DE2364129A1 - PHARMACEUTICAL VALUABLE NEW 1,2,4OXADIAZOLYL ACETIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION AND USE - Google Patents

Description

Dr. F. Zumsteln sen. - Dr. E. Assmann Dr. R. Koenigsberger - Dlpl.-Phys. R. Holzbauer - Dr. F. Zumstein Jun.

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53 / My Case DUI-2005

8 MUNICH 2.

BRÄUHAUSSTRASSE 4

GIST-BROCADES N.V., Wateringseweg 1, DeIft / Holland

Pharmaceutically valuable new 1,2,4-oxadiazolyl-acetic acid derivatives and processes for their preparation and their use

The invention relates to new 1,2,4-oxadiazolyl-acetic acid derivatives and new compounds derived therefrom, in particular new, therapeutically valuable 1,2,4-0xadiazolylacetamido-penicillanic acid and cephalosporanic acid derivatives, and pharmaceutical compositions containing them and methods to make the new connections.

The new 1,2,4-oxadiazolyl-acetic acid derivatives according to the invention are those of the general formulas I, II and III, as they are listed below, namely

(a)

COOH

Tl

wherein

R.J a (lower) alkyl group (e.g. a Methyl, ethyl, propyl ,. Isopropyl, butyl, sec-butyl, iso-

409830/108 2

butyl, t-butyl group), optionally substituted in the primary or secondary position, based on the carbon atom in the ring, with a fluorine atom, a chlorine atom, a hydroxyl group or a (lower) alkoxy group (for example a fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl group), or a cycloalkyl group, optionally substituted with one or more (lower) -alkyl groups, hydroxyl groups or (lower) -alkoxy groups, means "or in which

R ₁ denotes an adamantyl group or a phenyl group, optionally substituted with at most three substituents such as with an F, a Cl atom, hydroxy, a lower alkyl or lower alkoxy group, or in which

Rx is a mononuclear heterocyclic 5-membered Ring (for example a furyl, thienyl, isooxazolyl, isothiazolyl, oxadiazolyl ^ ring), optionally substituted with (lower) -alkyl groups, means, or in which

R _{1 is} an aralkyl group (for example a benzyl group), optionally substituted in the phenyl nucleus with the aforementioned substituents, denotes ₉ and in which

Z ₁ denotes a hydrogen atom, a (lower) alkyl group, an aralkyl group, a cycloalkyl group or a phenyl group, it being possible for the cycloalkyl or phenyl group to be optionally substituted by the aforementioned substituents, or in which

Zy, a (lower) alkyl group substituted with a mononuclear 5-membered heterocyclic group as previously defined.

Preferably, R * denotes a lower alkyl group (for example a methyl or ethyl group) which can optionally be substituted by a fluorine atom, a chlorine atom, a hydroxyl group or a (lower) alkoxy group, or a substituted phenyl group or a benzyl group, and Z _{1 represents} a hydrogen atom, a (lower) alkyl group or a phenyl group.

. 409830/1082

II

wherein

-Z _{2 is} a hydrogen atom, a (lower) alkyl group, a phenyl, cycloalkyl, aryl (lower) alkyl group, a carboxy group, esterified with a (lower) alkyl, phenyl, cycloalkyl or aralkyl radical, or denotes an N-disubstituted carbamoyl or N-monosubstituted carbamoyl group, and

Z-, a hydrogen atom 'or a phenyl group, optionally substituted with at most three substituents, as mentioned above, or an N-disubstituted carbamoyl group or a carboxyl group, esterified with - a (lower) alkyl, phenyl, cycloalkyl or aralkyl radical.

Preference is given to Zp and / or Z, a hydrogen atom, a (lower) alkoxycarbonyl group, an optionally substituted. tuted phenyl group or an N, N-di- (lower) -alkyl-carbamoyl group, where Z _{2 is} also a (lower) -alkyl group. can be.

