivative as known from British Patent No. 1,268,536 and South African Patent No. 70/8521 .

find another process for preparing the compounds of the general formulas XVIII and XXIV comprises reacting an acid of the general formulas XXX, XXXI and XXXII with a

- in situ produced phosphazo compound as obtained by reacting phosphorus trichloride and an amine salt (preferably a triethylamine salt) of a compound according to the formulas XXV, XXVI, XXVIII and

XXIX..

The reaction is preferably carried out at a temperature of about 30°C and lower in the presence of a previously precisely determined excess of the amine used and under anhydrous conditions.

Preferably, the ratio between the molar amounts of α-6-amlno-penicillanic acid and 7-*aminocephalosporanic acid and their derivatives is

triethylamine and phosphorus trichloride 2:3:1 and as reaction medium use-. tes dichloromethane. This type of reaction appeared to be well applicable in the case where a very sensitive substituted acetic acid derivative is used, as any reactive substituents present did not appear to be attacked or affected.

According to a further method, the cephalosporanic acid derivatives with the general formulas XVIII and XXIV where Q represents the group with the formula XX and where X originally means hydrogen, can be prepared by a ring enlargement reaction from the corresponding penicillanic acid sulfoxide derivatives (where Q means a group with the formula XXI and XXII) , e.g. by heating the penicillanic acid sulphoxide derivative up to 140°C in the presence of a catalyst and preferably a dehydrating agent.

These preparative methods are known e.g. from Belgian patents no. 747,113, 747,119, 747,120 and 763,104 as well as the American patents Mr. 3,275,626, 3,591,585 and 3-632,850.

The compounds with the general formulas XVIII and XXIV, where Q means one of the radicals with the formulas XXI, XXII and XXIII can also be prepared from the corresponding compounds where Q means one of the radicals with the formulas XIX and XX, by suitable oxidation methods.

E.g. the R-sulfoxides of the corresponding penicillins or ^osporins can be selectively produced by using in situ produced singlet oxygen or by acylation of the selectively produced intermediate R-sulfoxides of 6-aminopenicillanic acid and 7-aminocephalosporanic acid and derivatives.

The expression "in and of itself known methods" as used in the present description means methods that have previously been used or described in the literature.

New penicillanic acid and cephalosporanic acid derivatives corresponding to the general formulas XVIII and XXIV, where Q represents radicals of the formulas XIX, XX, XXII and XXII have antibiotic properties that make them potentially useful as medi- cines for humans and animals, alone or in combination with other known antibiotics. Some of these new compounds with the general formulas XVIII and XXIV have effects comparable to the well-known p-lactaia-containing antibiotics, they have special effects against gram-positive microorganisms (e.g. Bacillus subtilis, Staphylococcus aureus, Streptococcus h&emolyticus and faecalis as well as Di-plococcus pneumoniae), and further has a good effect against penicillin-resistant Staphylococci, especially the compounds in which R1 and Rg represent a methyl, ethyl, methoxymethyl, mesityl, benzyl and a 2,6-dichlorophenyl group, where a is a group with the formula XIX and XX and 7^ and Z^ mean hydrogen or methyl, as well as salts of such compounds. They are also effective against gram-negative microorganisms, e.g. Brucella melitensis, Pasteurella multoclda, Proteus rettgeri and Salmonella dublin.

The above-mentioned antibiotic compounds according to the invention are used either for therapeutic purposes in the form of a non-toxic salt such as the sodium, potassium or calcium salt. Other salts which may be used include non-toxically favorable crystallizing salts with organic bases such as amines, e.g. trialkylamines, procaine and dibenzylamine.

In the treatment of bacterial infections, the antibiotic compounds according to the invention can be administered topically, orally or parenterally, according to usual methods for administering antibiotics. They are administered in dosage units containing an effective amount of the active ingredient combined with suitable physiologically acceptable carriers or agents. The dosage units can be in the form of liquid preparations as follows

as solutions, suspensions, dispersions or emulsions

or in solid form such as soy powders, tablets and capsules.

Within the scope of the present invention, according to this synopsis, it contains an effective amount of a new penicillan or cephalosporan acid derivative according to the general formulas XVIII and XXIV, or a non-toxic salt thereof, 1 compound, a physiologically acceptable barrier or a stretching agent. Such therapeutic compositions can also include one or more therapeutically active ingredients in addition to a compound according to the invention. The term "effek-.

tive amount<1*>as used herein in connection with the described compounds means an amount sufficient to

Destroy; or to inhibit the growth of susceptible microorganisms when administered in the usual manner, in other words an amount sufficient to regulate the growth of the bacteria. The order of magnitude of an effective amount can be readily determined by those skilled in the art

by standard procedures for determining the relative activity of antibacterial agents when they are used against sensitive microorganisms via the various available administration methods.

Suitable barriers or spacers may be any physiologically acceptable component that serves to facilitate administration of the therapeutically active compound. The carriers can fulfill a further function such as e.g. in the form of a diluent, a taste masking agent, a binding agent, a delaying agent or as a stabilizer. Examples of driers include water, which may contain gelatin, acacia, alginate, dextran, polyvinylpyrrolidone or sodium carboxyethyl cellulose, aqueous ethanol, syrup, isotonic saline, isotonic glucose, starch, lactose, or any other material commonly used in pharmaceuticals. and veterinary-medical antibacterial compositions.

Another feature of the invention includes a method for inhibiting the growth of bacteria by applying to the bacteria's growth site an effective amount of the antibacterial compounds described herein. For example the method can be used in the treatment of antibacterial infections in animals by administering to the host an effective amount of an antibacterial compound according to the invention.

To make penicillanic acid or cephalosporanic acid derivatives

in

vatenc according to the formulas XVIII or, XXIV more suitable for febsorption in the body while maintaining the antibiotic effect, the conversion of the compounds with the formulas XVIII and XXIV, where U means -OH to special esters may be necessary. Preferred ester residues are e.g. those of the type: -CTL, - 0 - CO - V/, where W means an unsubstituted or substituted straight or branched alkyl radical with 1-3 carbon atoms, where the substituents are selected from lower alkoxy, lower alkylthio, halogen-lower-alkyl , phenyl,

cycloalkyl, ni tro, amino, guanidino, carboxy, carbalcoc&y, hy drok-■'. sew or halogen.

The new penicillanic acid and cephalosporanic acid derivatives according to the formulas XVIII and XXIV can also be used as growth promoters for ruminants such as cattle. They are also very useful for in vitro applications such as e.g. Disinfect e.g. ionizing agents (e.g. feeding bins) at a concentration of about 0.1-1 percent by weight of such compositions dissolved or suspended in a suitable inert carrier for use in washing or spraying. ->

Furthermore, some of the 3-substituted ε , 2,4-oxadlazol-g 5-yl-acetic acids according to formula I and especially 3-benzyl-1,2,4-oxadiazol-5-yl-acetic acid show an antiphlogistic effect.

The other derivatives according to the invention which are prepared using production methods known per se are those with the general formulas:

where Rlt R?, Zj_,<Z>2,<Z>3and Z^. as defined above, R^ means a hydrogen atom, a lower alkyl group, an aryl-lower-alkyl-or a cycloalkyl-lower-alpha-alkyl group, and Rg means a hydrogen atom or a lower alkyl-, phenyl-, a mononuclear 5-membered or 6-membered* heterocyclite, cycloalkyl* an aryl-lower-alkyl or cycloalkyl-lower-alkyl group where the phenyl and cycloalkyl groups are optionally substituted with at most one of the substituents as stated above, or where Rg means an amino group optionally substituted with lower alkylcarbonyl, arylcarbonyl, mononuclear heterocyclic carbonyl or lower alkoxycarbonyl, or where Rg and R^ together with the nitrogen atom to which they are attached mean a 5- to 7-membered mononuclear heterocyclic ring, such as soia norfolino or piperidino.

Compounds from the group of terminal ester and amide derivatives according to the formulas XII, XIII, XIV, and XXXV, XXXVI and XXXVII respectively, have also shown a depressant effect on the central nervous system and can be used as anticonvulsants, muscle relaxants and tremor antagonists" Furthermore, compounds from the classes of amide derivatives according to formulas XXXV, XXXVI and XXXVII have shown effects on some types of fungi, e.g. against Trichophyton and Microsp&rum races.

The invention shall be described in more detail with reference to the following illustrative examples.

. Example 1

Preparation of 5-methyl-1.2.4-oxadiazole-5-v-acetic acid

A solution of 4.0 g or 40.8 mmol of 3,5-dimethyl-1,2,4-oxadiazole and 6.0 ml of NjNjH* ^'-tetramethylethylenediaxnine (XNEDA) in 100 ml of dry toluene was prepared in a 250 ml . three-necked glass container equipped with a thermometer, a gas intake tube into which dry nitrogen was supplied continuously and a pressure equalizing dropping funnel. The magnetically stirred solution was cooled to -75°C using an acetone-carbon dioxide bath. Using a dropping funnel, a solution of approximately 40 mmol of n-butyllithium was obtained

in 20 ml of n-hexane added at a low rate to keep the temperature of the reaction mixture below -65°C. Then the reaction mixture was additionally stirred for 60 minutes at -55 to -60°C. Then, by means of a bent, ground glass tube, the reaction mixture was transferred to a second container containing powdered carbon dioxide covered with a layer of dry diethyl ether. After a couple

hour's delay, the carbon dioxide had practically disappeared from the mixture. 100 ml of water was added followed by the addition of IN

hydrochloric acid with stirring until a was obtained. pH value of 8. The layers were separated, the organic layer was discarded and the

aqueous layer bee shaken twice with 25 ml of diethyl ether. With IN hydrochloric acid, the pH value in the aqueous layer was brought to 2.0.

Seven extractions with approximately 25 ml portions of ethyl acetate at pH 2.0 resulted in an almost total removal of the desired product from the aqueous layer. The extracts were combined, dried over

anhydrous magnesium sulfate, filtered and the filtrate concentrated 1 vacuum to a small volume until the appearance of a crystalline,

white precipitate. When thin layer chromatography showed that the supernatant still contained a significant amount of the desired product and no byproducts, the solvent was hot removed in vacuo. The practically colorless residue was dried to constant weight. Yield 4.2 g (72$, purity: at least 96?6 (judged by thin layer chromatography and proton magnetic resonance spectrum).

Recrystallization of the product was carried out by dissolution in a minimal volume of chloroform, followed by slow addition of petroleum ether (boiling point 80 - U0°C) until a cloudiness appeared. Yield of 3-methyl-1,2,4-oxadiaz61-5-yl-acetic acid after recrystallization was 3.6 g, melting point 95°C (low decarboxylation occurred around 90°C). The pK value (determined in water) was 3.64 Elemental analysis:

Partial analysis of the IR spectrum (KBr disks, values in cnfr):<*>3450,

,1740, 1720, 1590, 1360, 1220. Thin layer chromatography: . Silica-dioxide south plate, eluent §n 10:2:1:0.2 volume mixture of diethyl ether, ethanol, water and formic acid. Drying by blowing hot air over the plate. Yellow spot (Rf value around 0.7) after 5 minutes 1 cylinder containing iodine crystals. Bluish stain after spraying with 1% starch solution in water.

Partial interpretation of the r,:asse spectrum:

Because the compound decarboxylates easily, the molecular the weight suggested as a rather weak molecular ion signal ( l<i>/ e = 142). The decarboxylation product, 3,5-dimethyl-1,2,4-oxadiazole was represented by M/e » 98. K/e 85, 59 and 57 presumably represent the fragments N=»CII2C00H, CHgCOOH and CH^CWO whose presence further proves the proposed structure.

The PMR spectrum of a solution of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in CDCl^ (60 Mc, δ values in ppm, tetramethylsilane as internal reference) showed signals at; 2.43 (s, 3H), 4.06 (a, 2H), 9.2 (s, about 1H).

Example 2

Preparation of 5-(2.6-dichlorophenyl)-1.2.4-oxadiazole-5-vl- acetic acid

To a solution of 10 g of 3-(2,6-dichlorophenyl)-5-methyl-1,2,4-oxadiazoi (melting point 83 - 85°C) and 6.4 ml of TKEDA in 140 ml of dry toluene was added dropwise a solution of an approximately equivalent amount of n-butyllithium in 22.2 ml of n-hexane (method analogous to that described in Example 1) over a period of about 30 minutes. The reaction temperature was -55 to -60°C. After stirring the reaction mixture for 1 additional hour at about -60°C, the mixture was added to powdered carbon dioxide covered with dry diethyl ether. After standing for a few hours, water and dilute hydrochloric acid were added until pH 8.0 was achieved. The layers were separated and the organic layer was extracted with 50

ml of water. The organic layer was discarded and the combined aqueous layers (about 300 mL) were washed twice with 100 mL of diethyl ether. Then the aqueous layer was extracted three times with 100 ml portions of diethyl ether at arrow 2.0. These extracts were combined, washed twice with a small amount of ice water and then evaporated in vacuo. The solid residue was stirred first with n-heptane and then with a small volume of toluene. After extensive drying in the desiccator, the final product weighed 7.6 g, corresponding to 63/S. The melting point was 124.5 - 125.5°C.

PMR (60 Kc>CDClj, tetramethylsilane as internal reference, values in ppm)

CH 2 : 4.09(s, 2H), CgH 2 : 7.45 (almost a singlet, 3H).

Example 3

Preparation of 3-(2.4.6-trimethylphenylphenyl)-1.2.4-oxadiazole-5-yl-acetic acid

Starting from 3-(2,4,6-trimethylphenyl)-5-methyl-1,2,4-oxadiazole with a melting point of 20 - 30°C, 3-(2,4,6-trimethylphenyl)-1, 2,4-oxadia2ol-5-yl-acetic acid prepared by the same method as described in example 2. A powerful mechanical stirrer was used in the reaction using n-butyllithium. Dividend 55.7$. Melting point 106 - 108°C.

IR (KBr discs, values in cm"<1>):<±>3450, 1740, 1720, 1608, 1590 and shoulder 1580, 1365 and 1240.

PI*JR (60 Mc, CDClj, tetramethylsilane as internal reference,w,i values ■'. in ppm): 213 (a,. 6H), 2.30 (s, 3H), 4.07 (s, 2H ), 6.92 (s, 2H).

Example 4

Preparation of 5- methyl- 1. 2. 4- oxadiazole- 5- acetic acid.

80 g or 0.816 M 3,5-dimethyl-1,2,4-oxadiazole and 240 ml or 1.6 K TMEDA were dissolved in 2050 ml dry toluene. The solution was cooled to -70°C, followed by the gradual addition of an approximately 20% strength solution (800 ml) of n-butyllithium in n-hexane (approximately 1.6-1.9 M). The degreasing rate was adjusted so that

- the reaction temperature varied between -60 and -65°C. Most of the addition time of about 70 minutes was taken up by the addition of the first equivalent of n-butyllithium. The reaction mixture was stirred for a further 60 minutes at -70°C. The mixture was then slowly reacted with a mixture of finely powdered carbon dioxide and dry diethyl ether. After standing for about 3 hours, 1 liter of water was added to the mixture of solid and liquid. The contents of the container were transferred to a separatory funnel. The aqueous layer was collected and when the solid was only partially dissolved, 250 ml of water was added to the mixture of salt and organic solvent. The mixture was shaken again and the aqueous layer added to the first extract. This was repeated until all solids had dissolved in water. The organic layer was discarded and the alkaline aqueous layer was washed three times with diethyl ether. Concentrated phosphoric acid was then added until a pH value of 2.0 was reached and the solution was concentrated in vacuo at 60°C to a volume of about 2 litres. During these working steps, the mixture of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 1,2,4-oxadiazole-3,5-diacetic acid (contaminated with very minor amounts of two or three unidentified by-products) already partially decarboxylated to 3,5-dimethyloxadiazole and

5-methyl-1,2,4-oc3adlazol-3-yl-acetic acid. The decarboxylation was completed by heating the acidic solution for 1 hour at a

steam bath. The majority of the desired product was extracted with three 300 ml portions of ethyl acetate. The residue was obtained by continuous extraction with diethyl ether (16 hours). They collected

organic layers were evaporated completely. The residue was dissolved in about 600 ml of diethyl ether, treated with activated carbon, filtered and evaporated completely. The partially solid residue of 54.6 g was subjected to column chromatography (length 38 cm, diameter 5.7 cm) over silica with diethyl ether mainly to remove valeric acid. A fraction of 1.6 g of an over 90$ pure $&&f§uct and an amount of

37.4 g of over 95% purity was obtained. The latter amount was calculated from toluene/n-heptane. Yield of 34.2 g or 29$ of 5-methyl-1,2,4-oxadia2ol-3-yl-acetic acid had at least 97% purity, calculated by thin layer chromatography and<P>NMR. Melting point 101 - 103°C (final melting point) - above 70°C sublimation, ■ melting occurred and the sample became solid again. pKa value (determined in water):

around 3.4.

Thin layer chromatography: Same system as used in example 1, Rf value around 0.25. The oxadiazol-3-yl-acetic acid is much less sensitive to the influence system than the isomer.

Analysis of the FMR spectrum of a solution of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid in CDCl^ and a drop of dg-DMSO (60 Mc,

α-values in ppm, tetramethylsilane as internal reference): 2.58

(s, 3H), 3.78 (s, 2H), 10 (s, about 1H).

Partial analysis of the IR spectrum (KBr discs, values in

cm"<1>): in 3450, 1740 and 1720, 1595, 1430, 1415, 1395, 1380, 1225-Analogously, but of course adapted to the individual case, other 1,2,4-oxadiazol-3-yl -acetic acids, e.g.: 5-bénzyl-1,2,4-oxadiazol-3-yl-acetic acid with melting point 109 - 111.5°C

By going out. From 13 g of 3-methyl-3-benzyl-1,2,4-oxadiazole, 5.8 g or 34# of pure compound were obtained. During the reaction, two equivalents of n-butyl lithium dissolved in n-hexane were added slowly to the solution of oxadiazole and two equivalents of TMEDA in toluene at -75 to -80°C. The resulting reaction mixture was additionally left undisturbed for 6 hours at -78°C and then poured onto finely powdered carbon dioxide. The reaction product was poured into about 600 ml of water, after which the pH value was brought to 7.0, the layers were separated and the organic layer was washed once with water. The solution in water was purified by continuous extraction with diethyl ether at pH 8*0 for 5 hours, acidified to pH.5.2 and then concentrated in vacuo to a volume pf* about 300 ml at about 45°C the pH value was brought to 7.0, followed by filtration under suction. the pH value. was brought to 1.8, after which continuous extraction with dichloromethane was carried out for 16 hours. The dissolution medium was removed and the residue dissolved in a minimal volume

water followed by extraction with a 1:1 mixture of diethyl ether and ethyl acetate at pH 1.8. The final extract was evaporated in vacuo and the residue crystallized from diethyl ether. As indicated earlier, the primary product (α-(5)-phenyl-1,2,4-oxadiazole-3,5-diyl-b<i>acetic acid) undergoes selective decarboxylation under relatively mild conditions. However, it was brought into experience that the

can also be obtained, by means *of extraction at room temperature, followed . of purification by column chromatography, etc. (see also remarks in example 39). IR (KBr disks, values in cm"<1>): 3400, 1725, 1580, 1495, i460,

1410, i380, 1330, 1225, 1190, 960, 940, 840, 820, 780, 730, 710. PRM (CDCl and a trace of dg-DMSO, 60 Mc, TI*IS, & values in ppm): 3»75 (p, 211), 4.21 (p, 2H)., 7.3 (p, 5H) about 8.9 (p, 1H). 5-etvl-l. 2, 4-oxadiazole-3-vl-acetic acid: melting point 58 - 60°C.