HOOC CH C .CR ₂ III

^Z 4

where R_

R _{2 is} a group - (CH ₂ ) - CH

denotes, in which η denotes 0, 1, 2 or J5 and R ₅ denotes a hydrogen atom, a (lower) -alkyl group and R. denotes a

409830/1082

Hydrogen atomυ a (lower) alkyl, cycloalkyl, phenyl or aralkyl group or R4 denotes a -COOE group-

or -a salt-forming group tetj in which E is a hydrogen atom / (if η ^ 1 /, or a

(lower) -alkyl- ,. Benzyl or phenyl ester group, ■ or R ^ denotes a carbamoyl group, optionally N-substituted with one or two (lower) alkyl or alkenyl groups, one phenyl group, one cycloalkyl group, one _v or two aryl (lower) alkyl or cycloalkyl (lower) alkyl groups _p where the Phenyl ™ and cycloalkyl groups can optionally be substituted with at most one of the aforementioned substituents, or where R 1 and R together with the carbon atom to which they are bonded _s an optionally substituted cycloalkyl group mean, and

Zr denotes a hydrogen atom or an optionally substituted aryl group.

Rp preferably denotes a (lower) alkyl group _? a benzyl group ^ optionally substituted in the phenyl ring ₉ a (lower) -Alkylaeetatgruppe or, an NpN-di- (lower) -alkyl = acetamide group and Z ^ a hydrogen atom or an optionally substituted phenyl group,

The term "lower" _s as it is used in the present application in connection with alkyl · = and alkoxy groups meant that the group in question contains at most 6 carbon atoms »The term" cycloalkyl ^s? _S 'as used in the application ^ means a carbocyclic ring with 5 to 8 carbon atoms o

The compounds of the general formulas I ₅ II and III can be prepared verschiedenenj method known per se by, wherein one den'substituierten Oxadiäzol basic core comparable '= applies the substituted 1 ₈ 2s, 4-0xadiazol-Grunderivate can by a wide variety of Manufacturing processes are produced as described, for example, in the following parts of the literature; F. Eloy, -Fortsciir-Chem * Forsch., Vol

409830/1082

4, pp. 807-876 (1965), P.Rajagöpalan, Tetrahedron Letters, No. 5, Pp. 311-312 (1969), F. Eloy and R. Lenaers, Bull. Soc. Chim. BeIg, 72, p.719-724 (1963). The substituted 1,2,4-oxadiazolyl-acetic acids are preferred according to the following described method produced.

The group of 3-substituted-1 ^^ - oxadiazol-S-yl-acetic acids, in which, for example, R ^, a 2,6-dichlorophenyl, 2,4,6-trimethylphenyl or 2-chloro-6-fluorophenyl group, denotes a t-alkyl group such as a t-butyl or adamantyl group and where Z * denotes a hydrogen atom or a lower-alkyl group, a cycloalkyl, aralkyl (for example a benzyl) or aryl group, can be obtained by cyclo-addition of stable and reactive Nitrile oxides are reacted with imidates of the various nitriles * whereby 1,2,4-oxadiazoles are obtained according to the following reaction scheme:

-OG ₂ H ₅

Ό.

IV. 'V VI. .

This implementation is described, for example, by P.Rajagopalan in TetralB-drori Letters, No. 5, pp.311-312 (in which R 1 and Z _{1 have} the definitions just given). Then the methylene {ie the -CI ^ -O group of. Compound of formula VI metallized and then the metal atom or the component is replaced by a carboxyl group, for example by the action of carbon dioxide. In the following, for the sake of simplicity, such a replacement is referred to as "carbon sieving". The reaction between the imidates and the mitriloxides is preferred under anhydrous conditions

"409830/1032

performed $ by tinter cooling the two reagents mixed together ^ the reaction mixture is stirred for about 1 hour at room temperature, then the excess imidate is removed by evaporation in vacuo. Some.

Recrystallizations of the product give the desired pure

1,2,4-öxadiazQ! Connection.

The imidates used as the starting material can be produced by processes known per se, such as those in Organic Synthesis _? Coll "Volume 1, pp. 5-6, and SA Glickmann et al, J. ACS (1945)" 67 _@ p. 102O ₉ .

The group of 3 = subst "= 1 _s 2 ₉ 4-0xadiazol-5-yl-acetic acids,

For Example wherein ü "a nledrig alkyl ₀ cycloalkyl and _s Phenyigrappe substituted with chloro fluoro _{9 8} is hydroxy, lower alkyl vein low = ₉ alkoxy or a heterocyclic group such as a 2 'or 5 ~ TM.eii.yl- 4 - = or 5-isoxazolyl or 4-iso-thiazolyl group means nad. wherein. Z ^ has the meaning given _{above s} -can by converting nitriles of the formula

wherein S ^ gegeben® the above significance has. ₉ into the corresponding imidoximes of the general formula

L-CsS-OH - VIII

IH ₂

by processes known per se and subsequent O-acyl

tion with, for example, Säureaiohydridenj, ring closure of the

Intermediate products to compounds of the general formula VI. be prepared irnd subsequent metallization and carbonization "This production method for the compounds of general formula ¥ 1 is known per se cf. _s", for example, Fo Bloy _5. To continue * ο Chem "Forsch" _ΰ Bsnd 4 ₅ S ο 814 "For example, the connections can be made by heating the corresponding O = äc] flated Ijaiciosim; until temperatures average 120 us at 170 ⁰ C _0, preferably around

150 ° C are reached. Then you can distill, being a hybrid of water and the desired 1,2,4-oxadiazole compound receives. The distillate is saturated by adding potassium carbonate, using a two-layer system receives. The top layer is removed, dried over calcium chloride, washed with small amounts of ether. and redistilled.

The metallization of the methylene group and the subsequent carbonization can be carried out by processes known per se, as described, for example, in Houben-Weyl, Methods of Organic Chemistry * 4th edition (197O) ₉ Volume 13/1, pp. 93 to 114, 173 through 174 and 296 through 350. A lithium atom or sodium atom, for example, can be introduced by using, for example, butyl-lithium / TMEDA, butyl-lithium / DABCO, lithium-diisopropylamine, lithium-isopropyl-cyclohexylamine, lithium-N, N-dimethylacetamide, lithium-bis-trimethylsilylacetamide , 2-lithium-1,3-dithiane and 2-lithium-1,3., 5-trithiane, sodium hydride, sodium amide, sodium methanolate ₈ Mapfittiyl-Matrium, phenyl-Watrium in inert solvents (for example, pentane _s hexane, toluene, diethyl ether, Tetrahydrofuran or 1 _S 2-dimethoxyethane) at very low temperatures _s for example at -60 ° C and. lower, used.

The replacement of the metal atom or the metal component by a carboxyl group can be carried out, for example, by adding a solution to the organometallic compound fresh, solid carbon dioxide is added, on which, if necessary, a layer of dry diethyl ether or tetrahydrofuran is present, or by passing gaseous carbon dioxide over or through a solution of the organometallic compound.

The amidoxime used as starting material can per se known processes are produced, as described, for example, by R. Lenaers, C. Mousebois and Fo Eloy in Helv.Chim.Acta, Volume 45 (1962), pp. 441-446 (and the literature listed therein

409830/1082

steep) and from CoD. Hurdg Inorganic Synthesis, Volume 1, p.89, to be discribed"

Path II

The substituted 1,2,4-0xadiazol-3 »5-yl-diacetic acids accordingly of the formula II can be obtained from compounds of the general r my formula

where Zp and Z ^ have the definitions given above, can be produced by double metallization and subsequent double carbonization.