Starting from 89.6 g of 3-methyl-5-methyl-1,2,4-ox,adiazole, 28 g or 21% of the desired product was obtained. uncomplete,

in situ carboxylation of the primary product <x(5)-methyl-1,2,4-oxadiazole-3,5-diyl-bisacetic acid, a relatively stable compound. The reaction conditions were analogous to those described above, but the addition of the solution of n-butyllithium was extended over an 8 hour period. The container was then sealed and kept overnight at -78°C. 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 aqueous layer acidified to pH 2.0 and heated in a steam bath over the course of 3.5 hours. The pH value was brought to 3.0, after which the reading in water was concentrated in vacuo to about half the volume. Precipitated salts were removed by filtration and the filtrate (pli 8.0) subjected to continuous extraction with diethyl ether for about 5

thaws. Then pH values were brought to 5.0, followed by continuous extraction with n-pentane for 30 minutes. The solution in water was acidified to pH 2.5, saturated with sodium chloride and extracted 5 times with an equal volume of acetone. These extracts were combined and activated carbon was added, after which half of the volume was removed by distillation at atmospheric pressure. After filtration, the filtrate was evaporated and the residue subjected to column chromatography over silica with n-hexane/chloroform. The pure fractions were combined and evaporated in vacuo. The residual oil was dissolved in a small volume of ether and the solution was filtered and evaporated to dryness. The colorless oil solidified on standing. IR (ibidem): ± 3500 and<*>2600, 3000, - 2960, 1730, 1580, 1465, 1425, 1380, 1360, 1300, 1210 - 1230, 1190, 900, 825, 805, 725. PMR (CDClj, 60 Mc, TMS, £ values in ppm): 1.40 (t, J»7.5 eps, 3H),

292 (q, J=7.5 eps, 2H), 3.84 (s, 2H), about 8.6 (s, lH), from Example 5 L

Preparation of methyl-3-methyl-1.2.4-oxadia2ol-5-yl-acetate.

A solution of an excess of diazomethane in diethyl ether was added to a stirred, cold (about 2°C) solution of 14 g of 3-ethyl-1,2,4-oxadiazol-5-yl-acetic acid in 500 ml of diethyl ether. After the initially violent release of nitrogen had finished, the solution was concentrated on a steam bath to about 250 ml. The solution was washed three times with 100 ml of water. The washings were combined, adjusted to pH 9.0 and extracted with diethyl ether to obtain the portion of the product which was dissolved in water" during the washing. The combined ether extracts were filtered through a water-repellent paper filter and then evaporated in vacuo. After the residue was kept 1 hour at 8 mm Hg, the residual oil weighed 14.8 g. The yellow oil was distilled at 0.4 - 0.5 mm Hg. The combined fraction with a boiling point of 70 - 71°C consisted of methyl-3-methyl -1,2,4-Ocoadiazole-5-yi-acetate and weighed 12.3 g. nj^<5>",,1.4472. PMR (60 Kc, CDCl 3 , TMS, S values in ppm): 2 .38 (s, 3H), 3.76 (s, 3H), 3.99 (s, 2H).

IR (NaCl windows, values in cm"<1>): 3020, 2985, 2870, 1760 and 1600.

Example 6

Preparation of sodium DL- 6-/ Ta-fenvl- 3- methyl- 1. 2. 4- oxadiazol-5- yl)- acetaaido7- penicillanate

A solution of about 9 ml of n-butyl lithium in a

mixture of 4.5 ol n-hexane and 4.5 ol toluene at -95 to -90°C.

The resulting yellow liquid reaction mixture was further stirred for 50 minutes at -90°C. Then a solution of 2.6 g or 3.3 mmol of trimethylsilyl-6-isocyamtopenicillanate in tetrahydrofuran was slowly added dropwise and the actual ion temperature remained slightly above -90°C. After 30 minutes of further stirring at

-90°C, 1.2 ml of trimethylchlorosilane was added by means of a pipette. The resulting, still clear solution was stirred for a few minutes at about -80 C and then poured into 25 ml of ice water. A dilute sodium hydroxide solution was added until pH

7.0 had been reached. The layers were separated, the organic layer was discarded and the aqueous layer was shaken twice into 30 ml of diethyl ether.

The aqueous layer was acidified to pH 4.5, followed by three extractions with 20 ml of diethyl ether*

Additional. three extrgks^^raear^were carried out at pH

5 with 20 ml of ethyl acetate each time.

The acidic organic layers were combined, washed twice with a small volume of ice water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to about 5 mL. A slight excess of sodium α-ethyl capronate dissolved in a small volume of acetone was added cold. The resulting solution was treated with an excess of diethyl ether, which caused the precipitation of an essentially colorless solid. The solid was collected by <>filtration and washed repeatedly with cold, dry diethyl ether. Yield 760 mg. The product was somewhat contaminated with sodium urea-a.-ethyl capronate and contained about 2 mol of water. The D/L ratio was about 1:1.

Analysis of the PMR spectrum of a solution of the cneadable penicillin product in a d-dimethylsulfoxide (2 micro drops of DCOgD added, 60 Mc, 4/-values in ppm, 2,2-dimethylsilapentane-5-sulfonate as internal reference): 1 .46, 1.52, 156 and 1.62 (about 6HX, 2.34 (s, 3H), 4.22 (2 singlets,<«V>» 1.2 eps, 1H), ± 5.5 ( q-like,

2H), 5.67 (partially deuterated, broader singlet), 7.4 (5H), about 9.15.

Example 7

Preparation of 7-/ T5- benzvl- 1. 2. 4- ok3adiazol- 5- vl)- acetamido7-desacetoxvcefalosporansvre

To a solution of 1.74 g or 10 lamol of 3-benzyl-1-5-ethyl-1,2,4-oxadiazole, a mixture of 20 ral terr toluene and 5 ni t*dr tetrahydrofuran was added 1, 5 ml or 10 mmol TMEDA

after which the solution was cooled to -100°C. Then...a solution of about 10 mmol of n-butyllithium in 5 ml of n-hexane was added dropwise at -100 to -105°C and this was followed by further stirring for 1 hour at -100 ±5°C. A solution of 2.81 g or 9 mmol of triethylsilyl-7-isocyanato-desacetoxycephalosporanate in a mixture of 20 ml of toluene and 5 ml of tetrahydrofuran was added

drop by drop at a temperature below -95°C. The resulting reaction mixture was stirred for 90 minutes at -95°C and then, over about 15 minutes, the temperature was slowly raised to

-S5°C. The reaction mixture was then added to a well-stirred mixture of 25 ul of ice water and 25 ml of ethyl acetate. Diluted....hydrochloric acid was added at the same time to keep the pH near 4# After a few minutes of stirring, the pH was raised to .7.0 and the layers separated. The organic layer was discarded and the aqueous layer was extracted

twice with 80 ml of ethyl acetate at pH 6.5 and pH 6.0, respectively, which resulted in the removal of a by-product and a small amount of the desired product. The majority of the desired product was removed from the aqueous layer by six extractions with 40 ml of ethyl acetate at pH values gradually decreasing from 6.0 to 4.5» These extracts were combined, washed twice with a small volume of ice water, treated with .ed activated carbon, dried over anhydrous magnesiuEsulphate, filtered and evaporated completely in vacuo. The residue was triturated with diethyl ether, filtered using a suction pump, washed with cold ether and dried in vacuo.

The yield was 1.0 g or 25% of a colorless solid.

The purity of the final desacetoxycephalosporanic acid product was determined to be 90 - 95S* (thin layer chromatography and PMR).

IR (KBr archives, values in cm"<1>):<*>3500 and - 2600, 3280, 1780,

1720, 1670, 1590, 1550, 1495.

PMR (60 Mc, dg-DMSO, 2,2-dimethylsilapentane-5-sulfonate, ^-values in ppm): 2.06 (s, 3H), 3.5 (q, ^«17.5 eps, 2H) , 4.06 (s) and 4.10 (s) together 4-H,<±>5.1 (d, J»« 4.6 eps, 1H),<±>5.6 (q, J = 4.6 eps, J» 8.0 eps, 1H), 7.35 (s, 5H), 9.3 (d, J<»>^3.0 eps, 0.SH).

Example Q Preparation of N-phenyl-5-(2.4.6-trimethylphenyl)-1.2.4-oxadiazo_1-5-yl-acetaamide

(a) Preparation of an acidic chloride-like reactive melloanrofluct of 2.4.6-trimethylpheniyl)-1.2.4-oxadiazole-5-yl-acetic acid

A solution of 250 mg or 1 mmol of 3-(2,4,6-dimethyl-phenyl)-1,2,4-oxadiazol-5-yl-acetic acid, 0.005 ml of DIIF and 0.11 ml of pure thionyl chloride in 5 ml of carbon tetrachloride was refluxed under water-free conditions for 1 hour. Several samples were taken at different times. Carbon tetrachloride was removed, by blowing with dry nitrogen, over the samples. The residues were then dissolved in anhydrous chloroform and IR spectra were taken to investigate how the reaction progressed. It became clear that the reaction mixture should not be refluxed for more than 10 minutes (5 5 minutes is sufficient)* The reactive intermediate produced is not the acid chloride as such, but instead a reactive intermediate. This reactive intermediate nevertheless gave the desired amides in moderate yields by reaction with amines.

The empirically found changes in the IR spectra are as follows. The relevant features for a solution of the starting acid in chloroform are a monomeric OH at 3500, a dimeric OH at about 3000 - 3200, monomeric C«=0 (shoulder) at - 1760 and a dimeric C=0 at 1730 cm"<1> After three minutes of refluxing, both the 0H* signal and the C«0 signal at 1760 cm"<1> had completely disappeared. There remained a sharp and intone absorption at 1740• cm"1 representing the reactive compound. Reflux times of more than about 10 minutes result in the breakdown of the absorption at 1740 cm"1 and the appearance of at least four other absorptions between 1160 and 1800 cm , one of which (at 1790) possibly represents the correct acid chloride.

(b) Preparation of the anilide of 3-(2T4.6-triethylphenyl)-1.2.4-oxadiazol-5-yl-acetic acid

As indicated above, 1 mmol of the starting compound is treated with 0.11 ml of thionyl chloride in 5 ml of carbon tetrachloride in the presence of about 0.005 ul of dimethylformamide. The mixture was refluxed for 3 minutes. Then 0.3 ml of aniline was added, followed by 5 minutes of boiling. The mixture was evaporated in vacuo. To the residue was added 35 ml of toluene and 25 ml of water and further diluted hydrochloric acid until a pH value of 1.5 was reached.

After separation of the layers, the organic layer was washed with

20 ral 4N hydrochloric acid and then with 25 ml of water. The organic

layer was completely evaporated and the residue dissolved in ethanol and treated with activated carbon. The resulting colorless solution in ethanol was again evaporated and the colorless crystalline residue washed with n-heptane and dried in vacuo. IR and PMR spectra confirmed the structure.

PMR (60 Mc, CDClj + dg-DMSO, TMS as internal reference, 6 values

in ppm): 2P6 (s, 6H), 2.31 (s, 3H), 4.18 (s, 211), "about 5.1 (broad,, about 1H), 6.91 (s) and about 6.8 to 7»8 (multiplet) together 7H.

IR (KBr, values in cm"*1): 3300, 1660, 1600, 1580, 1545, .1.355 and 1240. Example 9 Preparation of 7-/T3-(2.4.6-trinethylphenyl)-1.2. 4- oxadia20l- 5- v3l-acetamido7- cephalosporan acid.

Starting from 9#7 mg or 3.66 mmol of 7-aminocephalosporanic acid (7-ACA) suspended in 20 ml of ethyl acetate, a mixture of a major proportion of 21,0-bis-triraethylsilyl-7-ACA and a smaller amount of trimethylsilyl-7-aminocephalosporanate in the usual manner by successively adding 1.02 ml or 7.32 mmol of triethylamine and 0.92 ral or 7.32 mmol of trimethylchlorosilane at 5°C, followed by 30 minutes of further stirring at 30°C . To the resulting reaction mixture was added 0.43 ral or 3.66 mmol of quinoline.

Meanwhile, 900 mg or 3.66 mmol of 3-(2,4,6-trimethylphenyl)-1,2,4-oxadiazol-5-yl-acetic acid9 had been converted into the reactant. tive intermediate according to the method described in Example SA, using 15 ml of dry carbon tetrachloride, 0.4 ml of thionyl chloride and about 0.02 ml of dimethylformamide. After 5 minutes of boiling at reflux, the purple solution was completely evaporated in vacuo and the residue was dissolved in 6 ml of tert ethyl acetate.

The resulting solution was added quickly to the first solution after it had again reached room temperature (around 20°C). Addition of the "acid chloride" caused a temperature rise of about 5°C. The reaction mixture was then stirred for 30 minutes at 30°C.

The reaction mixture was poured into 175 ml of ice water and

pli adjusted to 7.0. The layers were separated, the organic layer was discarded and the aqueous layer was washed twice with 50 ml portions of diethyl ether. The aqueous layer was brought to a pli value of 3.7 and then extracted four times with 25 nine parts of ethyl acetate. The extracts obtained were combined, washed with a small volume of ice water, treated with activated carbon, filtered, dried over anhydrous magnesium sulfate and filtered again using a suction pump. Total evaporation of the almost colorless filtrate and

extensive drying of the residue in vacuum gave 650 mg of solid product» This was according to thin-layer chromatography fifl. not completely pure, but the crude product was purified by column chromatography. However, the IR spectra of the crude product and the pure product were almost invisible.

IR (KBr disks, values in cm"<1>): - 3500 and - 2600, 3280, 1780, 1735, 1700, 1660, 1610, 1575, 1540, 1380 and/or 1355 and 1230•

(very intense).

Example 10 Preparation of 7-/T3-metvl-1.2.4-oxadia2ol-5-vl)-acetantido7-cephalosporanic acid

By. continuously to maintain dry conditions at

passing dry nitrogen over the surface of the liquid reaction mixture, a solution of 10 mmol of trimethylsilyl-7-iso.cyanato-cephalosporanate in 19 ml of toluene was added rapidly to a solution of 1.42 g or 10 mmol of impure (92 - 95% purity) and possibly some moist 3-methyl-1,2,4-oxadia2ol-5-yl-ethyl-acid in 25 ml of dry dichloromethane. The solution also contained 0.05 ml of N-vinylimidazole (catalyst). A relatively rapid reaction was indicated by the rapid evolution of carbon dioxide and by a rapidly formed precipitate which gradually dissolved during the further progress of the reaction. The precipitate was the poorly soluble mixed anhydride formed by addition of the carboxylic acid. to the isocyanate. Decomposition of the labile mixed anhydride mainly to the soluble trimethylsilyl ester of the desired cephalosporin and carbon dioxide is promoted and supported by the catalyst.

The release of carbon dioxide had practically ceased after 4 hours of stirring at room temperature. Dichloromethane was removed from the solution by concentration in vacuo. The remaining solution was slowly poured into a well-stirred mixture of 50 ml of ice water and 50 ml of ethyl acetate while at the same time diluted sodium hydroxide was added to maintain the pH value of 7.0. The layers were separated, the organic layer discarded and the aqueous layer repeatedly extracted with ethyl acetate, first at pH 5.5, and then with subsequent extractions at pH 5.0. 4.5, 4.0, 3.5 and finally at pH 3.0, to effect a separation between the desired product and the relatively smaller amount of the by-product N,N'-dlcephalosporanylurea. The extracts, from

pH 5.5 to 4.5 which only contained small amounts of the desired product and the aqueous layer from pH 3.0, which still contained some of this, was discarded. The extracts from pH 4.0 to pH 3.0

were combined, washed with a small volume of ice water, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was triturated with diethyl ether, filtered using a suction cup and washed with diethyl ether. After extensive drying in vacuum, the final crystalline solid weighed 2.3g, corresponding to a yield of approximately 55%. Because it contained a maximum of 5 mol?J> urea, the purity of the final product was over 90%, calculated by weight, according to thin layer chromatography and PMR....4

IR (KBr discs, values in cm""<1>):<*>3500 and 2600 , 3285, ,.1,780, 1740, shoulders at<*>1720 and 1710, 1390 and/or 1350, 1230.

PMR £60 Mc, dg-DHSO, 2,2-dimethylsilapentane-5-sulfonate as internal reference,£. -values in ppm): 2.05 (s, 3H), 2.34 (s, 3H),...3.6 (broad. s, 2H), 4.05 (s, 2H), 4.87 ( q, • 12.7 eps) and 5.2

(d, J « 4.7 eps) together. 3H, - 5.7 (q, J ■ 4.7 and J<1>= 8.2

eps, UT), i 9.3 (d, J' ■ 8.2 eps, about 0.8H).

Example 11

The following penicillins, cephalosporins and desacetoxy-cephalosporins were prepared by the method described in Example 10, starting from the appropriate 1,2,4-oxadiazoleacetic acid and the isocyanate of a trimethylsilyl ester of 6-aja[»penicillanic acid ( G-JPA) or 7-<p>ratnocephalosporanic acid or 7-e»na-desacet-oxycephalosporanic acid (7-jDCA): A. 6-^t3-(2,6-aichlorophenyl)-1,2,4-oxadiazole- 5-yl)-acetemido7-penicillanic acid, b. 6-^3-ethyl-1,2,4-ocBadiazol-5-yl)acetaraido7-penicillanic acid, sodium salt. R^O, C. 7- 1X3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-acetamido7-cephalosporanic acid, D. 7-^T5-methyl-1,2,4- oxadiazol-3-yl)acetamido7-cephalosporanoic acid, E. 7- 1X3-(2,6-dichlorophenyl)-1,2,4-oxadiazol-5-yl)-acetamido7-desacetoxycophalosporanoic acid, F* 7-^T3-methyl -1,2,4-oxadiazol-5-yl)acetamido7-desacetoxy-cephalosporanic acid, G. 6-^X3-e^l-1,2,4-oxadiazol-5-yl)acetamido7-penicillanic acidf sodium salt.HgO, II. DI^6-/α-me^l-(3-methyl-1#2f4-oxadiaxol-5-yl)~acetamido7-penicillanic acid, I. DL-7*^c-ethyl-(3-methyl-1,2 ,4-oxadiazol-5-yl)-acetamido7-cephalosporanic acid, K. DL-7-α-methyl-(3-ethyl-1,2,4-oxadiazol-5-yl)-acetamido7-cephalosporanic acid, L 7-[(3-ethyl-1,2,4-oxadazol-5-yl)-acetamido7-cephalosporanic acid and. M. &~ la-methyl-(3-ethyl-1, 2, Voxadiazol-5-yl)-acetanddo7-penicillanic acid, sodium salt.HgQ.