The compounds of formula IX can, for example, by conversion of nitriles into the corresponding amidoximes and subsequent O-acylation with, for example, acid anhydrides and ring closure of the intermediate products are produced »

Path III

The 5-substituted-1, Z ^ -oxadiazol-J-yl-acetic acid compounds, in which Rg denotes a straight-chain lower alkyl (preferably a methyl) group, _s optionally substituted with a branched alkyl group, or a cycloalkyl, phenyl or an unsaturated heterocyclic group (for example corresponding to the formula -CH ₂ -R ^) and Zr is a hydrogen atom, can be obtained by double metallization of compounds of, for example, the general formula

Λ09830 / Ί082

be prepared, wherein R. has the meaning given above. This is followed by double carbonization and monodecarboxylation of the substituent at the 5-position of the oxadiazole nucleus.

The compounds of the formula X can accordingly, for example corresponding to the two preferred reaction routes for the formation of the oxadiazole ring as indicated above for route I was-, to be produced.

In various cases, 5-substituents can, for example, by selective reaction of the 5-acetic acid group of the corresponding. corresponding bis-acetic acids are produced with isocyanates, with Rp-substituents of the type _Q

-CH-C-NH-R

Z ₂

obtained where R is the group derived from the isocyanate.

The compounds of the general formulas I, II and III as well as the intermediates, namely the organometallic precursors therefor, can be used as raw materials for the manufacture of other products that are new c. and are also the subject of the present invention. :

The acids of the formulas I, II and III as such or active derivatives of these acids can be used as starting materials like the different types of anhydrides (including the mixed anhydrides), acid chlorides and the activated esters thereof.

The following end products can be prepared: (A) Esters of the general formula

C-CH C-OE ^ XII

Λ 0 9 8 3 0/1082

wherein R and Z "have the same meanings as they are above

1 '
Formula I have been given and E ^ is a (lower) alkyl, cycloalkyl, benzyl, benzhydryl or phenacyl group, or

B ₂ OCCHC CC

O Z ₃ VO · Z ₂ °

in which Z ₂ and Z- have the definitions given _{above and E 2 is} a (lower) -alkyl, cycloalkyl, aralkyl, phenyl, phenacyl or benzhydryl group, it being possible for the phenyl groups to be optionally substituted by halogen, optionally esterified Carboxyl groups, (lower) -alkoxy _r (lower) -alkylthio-, (lower) -alkyl-lower- (alkoxy) - and lower- (alkoxy) -lower-alkylcarbonyl groups, or

E ₀ -O C-CH Cf ^ ^ C - δ «

5- Z

v / orin R ₂ and Σ 'have the same meanings as given above for formula III and E ^ a low-alkyl, cycloalkyl, aralkyl, phenyl, phenacyl or benzhydryl group means _9, wherein the phenyl groups may be optionally substituted by Halogen, optionally esterified carboxy, (lower) alkoxy, (lower) alkylthio, (lower) alkyl (lower) alkoxy, (lower) alkoxy (lower) alkylcarbonyl groups.

The conversion of compounds of formulas I, II and III into the corresponding esters can be carried out according to processes known per se take place, in the case of less stable acids I and II, the reaction conditions according to the sensitivity of the very reactive acetic acid groups that are present must be selected «

The esters of formulas XII and XIV can also be made

409830/1082

by removing the organometallic precursors that occur as intermediates (such as those used in the production of acids are used), and preferably the lithium-containing precursors with chloroformic acid esters that have the corresponding Contain ester group, converts.

(B) amides

Primary, secondary and tertiary amides can be prepared from reactive intermediates (for example the acid chlorides and -anhydrides), which are derived from the acids of the general formulas I, II and III «, according to known processes or by Conversion of these acids with phosphazo intermediates, which are prepared in situ from amines and phosphorus chloride, can be obtained. A wide variety of secondary Amides can also be produced by two methods which are quite widely used and in which a wide variety of isocyanates are used as reactive agents.

In the first of these two methods, the α-metallized 1 _f 2,4-Oxadiazole3 as examples of the preparation of oxadiazolyl-acetic acids of the formulas I and II are used, in accordance with the general formulas

N-O

or

B CH C C -σΐ-B XVX

3 2

A09830 / 1Ü82

, Own or Rf Zx, Zßf and Z ^ are as above for R ^, Z ^ ₉ Z ₂ and Z ^ given represent groups that are easily converted into the groups of the definitions of R ^, Z ^, Z ₂ and Z can and can be influenced or react in the reaction conditions,

B denotes a metal atom Me or a group Me-HaI where the Roman number indicates the metal valency and Hal a halogen atom, preferably a chlorine or Bromine atom, means

reacted with isocyanates under suitable conditions. Suitable substituted metal atoms or containing metal Groups are lithium, sodium and magnesium chloride or Magnesium bromide, lithium is preferred.

According to a preferred method, a lithium atom is used introduced by H-Li exchange, using reagents such as n-Butyllithium is used. In general, moderate ones are obtained to very good yields, if one of metalated (for example Lithium or sodium containing) species, in which at least two substituents (such as phenyl, unsaturated heterocyclic groups or other groups such as carboalkoxy groups are present which are capable of the The carbanion formed to stabilize at low temperatures, and directly attached to the metallized carbon atom are bound.

According to the second manufacturing method for the secondary amides are acetic 1,2,4-oxadiazolyl with different isocyanates in suitable solvents selected which, for example, 3,5-dimethyl-1,2,4-oxadiazol _f and preferably reacted in the presence of special catalysts . These production processes expand the possibilities of the first process in that in this case species of the general formulas I, II and III likewise give moderate to very good yields of amide, so that compounds of the formula XVII. C.

409830/1082

H-HH- G-

O 2 ₄ ^ NO

in which R denotes the radical originating from the isocyanate, in addition to the amide derivatives of the formulas

XVIi A:

•. XVII B: r_hh_C-_ch c _v Jfc__CT-C-NH- R

o ■: L

can be obtained.

In the compounds of general formula II, the acetic acid group in the 5-position of the oxadiazole nucleus appears to be more reactive than the acetic acid group in the 3-position, which often increases the possibility of an almost selective conversion of the acetic acid group in the 5-position when Z ₂ and Z -, are selected appropriately, with an isocyanate in a suitable solvent under anhydrous conditions under an inert gas atmosphere and in the presence of small amounts of a suitable, not strongly basic catalyst.

The conditions for using different types of catalysts are already from the South African patent 71/7432 known.

(C) A wide variety of salts can be obtained from the 1,2,4-oxadiazolyl acetic acids according to the invention by methods known per se.

409830/1082

Are esters and amides from the starting acids and organometallic Compounds of the general formulas I, II, III, "XV and XVI corresponding to those described above, shown Prepared ways, the substituents present in these compounds can be converted into other groups (for example, by removing the protecting groups) or other substituents that affect the structure of the manufactured Do not adversely affect compounds, can be introduced later by methods known per se.

A particular feature of the present invention are new penicillanic acid and cephalosporanic acid derivatives, processes for their production and means in which they are contained.

The new penicillanic acid and cephalosporanic acid derivatives according to the invention are compounds of the general formulas

(a) R C 1 -C 4 -C H C -NH-Q XVIII

^ / IU • NOZ ₁ "°

where Q is the group

- CH - CH C- ^ -ch - ch ^ q ₁

1 I · I ^ 3 ■ I - l · ι ²

_{) S} -CK r-CH COU, _O ^ CN C-QI ₂ -X,

XJX. · .. · ■. ".XX cou ■ ο

CH ^
-CH CH "C ^ _

N CH COU s _{n <} ß N - CH COU

-4098 3 0/1082

or ";. * ', 9.

■ ■ * ι-

. ~, αί— CH. CH · XXIII

i II ² .