With a few exceptions, which are indicated below, all reactions were carried out at room temperature (around 20°C) with equimolar amounts of isocyanate and carboxylic acid and with 5-10 molSS of the catalyst N-vinylimidazole. The isocyanates of the trimethylsilyl esters of 6-APA and 7-ADCA were used in the solid state with a purity of over 901*. Triethylsilyl-7-isocyanato-cephalosporanate was used in the form of stable solutions of good quality in toluene down to predetermined contents.

For each example, the reaction medium, the approximate reaction time, some indication of the purity of the final product, the yield and the IR spectrum (KBr discs, values in cm"<1>) and/or the PMR spectrum (60 Mc, d (^-DKSO, 2,2-dimethylsilapentene-5-sulfonate as internal reference, t values in ppm). The isolation procedures were similar to that described in Example 10, but of course adapted to the individual compound. The indicated yields were obtained in all cases in the same way as in the first attempt. The yield figures therefore have no absolute value..„„.,

A. Dichloromethane, 2 hours, isocyanate in 10 mol# excess, light yellow crystals, purity at least 959(5, yield 90$ (calculated on the acid,

80% calculated on the isocyanate).

IR: .+ 3500 and 2600, 3300, 1780,<±>1730, 1630, 1530, 1560,<±>1540, 1430, 1330, 300 and 735.

PMR: 1.5 and. 1.65 (2 singlets, 6H), 4.5 (coinciding singlets, 3H), i* 5»6 (mulispot, 2H), 7.7 (narrow split monster, 3H), and 9.25 (d , j^8.5.eps, 0.8H).

B. Dichloromethane, 2 hours, colorless crystalline solid, pure

hot over 90tf, yield 5254.

IR: i 3350, + 3400 - 36OO, 1780, 1690, 1620,<±>1570, 1400, 1380

shoulder, 1350 slculder, 1330 and 1250.

PMR: 1.51 and 1.62 (2 singlets, 6h)t 2.35 (s, 3H), 4.07 (s, 2H), 4.2 (overlapping singlets,<*>3H), 5.45 (center of multiplet,

2H), 9.1 (d, J 8.5 eps, 0.8H).

C. Dichloromethane-toluene mixture, 6 hours, purity about 90%, yield 43#.

IR: i 3500 and - 2600, 3300, 1780, 1735, shoulders at i 1720 and

1700, 1680, 1580, 1560, i 1540, 1435, 1410 shoulder, 1380, 1350»1230 (very intense), 795 and 7B5.

PMR: 2.07 (s, 3H), .3.6 (broad s, 2K), 3.76, 4.29 (s, 2H), 4.92

(q, Jj\jB - 12.7 eps) and - 5.2 (d, J = 4.7 eps) in addition to 3H,

5.75 (q, J =4.7 and J' » 8.0 eps, 1H), 7.7 (narrow split pattern, 3H) and 9.45 (d, J' » 8.0 eps, 0, 81-1).

D. Dichloromethane-toluene-tetrahydrofuran mixture, 7 hours, purity

over 90?*, dividend 1052.

IR: in 3500 and in 2600, 3290, 1780, 1735, 1715, 1660, 1690, 1550, 1430, 1385, 1370 and 1240.

PMR: 2.05 (s, 3K), 2.58 (s, 3H), 3.6 (wide s, 2K), 3.76, 4.90

(q, = 12.7 eps) and - 5.15 (d, J = 4.7 eps) together 3H,

5.7 (q, J = 4.7 and J' 8.0 eps, 1H) and 9.2 (d, Jf = 8.0 eps, 0.8H).

E. Dichloromethane, 6 hours, catalysts: N-ynyl-imidazole and a trace amount of 4-methoxy-pyrlidine-K-oxide.lIi20, purity above. 95?é, yield over 90# (calculated on the acid, over 80% calculated on isocyanate-éb which was used in 10% excess).

IR: t 3500 and - 2600, 3300, 1778, - 1700 (broad, intense), 1580, 1560, 1540, 144Q, 1410 shoulder, 1380 shoulder, 1360,<±>1240, 800

and 790 shoulder.

PMR: 2.08 (s, 3H), 3.5 (q, «^^17.5 eps, 2H), 4.29 (s, 2H), i 5.15 (d, J = 4.5 eps , 1H), J 5.65 (q, J = 4.5 and J' = 8.0 eps, 1H), 7.7 (narrow split pattern, 3H) and 9.4 (d, J<*>8 .0Tcps, 0.9H).

F. Dichloromethane, 2 hours, purity at least 93?*, yield 68$.

IR: i'3500 and<±>2600, 3300, 1765, 1720, 1665, 1635, 1*95, 1550,

1435, 1400, 1370 (strong), 1345 and 1240.

PMR: 2.06 (s, 3H), 2.34 ( s, 3H), 3.5 (q, JAB^18 eps, 2H),

4.06 (s, 2H),<±>5.1 (d, J « 4.5 eps, 1H),<±>5.6 (q, J « 4.5 and J' = 3.0 eps, lii ) and 9.3 (J<1>= 8.0 eps, 0.9H).

G. Dichloromethane, 5 hours, colorless crystalline solid, purity at least 9055, yield 60#. IR: - 3450, * 3300, 1780, 1685, 1600, 1580 and 1560.

PMRi 1.25 (t, J * eps, 3H), 1.51 and 1.61 ( 2 singlets, 6H), 2.7 (q, J « 7.5 eps, 2H), 3.98, 4.03 ( s) and 4.08 (s) together around 5H, 5.45 (center of multiplet, 2H) and 9.1 (d, J^8.5 eps, 0.9H).

H. Dichloromethane, 2 hours, light colored solid, purity about 90#, yield 15#. PMR: about 1.4 to 1.7 (6 lines, 9H), 2.34 (s, 3H), 4.08 (2 singlets, £V=> 1.3 eps, 1H), 4.33 (q , J - 7.5 eps, 1H), about 5.2 to 5.6 (multiplet, 2H) and 9.1 ( 2 overlapping doublets, 0.811). I. Dichloromethane-toluene mixture, 9 hours, light colored solid,

purity about 90%, yield 40#. ^

IR: at 3500 and at 2600, 3290, 1780, 1740, shoulders at 1720 and 1700, 1660, 1580, 1550, 1230 (very intense.

PMR: 1.48, 1.50 and 1.62 (2 duplicates, £v^ 1.2 eps, J « 7.2 eps, 3H), 2.06 (s, 3H), 2.35 (fl, 3H), 3.6 (broad s, 2H), 4.25 (2 quartets, £v'=v 1.2 eps, J 7.2 eps, 1H), 4.90 (q, J/J3« 12 ,6 eps) and - 5.2 (2 doublets, £0^1,o eps, J « 4.8 eps) together 3K, i 5.65 (2 multiplets, III), 9.35 (2 doublets, £ v« 4 eps, Cf .es S eps, 0.83!). IC. Dichloromethane-toluene mixture, 10 hours, colorless solid, purity above 90%, yield 45$.

IR: - 3500, i 2600 , 3300, 1785, 1745, shoulders at 1725 and 1-705, 1660, 1535, 1560 and 1235 (very intense).

PMR: 1.4 (t, J * 7.5 eps, 3H), 1.55 (2 duplicates, 1.6 eps, J = 7.2 eps, 3H), 2.06 (s, 3H), 2 .75 (q, J = 7.5 eps, 2H), 4.25 (2 quartets, S V 1.2 eps, J = 7.2 eps, 1IJ), 3.6 (broad s, 2H), 4, 90 (q, J^ = 12.6 eps), - 5.15 (2 duplicates ^0»1.0eps,

J = 4.8 eps) together with 3H, r-.i 5.7 (2 raul tips, lii) and 9.35

(2 duplicates,£y>^3.5 eps, Jr «ss 8 eps, 0.8 H). L. Dichloroethane-toluene mixture, 9 hours, crystalline solid, purity conversion 95%, yield 60#.

IR: i 3500 and i 2600 , 3300, 1780, 1740, shoulders at 1720 «ig 1705, 1665, 1590, 1550 and * 1240 (very intense).

"PMR: 1.25 (5, J - 7.5 eps, 3H)t2.06 (s, 3K), 2.75 (q, J - 7.5.

eps, 211), 3.6 (broad s, 2H), 4.07 (s, 2K), 4.90 (q, J^ » 12.8 eps) and i 5.15 (d, J « 4, 7 eps) together 3H, ± 5.75 (q,. J « 4.7 eps and J<1>« 8.0 eps* 1H) and 9.35 (d,J1«8.0 eps, 0.8H ).

H. Dichloromethane, 4 hours, crystalline solid, purity about 95%, yield 30tf.

IR: i 3500, i 3350, 1735 and 1775, 1680,<±>1600, 1580 and<±>,1550. PMR: 1.25 (t, J m 7.5 eps, 3H), about 1.4 to 1.7 (6 lines, 9H), 2.75 (q, J «= 7.5 eps, 2H), 4.09 (2 singlets, = 1.7 eps, 1H), 4.34 (q, J 7.2 eps, 1H), about 5.2 to 5.6 (multiplet, 211) n and 9.1 ( 2 duplicates, 0.8H).

" Example 12

The following substituted 1,2,4-oxadiazol-5-yl-acetic acids were prepared by methods which were identical to or very analogous to the method used in examples 1 and 2 by reacting a slight excess of the 3,5 -disubstituted I,2,4-bxadiazole with the 1:1 complex of n-butyllithium with TMEDA

in a tolucn/n-hexane mixture (or alternatively with n-butyllithium in a tetrahyorofuran/n-hexane mixture) followed by reaction of the intermediate with solid carbon dioxide.

A. 3-benzyl-1,2,4-oxadiazol-5-yl-acetic acid..

B. 3-Ethyl-1,2,4-oxadiazol-5-yl-acetic acid

C. α-methyl-3-methyl-1,2,4-oxadiazol-5-yl-acetic acid

D. α-methyl-3-ethyl-1,2,4-ocgadiezol-5-yl-acetic acid

E. 3-Methoic Acid Tyl-1,2, 4-oxadiazol-5-yl-acetic acid.

For each product, given below is the original 1,2,4-oxadiazole, the Brings method for lithium, the solvent mixture, the reaction temperature and the approximate reaction time for the lithium introduction, some hints as to the purity of the end product, the melting point if it is a solid end product and The Irfc spectrum (KBr discs, values in cm"<1>) and/el|er the Pl"Jl spectrum

(60 Mc, CDClj, tetramethylsilane as internal reference, h values

1 ppm). The yield figures have no defined values as they are derived from the first or second attempt.

A. 3-Benzyl-5-methyl-1,2,4-oxadiazole, 6.95 g, n-butyllithium/THF-hexane, below -80°C, 80 minutes. Yield: crude product 4.3 g. After recrystallization from toluene (dissolved at 60°C) 3.6 g or 4l#. Melting point 106 - 109°C (during langsoB decarboxylation).

Purity above 96%.

IR: i 3430, 1730, 1585,<*>1600 shoulder, 1498, 1420, 1390, 13&5,

1300, 1248, 1230, 1215, 1165, 720 and 705. PMR: 3.67 (s, 211), 4.06 (a*2H), 7.27 (s,' 5H),~9.8 (s , around 1H). B. 22.4 g >ethyl-5-methyl-1,2,4-oxadiazole, n-butyllithium, TMEDA/

toluene-hexanoe, -70 to -80°C, 2 hours, yield 16 g or 50$, purity over 96%, mp 86 - 90°C (under slow decarboxylation), crystallization (not necessary) possible by dissolution in a minimal amount of a 2:1 mixture of carbon tetrachloride and

chloroform at about 45°C followed by slow addition of hexane. IR: ± 3440, 1730, 1715 and 1580.

PMR: 1.35 (*, J = 7.5 eps, 3H), 2.8 (q, J » 7.5 eps, 2H), 4.04

(s, 2H), ^10.4 (about 1H).

C. 22.4 g 3-ethyl-5-ethyl-1, 2,4-oxadiazole, n-butyllithium, TMEDA/toluene-hexane, -70 to 80°Cf 1.5 hours, yield 7 g or 22%,

x purity above 96flé, melting point 64.5 - 65°C (slow decarboxylation occurs at 57°C). IR: i 3450, ± 1730, 1600.

PMR: 1.70 (d, J = 7.5 eps, 3H), 2.41 (s, 3H), 4.16 (q, J - 7.5

eps, 1H), «—9.6 (s, about 1H).

D. 24.2 g of 3,5-diethyl-1,2,4-oxadiazoi, n-butyllithiura, TMEDA/toluene-hexane, -70 to -80°C, 3 hours, yield 18.1^ or about 53% , purity about 95% (contains a small amount of Valerian), melting point 30 - 32°C.

IR: i 3500,<±>2600, * 1740, 1580.

PMR: 1.35 (t, J « 7.5 eps, 3H), 1.70 (d, J = 7.5 eps, 311), .. 2.75

(q,<*>J - 7.5 eps, 2H), 4.6 (q, J 7.5 eps, 1H) and - 9.4 (s, about 1H).

E. 40 g of 3-methoxymethyl-5-methyl-1,2,4-olcsadiazole, n-butyllithium,

.TMEDA/toluene-hexane, -75 to -80°C, 150 minutes, yield 31.5 g or about purity above 96#, melting point: melting and extensive decarboxylation between about 50 and 75°C

IR: -<±>3450, 1725, 1590, 1410, 1395, 1360, 1335, 1325, 1240,

1210 (shoulder), 1195, 1170, 1005.

HIR: 3.45 (s, 211), 4.07 (a, 2H), 4.59 (s, 2H and 10.65 (scores around 1H).

Example 13

Preparation of sodium >»6- »/ T9- »methyl- l. 2. 4- oxadiazole-- 3- vl) acet-an. 1. do7»penicillanate

1.42 g or 10 mmol of 5-methyl-1,2,4-oxaliazol-3-yl-acetic acid was added to 20 ml of dry carbon tetrachloride. 1 ml thionyl chloride and 2 drops of dimethylformamide are added to the suspension at room temperature. The mixture was boiled for at least 10 minutes to obtain a clear solution and a complete conversion of the substituted acetic acid to the acid chloride.

At the same time, a suspension of 2.15 g or 10 mmol of 6-aminopenicillanic acid in 30 ml of dry ethyl acetate was treated with 2.8 ml or 20 mmol of triethylamine and 2.5 ml or 20 mmol of trimethylchlorosilane and then stirred for 30 minutes at room temperature .

To this mixture was first added 1.2 ml or 10 mmol of quinoline and then the solution of the acid chloride in carbon tetrachloride. The rapid addition of the dissolved acid chloride resulted in a temperature rise of about 10°C to about 30°C. The reaction mixture was further stirred for 30 minutes and then poured into 50 ml of ice water. The pH was adjusted to 7.0, the layers were separated, the organic layer was discarded and the aqueous layer was extracted once with 50 ml diethyl ether" To obtain the desired penicillin, the aqueous layer was extracted six times at pH 3.0 with a 1:1 mixture of diethyl ether and ethyl acetate. The organic layers were combined, washed twice with a small volume of ice water, treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of about 20 ml. 40 ml of diethyl ether was added and then a solution of sodium cc-ethyl capronate in ethyl acetate was added until no further precipitation occurred. The solid precipitate was collected on a suction filter, washed repeatedly with a 2:1 mixture of diethyl ether and ethyl acetate and finally with diethyl ether alone. After extensive drying in vacuum, the final product weighed 2.5 g.

The structure and high purity were confirmed by IR and PMR spectra. According to the PMR spectrum, the final product contained 1 mol

water per moles of penicillin.

IR: (KBr discs, values in ca"<1>): ± 3400, 1775, 1685, 1610,

1590, in 1540, 1390..

PMR: (60 Hc, dg-diethyl sulfoxide, 2,2-dimethylsilapentane-5-sulfonate as internal reference, £ values in ppm): 1.52, and lt62 (2 singlets, 6H), 2.58 (s, 3H ), 3.78 (s, 2H), 4.02 (s, lii), 5.45 (center of multiplet, 2H) and 3.9 (d, J «8.5 eps, 0.9H).

Example 14

Preparation of methyl-(c-phenyl)-3-methyl-1.2.4-oxadiazole-5-yl-acetate.

A mixture of 14 g or 80 mmol of 3-methyl-5-benzyl-1,2,4-oxadiazole and 14 ml of TMEDA in 140 ml of toluene was cooled to -65°C. A solution of about 75 mmol of n-butyllithium in 80 ml of a 1:1 mixture of n-hexane and toluene was added dropwise. The addition rate was adjusted so that a reaction temperature was obtained which varied between -60 and -70° C. The reaction mixture was stirred. for a further 2.5 hours at <-75°C and then poured into finely divided solid carbon dioxide. About 3 hours later, 120 ml of water and 120 ml of diethyl ether were added. The resulting bilayer QiSbem was treated with dilute hydrochloric acid until the vigorously stirred mixture had reached a pif value of 8.0. The layers were separated, the organic layer was discarded and the aqueous layer purified by three extractions with 30 ml portions of diethyl ether at pH .8.0.

The aqueous layer was mixed with 80 ml of ethyl acetate, cooled to below 0°C and cured with dilute hydrochloric acid to pH 3.0. The layers were separated and the aqueous layer extracted once more with 80 ml of ethyl acetate. The organic extracts were combined, washed once with a small volume of ice water and shaken for a few minutes with anhydrous magnesium sulfate. The salt was filtered by cold and

, the resulting colorless solution was treated carefully with a simultaneously prepared solution of diazomethane in diethyl ether (prepared in the usual way from 25.6 g of N-nitroso-N-methyl-p-toluenesulfonamide) • The solution of diazomethane in ether was distilled

.directly to the solution of the carboxylic acid 1 ethyl acetate. The reaction was continued until no further decolorization of the reaction mixture was noted. The resulting solution was decolorized directly with a small amount of acetic acid, washed three times with a small volume of neutral water, dried over anhydrous mag-

nesiuiasulphate, filtered and concentrated entirely in vacuo. The remaining oil weighed 10 g. This crude product was only slightly contaminated by the starting material. The pure product was obtained by distillation in vacuo (melting point 135°C at 0.8 mm Hg). Yield 6 g.

njp'5 : 1.5230 -IR: (KBr slices, values in ca"1): 1750, 1580, 1498, 1435 j A1390, 1340, 1270, 1220, 1160, 1010, 740 and 650.

PMR: (60 Mc, CDCl^, TMS, ^ values in ppm): 2.37 (s, 3H), 3.77 (s, 3H), 5.26 (s, 1H)", about 7.4 (narrow multiplet, 5H).

Example 15

Preparation of 5-methyl-1.2«4-oxadiazol-5-yl-acetamide

A mixture of 6.5 g of 5-methyl-1,2,3-oxadiazol-3-yl-acetic acid, 0.21 ml of diethyl formaldehyde, 4.6 al of thionyl chloride and 100

sl carbon tetrachloride was boiled gently for 12 minutes. The resulting brownish solution was added over 10 minutes to 100 al 259" of ammonia. During the addition, it was well stirred.' reaction mixture cooled by means of an ice-salt mixture. The reaction mixture was further stirred at room temperature for 1 hour.