_O ^ C-N C-CH ₂ -X C ^

COU

means where U is an amido group (for example a Sacchary DL, succinimido or phthalimido group) or a group OE ¹ , where E 'is a hydrogen atom, a salt-forming cation (for example an alkali metal, an alkaline earth metal or an amine cation, an ester radical such as a (lower) -alkyl group, which is optionally substituted by a (-lower) -alkanoyloxy group, which can also be substituted by a silyl, a phenacyl, a benzyl, a benzhydryl, a trichloroethyl or tert-butyl group, X denotes a hydrogen atom, a hydroxyl group, a (lower) alkanoyloxy group (preferably an acetoxy group) or the residue of a nucleophilic agent v / ie a halogen atom, an azido group or a cyano group, a carbamoyloxy group, an optionally substituted mononuclear heterocyclic group, the contains a sulfur or nitrogen atom

(for example a pyridiny group), a group -SQ ¹

/. optionally substituted _m , _ _ _,, _ _

(worm Q ¹ eiiie / diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl or -purinyl group) represents or in which X is a Amino group, when Q is a group of the formula XX , R ^ has the meaning given above for formula I and also means a carboxymethyl group, Z ₁ "has the meaning given above in the definition of R ^ and also a hydrogen atom, a (low ) Alkyl group, optionally substituted by a chlorine or fluorine atom, a (lower) alkoxy group, a cycloalkyl group, a

409830/1082

Phenyl group, which itself can optionally be substituted with at most three substituents as mentioned above, or in which Z ₁ "denotes a carboxy group, esterified with a (lower) alkyl, phenyl, cycloalkyl or aralkyl group, the phenyl groups optionally can be substituted with at most one of the aforementioned substituents, or in which Z ₁ "is a carbamoyl group which may optionally be terminated with one or two (lower) alky groups, a phenyl group, a mononuclear 5-membered heterocyclic group, a cycloalkyl group, may be substituted one or two aryl (lower) alkyl or cycloalkyl (lower) alkyl groups _s being the phenyl and cycloalkyl groups may be optionally substituted with at most one of the substituents as previously mentioned, or in which Z ₁ "represents a carbamoyl group with the nitrogen atom as part of a heterocyclic ring (e.g. morpholino), or wherein Z ₁ " represents hydrogen means in combination when R _{1 means} an acetic acid residue.

The term "low" as used herein in connection with Alkanoyloxy groups are used means that the group Contains a maximum of 6 carbon atoms.

wherein Q has the definition given above and R ₂ and Z ^ have the definitions given for formula III.

A preferred group of compounds according to the invention are compounds of the general formula XVIII, in which the symbol R _{1 is} a lower alkyl, an adamantyl, halomethyl, hydroxymethyl, ₉ carboxymethyl, (lower) alkoxymethyl, benzyl or phenyl Group means, optionally one, two

409830/1082

or contain three substituents such as chlorine and lower-alkyl groups or which contain a single nitro group can, and more preferably FL means a methyl, ethyl, Methoxymethyl-, 2,6-dichlorophenyl-, 2,4,6-trimethylphenyl- or a carboxymethyl group, Z ^ "a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, containing the aforementioned substituents, an esterified carboxy group or a carbamoyl group and their alkali metal! - *, alkaline earth metal and amine salts.

Another group of preferred compounds is that of the general ones Formula XXIVi in which Rp is a methyl or ethyl group or a group -CEU-Ra in which R / is a branched one Alkyl, cycloalkyl, phenyl, a (lower) alkoxycarbonyl, an N-monosubstituted carbamoyl group or an unsaturated group heterocyclic group and wherein Z ^ is given above Has meaning, and the alkali metal, alkaline earth metal and amine salts thereof.

The therapeutically valuable compounds according to the invention can be manufactured by various methods, each of which involves the use of a method of manufacture known per se of penicillins and cephalosporins is. Corresponding According to a feature of the invention, the compounds of the general formulas XVIII and XXIV can be prepared by a salt, an ester or an amide of the 6-aminopenicillanic or 7-aminocephalosporanic acid compound of the formulas

H ₀ N-CH-CH C (CH-.) _O H _n N-CH-CH CH

i! I ^{3 2 2} I | !

Γ CH-COOH _{0 <} £ N C-CH ₂ K

. or. "\ β:

.-. ■■■ ι

;. '- COOH

XXV.

■ - 409830/1082

H ₉ N-CH-CH C (CH,) _O - H ₀ N-CH CH C (CH,).,

² SI I 3 2. 2 yy y. 3 2

N -CH-COOH j. ^ C N CH-COOH

1ΩΧ7ΙΧ . - XXVIII

■ ■■ - or

₀ N CH CH CH ₀

² ■ I "II ² ·

CNC — CH ₀ X

⁰ V

COOH

wherein X has the definition given above, where, if the substituent X is a hydroxy or an amino group, these are preferably protected with an active ester (for example the 2,4-dinitrophenyl ester, p-nitrophenyl ester or N-Hydro xysuccinimidoester) of an acid of the general formula

R * C C — CH — COOH '

¹ ^ / I »oc

CC

/ I

O Z *

vrarin FL and Z ^ have the meanings given above for R ^ and Z ^ "or denote a group which can easily be converted into a group according to the definitions given for R ^ and ZJ ^% and which is also" influenced in the reaction conditions or can react, for example ge ~

409830 / -1082

protected amino, hydroxy and carboxy groups, or

Z *. N O

can wherein R ₂ and Z * are as defined above for R ₂ and Z ^ given or groups mean that easily into groups according to the definitions of R ₂ and Z ^ transferred v / to earth ground and which are influenced under the reaction conditions or react , and optionally further substituting the compounds obtained in this way or converting the substituents present into other substituents in accordance with processes known per se.

Instead of the active esters, which differ from the acids of the general Formulas XXX and XXXI can derive other functional derivatives of these acids, which act as acylating agents for a primary amino group are suitable can be used. Such Derivatives include, for example, the corresponding carboxylic acid chlorides , -bromides, acid anhydrides including mixed anhydrides made from stronger acids become, like the lower aliphatic monoesters, of carbonic acid, of alkyl and aryl sulfonic acids, and of more strongly steric hindered acids such as diphenylacetic acid. One can also use an acid azide or an active thioester (for example with Use thiophenol or thioacetic acid) of the acids. Alternatively, the free acids of the general formulas XXX and

oo. XXXI with the 6-aminopenicillanic acid or 7-aminocephalosporan-Q acid compound can be coupled using a carbodiimide reagent ^. Instead of the active one ο Ester you can use a corresponding azolide, i.e.

κ »an amide of the corresponding acid, whose amide nitrogen is a Is part of a quasi-aromatic 5-membered ring which contains at least 2 nitrogen atoms, for example imidazole,

Pyrazole, the thiazoles, benzimidazoles, benzotriazole and their substituted: derivatives. The procedures for carrying out these reactions to produce a penicillin or a cephalosporin and the procedures used to isolate the compounds so prepared are for similar Compounds well known (see British patents 932 644, 957 570, 959 054, 952519, 932 530, 967 108 and 967 890).

The ester, the salt or the amide of the product obtained according to the process described above can be according to Methods known per se can be converted into the corresponding penicillanic acid or cephalosporanic acid derivatives. Will for example a silyl (e.g. trialkylsilyl) ester of the starting materials of the formulas XXV to XXIX are used as reactants, the ester group are easily hydrolyzed, using the corresponding acid compound of the general formulas XVIII and XXIV receives.