20% hydrochloric acid was added until a pH value of 8.0 was reached. The layers were separated, the aqueous layer shaken once with 10 mL of carbon tetrachloride and the combined organic layers washed once with 10 mL of water. The organic layer was discarded and the combined aqueous layers evaporated in vacuo. The residue was subjected to continuous extraction with acetone for 16 hours. 7 g of a semi-solid brownish product was obtained. The majority of this product could be dissolved in dry ethyl acetate. This solution was again evaporated to dryness and the residue dissolved in ethanol, treated

with activated carbon and evaporated again. The solid residue was dissolved in warm acetone followed by the addition of n-hexane until the solution became cloudy. After standing for several hours at room temperature and finally at 0°C, the crystals were filtered off using a suction pipe, washed with a cold 9:1 mixture of n-hexane and acetone and dried in vacuum. The lightly colored final product weighed 4.8 g, which was equivalent to 72?. Melting point 112 - 114°C.

IR: (KBr disks, values in cm"<1>): 3380 and 3220, 1680, 1630, 1590, 1420, 1380, 1270, 1185 and 895.

PMR: (60 Kc, dg-diethyl sulfoxide, 2,2-dimethylsilapentane-5-sulfonate, .-values, in ppm): 2.58 (s, 3H), 3.60 (s, 2H), 7.1 and 7.6 (.centers in broad absorptions, around 2H).

Example 16

Preparation of ractvl- 5- methyl- 1. 2. 4- oxadiazole- 3- vl- acetate

In the same way as described in example 10, 10 g of impure 5-methyl-1/2,4-oxao-a-ol-3-yl-acetic acid were converted to the methyl ester by reaction with diazomethane. Yield 5.9 g, boiling point 70 - 72°C at 0.6 - 0.7 mm Hg, n^* 1.4495

IR (NaCl windows, values in cm<*>"<1>): 3020, 29Q0, 2865, 1750, 1595. PMR: (60 Mc, CDCl,, TMS, -values in ppm): 2.59 (s , 3H), 3.73

(p, 3H), 3.80 (p/ffl).

Example 17

Preparation of cyclohexyl-5-methyl-1.2.4-oxadiazol-3-yl-acetate 8 g or 56.3 nmol of 5-aotyl-1,2,4-oc3adiazol-3-yl-acetic acid was suspended in 8 g or 80 mmol of undistilled dry cyclohexanol. Under anhydrous conditions, 8g or 52f5mmol of phosphorus oxychloride was added dropwise over about 7 minutes to the mixture. During the addition, the mixture was heated on a water bath. The heating continued for 45 minutes". After

that the reaction mixture had reached room temperature became 75 ral of ice water

and 50 ml of diethyl ether added. The mixture was stirred until

a clear two-layer system had been achieved. The flask was placed on a ls salt bath and solid potassium hydroxide was added until pH 10.5

had been achieved. The layers were separated and the aqueous layer was extracted three times with 40 ml portions of diethyl ether. The four ether extracts were combined, washed once with a small volume of ice water and then concentrated in vacuo. The residue of 10 g was distilled in vacuo. Yield 7.9 g" corresponding to 62%, boiling point 120 - 121°C at 0.9 - 3.0 mm Hg. njp « 1.4715

IR (NaCl windows, values in cm"<1>): 2960 and 2880, 1-740 and 1595. PMR (60 Mc, CDClj, TMS,.& values in ppm): about 1.05 to 2.2 (broad, 10H), 2.58 (s, 3H), 3.-75 (s, 2H) and about 4.35 (broad, ' lii).

In a similar way, it was e.g. prepared cyclopentyl-5-ethyl-1,2,4-oxadiazol-3-yl-acetate in a yield of 43?S by

from 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid and cyclopentanol:

Boiling point 108°C at 0.5 billion Hg. n^<50>* 1.469.

■Ig (WaCl windows, values in cm"<1>): 3000, 2915 (shoulder), 1755, 1600, 1430, 1400, 1350, 1280, 1220 - 1240, 1185, 1060, 1000. PMR (CDC15, 60 Mc, TMS, o values in ppm): 1.39 (t, J « 7.5 eps).

and from about 1.5 to 2.2 shows 11K, 2.91 (q, J 7.5 eps, 211), 5.76 (c, 2H), about 5.25 (center of multiplet, 1H).

Example 18

Preparation of 7-/ T5- methyl- I. 2. 4- oxa<iazol- 3- vl) acetamido7- 5-azldometvl- 3- cefet^ 4- carboxylic acid

A mixture of 0.71 g or 5 mmol of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid, 0.5 ml of thionyl chloride, 1 drop of diethylform amld and 10 ml of dry carbon tetrachloride was boiled gently for 13 minutes" Under anhydrous conditions, the dissolution medium was removed in vacuo

and the colored residue dissolved in 10 ral of dry ethyl acetate.

Meanwhile, 1.39 ml of triethylamine and 1.26 ml of trimethylchlorosilane were added successively to a suspension of 1.225 g or 4.8 mmol of 7-amino-3-α;adomethyl-3-cephem-4-carboxylic acid (prepared according to D. Y /illner, The Journal of Antibiotics, Vol. 25 (No. 1), 64 (January 1972)). in 12.5 al ethyl acetate. The mixture was stirred for 45 minutes at room temperature and then cooled to -0°C and then 0.66 ml quinoline and

the prepared solution of the acid chloride in ethyl acetate. After

After 5 minutes, the ice bath was removed and the reaction mixture was stirred

a further 60 minutes at room temperature. The reaction mixture was poured into a well-stirred ice-cold mixture of 50 ml water and 40 ml ethyl acetate at arrow 2.0. The pH was brought to 7.0 and the layers were separated. The organic layer was discarded and the aqueous layer extracted once with 50 ml of ethyl acetate. The aqueous phase was purified once more by extraction with 50 µl ethyl acetate at pH 6.0 and then extracted six times with 50 ml volumes of ethyl acetate successively at pH 5.0, 4.0 (twice), 3.5 (twice times) and 1.0. These extracts were combined, centrifuged to remove any insoluble solids, washed twice with a litho volume of ice water, treated with activated carbon. dried over* anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was triturated with diethyl ether, filtered using a suction pump, washed with diethyl ether and dried in vacuo to constant weight. Yield 1.17 g corresponding to 64#. The final product consisted of about 90 Jo of the desired compound and about 10? of the corresponding ~ y -cephem deriv.

IR: (KBr discs, values in cm"<1>):<*>3450 and<£>2600, -£9i*H 3305, 2L35,. 1790, 1710, 1660, 1585 and 1540.

PMR: (dg-dimethyl sulfoxide, 60 I c, 2,2-dimethylsilapentane-5-sulfonate, 6 values in ppm): 2.50 (2, 3H), 3.3 to 3.95 (q, ^ ^16.3

eps), 576 (s) and about 3.8 to 4.6 (q, J^g =13.1 eps) together 6H, ± 5^?(d, J - 4.7 eps, 1H),<± >5.75* (q, J = 4.7 eps, J' 8.3 eps, 1H) and 9.3 (d, J" = 8.3 eps, 0.9K).

Example 19

Preparation of the R-sulfoxide of 7-/T5-netyl-1.2.4-oxadiagol-5-yl)acet6mid<y- 5- a2ldomethvl-5-cepheia-4- carboxylic acid

A solution of 730 mg or 2 mmol of 7-(5-methyl-1,2,3-ox-azol-3-yl)acetamido-3-azidomethyl-3-cephem-4-carboxylic acid

(prepared according to the method indicated in Example 18)

in 20 ml of anhydrous tetrahydrofuran (THF) was cooled to -75°C. To this solution was added at -70 to -75°C a solution of 400 mg or 2.5 mmol of N,N-dildorurethane (ClgKCOgCgl^) in 7 .5 ml anhydrous TIJF. The resulting reaction mixture was stirred for 1 hour at -70 to -75°C and then poured into a well-stirred mixture.

of 300 ml of ice water and 200 ml of ethyl acetate. The layers were separated

. at pH 1.7 and the aqueous layer extracted three times with 200 ml volumes of ethyl acetate. The four ethyl acetate layers were combined and washed twice with 100 ml volumes of a saturated solution of sodium chloride in water. Because the original aqueous layer still contained the desired product according to thin layer chromatography, it was combined with the 200 ml water used for washing of the organic layer.The combined aqueous layers were acidified to pH 1.7 and then extracted twice with 100

ml volumes of n-butanol. The butanol extracts were combined, washed with a small volume of ice water and evaporated to dryness in vacuo. This predicted yield was 110 mg.

The ethyl acetate layer was mixed with 100 ml of water and then sodium bicarbonate was added to give a pH value of 7/5. The layers were separated and the ethyl acetate layer was extracted twice more with 50 ral volumes of water. The ethyl acetate layer was discarded, the three aqueous layers were combined, mixed with 500 ml of ethyl acetate and acidified to pH 1.7. The layers were separated and the aqueous layer was extracted two more times at pH 1.7 into 100 mL volumes of ethyl acetate and once with 100 mL volumes of ethyl acetate at pH 1.0. The aqueous layer was discarded and the combined ethyl acetate layer was dried over anhydrous magnesium sulfate. , filtered and concentrated in vacuo to a small volume after which a second yield was obtained by precipitation by addition of n-hexane. Yield 148 mg. The IR spectra of the two yields were virtually identical.

Total yield £53 mg equivalent to 35S*.

- IR (KBr spoons, values in cm"<1>): * 3450, 3300 , 2550, 2130,

1790, 1720, 1680, i 1655 (shoulder), 1590, 1540, 1040.

GKR (dg-DMSO, CO lic,0 values in ppm, DSS as reference): 2.58

(s, 3H), 3.75 (s) and 4.0 (center in about 0.8 ppm wide AB-q,

- J es 16.5)eps) and 4.2 (center in about 0.55 wide AB-q, J^13»5eps) together 6H, 4.85 (d, J <* 4.6 eps, IK) , 5.7 (q, J = 4.6

cps and J' ~ 8.0 eps, 1H)" 9.7 (d, J" c-.8.0 eps, about 0.8H).

Example 20

Manufacturing; of ??-/ T5- metvl) isolcsazol- 5- vl7- 3- metvl- l. 2. 4^ oxadiazole-5- vl- acetamide

The procedure used below is essentially

"just stated in "Houben-Weyi, Methoden der 0rgani3Chen Cheraié1*, vol. 11/2, pages 5 and 6.

7.8 g or 0.055. mol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid was dissolved in 80 ml of a dry solvent mixture consisting of equal parts dioxane and toluene by volume." To this solution 6.9 g were successively added or 0.07 mol of 5-methyl-3-anino-isoxazole dissolved in 50 ml of the same mixture of dioxane and toluene and 4.2 g or 0.031 noi of phosphorus trichloride (PCl-). After the addition of PCl^ the mixture became lukewarm and cfet a deposit of a heavy yellowish oil was noted. Within a very short time crystallization of the oil occurred and the mixture was heated for 5 minutes to 90°C on a steam bath. The mixture was then stirred for an additional 60 minutes at room temperature

and then evaporated in vacuo. The residue was suspended in 80 ml of water. The acidic suspension (pH 1.5) was heated for 60 minutes

on the steam bath to decarboxylate residual oxadiazolyl acetic acid. The suspension was cooled and continuously extracted for 16 hours

with dichloromethane. It achieved. extract was cooled to room temperature and the resulting mixture of crystals and solution was completely evaporated. The crystalline residue was dissolved in a slight excess of dichloromethane. The resulting solution was slowly cooled to room temperature and then to 3°C, -15°C and finally to -70°C. The crystals were filtered quickly using a 3-week

pump, washed with dichloromethane at a temperature of -70°C and finally with n-heptane. After drying in vacuum, the product weighed 10.45 g (85.755, yield calculated on the amount of 3-ethyl-1,2,4-oxadiazol-5-yl-acetic acid used). Melting point 191 - 193°C. IR (KBr disks, values in cm"<1>): 3240, 3290, 1715 1650, 1605, 1585, 1500, 1450, 1365, 1280, 1220, 1045, 940, 900, 750 and 650.

PMR (about 4:1 mixture of CDCl^ and dg-BMSO, 60 Mc, $ values in ppm, TMS as reference): (s) and narrow d together at 2.4 (6ll), 4.1 (s , 2H), 6.58 (narrow q, 1H), 10.5 (somewhat wide s, IK).

Example 21

Preparation of 3- metvI- 1. 2. 4- oxadiazole- 5- vl- acetamld

The method used is an adaptation of the transgenic soy described in "Ifouben-Veyl, Methoden der Organischen Chemie", volume 11/2, pp. 5 and 6.

8 g or 0.056 M of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid was dissolved at room temperature in 150 ml of a dry solvent mixture consisting of equal parts by volume of dioxane and toluene. At room temperature, 3.5 g of dry, gaseous ammonia was added to the solution, which resulted in precipitation of the ammonium salt of the oxadiazolyl acetic acid in the form of a white thick slurry. While gaseous ammonia was added slowly below the surface of the vigorously stirred mixture, a solution of 4 g or 0.029 mol of phosphorus trichloride in 150 ml of the same solvent mixture of dioxane and toluene was added over 10 minutes. During the addition, the mixture became lukewarm and acquired a yellowish color, after which the reaction mixture was heated to about 90°C on

a steam bath for 5 minutes. The reaction mixture was further stirred for 60 minutes at room temperature and then completely evaporated in vacuo. The residue was dissolved in 75 ml of water and the resulting acidic solution (pH 2.0) was heated for 60 minutes on the steam bath. The solution was cooled to room temperature, saturated with sodium chloride and extracted continuously for 16 times with dichloromethane. The extract obtained was completely evaporated leaving a crystalline residue which resisted several recrystallization attempts from different solvents. Therefore, the residue was filtered through a short silica column using diethyl ether. Ethers were removed

and the residue recrystallized from a 9:1 mixture of diethyl ether and di-

. chloromethane using stepwise cooling of the solution from '

room temperature down to -70°C (the crystals were washed with very cold diethyl ether). Yield 5.1 g corresponding to 64.5?*. Melting point 77 - 77.5°C

IR (KBr discs, values in cm""<1>): 3180,<±>3240, 1685,<*>1635,

1595, 1445 (s), 1425, 1400, 1360, 1315, 1270, 1260, 1180, 1060, 890, 730 and 635.

PMR (CDCl₂ and a trace of d₂-DISO, 60 Mc, f. values in ppm, TMS as reference): 2.40 (s, 3H), 3.88 (s, 2H), . * 6.6 and.i 7.2 (centers for two broad absorption ions, around 2H)....:

Example 22

Preparation of 3- methyl- 1. 2. 4- oxadia2ol- 5- vl- acetmorpholide

The method used is an adaptation of the method which is* stated in "Houben-Veyl, Methoden dor organischenCheraie", volume 11/2, pages 5 and 6.

To a mechanically stirred solution of 7.8 g or 0.055 mol of 3-netyl-1,2,4-oxadiazol-5-yl-acetic acid in a dry mixture of 50 ml of dioxane and toluene, prepared at room temperature, was added 12, 3 g or 0.014 mol of freshly distilled morpholine. After a few minutes of stirring, a thick precipitate of the morpholine salt of the oxadiazolyl acetic acid occurred. To the vigorously stirred © suspension, 4.2 g or 0.031 mol of phosphorus trichloride was added at once, resulting in a thick yellow slurry and in a significant rise in temperature. Shortly after the addition...' of PCI, the reaction mixture was heated for 5 minutes to about 90 C on a steam bath and then stirred for 60 minutes at room temperature. The reaction mixture was completely evaporated in vacuo. The residue was dissolved in 75 ml of water, the solution at pH 1.5 was heated for 60 minutes on the steam bath and then saturated with sodium chloride at room temperature. The solution in water was continuously extracted with dichloromethane for 16 hours, the extract obtained evaporated and the residue first recrystallized from carbon tetrachloride and then from toluene, and then the hot solution was treated with activated carbon. The resulting colorless crystalline product was dried in vacuo. Yield 8.1 g corresponding to 69.5%. Melting point 79 - 80.5°C. Elemental analysis:

0: 22.76 0: (22.84)

IR (KBr discs, values in cm"<1>): 1650, 1595, 1450, 1595, 1240, 1130, 1045, 865, 2980, 2940, 2g65, 1470 (shoulder), 1420, 1370 (.shoulder)i 1350, 1310, 1290, 1280, 1180, 1080, 1030 (shoulder), 935, 920, 900, 840 (shoulder), 770, 715, 680.

PMR (CDClj, 220 Mc, .^ values in ppm, TMS as reference): 2.4/

(s, 3H), 3.54 (center of 3 or 4 lines, 2H), from 3.62 to

3.73 (at least 9 lines, 6H), 4.02 (s, 2H) Example 23

Preparation of Nt-(fur-2-ylcarponyl)-3- methyl«- 1. 2. 4.- oxa-'

di aaol- 5- we- acethvdrazld

Approach! which was used is an adaptation of the method stated in<M>Houben-Weyl, Methoden der ...Organischen Chemie", volume 11/2, pages 5 and 6.

Under water-free conditions and forced mechanical stirring

to a solution of 6 g or 0.042 mol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in a mixture of 50 ml of dry dioxane and 50 ml of toluene added six-sequentially at room temperature 5 g or 0.063

moles of pyridine and 6.3. g or 0.05 moi of fur-2-ylcarbonylhydrazide.

To the resulting clear solution was added at once 3.4 g or 0.025 mol of phosphorus trichloride. A heavy yellow oil is produced which quickly became fact. The reaction mixture was then heated for 5 minutes to about 90°C on a steam bath, followed by further stirring at room temperature for 60 minutes. The reaction mixture was evaporated in vacuo and the residue suspended in 75 ml of water.

The acidic suspension at pH 2.0 was heated for 60 minutes on the steam bath, which resulted in a clear yellow solution. After cooling the solution to room temperature, crystallization occurred

of a yellowish solid. This product was isolated by filtration using a suction pump and washed in ice water. The weight was 7.2 g. The product was recrystallized from acetone using stepwise cooling down to about -20°C. Yield 5.1 g corresponding to approx. 46% of a light yellow crystalline solid with a purity of about 95% according to thin layer chromatography and PMR. Melting point 169 - 171°C.

IR (K3r-sleiver, values in cm<*>"<1>): ± 3180, 1700 and 1675, 1620,

in 1590, in 1570, in 1510, 1480, 1435, 1205, 945 and 790.

PMR (dg-DMSO, 60 Mc, values in ppm, DSS as reference): 2.36

in

(s, 3H)f4.04 (s, 211), 6.65 (q, J = 3.6 and J<»>- 1.7 eps, l!l),

7.25 (q, J <= 3.6 and J" = 0.7 eps, 111), 7.9 (q, J<*>= 1.7 and J» 0.7 eps, 1H), 10 .35 (s, about 1.8H).

Example 24

Preparation of K'-(ethoxycarbonyl)-5-methyl-1.2.4-oxadlazole-3-yl-acethydrazide

The procedure that was used is an adaptation of the procedure stated in "Houben-V/eyl, Iléthoden der Organischen Cnende<1>*, volume 11/2, pages 5 and 6.

Under anhydrous conditions and with vigorous mechanical stirring, 6.7 ml or 0.079 mol of pyridine, 5.9 g or 0.056 mol of ethoxycarbonylhydrazide and 2.58 ml or 0.03 ole of phosphorus trichloride were successively added to a solution of 8.0 g or 0.056 mol of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid in a mixture of 50 ml of dioxane and 50 ml of toluene at room temperature. The resulting mixture was stirred at room temperature for 90 minutes and then evaporated to dryness in vacuo. The residue was dissolved in 50 ml of ice water, the pH value of the solution (0.8) was raised to 3.0, followed by continuous extraction with dichloromethane for 16 hours. The resulting solution in dichloromethane was completely evaporated, resulting in 13 g of partially crystalline residue. The residue was triturated with n-hexane and then collected by filtration using a pump. The light yellow crystalline product weighed 12.2 g. It was crystallized from a toluene/ethanol mixture cooled to 5°C. The first yield of pure product weighed 9.4 g corresponding to 73.2% and had a melting point of 122 - 123°C The filtrate from the first crystallization was completely evaporated in vacuo and the residue was dissolved in a mixture of dichloromethane and diethyl ether. Cooling this solution to -30°C crystallized part of the product. The crystals were collected by filtration using a pump at room temperature and washed with cold diethyl ether. Yield 1.0 g corresponding to 7.Q%. Melting point 121.5 - 123.5°C. Total yield 10.4 g corresponding to Bl%.

Based on the product's behavior and based on the obtained IR

and PMR spectra, it is concluded that the compound can exist in at least two different forms.

IR spectra (values in a<*>"<1>):

First yield: KBr disks: 3320 and 3250 (equally intense), 3065, 2935, 2945, 1738 and 1660 (equally intense),<*>1640 (r shoulders), 1595, 1560, 1495, 1450 (shoulders), 1415, 1395, 1360, 1305, 1270 (shoulder), 1255.

.Other yields: KBr slices: 3310 (shoulder), 3210 (very intense), 3060, 2985, 1760 (shoulder), 1735 and 1710, 1660 (shoulder), i 1630 (very intense), 1590, 1560 (shoulder) , 1500, 1475, 1445 (siwlder), 1413, 1395,<1340, 1300 (shoulder), 1230, 1255.

IR spectra for solutions in CHClj were identical: 3400,. about .

3280 (broad), 1750, 1710, 1650 (shoulder), 1590, 1480, 1390, 1370. PMR spectra for. the compound dissolved in dg-DHSO (60 Mc, % values

1 ppm, DSS as internal reference) also showed the presence of tautomers: 1.18 (t, J « 7.0 eps, 3M), 2.57 (s, 3H), 3.63 (slightly broad s, 2H), around 4.05 (center of complex absorption containing a large quartet (J ■ j?,0 eps), 2H), about 9.0 (broad s, about 0.75H), about 9.3 (broad s, about 0.15H) and 9.3 (slightly broad s, around 0.75H).

Example 25

Preparation of (4-bromo)phenyl-3-methyl-1.2.4-oxadiazol-5-yl-acetate

Under anhydrous conditions, 6 g or 0.042 moi of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid, 7.3 g or 0.043 raol of 4-bromo-phenyl and 3.6 ml or 0.042 mol of pyridine were dissolved 1 a mixture of 25 ml dioxane and 25 ml toluene. 2 ml or 0.024 mol of phosphorus trichloride was added whereby it. stirred tea mixture became lukewarm. The mixture was stirred overnight at room temperature. The supernatant liquid was decanted from the precipitate. The precipitate was washed twice with 10 µl portions of a 1:1 mixture of dioxane and toluene. Vackevsskeno was added to the decanted solution, after which the solution raidle holt was evaporated in vacuo. The slightly moist crystalline residue weighed 12.3 g. It was dissolved in 15.0 ml of diethyl ether. This solution was washed three times with a total of 75 ml of water and then evaporated completely. The residue weighed 10.8 g. It was dissolved in a boiling mixture of diethyl ether and n-pentane, after which the solution was gradually cooled down to -15°C. The precipitated crystals were collected by filtration, washed with a cold mixture of diethyl ether and pentane of about 1:1 and finally dried, in vacuo. Yield 8.0 g corresponding to 64.5$. The final product melted at 73 - 74°C.

IR (KBr disks, values in cm"<1>): 1745, 1535, 1480, 1440, 1400, 1370, 1335, 1290, 1210, 1180 (shoulder), 1165, 840, 770, 705, 630. Fl « R (CDC1-, 60 Mc, values in ppia, HIS soia internal reference): 2.41 (s, 3H), 4.16 (s, 211), about 6.85. to 7.65 (typical AA' BB' splitting pattern, 4H).

Example 26

Preparation of Sec. butvl- 5- methyl- 1. 2. 4- oxadiazole- 5- vl- acetate

Essentially as described in Example 17, 12 g of phosphorus oxychloride was added slowly to a mixture of 12 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 8.9 g of dry sec.butanol. The addition rate was adjusted so that the reaction operator was

65 - 5°C. The resulting reaction mixture was stirred for a further 90 minutes at 65°C and then treated in the same manner as described in Example 17. The product was distilled at 68°C

and 1.5 mm Hg. Yield 6.1 g corresponding to 35?'. The purity of the final product was about 955*. njj= 1.438.

IR (NaCl windows, values in cm""1): 3000 , 2960, 2900, 1745, 1600. PMR (60 Mc, CDCl 3 , TMS, £ values in ppm): 0.9 (triplet-like, J - 7.0 eps, 3H), 1.25 (d, J - 6.3'eps, 3H), about 1.55 (quin-dense-like, 2U), 2.40 (s,. 3H), 3.93 (s, 2H), 4.93 (regular six-tight, J » 6.2 eps, 1H).

Example 27

Preparation of benzyl-3-methyl-1.2.4-oxadiazol-5-yl-acetate

Essentially as described in example 17 was

8 g of phosphorus oxychloride added slowly to a mixture of 8 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 6.2 g of dry benzyl alcohol. The addition rate was adjusted to achieve a reaction temperature of 40-45°C. The resulting reaction mixture was further stirred for 5 hours at 40°C and then worked up in the usual manner. The yellow oil obtained was subjected to carbon chromatography over silica, using n-hexane and 3:1-hexane/toluene, 1:1-toluene/hexane, 3:1-toluene/hexane mixtures, toluene and finally a 3: 1-toluene/diethyl ether mixture as elution agent. The finally obtained colorless oil weighed 6.1 g corresponding to 47vi. The purity was about 955=6 according to thin layer chromatography and PMR. nj<p>=1.518.

IR (llaCl windows, values in cm"<1>): 1745, 1590, 1500, 1395, 1355, 1200, 750, 700.

PMR (60 Mc, CDCl,, TMS, ^ values in ppia): 2.35 (s, 3H), 3.93

(s, 2H), 5.17 ( sl 2H, 4.3 (5H).

Example 28

Preparation of 11-(2-chlorophenyl)-5-methyl-1.2.4-oxadiazole-5-11-acetamld

Essentially as described in Example 20, 1.65 mL of dry pyridine and 1.33 mL of 2-chloroaniline were added successively to a solution of 2.0 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in a mixture of 13 ml of dioxane and 13 ml of toluene. A precipitation of a viscous oil was noted. The reaction mixture was stirred for an additional 90 minutes at room temperature and then evaporated

to dryness. The residue was thoroughly stirred with 10 ml of ice-cold water, after which dichloromethane was added. The pH of the resulting clear bilayer system was 0.8. The pH was raised to 3.0 and the layers were separated. The aqueous layer was extracted four times with 25 mL volumes of dichloromethane. The five extracts were combined, washed with a small volume of ice water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was crystallized from carbon tetrachloride. Yield was 2.7 g or 77?$ of pure product.

Melting point 118.5 - 119.5°C.

IR (KBr discs, values in cm"<1>): 3260, 1660, 1590, 1535, 1480,

1440, 1295, 890, 870, 750, 680.

PHR (60 No, CDCl3, 'IMS, S values in ppm): 2.45 (s, 3H), 4.08

(s, 2H), about 6.85 t±l 7.5 (multiplet, 3H), 8.32 (q, J * 7.5 eps and J' 2.2 eps, 111), about 9.6 ( wide s, about 1H). Example 29 Preparation of M-monosubstituted 3-substituted 1.2.4-oxadiazol-5-yl-acetamides and of li-monosubstituted 5-substituted 1.2.4-okaa-dlazol-3-yl-acetamides. by suitably catalyzed reactions of 5(5)-substituted 1.2,4-oxadiazole-5-(3)-voladollic acids with isocyanates As an illustration of the wide applicability of the reaction, reaction and product details shall be given for the following examples:

A. N-propyl-α-(3-ethyl-1-1,2,4-oxadiazol-5-yl)propionamide

B. N-propon-3-yl-α-(3-ethyl-i,2,4-oxadlazol-5-yl)propionamide

C. α-(3-ethyl-1,2,4-okeadiazol-5-yl)propion-(4-chloro)anlide

D. N-(propen-3-yl)-3-benzyl-1,2,4-oxadiazol-5-yl-acetaniide

E. 5-Methyl-1,2,4-oxadiazol-3-yl-acet(4-chloro)anilide

F. 3-Methoxymethyl-1,2,4-oxadiazol-5-yl-acet(4-chloro)anilide.

Reactions of isocyanates with 1,2,4-oxadiazol-5-yl-

acetic acid was carried out at room temperature (around 20°C) using solvents such as dichloromethane, toluene, chlorobenzene, 3,5-dimethyl-1,2,4-oxadiazole, etc. The reactions with 1,2,4-oxadiazol-3-yl -the acetic acids are carried through in much the same way, but are completed by heating the reaction mixtures to around 60 - 100°C for 15 - 30 minutes. Unless otherwise stated, all reactions were catalyzed in the presence of 2-5 moles of M-vinyl-imidazole. The isocyanates used below were impure commercial samples. For this reason and also for other reasons such as volatility

for some of the isocyanates and accidental moisture in the 1,2,4-oxadiazoleacetic acids used, the isocyanates were used in excess

of 10 - 20 nol'1.

An extended description shall be given in Example A. For the other samples, the starting products, the reaction medium, the approximate reaction time, some hints regarding the purity and/or purification of the final products as well as the melting points and IR and/or FL1R spectra of the final products are given. The isolation method comprising separation of the desired amides from the by-products in the reaction -

(generally only relatively small amounts of 1,3-disubstituted urea and 1,2,.4-oxadiazole-acetic acid) and catalyst, was more or less equivalent to the isolation method indicated in example A, but of course adapted to the individual case. The yields were obtained in the first experiment. The dividend figures therefore have no absolute value.

A. Under anhydrous conditions, 17 mmol about 905' of pure α-(3-ethyl-1,2,4-oxadiazol-5-yl)propionic acid (= 3Tc^$&aethyl--1>2,4-oxadiazol-5- yl-acetic acid) dissolved in 40 ral toluene. Around 20.5

mmol of ri-propyl isocyanate and about 60 sg of catalyst (a saturated solution of 4-methoxy-pyridine-1-oxide. 12 O in N-vinyl-iniidazole) was added to the solution. While a slow stream of nitrogen was continuously passed over the surface, the realts ion mixture was stirred for 15.5 minutes at room temperature. The reaction mixture was evaporated in vacuo and the residue was dissolved in 1100 ml of a 1:1 mixture of ethyl acetate and diethyl ether. This solution was extracted four times at pH 2.0 with 10 ml of water. The combined acidic washings were extracted once into 10 ml ethyl acetate and discarded. The two organic layers were combined and extracted three cycles at pH 7.0 with 10 ml of water. The combined washing liquids were extracted once into 10 ml of ethyl acetate and discarded. The combined organic layers

was treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and evaporated completely in vacuo. The residue was stirred up in 20 ml of n-hexane, after which diethyl ether was added slowly until the solid was, so to speak, completely dissolved. After filtration, the solution was gradually cooled to -18°C. The crystalline precipitate was collected by filtration, washed repeatedly with n-hexane

and with very cold diethyl ether. The yield was 1.7 g, corresponding to around 50%. The purity of the final product was 95% according to thin layer chromatography and RIR. Melting point 52 - 53°C PMR (60 Mc, CDCl,, TMS, & values in ppm): 0.95 (triplet-like, J ss 7.0 eps, 3H), complex 8K absorption area from 1.2 to 1.75

consisting of a CH^ triplet at 1.35 (J"<=, 7.5 eps, a partially obscured CM2 multiplet and a CH^ doublet at 1.67 (J<M>=7.2 eps), 2.78 (q, J<*>sj 7.5 eps, 2H), 3.25 (quartet-like, medium 6.5 eps, 2H), 3.93 (q, J" ■ 7.2 eps, 1H) , about 6.8 (broad s, about 0.8H). B. α-(3-ethyl-1,2,4-oxadiazol-5-yl)propionic acid (20 mmol of about 90$ purity), allyl isocyanate (about 24 mmol), toluene, 3.5 hours, yield otter column chromatography 2.7 g corresponding to 64?£ pure product, melting point 70 - 71°C

IR (KBr discs, values in cm"<x>): 3280, 3070, 2980, 2940,. l£50, 1580, 1550, 1240, 990, 940, 890, 750, 685.

PMR (60 MC, CCl^, TMS, l values in ppm): 1.35 (t, J 7.5 eps, 3H), 1.6J, (d, J<»>= 7.2 eps, 3H) , 2.72 (q, J = 7.5 eps, 2H), about 3.65 to 4.1 (multiplet, 3H), about 4.9 to 5.35, . (multiplet, 2H), about 5.5 to 6.2 (multiplet, 1H), about. 7.1 (broad s, about 0.9H). C. α-(3-ethyl-1,2,4-oxadia2ol-5-yl)propionic acid (11.8 nuaol.., with about 90% purity), 4-chlorophenyl isocyanate (14 sasol), dichloromethane, about 50 mg of a saturated solution of 4-reethoxy-pyridine-1-oxide. 1 H 2 O in M-vinyl imidazole (catalyst), 4 hours, yield 1.85 g corresponding to about 60% of an at least 95% pure product by thin layer chromatography and PMR. Melting point 130 - 131°C (after crystallization from benzene).

IR (KBr slices, values in cm"1): 3260, 3190, 1675 (shoulder), .

1655, 1505, 1540, 1490, 1400, 1250, 840, 765.

IR (chloroform, values in cm"<1>): about 3400, about 3300, 1690, 1600, 1580, 1510 - 1550, 1495, 1395.

(the compound shows monomer/dimer features).

PMR (60 lic, CDC13, TMS, 8 values in ppm): 1.37 (t, J =*7.5 eps,

3H), 1.74 (d, J = 7.2 eps, 3H), 2.82 (q, J « 7.5 eps, 2Ii), 4.07 (q, J 7.2 eps, 1H), 7.38 (center of AA<*>BB<*>splitting pattern, 411), about 9.0 (broad s, about 0.9H). D. 3-Benzy1-1,2,4-oxadiazol-5-yl-acetic acid (10 mmol), allyl isocyanate, toluene, 3.5 hours, yield 1.54 g corresponding to 60 Jé of a

pure product crystallized from chloroform. Melting point 107.5 - 108.5°C.

IR (KBr discs, values in cm"<1>): 3290, 3100, 1655 and 1640 (shoulder),'.

1590, 1570, 1495, 1370, 1240, 1165, 1000, 735, 700.

PM^(60 Mc, CDClj, TMS, £ values in ppm): 6JI absorption area

from about 3.75 to about 4.15 consisting of a Ctlg singlet at 3.83, a CJig singlet at 4.06 and a CH2 multiplet, about 4.85 to about 5.35 (extended multiplet, 2H) , about 5.5 to 6.1 (extended multiplet, 1H), about 7.3 (CgH^) and about 7.1 (broad s) for a total of about 5.8 H.

E. 5-Methyl-1,2,4-oxadiazol-3-yl-acetic acid. (9.1 mmol), 4-chloro-phenylidocyanate (11 mmol), chlorobenzene, about 40 mg of a saturated solution of 4-methoxy-pyridine-1-oxide. 1HgO in N-vinyl-imidazole, 4 hours at room temperature and 15 minutes at or around 70°C, yield 1.56 g corresponding to 60% so-called pure product. Melting point 139 - 141°C.

IR (KBr disks, values in cm"<1>): 3255, 3195, 3130, 3075, .2950,. 1660, 1610, 1590, 1545, 1495, 1400, 1450, 1260 , 975 , 895,..840 ,

760, 710, 690i

PMR (60 Mc, CDCl 3 , TMS, i . -values in ppm): 2.66 (p, 31!), 3.85.

(p, 211), 7.35 (center of AA'B3' splitting monster, 4M), about 8.6 (broad s, circumference 0.8H) F. 3-methoxymethyl-1,2,4-oxadiazole-5 -yl-acetic acid (6.5 mmol), 4-chlorophenyl isocyanate (7.5 mmol), 3.5 hours, yield 1.4 g of an almost pure product. After crystallization from toluene 1.15 g corresponding to 63#. Melting point 114.5 - 115.5°C.

PMR (60 Mc, CDC15, TMS, i—values in ppm): 3.49 (s, 3H), 4.06 (s, 2H), 4.61 (s, 2K), 7.35 (center of AA <*>B3' splitting pattern, 4H), about 3.95 (wide s, about 0.811).

Example 30

Production of p. Nt-bis-(propen-3-vl)-1.2.4-dioxadiazol-5.5-yl-blacetamide

To a solution of 2 g or 10.7 omol of virtually pure 1,2,3-octadiazole-3,5-<y>1-bis-acetic acid in 15 ral of 3,5-dimethyl-1, 2,4 -oxadiazole, 40 mg of M-vinyl-imidazole was added, followed by dropwise, but rapid, addition of a solution of about 12 mmol of allyl lycocyanate in 10 ml of toluene. Under waterTrio conditions, the reaction mixture was stirred for 2 minutes at room temperature. Because a thinly related crocia bogram suggested only partial transformation of the output-. the product of three compounds, but mainly the bisamide, a solution of allyl isocyanate (about 10.5 mmol) in about 10 ral of toluene was once more added. After 4 hours of further stirring, the reaction mixture was mixed with 40 ml of ice-cold water. The pH value was brought to 7.0. A solid sediment (such as

(appearing to resemble a mixture of mainly bisamide and a minor amount of 1,3-bisallyl urea) was collected by pump filtration. The two layers of the filtrate were separated and the organic layer discarded. The remaining water layer which contained the ureaderl wad,. the unconverted starting product and the three reaction products were acidified to pH 2.0 and then extracted fifteen times with 20 ml volumes of ethyl acetate, resulting in total extraction of urea and bisamide, but only partial extraction of the other two reaction products. The precipitate was added to the combined extracts and the resulting solution completely evaporated in vacuo. The residue was subjected to column chromatography over silica with diethyl ether, mixtures of diethyl ether with increasing amounts of a 5:4 mixture of ethyl acetate and acetone and this mixture containing very small, ten increasing amounts of auric acid, as a cluering agent. A satisfactory separation of urea and bisamide was achieved, but separation of the bisamide from the two acidic nonoamides Cl elution order II-(propen-3-yl)-1,2,4-oxadiazol-5-yl-acetaiaid-3-yl -acetic acid and H-(propen-3-yl)-1,2,4-oxadiazol-3-yl-acetamid-5-yl-acetic acid) was somewhat less effective.

In an essentially pure state after crystallization from ethyl acetate, 1.3 g or 46$ of bisamide with melting point 170 - 172°C and 0.34 g or 149$ of H-(propen-3-yl)-1,2 were obtained ,4-oxadiazol-5-yl-acetanid-3-yl-acetic acid with a melting point of 97 - 98°C. ,..

IR bisamide (KBr slices, values in cm"<*1>): 3300 , 3185 , 2930, 1645, 1590, 1565, 1415, 1380, 1245, 990, 935, 755, 710.

PMR bisamide £60 Mc, dg-DMSO, DSS, - -values in ppm): 8H absorption area from about 3#5 to 4.05 consisting of a CH2 singlet at -3.67, a CI-J0 singlet at 3 .95 and a multiplet (two N-CII2 groups), about 4.9 to 5.4 (extended multiplet, 411), about 5.5 to 6.2 (extended multiplet, 2U), circ. 8.4 (circ. 1.311) . PMR byproduct (ibidem): 6H absorption area from about 3.6 to 4.1 consisting of a CHg singlet at 3.61, a CK2 singlet at 3.97 and a CUg multiplet, about 4.95 to 3, 4 (multiplet, 2H), circumference 5.55 to 6.25 (multiplet, 1H), circumference 8.5 (about 0.3H). On analogue, it must be e.g. prepared: 3-α-(4-fluorophenylcarbamyl)benzyl-1,2,4-oxadiazol-5-yl-acet(4-fluoro)anilide starting from 3-(α-carboxy)benzyl-1,2, 4-oxadiazol-5-yl-acetic acid and two equivalents of 4-fluorophenyl isocyanate in 4555

yield (crystallized with about 1 mole of water). Melting point 85 - 87°C (sublimation)

IR (KBr disks, values in cm"<1>): 3400 - 3500, about 5200 - 3300, 3150, 3075, 1670, 1620 - 1640, 1585, 1560, 1550 (shoulder), 1510, 1415, 1235 (shoulder ), 1225, 1165, 845. PMR (about 7:1-olanding of CDCl and dg-BMSO, 60 Mc, TMS, S' values in ppm): 4.06 (s, 2H), .5.35 (s , 1H), 6.95 (center of six-dense, similar absorption, apparent J values of 8.5 and 1.3 eps, 4!I), from ordering 7.2 to 7.7 (multiplets, 9H) .

Starting from 1.5 g or 8 mmol of 1,2,4-oxadiazole-3,5-diyl-bisacetic acid and about 14 mmol of 4-chlorophenyl isocyanate, 1.1 g or 35# of the bisanilide and 0 .8 g or 345' of 1,2,4-oxadiazol-3-yi-acetic acid~5-yl-(4-chloro)acetanilide. The bisanilide melted with decomposition at 240 - 247°C (decolorization at 220°C). Bit second product melted at 182 - 184°C. 1,2,4-oxadiazole-3,5-diyl-bis-acet(4-chloro)anilide: IR (KBr slices, values in cm"<1>): 3280, 3130, 3065, 1670, 1600, 1550 , 1500, 1415, 1390, 1355, 1325, 1295, 1265, 1235, 1190, 1100, 905, 855, 830, 770, 720, 700.

PMR (d<g>-DMSO, 60 Mc, DSS, & values in ppm): 3.95 (s, 2H), 4.23 (s, 211), about' 7.5 (center of typical AA' BB<f>splitting monster, 811), 10.5 (somewhat wide s) and 10.6 (ibidem) together about 1.8H. 1,2,4-oxadia201-3-yl-acetic acid-5-yl-(4-chloro)acetanilide: IR (KBr slices, values in cm"<1>): 3500,<*>2550 - 2650, 3265 , 3120, 3040, 2950, 1710, 1665, 1595, 1540, 1500, 1435, 1405, 1330, 1250, 1195, 1100, 850, 755..

PMR (dg-DMSO, 60 Mc, D3S,f> values in ppm): 3.83 (s, 2H), 4.22 (s, 2H), about 7.5 (center of AA'BB<*> splitting pattern,, 4H),

10.6 (somewhat wide s, about 0.9H).

Example ?1

Preparation of 7-/ 5- 0l^ propen- 3- vl) carbamovlmetvl- 1. 2. 4rToxadia- zol- 5- yl- acetamido7cephalosporanavre

To a suspension of 390 ml or 1.45 mmol of 7-amino-cephalosporanic acid in 8 ml of tert dichloromethane was added Q:*3tal

or 2.18 mmol triethylamine. Under anhydrous conditions, the mixture was stirred for about 5 minutes, after which 0.067 ml or 0.77 mmol of PCl 2 was added. The resulting suspension was stirred for about 5 minutes, followed by the addition of 327 mg or 1.5 mmol of 5-(M-propen-3-yl)-carbamoylmethyl-1,2,4-oxadiazol-3-yl-acetic acid suspension in 4 ml of dichloromethane. The resulting yellow reactive ion mixture was stirred at room temperature for 16 hours and then poured into 19 ml of ice-cold water, while at the same time dilute sodium hydroxide solution was added.

The layers were separated at pli 6.5. The organic layer was discarded and the aqueous layer extracted at pH 6.5, 5.0 and 4.0 with 25 mL volumes of ethyl acetate. These extracts were discarded. The remaining aqueous layer was further extracted at pH 3.8, 2.5 and 1.5 with 25 ml volumes of ethyl acetate. These extracts were combined, washed with a small volume of ice-cold water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to about 10 mL, which caused a precipitation of the desired product in

so and sl pure state in a yield of 250 mg.

IR (KBr disks, values in cm"<1>): 3550, * 2600, 3290, 3090,

3050 , 2950, 1780, 1740, 1720, 1660., 1585, 1545, 1420, 1385, 1355, 124Q.

PMR (60 Mc, about 4:1 mixture of dg-DMSO and DCOgD, DSS*o values in ppm): 2.06 (s, 3H), 8H absorption area from about 3.45 to about 4.15 consisting of^-CH^ absorption at about 3.6, a CUg singlet at 3.84, a CHg singlet at 3.97 and an N-CHg"" multiplet, 5H absorption area from about 4.6 to 5.4 consisting of an AB quartet at 4.63, 4.85 , 4.97 and 5.20 (J^g ^-12.8 eps), a doublet at 5.12 (J = 4.8 eps ) and a CH2 multiplet, a 2H absorption area from 5.55 to 6.1 consisting of a multiplet and

a doublet at 5»76 { J » 4.8 eps).

The spectrum in d^-DMSO alone showed a triplet-like NH absorption at 8.45 and an MH doublet (J « 8.0 eps) at 9.25 Example 52

Preparation of 7-/ B- benavl- 1. 2. 4- oxa^ azol- 3- yl- acetaiaido7-cephalosporansvre

In the same manner as described in Example 13, 1048 mg or 4 mmol of 5-benzyl 1-1,2,4-oxadiazol-3-yl-acetic acid was converted to the acid chloride using 12 ml of dry carbon tetrachloride,

6.4 ml of thionyl chloride and 2 drops of dimethylformamide. The solution was boiled gently for 15 minutes, ^<prpå->:; carbon tetrachloride was removed

in vacuo and the colored residue was dissolved in 5 al of dry ethyl acetate.

At the same time, a suspension of 1.088 g or 4 mmol of 7-aminocephalosporanic acid in 25 ml of dry ethyl acetate was treated with 1.14 ml or 8 mmol of triethylamine and 1.04 ml or 8 mmol of trimethylchlorosilane. After 30 minutes of stirring at room temperature, 0.47 al or .4 mmol quinoline was added and likewise the solution

of the acid chloride (dropwise). The reaction mixture was stirred. for another 30 minutes and then treated as usual. In the isolation procedure, the desired compound was obtained by extractions with ethyl acetate at pH values falling from 6*0 to 4.5. Yield was 1.35 g or 70# of practically pure product.

IR (KBr discs, values in cm"<1>)*. 3275, 3075, 2975, 3550 and * 2600, 1790, 1735, * 1700 (shoulder), 1675, 1640 (shoulder), 1580, 1555, . 1420 , 1390, 1285, 1250, 1220, 750, 715.

PMR (60 Mc, dg-DMSO, DSS, £ values in cm"<1>): 2.06 (s, 3H),<*>3.4 (widespread s, 2H), 3.79 (s, 2H), 4.34 (s, 2U), 4.60 to 5.17 (AB^, J * 12.4 eps) and i 5.1 (d, J = 4.8 eps) together 3H, - 5 ,7

(q, J » 4.8 and J' 8.2 eps, 1H), 7.35 (5H),<*>9.2 (d, 8.2

eps, about 0.8H).

Example 55

Preparation of amides by reaction of 1.2.^ oxadiazole-acetic acid with primary and secondary amines in the presence of phosphorus trichloride

The method described in example 23 and which uses amine, 1,2,4-oxadiazole-acetic acid and phosphorus trichloride in a 2.5:1:0.58 mol ratio was found to be very applicable in the preparation of amides when it concerns about secondary amines and primary amines. In particular, this method is applicable to

amines of a somewhat complicated nature, e.g. on those where the production of the isocyanates is difficult (e.g.* 4-amino-pyridine, .,.J2-amino-thiazole). For the purposes of the examples given, the reaction conditions were the same as described in Example 23, but the isolation procedure was adapted to the individual cases. It was found that the 60 minute heating of the solution of the reaction residue in acidic water as indicated in Example 25 is not necessary in general and should be excluded when sensitive amides are treated. when they were achieved in the first attempts.

A. N-(thiazol-2-yl)-3-ethyl-lt2,4-ofesadiazol-5-yl-acetaride

. B. N-(4-pyridyl)-3-methyl-1,2, 4-oxadiazol-5-yl-acetamide, hydrochloride salt C. N-methyl-N-phenyl-3-ethyl-1,2, 4-oxadiazol-5-yl-acetania

D. N,14-di(n)-butyl-3-phenyl%1-1,2,4-oxaMazol-5-yl-acetamide. A. Yield 76#, mp 170.5 - 171»5°C under sub.Hmering. . Isolated by assisted extraction with ethyl acetate; and crystallization from ethyl acetate.

IR (KBr slices, values iCH<rl>): 3300, 3200, 3090, 2980, 2940,

2880,<*>2760, 1680, 1600,(very intense), - 1570 (shoulder),

<*>1550 (slmlder,<±>1530 (shoulder), 1420, 1385 (shoulder), 1370, 1350, .1300, 1280, 1260, 1200, 1180, 1160, 965, 890, ± 830, .790, 750 .

PMR (about 6:1 mixture of CDCl^ and dg-DMSO, 60 Mc, TMS, & values in ppm): 1.3 (t, J » 7.5 eps, 3H), 2.75 (q, J 7.5 eps, 2H), 4.2 (s, 2H), i 6.9. (d, J » 3.5 eps, 1H), 7.4 (d, J » 3.5 eps, 1H), below 9 (very wide, about 1H). •

B. Yield 40$, mp 211 - 212°C during decomposition. Purification of the solution in water by washing with dichloromethane at pH 2.0. Extracted from water with dichloromethane at pH 6.0. Because the free base did not solidify easily, the residue was dissolved in acetone; -followed by the addition of 4N HCl. The isolated HCT salt was pure but somewhat moist.

IR (KBr disks, values in cm"<1>): 3220, - 3100 (slculder),

in 3020 (shoulder),<±>2950 to 25Q0, 1720, 1630, 1595, 1535,

1500 (shoulder), 1420, 1400, 1380, 1355, 1335, 1310, 1280, 1200, 1165, 840.

PMR (dg-DMSO, 60 Mc, DSS, £ values in ppm): 2.38 (s, 3H), 4.48

(p, 211), 8.1 to 8.85 (AA'HB? splitting pattern, 4H), 12, 6

(HH, somewhat wide s, about 0.9H)..

C, Yield 58?o, melting point 53°C. Because the obtained crude product did not stick so easily, it was subjected to column chromatography over silica using n-hexane, n-hexane/toluene mixtures, toluene and finally a 3':1 mixture of toluene and diethyl ether as eluent. The compound was subsequently crystallized from toluene/heptane.

Ili (KBr discs, values in cm"1): 3000, 2950, 16750, 1505, 1420, 1400, 1375, 1315, 1270, 1180, U35, 785, 720. PMR (CDCij, 60 Mc, TMS, S - values in ppm): 1.21 (t,. J - 7.5 eps, 3H), 2.73 (q, J - 7.5 eps, 2H), 3.33 (s, 311), 3.76 (s, 2IJ), 7.1 to 7.6 (multiplet, 5H).

D. Yield 65%, Oil. So to speak, pure raw product with profit left over

00%, purified by column chromatography over silica in the same manner as. described under C. IR (NaCl-vlnduer, values in. cm"<1>): 2965, .2885, 1655, 1595»1440 - 1480, 1400, 1360, 1305, 1230, 745.

PMR (CDClj, 60 Mc, £ values in ppm, TMS): from about 0.7 to about 1.9 (complex splitting pattern, 14H), 2.37 (s, 3H), about 3.1 to 3, 5 (multiplet, 411), 3.96 (p, 2H).

Example 34

Preparation of 7-/ 5- ethyl- 1. 2. 4- oxadiazole- 3- vl- acetamido7-cephalo sporansvre

Under anhydrous conditions, a mixture of 3.1 g or 20 mmol of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid, 2.2 ml of thionyl chloride, 2 microdrops of dimethylformamide and 60 ml of carbon tetrachloride was gently boiled for about 20 minutes. According to an IR spectrum, total conversion of the carboxylic acid to the acid chloride was achieved. The resulting solution was evaporated in vacuo and the residue was dissolved in 20 ml of ethyl acetate.

In the meantime, 5.6 ml of triethylamine was added at 10°C to a suspension of 5.44 g or 20 mmol of impure 7-aminocephalosporanic acid in 50 ml of ethyl acetate followed by the addition of 5.1 ml of trimethylchlorosilane. The mixture was stirred for 60 minutes at room temperature. . Then 2.36 ml of quinoline and the solution of the acid chloride were added dropwise. The reaction mixture was stirred for a further 30 minutes at room temperature. The contents of the flask were poured into 75 ral of ice-cold water. The pH was brought to 7.0, the layers were

. separated and the organic layer was discarded. Bone ash compound was removed from the aqueous layer by a number of oxtrax ions with 100 ml volumes of ethyl acetate at pH values that were gradually lowered from 5.0 to 2.0. The combined extracts were washed twice with small volumes of ice-cold water, once at pH 1.0 and once for 4 hours at pH 2.0. The extracts were treated with activated carbon, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to approximately 25 mL. The resulting crystalline precipitate was filtered by means of a pump, washed with 1/2 ethyl acetate and carbon tetrachloride and dried to constant moisture. Yield 5.9 g corresponding to around 70%. This product was of a purity of 90 - 9555-

The combined filtrates were evaporated in vacuo to give 1.3 g of some yellow material which was purified by repeated trituration with diethyl ether to give 0.63 g of additional product. According to thin-layer chromatograms and IR spectrum, this was the second yield of approximately the same purity.

1$ (KBr discs, values in cm"1): ± 3550 and<*>2600, 3290 , 3060, fl£«559> 2955, 1790, 1750, 1725, 1670, 1645 (shoulder), 1580, 1555,

1420, 1385, 1230, 1210 (shoulder), 750, 720.

PMR (dg-DMSO, 60 Mc, £ values in ppm, DSS): 1.30 (t, J « 7.5 Ops, 3H), 2.05 (s, 3H), 2.95 (q, J « 7.5 eps, 2H), 3.6 (widespread s,-2H), 3.77 (s, 211), 4.60 to about 5.25 (AB-q, J - 12.8 eps) and about 5.15 (d, J «* 4.8 eps) together .311, omlcring 5.25 (q,.. J * 4.8 eps and J<1>« 8.0 eps, Hi), 9, 2 (d, J<*>* .8.0 eps, about 0.8H),

In a common procedure, a solution of 5$ 7 g of the first yield in 250 ml of acetone was treated with a solution of an equivalent amount of sodium α-ethyl capronate dissolved in 12.5 ul of ethyl acetate. 5.3 S of the somewhat purer sodium salt of cephalosporin was obtained.

Example 35

Preparation of 7-/* 3- carboxymethyl- 1. 2. 4-- hTr3adiazol- 5- yl-acet-amido7cefalosT) orange acid

2.79 g or. 15 mmol of possibly some moist 1,2,4-oxadiazole-3,5-bis-acetic acid was dissolved in 20 ml of 3,5-dimethyl-1,2,4-oxadiazole. Under anhydrous© conditions, 0.05 ml of N-vinyl-imidazole

(catalyst) and a solution of 18 ramoles of triethylsilyl-T-iso-cyanatocephalosporanate added. This caused the precipitation of a small amount of a solid which was dissolved during the course of the reaction. The reaction mixture was stirred overnight at room temperature and then poured into a stirred mixture of 50 mL diethyl ether and 25 mL ice-cold water. The pll value was raised to 7.0 and

the layers were separated. The organic layer was discarded and the aqueous layer was extracted several times with 50 ml volumes of ethyl acetate at pH 5.0, 4.5 and 4.0. These extracts were discarded and the remaining aqueous layer was again extracted several times with 50 ml. volumes of ethyl acetate at pH 3.5, 3.0, 2.5 and 2.0. These extracts were combined and filtered using a pump to remove small amounts of precipitate (about 300 mg), which was discarded. The clear filtrate was partially decolorized using activated carbon and then evaporated in vacuo. The residue was dissolved in 200 ml of dry acetone. A concentrated solution of sodium α-ethyl caprionate was

added slowly until no further precipitation of solids occurred. The flask was kept at 3°C overnight. The solid was separated by filtration. It was washed with dry acetone and dried in vacuo to constant weight. The product weighed 6.2 g.

It contained the desired monosodium salt in an amount of 65% according to an HIR spectrum. 6.0 g of this product was dissolved in a

stirred mixture of 50 ml ethyl acetate and 50 ml ice-cold water* the pH value in the mixture was 3.5. The layers were separated. The colored organic layer contained a small amount of the desired product and was discarded. At pH 3.4 and pH 2.7, the remaining aqueous layer was extracted eight times with 50 ml volumes of ethyl acetate. These extracts were combined, treated with activated carbon, dried over anhydrous magnesium sulfate and completely evaporated in vacuo. The residue was repeatedly stirred with diethyl ether, filtered and dried in vacuo to constant weight. Yield 4.0 g. The purity of the product was estimated to be at least 85%. It contained no major by-product, but small amounts of about three impurities. This product could also be converted to its monosodium salt.

FER (dg-DMSO, 60 Me, DSS,' i values in ppm): 2.05 (s, 3H), 3.6

(slightly widespread s, 211), 3.81 (s, 2H), 4.09 (s, 2H), from 4.59 to about 5.2 (AB-q, J ■ 12.8 eps) and around 5 .15 (d, J - 4.8 eps) together 3H, about 5.7 (q, J = 4.8 ops and J<*>«s, 8.1 eps, III), 9.35 (d, J' es 8.1 eps, about 0.9H).

■- A

IR of the monosodium salt (KBr slices, values in cm"1): about 3500 and about 2500, about 330,<±>1770,. * 1740, 1720, 1690,

in 1610, in 1590, around 1550, 1420, 1390,<±>1360, around 1270, 1240. Example 56

Preparation of n-heptyl-3-methyl-1.2.4-oc8adiazole-5-yl-acetate Under anhydrous conditions, a stream of gaseous hydrochloric acid was passed through 25 ml of n-heptanol. As soon as a saturated solution was obtained at room temperature, 5.7 g or 0.04 mol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid was added. The addition of a slow-flow hydrochloric acid was continued for 2 hours. The reaction mixture was stirred for a further 60 hours at room temperature, whereby the conversion of carboxylic acid was essentially complete. The reaction mixture was mixed thoroughly with 75 ml of cold water. The layers were separated and the organic layer was washed three times with 10 ml volumes of a saturated solution of sodium bicarbonate in . water and twice with 10 ml of cold water. All aqueous layers were combined and extracted twice with 20 ml volumes of ethyl acetate. The combined ethyl acetate extracts were washed once with 10 ml of ice-cold water. The aqueous layers were discarded and the two organic layers combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was distilled and fractionated under reduced pressure. 6.8 g of the desired product were obtained with a purity of about 959% (impurity mainly a small amount of n-heptanol). Boiling point 108°C at 0.25 mm Hg. n|° • 1,450.

IR (NaCl windows, values in cm"<1>): 2940, 2860, 1745, 1590, 1465, 1440 (shoulder), 1395, 1350, 1290, ± 1250, 1200, 740.

PMR (CDClj, 60 Mc, TMS, S values in ppm): 0.88 (disordered triplet, 3H), from about 1.0 to 1.9 (broad absorption area, 10H), 2.38 (s, 5H) , 3.93 (s, 2H), 4.17 (t, J =6.4 eps, 2H).

The above-mentioned method is generally applicable in the preparation of primary alkyl esters of the rather sensitive but reactive 1,2,4-oxadia2ol-5-yl-acetic acids in yields of over 50%. E.g. gave esterification of the same oxadiazole-acetic acid with

a 2:1 technical mixture of 3-methyl-butanol-1 and dl-2-methyl-butanol-1 in 54# yielded a mixture of both esters in exactly the same ratio as they were present in the mixture of alkanols used.

Eczema! 57

Preparation of 7-/ 3- methoxymethyl- 1. 2. 4- oxadiazole- 5- vI- acetamido7-cephalosporanic acid

To a suspension of 6 g or 22 mmol of 7-amino-cephalosporanic acid in 100 ml of dry dichloromethane was added A.60 ml or 33 mmol of triethylamine under anhydrous conditions, the mixture was stirred for about 5 minutes, after which 0.96 ml or 11 .1 mmol of PCl was added. The resulting mixture was stirred for 5 minutes followed by the rapid addition of 4.0 g or 21.5 mmol of 3-methoxymethyl-1,2,4-oxadiazol-5-yl-acetic acid, partially dissolved in 60 ml of dry dichloromethane. The resulting reaction mixture was stirred

for 18.5 hours at room temperature. About 200 ml of ice water was added, immediately followed by the addition of 4N NaOH to a pH value of 7.2. The layers were separated. The aqueous layer was shaken twice with dichloromethane and once with 100 ml of ethyl acetate, after which the organic layers were discarded. The aqueous layer was acidified to pK 2.0 and extracted repeatedly with ethyl acetate. These extracts were combined, filtered through "Celite" and completely evaporated in vacuo. The residue was dissolved in 175 ml of acetone, treated with activated carbon, filtered through filter aid and evaporated again in vacuo to dryness. The light brown, crystalline residue was repeatedly stirred with dry dichloromethane, filtered using a pump and washed with dichloromethane and diethyl ether. After drying in vacuum, 3.5 g or 37% of essentially pure, so to speak, colorless product was obtained.

IR (KBr disks, values in cm"<1>):<*>3550 and<*>2550, 3235, 1780, 1740, 1715, 1660, 1630 (shoulder), 1580, 1540, 1410, 1380, 1350,

* .1250 (intense with shoulders), 1150, 1120, 1105, 1070, 1040, 725, 700.. PMR (dg-DMSO, 60 Mc, DSS, £ values in ppm): 2.06 (s, 3H) , 3.70 (s, 3H), 3.6 (slightly widespread s, 2H), 4.12 (s, 2H), a 5H absorption area comprising a CHg singlet, (at 4.56) an AB-q at 4.6

to 5.2 (Jtø12.8) and a doublet at about 5.15 (J = 4.7

eps and J' æ-8.2 eps, 1H).and 9.35 (d, J<*>8.2 eps, about 0.9H).

Example 38

Preparation of 7-/ 3- methyl- q- carbomethoxy-l. 2. 4- oxadiazole- 5- vl-acetamido7cef allosporanic acid

Using anhydrous conditions, a solution of 1.09 g or 7 grams of methyl-3-methyl-1,2,4-oxadazol-5-yl-acetate in . 15 ml of tetrahydrofuran cooled to -100°C, followed by dropwise addition addition of 3.3 dl of a 2.34 N solution (7.7 mmol) of n-butyllithium in n-hexane,. whereby the reaction temperature was kept below -90°C. The resulting solution was additionally stirred for 60 minutes at -90°C. A solution of 7 mmol of trimethylsilyl-7-iso-cyanatocephalosporanate in 9 ml of toluene was added dropwise at -<9->0

to -95°C. The resulting reaction mixture was additionally stirred for 45 minutes at temperatures which slowly rose to -75°C

With the simultaneous addition of 4N HCl, the reaction mixture was poured into a mixture of 25 ml of ice-cold water and 25 ml of diethyl ether. After the mixture had reached a constant pH of 4.0, the pH was raised to 7.0, after which the layers were separated and the organic layer discarded. The aqueous layer was extracted with 25 ml of ethyl acetate at pK 6.0 and the extract was discarded. The desired

cephalosporin (approximately 1:1 mixture of the D-form and the L-form) was obtained by repeated extraction of the aqueous layer with ethyl acetate

at pH 4.5 to 4.0. Yield 1.1 g (about 34%). The final product was contaminated with at least 5 mol% N 2 -dicephalosporanyl urea.

IT (KBr disks, values in cm"<1>): - 3500 and<±>2600, about 5150 to 3270, 2950, 1785, 174o, 1710 (shoulder), 1670, 1625, 1520 - 1560, 1440, 1425 (shoulders), 1390, 1360, 1300, 1240 (with shoulders),

1170, 1120, 1080, 1050, 805, 725.

PMR (about 3:1r mixture of .dg-DMSO and DCO^D, 60 Mc, DSS, ^-values in ppm): 2.07 (s, 3H), 2.33 (s, 3H, about 3.6 ( center of uopp!03t AB-q, 2H), 3.60 (s, 3H), from about 4.65 to 5.25 (Ab-q, J 13 eps) and 5.17 (center of doublet, J 4 .7 eps) ti Isammen 3H, 5.78 (center of doublet, J~4.5 eps, about 0.5H), 6.00 (center of doublet, J 4.7 eps, about 0.5H).

Due to yield phenomena Ca-K and K-H not visible in this spectrum. These signals appeared in the more complex spectrum of 1 dg-DMSO alone at 5.5 ppm (somewhat broad s, about 1H) and 9.55 ppm (doublets, about 0.8H).

By an analogous method, the following was prepared: 7-[3-methyl-α-(morpholinocarbonyl)-1,2,4-oxadiazol-5-yl-acetamido7-cephalosporanic acid starting from 3-methyl-1,2,4 -oxadiazql-5-yl-acet-ELorfolide, etc. (extraction of desired cephalosporins at pH 4.0 to 2.5 with ethyl acetate). Yield around 75% »

IR (ibidem): * 3500 and - 2600, about 3230 to 3330, - 3050,

. i 2980,<±>2940, £ 2370, 1785, - 1735, - 1700, 1640 - 1660, 1585, 1530 - 1555, 1450, 1390,-1240 (with shoulders), 1165,1125, 1080, 1045, 720.

PMR (about 4:1 mixture of dg-DM SO and DCOgD, 60 Mc, DSS, values in ppm): 2.05 (s, 3H), 2.39 (s, 3H), about 3.6 (10H ),

from about 4.65 to 5.2 (AB-q, J -13 eps) and 5.15 (d, J 4.6 eps) together 3H, 5.60 (d, 0.7 eps, about 0.2H ), 5.78 (center of 2 duplicates, J ^ 4.6 eps and f>\) c=; 1.2eps, 1H).

The complex spectrum of the compound in dg-DMSO alone showed a full Ca-PI singlet at 5.6 ppm and two superimposed NH doublets at 9.4 ppm (Jf^7.5 to 8.0 eps).

Example

Preparation of 1. 2. 4- oxadiazole- 3. 5- divl- acetic acid

Under anhydrous conditions, a solution of about 1 mol of n-butyllithium in n-hexane was added dropwise to a solution of 50 g or 0.51 mol of 3,5-dimethyl-1,2,4-oxadiazole and 150 ml or 1 moles of TMEDA in 1400 ml of toluene. In order to keep the reaction temperature between -7a and -76°C, the time period for the addition was extended to 105 minutes. The reaction mixture was additionally stirred for 90 minutes, at -73°C. The react ion mixture was poured into a mixture of finely powdered carbon dioxide. and a small volume of diethyl ether. After a few hours' standstill, the precipitate formed was collected by filtration through Etf glass filters and under a blanket of dry air. The filter cake was washed with ethyl acetate and diethyl ether. The solid was suspended in a mixture of 250 ral of distilled water and 10 ml of diethyl ether. Concentrated phosphoric acid was added slowly and carefully to the stirred suspension until a clear brown solution was obtained at arrow 2.0. The solution was saturated with sodium chloride, cooled externally with ice and extracted continuously with dichloromethane. At the beginning of this extraction, the water layer is heavier. The extraction was stopped after about 2 hours, when the two layers have became equally heavy. The organic extract containing much valeric acid, much 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid, a relatively small amount of re-stored product and also a significant proportion of the desired biacetic acid derivative was evaporated in vacuo. The remainder of 53 g which had partially solidified,

was stirred three times with 50 ml volumes of n-hexane containing

2% by volume of diethyl ether to remove any valeric acid present, which caused a slight loss of oxadiazole-acetic acids. The solid residue (product 1) was temporarily stored in a refrigerator. The remaining aqueous layer was placed in crushed ice and extracted continuously with diethyl ether until practically all 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid had been removed from the aqueous layer. However, in the ether extract there was also present a small amount of the unreacted product and a significant amount of the bisacetic acid derivative. The remaining amount of the biacetic acid derivative was completely removed from the cooled aqueous layer by continuous extraction tion with ethyl acetate at reduced pressure (ethyl acetate boils at 35 - 40°C). The resulting extract and the ether extract were combined and evaporated in vacuo. The remaining solid (product 2) was combined with product 1 and dissolved 1 in about 250 ml of water. To this solution were added a few drops of concentrated fbs-foric acid (to pH 2.0) and a small amount of sodium chloride. resolution- one was cooled with an ice bath during 18 hours of continuous extraction with dichloromethane (heavier than the aqueous layer). This practically pure extract of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid was evaporated in vacuo. The light yellow crystalline residue (product 4) weighed 27.5 g (about 37% of the 3,5-dimethyl-1,2,4-oxadiazole used). By recrystallization of the rate, 24.0 g of completely pure substance could be obtained.

The remaining aqueous layer from which 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid had been completely removed was subjected to continuous extraction with ethyl acetate as described above. The extract was treated with activated carbon and evaporated completely. The almost colorless crystalline residue weighed 23 g (product 5). To remove stored by-product, this residue was stirred up several times in a mixture of 60 ml of dichloromethane and 40 ml of ether. The undissolved, colorless crystalline mass was collected by filtration, washed with dichloromethane and n-hexane and dried to constant weight. Yield 18.9 g or 20% pure 1,2,4-oxadiazole-3,5-diyl-bisacetic acid with melting point 109 - 111°C (partial decarboxylation occurs from about 100°C).

IR (KBr disks, values in cm"<1>): very intense absorptions at

in 2900 - 3200, 1700 - 1720, 1430 and 1240. A number of others, smaller

intense absorptions at - 3400, 2500 - 2700, 1595, 1410 (shoulder), 1375, 1320, 1290, 1200, 1170, 945, 920,<±>890, 850, 730 occurred. PMR (about 1:1 mixture of CDCl and dg-DMSO, 60 Mc, TMs, - values in ppm): 3.75 (a, 2H), 4.02 (s, 2H), about 9 (broad s, about 211).

The stability of 1,2,4-oxadiazole-3,5-diyl-bisacetic acid: A small sample was dissolved in slightly moist diethyl ether. The solution was refluxed for about 24 hours. By means of thin layer chromatography it was found that less than 5% destruction of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid had occurred.

Remarks to reaks. loan conditions and 1 solas. Isolation methods for the production of 1.2.4-oxadiazole-5.5-divl-;bisacetic acids: The method described above is intended only as an illustration of the problems with regard to reaction conditions and isolation methods. It was found that the second lithium lnn bearing entering 1 a position lateral to C, in the oxadiazole ring in many cases. (if not further activating

substituents (such as phenyl) are present) occurs somewhat more slowly than the often very rapid and total first lithiation lateral to C^. In the above example, the second lithium input was not greater than at most 30-35% because no more than unimportant amounts of re-stored product were formed and the loss of biacetic acid was small, mainly or essentially exclusively due to non-optimized purification of product 5 (see above), because

the product of decarboxylation (5-methyl-1,2,4-oxadiazol-3-yl-acetic acid) could not be isolated or its presence suggested by thin-layer chromatography. The product balance suggested by the isolated reaction crude products (about 60%) suggests pronounced decarboxylation (under the conditions used in the isolation) of the product of single lithium introduction, thus of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid , which is significantly less stable than biacetic acid.

As shown in example 4, the degree of dilithium introduction can be increased. If this is applied to the present example, this can be achieved by proceeding from two alternatives. Firstly, the addition of the second equivalent of n-butyllithium as well as a short further stirring period can be carried out at a somewhat higher temperature (approx. -60 to -65°C). This procedure will on it

on the other hand also result in a somewhat more pronounced formation of re-stored product (re-stored products) as in the present case

will not impair a satisfactory isolation of the desired biacetic acid. Second, the further stirring period at low temperature can be significantly extended. Generally, it depends on the additional substitution quantity for the starting product 1,2,A-okGadiazole which yield-increasing method is possible or advantageous. Relatively lower reaction temperatures (approx

-75 tii -80°C) when adding the reagent and during the extended

a further stirring period is decisive in those cases where there is a significant risk of a more pronounced formation of redistribution products. This situation can exist in cases where both lithium introductions occur relatively slowly, thus generally when introduction of lithium laterally to C,- is slowed down. This occurs when the cy-substituent is not methyl, but a longer alkyl chain (e.g. ethyl).<.>

Double li tiumlnnf Earing often requires the use of a powerful agent. Therefore, often, but not generally, the very powerful complex n-butyllithium tTHEDA is the correct reagent. Other agents which are of a somewhat different nature and/or which are less reactive sometimes give better results, e.g. when 11 tium insertion lateral to C- is relatively easier. Such a situation exists when the Cj substituent is benzyl. Here, the use of diiso-propyl lithium amide results in a not far from quantitative isolation of the so-called pure dilithium salt of the corresponding bisacetic acid.

A correct isolation procedure is also an important feature for a successful production. Even if good conversion is carried out, isolations in correspondingly high yields are difficult to achieve because these biacetic acids are relatively strong acids and very soluble in water. Regardless of the fact that relatively speaking, these compounds are usually considerably more stable than one would expect, they can still be considered sensitive compounds. Therefore, a suitable isolation method is somewhat variable with regard to the substitution pattern and the composition of the reaction medium. As indicated in this example and in example k, there are two ways of treating the crude product obtained after the reaction with carbon dioxide. The reaction mixture as a whole can be mixed with water, but this usually requires a lot of water before dissolution is achieved and it also requires a number of manipulations afterwards which can be largely omitted if it is possible first by filtration to isolate the double lithium salt of bis- the acetic acid because in this case only a fraction of the volume of water is required to dissolve the double lithium salt. Depending on the individual case (the nature of bisacetic acid and the relative degree of its formation, the origin of the by-product(s) and the relative degree(s) of their formation as well as the nature of the reaction medium) it is often advantageous or necessary to subject solutions of the reaction product in water to a number of purification steps before the actual extraction of the biacetic acid is carried out. Such work steps can be concentrations in vacuum at pH values around 3 or 5»5 or continuous extractions with n-pentane at pli 5.0 to remove by-products or constituents such as valeric acid, TMEDA and diisopropylamine.

Taking such factors into consideration, a number of bls-acetic acids were prepared and isolated. Some data shall be given for two examples which also illustrate the possibility of having an additional substituent at one or both possible locations:

α-(5)-phenyl-1.2,4-oxadiazole-5. 5- divl- biseddiksvre

By proceeding from 3-benzyl-5-methyl-1,2,4-oxadiazpl and

using n-butyllithium/TMEDA the compound was obtained in a yield of 30% taking into account that the compound crystallized

with about 0.5 moles of diethyl ether. The product in this state is a solid at room temperature.

PMR (CDCT,. with a trace of dg-DMSO, 60 Mc, TMS, -i values in ppm): 3.9 (s, 2H), 5.3 (s, Hl), about 7.35 (center of a multiplet covering about 0.5 ppm, 5H), about 10.5 (somewhat broad s, 2H).

Further chemical evidence of this compound's structure was obtained by conversion to the corresponding dimethyl ester and to the corresponding bis-(4-fluoro)anilide.

g- ( 5)- carbomethokBY- l. 2. 4- oxadi g' zol- 5.5-di vi-bi seddiksvre

Starting from methyl-3-methyl-1,2,4-oxadiazol-5-yl-acetate and using n-butyllithium/TMEDA, the almost pure compound was isolated in a yield of about 25%. The product is a light yellow, hydroe:copic,. crystalline solid.

IR (KBr discs, values in cm"<1>): ± 3500, 2950 - 3130 (intense, 1710 - 1745 (very intense),.1600, 1450, 1245 (intense), 1420, 1390, 1330, 1210, 1180, 860, 743.

PMR (about 5:2 mixture of CDCl3 and d6-DKS0, 60 Mc,-TISS., i" values in ppm): 3.65 (s, 3H), 3.95 (s, 2H), about 7.1 ( asymmetrical, widespread s, circumference 3H).

Hulii^ens as a consequence of a presence of a small amount of water, present in the compound and/or in dg-DIIS0, due to its nature rather acidic C^-C^H is not noted separately, but is possibly switched so that the signal appears together with the C00H signals at low field.

Further chemical evidence of the structure was obtained by converting the bis-acetic acid to the corresponding bis(4-chloro)anilide.

Example 40

Production of 5-hydroxvmetvl- l. 2. 4- oxadiaaol- 5- vl- acetic acid

Using anhydrous conditions, a reading of approximately 1.2 mol of n-butyllithium in n-hexane was added dropwise over 3 hours to an effectively cooled solution of 66g or 0.58 mol of 3-hydroxymethyl-5-methylr1,2, 4-oxadiazole and 87 ml of N,!!,!!1 yl?1- ■

tetramethylethylenediamine in 1200 ml of tetrahydrofuran. During to-

. statement, the reaction temperature was not allowed to rise above -70°C. The reaction mixture was additionally stirred for 1 hour at -70°C. During effective cooling, gaseous carbon dioxide was dried

passed over the surface of the stirred reaction mixture for 10 hours at -70°C. The temperature was then allowed to rise gradually to -5°C. The precipitate formed was collected by filtration and washed with dry ethyl acetate and with n-hexane. The precipitate was dissolved slowly by addition in small portions to a stirred ice-cold mixture of 500 ml of water and 500 ml of diethyl ether. Concentrated phosphoric acid was added to pH 4.0; The layers were separated and, that. organic layers were discarded. The aqueous layer was further acidified to pH 2.0 and then evaporated in vacuo. Remaining water in the residue was removed in vacuo using benzene. The residue was dried in vacuum over phosphorus pentoxide for 16 hours. The syrupy product was stirred with 500 ml of acetone at about 35°C. The acetone was decanted. This was repeated once more after which the residue became a solid mass. The solid mass was transferred to a filter and repeatedly stirred with 500 ml portions of acetone until, according to thin-layer chromatograms, the desired product was not present in

the filtrate. All the filtrates were combined (total ca

4000 ml) and concentrated in vacuo to a volume of about 300 ml. 600 ml of ethyl acetate was added and the resulting solution was again concentrated in vacuo to a final volume of about 250 ml. The resulting crystalline precipitate was filtered using a pump, washed with dry ethyl acetate and with carbon tetrachloride. After drying in vacuo, 41 g was obtained. Melting and decomposition occurred between about 96 and 98°C. The filtrate was evaporated in vacuo. The oily residue was repeatedly stirred

. up with small volumes of dichloromethane. The resulting solid was transferred to a filter and washed with ethyl acetate and carbon tetrachloride. After drying, the second yield weighed 14.1 g. It melted with extensive decomposition at 92-96°C. According to thin-layer chromatograms, IR and PMR spectra, both yields were so

and say identical. Total yield 45.1 g corresponding to about 55%, purity about 96%. IR (KBr disks, values in cmT<1>): 3440, 1745, 1720, 1600, 1430,

1390, 1320, 1240, 1220 (shoulder), 1180, 1070, 1040, 7S0, 735, 650. PMR (about 6:1 mixture of CDCl3 and dg-TJMSO, 60 Mc, TMS,

values in ppm): 3.95 (s, 2H), 4.66 (s, 2H), about 7.5 (widespread s, about 2H).

Example 41 Preparation of natrlum-7-/5-etvl-1.2.4-oxadiazole-3-vl-acetamido7-5-/5-methyl-1.5.4-thiadlazole-2-vl-mercaptomethyl7-3- cephem- 4- carboxylate.

The conditions used were very similar to those that . is described in example 34. Starting from 1.55 g or 10 mmol of 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid and 3.44 g or 10 mmol of 7-amino-3-( 5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl)3-cephemyl-carboxylic acid with a purity of about 92%, 2.58 g of the so-called pure desired product were obtained.

During the isolation, the compound was removed from the water by a number of extractions with ethyl acetate between pH 5.0-pg pH 3.5. The combined extracts were washed with water at a pH of 1.0 and 2.5, decolorized with activated carbon and completely evaporated in vacuo. The remains weighed 3.2 g, corresponding to around 65%. Don was dissolved in a mixture of 65 ml of acetone and 250 ml of ethanol. A concentrated solution of 6 mmol sodium c-ethyl capronate i

ethyl acetate was added and the resulting solution was concentrated in vacuo to a volume of 50 ml. To the well-stirred solution, 100 ml of diethyl ether was added slowly. The precipitate formed was collected by filtration, washed with ether and dried in vacuo. ' IR (KBr disks, values in cm"<1>): ± 3450 (Hg0), 3280, 3050, 2985,

2940, 1765, 1680, 1610, 1580, 1550, 1415 (shoulder), 1390, 1370. PMR (dg-DMSO, 60 Mc, DSS,^ values in ppm): 1.28 (t, J * 7.5 eps,. 3H), 2.69 (s) and 2.93 (q, J * 7.5 eps) together 5H, about 3.6 (2M), 3.77 (s, 2H), from about 4, 25 to 4.7 (AB-q, J ^ 13 eps, 2H), 5.0 (d, J 4.9 eps, 1H), 5.55 (q, J~4.9 eps, J<»> 8.2 eps,. 1H), 9.2 (d, J<*>8.2 eps, about 1H).

Example 42

. Most of the penicillins and cephalosporins prepared according to the corresponding examples were tested for their antibiotic activity in vitro by means of an agar serial dilution test and/or in some cases by means of a microvérie dilution test. carried out as indicated below:

Å., Agar serial dilution test.

A stock solution of the compound at 2000 µg/ml is prepared in a sterile suitable vehicle. Twofold dilution takes place with the help of sterile 1/20 mol phosphate buffer pH 6.5 (KHgPOj-KaOH). 1 ml aliquots of each dilution are incorporated into a 19 ml brain-heart infusion agar in sterile Petri dishes. The hard surface is incubated with test organisms and incubated for 24 hours at 37°C.

B. Microserial dilution sample.

Two drops of a stock solution of the test compound (antibiotic) at a known concentration are introduced into the first hole of a 9 numbered well sample plate using a sterile Pasteur pipette. After rinsing this pipette three times with a physiological NaCl solution, two drops of a basic solution of the test organism in a culture medium were placed in all the holes, except for hole 8. In the first hole, the solution of the tested compound had been half diluted,

and then, by stirring the liquid in the first hole and by adding two drops of this mixture to the second hole, etc. up to hole 8, dilutions of the tested compound in geometric progression are obtained.

Hole 9 contains no antibiotic and serves for checking the growth of pr 0 veer gani sperm in a "blank" medium.

The sample plate is incubated at approximately 30°C or 37°C

18 hours. '

The minimum inhibitory concentration (MIC) of the tested compound, i.e. the smallest amount of antibiotic which completely inhibits the growth of the test organism is expressed as µg/ml in both cases.

The MICs of the tested compounds and of benzylpencillin, phenoxymethylpenicillin, ampicillin, cephalexin, cephalothin, benzylcephalosporin and benzyldesacetoxycephalosporin as references are shown in the following tables. The MIC values, determined by microserial dilution tests, are placed in parentheses.

Eczema! 45

Initial in vivo screening with respect to some of the prepared penicillanic acid and cephalosporanic acid derivatives gave the following results: a) from the compound sodium-7-/T3-meth<y>1-1,2,4-oxadiazole-5-<y>D -acetamido7cephalosporanate (as prepared in Example 10), the acute toxicity was determined in mice (Swiss) by means of an intraperitoneal administration» LD^Q was found to be greater than 6000 mg/kg (Cefalotin LO^q greater than 6000 mg/ kg).

In a protection test, the ED^ values for this compound were found to be as given below:

Blood levels of the indicated test compound and of cephalothin were determined after intramuscular administration of 50 mg/kg of these compounds in an aqueous solution to rabbits. After half an hour it was for the connection According to example 10

found a value of 38.3 yug/ml and for cephalothin a value of

33.9 µg/ral.

In urine, 25.9% of the administered compound (according to Example 10) was recovered, while for cephalothin 22.2% was recovered within 6 hours. b) The ED-Q value of sodium 7-(T3-methoxymethyl-1,2,4-oxadiazol-5-ylacetamido7cefolosporanate (prepared in Example 37) was found

to last 1.2 mg/kg in a protection test against a penicillin-iot-resistant Staphylococcuc aureus race after subcutaneous administration, while for cephalothin a value of 1.3 mg/kg was found. The compound according to example 37 gave good blood levels in samples with mice

and a strong urinary activity iaot pathogenic germs. The compound can preferably be used parenterally.

c) The ED^Q value of sodium 7-(T3-ethyl-1,2,A-oxadiaspl-5-yl)-acetamido7cephalosporanate (prepared according to Examples UL and 34)

was found to be 4.4 mg/kg in a protection test against a penicillin-resistant Staphylococcus aureus strain after subcutaneous administration, while for cephalothin a value of

1.3 mg/kg.

d) Relatively high blood levels were determined in mice and interesting''

effects against Proteus strains, Salmonella strains and penicillin"

resistant Staphylococcus races in urine after parenteral administration of the compounds: sodium 6-/X3-ethyl-1,2,4-oxadiazol-5-yl)acetainido7penicillanate sodium 6-/T5-methyl-1,2,4-oxadiazole -3-yl)acetamido7penicillanate . sodium G-[iK-methyl-CF-methyl-1,2,4-oxadiazol-5-yl)acetamido7-penicillanate 7-(X3-(2,6-dichlorophenyl)-1,2,A-oxadiazol- 5-yl)acetamido7cephalosporanic acid. ■ ■ <,.

Example 44

Syrups were prepared from penicillins and cephalosporins prepared according to the preceding examples by mixing the following ingredients:

These prepared syrups can be used for oral administration.

Example 45

Capsules, which as active ingredient contained a penicillin-eiler cephalosporin prepared according to the preceding examples, were prepared in the usual way. The ingredients for these capsules are listed below:

These capsules can be used for oral administration. Example 46 Tablets which as active ingredient contained a penicillin or cephalosporin prepared according to previous examples were prepared in the usual way. The ingredients for the tablets are listed below:

These tablets can be used for oral administration.

Example 47

From the penicillins and cephalosporins prepared according to the previous examples, a dry powder for injection was prepared in the usual way. An amount of 100-2000 mg of the sterile sodium salt of the subject compound was aseptically introduced into an ampoule suitable for injectable wound compositions under a nitrogen atmosphere; The ampoules were closed using gourami plates which were secured in position by means of aluminum joints to eliminate exchange of gases or penetration of micro-organisms. Before use, the powder was dissolved in a suitable amount of sterile and pyrogen-free water.

Claims (9)

1. Process for the preparation of substituted r.. 1,2,4-oxadiazol-yl-acetic acids with the general formula: where R^ is a lower alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, sec.butyl, isobutyl, t.butyl group, optionally substituted in the primary or secondary position with respect to the carbon atoms in the ring with fluorine, chlorine, a hydroxy or lower alkoxy group such as a fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl group, or a cycloalkyl group, which is optionally substituted with one or more lower alkyl groups, hydroxy groups or lower alkoxy groups, or R^ is adamantyl group or a phenyl group, optionally substituted with no more than three substituents from the group fluorine, chlorine, a hydroxy, lower alkyl or lower alkoxy group, or R-^ is mononuclear, heterocyclic, 5-membered group, e.g. a furyl, thienyl, isoxazolyl, isothiozolyl, oxadiazolyl group, optionally substituted with lower alkyl groups, or R 1 is an aralkyl group, such as a benzyl group which is optionally substituted as indicated above in the phenyl radical, andZ^ is hydrogen, a lower alkyl, aralkyl, cycloalkyl or phenyl group, whereby the cycloalkyl or phenyl group may, if desired, be substituted with one of the previously stated substituents, or is a lower alkyl group, substituted with a mononuclear 5-membered heterocyclic group of the type indicated above, or: where Z 2 is hydrogen, a lower alkyl, phenyl, cycloalkyl, aryl-(lower) alkyl group, a carboxy group, esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl residue, or an N-disubstituted carbamoyl or N-monosubstituted carbamoyl group, and Z-j is hydrogen or a phenyl group, optionally substituted with at most three of the above-mentioned substituents, or an N-disubstituted carbamoyl or carboxyl group, esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl group, or : where R2 denotes a group with the formula: where n is 0, 1,2 or 3 and FU is hydrogen or a lower alkyl group, and R^ is hydrogen, a lower alkyl, cycloalkyl, phenyl or aralkyl group, or R^ denotes a group -C00E -where E is hydrogen or a salt-forming residue (when nil) or a lower alkyl, benzyl or phenyl ester group, or R^ is a carbamoyl group, optionally N-substituted with one or two lower alkyl or alkenyl groups, a phenyl group, cycloalkyl group, one or two aryl-(lower)-alkyl or cycloalkyl-(lower)-alkyl groups, whereby the phenyl and cycloalkyl groups may optionally be substituted with at most one of the above-mentioned substituents, or R-,, and R^ together with the carbon atom to which they are bound form an optionally substituted cycloalkyl group, and Z^ is hydrogen or an optionally substituted aryl group as well as salts and esters thereof, characterized by the fact that A) reacts a stable reactive nitrile oxide with an imidate of a suitable nitrile corresponding to the equation: then metallizes the methylene group of the obtained compound VI (1,2,4,-oxadiazole) and replaces the metal atom, respectively, the metal component with a carboxyl group by reaction with carbon dioxide (carbonization) under anhydrous conditions by mixing the reaction components under cooling, or transfers a nitrile with the general formula: to a corresponding amidoxime of the general formula: and then O-acylate this amidoxime with an acid anhydride and effect a ring closure to the intermediate compound VI and then metallize and carbonize, B) transfer a nitrile to the corresponding amidoxime, then O-acylate the amidoxime with an acid anhydride and close the ring in the intermediate compound obtained , whereby a compound with the general formula is obtained: and then metallizes and then double carbonizes this compound, C) using the methods described under A) and B) produces a 1,2,4-oxadiazole derivative with the general formula: carbonizes this doubly and then selectively monodecarboxylates the 5-substituent to the correspondingly substituted 1,2,4-oxadiazol-3,5~ (;di)yl-acetic acid derivative and, if desired, transfers the obtained free acid to a salt or an ester. 2. Process according to claim 1, characterized in that for the preparation of the compounds where R 1 is a lower alkyl group or phenyl group, optionally substituted with fluorine, chlorine, a hydroxy, lower alkoxy or benzyl group, correspondingly substituted starting compounds are used. 3. Method according to claim 2, characterized in that for the preparation of the compounds where Z is hydrogen, a lower alkyl or phenyl group, corresponding starting compounds are used. 4. Method according to claim 1, characterized in that for the production of compounds containing hydrogen, a lower alkoxycarbonyl group, an optionally substituted phenyl group, an N,N-di(lower)alkylcarbamoyl group or a lower alkyl group, correspondingly substituted starting compounds are used. 5. Process according to claim 1, characterized in that correspondingly substituted starting compounds are used for the preparation of compounds where Z^ is hydrogen, a lower alkoxycarbonyl group, an optionally substituted phenyl group or an N,N-di(lower)alkylcarbamoyl group. 6. Process according to claim 1, characterized in that for the preparation of compounds where R2 is a lower alkyl group, a benzyl group optionally substituted in the phenyl nucleus, a lower alkylacetate group, or an N,N-di(lower)alkylacetamido group, the corresponding starting formula is used ordinal compounds. 7. Process according to claim 1, characterized in that for the preparation of compounds where Z 1 is hydrogen or an optionally substituted phenyl group, corresponding starting compounds are used. 8. Method according to claim 1, characterized in that the following compounds or salts or esters thereof are produced: 3-methyl-1,2,4-oxadiazole-5-yl-acetic acid, 3-(2,6-Dichlorophenyl)-1,2,4,-oxadiazol-5-yl-acetic acid, 3-(2,4,6-trimethylphenyl)-1,2,4-oxadiazol-5-yl-acetic acid , 5-methyl-1,2,4-oxadiazole-3-y1-acetic acid, 3-ethyl-1,2,4-oxadiazole-5-y1-acetic acid, 5-ethyl-1,2,4-oxadiazole-3- yl-acetic acid, . 5-benzyl-1,2,4-oxadiazol-3-yl-acetic acid, α-methyl-3-methyl-1,2,4-oxadiazol-5-yl-acetic acidj α-methyl-3-ethyl-1,2 ,4-oxadiazole-5-yl-acetic acid, α-(5)-methyl-1,2,4-oxadiazole-3,5-diyl-bisacetic acid, α-(5)-phenyl-1,2,4-oxadiazole -3,5-diyl-bisacetic acid 3-(4-chlorophenyl)1,2,4-oxadiazole-5-y1-acetic acid, 1,2,4-oxadiazole-3,5-y1-acetic acid, 3-benzyl-1 ,2,4-oxadiazole-5-y1-acetic acid, α-(5)-phenyl-3-methyl-1,2,4-oxadiazole-5-y1-acetic acid, 3-methoxymethyl-1-1,2,4-oxadiazole -5-y1-acetic acid, 3-ethyl-a-methyl-1,2,4-oxadiazol-5-y1-acetic acid, a-(3-ethyl-1,2,4-oxadiazol-5-yl)-propionic acid ,_ 3-(α-carboxy)-benzyl-1,2,4-oxadiazol-5-yl-acetic acid, 5-(N-propen-3-yl)carbamoylmethyl-1,2,4-oxadiazol-3-yl-acetic acid, α-(3)-phenyl-1,2,4-oxadiazole-3,5-diyl-bisacetic acid, α-(5)-carbomethoxy-1,2,4-oxadiazole-3,5-diyl-bisacetic acid, and 3-Hydroxymethyl-1,2,4-oxadiazole-5-yl-acetic acid. 9. Substituted 1,2,4-oxadiazolyacetic acids, characterized by the general formula: where R^ is a lower alkyl group such as methyl-, ethyl-, propyl-, isopropyl-, -butyl-, sec.butyl-, isobutyl-, t.butyl group, optionally substituted in the primary or secondary position with respect to the carbon atoms in the ring with fluorine, chlorine, a hydroxy or lower alkoxy group such as fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl group, or a cycloalkyl group, which is optionally substituted with one or more lower alkyl groups, hydroxy groups or lower alkoxy groups, or is adamantyl group or a phenyl group, optionally substituted with no more than three substituents from the group fluorine, chlorine, a hydroxy, lower alkyl or lower alkoxy group, or R-^ is mononuclear, heterocyclic, 5-membered group, e.g. a furyl, thienyl, isoxazolyl, isothiozolyl, oxadiazolyl group, optionally substituted with lower alkyl groups, or R-L is an aralkyl group, such as a benzyl group, which is optionally substituted as indicated above in the phenyl residue, and Z-^ is hydrogen, a lower alkyl, aralkyl-, cycloalkyl or phenyl group, whereby the cycloalkyl or phenyl group may, if desired, be substituted with one of the previously stated substituents, orZ-^ is a lower alkyl group, substituted with a mononuclear 5-membered heterocyclic group of the above type, or: where Z 2 is hydrogen, a lower alkyl, phenyl, cycloalkyl, aryl-(lower) alkyl group, a carboxy group, esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl residue, or an N-disubstituted carbamoyl - or N-monosubstituted carbamoyl group and Z-j is hydrogen or a phenyl group, optionally substituted with no more than three of the above-mentioned substituents, or an N-disubstituted carbamoyl or carboxyl group, esterified with a lower alkyl, phenyl, cycloalkyl or aralkyl group, or: where denotes a group with the formula: where n is 0j 1, 2 or 3 and R 1 is hydrogen or a lower alkyl group, and Rjj is hydrogen, a lower alkyl, cycloalkyl, phenyl or aralkyl group, or R^ denotes a group -COOE where E is hydrogen or a salt-forming residue (when n. > 1) or a lower alkyl, benzyl or phenyl ester group, or R^ is a carbamoyl group, optionally N-substituted with one or two lower alkyl or alkenyl groups, a phenyl group, cycloalkyl group, one or two aryl-(lower)alkyl or cycloalkyl-(lower)alkyl groups, whereby the phenyl and cycloalkyl groups may optionally be substituted with at most one of the above-mentioned substituents, or R^ and R^ together with the carbon atom to which they are attached form an optionally substituted cycloalkyl group, and Zh is hydrogen or an optionally substituted aryl group, as well as salts and esters thereof.. I