Another method according to the invention for the production of Compounds of the general formulas XVIII and XXIV is characterized in that an acid of the general Formulas XXX and XXXI and the general formula

HOOC-CH C ^. C - CH COOH

J ^ N Q ^ j XXXII

where Z * and Z ^ are the meanings given above for Zp and Z. own or mean groups that can easily be converted into groups that fall under the definitions of Zp and Z ^ fall and which is influenced by the reaction conditions or react with a 6-isocyanatopenicillanic acid or a 7-isocyanatocephalosporanic acid compound of Formula O = C = N-Y, where Y is the groups of the formulas XIX and XX, and atoms or groups for protecting the carboxy

409830/1082

group and optionally the hydroxy or amino group if it is present, i.e. if X in formula XX Hydroxy or amino "means. The protective group is preferred the carboxyl group or the hydroxyl group, if present, in the 6-isocyanatopenicillanic acid or 7-isocyanatocephalosporanic acid reactant a di- or tri-alkylsilyl group, which can easily be removed from the corresponding product by hydrolysis.

The reaction between a carboxylic acid of the formulas XXX, XXXI and XXXII and an isocyanate of the formula O = C = N-Y is preferably in an inert organic solvent medium such as toluene, dichloromethane, benzonitrile or 3> 5-dimethyl-1,2,4-oxadiazole carried out. A small amount of an organic base such as a substituted imidazole such as N-vinylimidazole, N-methylbenzimidazole or N-isopropylbenzimidazole, can serve as a catalyst. These and other conditions are more appropriate in the use of various types Catalysts are described in the South African patent ΤΙ / 7432. The implementation is proceeding accordingly the reaction scheme, which is given below as an example for penicillanic acid derivatives.

A-COOH +

A-CO-NH-CH CH

I i

C (CH,) -

I ^{3 2}

CH-COOB ¹ '

C (CH-,)., + CO ₀ +

ι ° ^{2 2} CH-COOH.

E '* OH

· ■ 409830/1082

In the formula, E "means a group that represents the carboxy group protects during the reaction and that after the reaction, for example by hydrolysis, hydrogenation or a substitution reaction is removed with basic or nucleophilic agents.

In another process for the preparation of the penicillanic acid and cephalosporanic acid derivatives of the general formulas XVIII and XXIV is a 6-isocyanatopenicillanic acid or 7-isocyanatocephalosporanic acid compound O = C = N-Y (where Y has the meaning given above), in which the carboxy group and the hydroxyl or amino group, if present, are protected in a suitable manner, reacted with an organometallic compound of the formula A-Me, A-I-Te-HaI or A-Me-A, [wherein A is a group of the general formula

^R i

(where Rf and Z $ have the definitions given above) or

CH Ci ^ C - ^ CH

N ^ -O

, XXXIV

(where zt and Z * have the definitions given above) Me denotes a metal atom, for example lithium, sodium or magnesium, the digits I or II denotes its valence indicate and Hai a halogen atom, preferably a chlorine or Bromine atom means]. Subsequently, the intermediate product thus obtained is hydrolyzed to give the metal ion and any hydrolyzable Group that protects the carboxy (or hydroxy) group. The implementation is carried out in an anhydrous organic

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see solvent medium running at conditions that favor implementation of the Grignard, Reformatsky type or analogous implementations. A similar reaction process is known from British patent specification 1,268,536 and South African patent specification 70/8521.

The isocyanate starting materials of the general formula O = C = N-Y (where Y has the meaning given above) can can be obtained by reacting phosgene with a penicillanic acid or cephalosporanic acid derivative, as described in the British Patent 1,268,536 and South African Patent 70/8521.

Another method of making connections of the general formulas XVIII and XXIV is an acid of the general formulas XXX, XXXI and XXXII with an in situ produced phosphazo compound implemented how to use them by reacting phosphorus trichloride and an amine salt (preferably a triethylamine salt) of a compound accordingly the formulas XXV, XXVI, XXVII, XXVIII and XXIX.

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

The ratio between the molar amounts of 6-aminopenicillanic acid or 7-aminocephalosporanic acid is preferably and the derivatives thereof, triethylamine and phosphorus trichloride -2: 3ί1 and dichloromethane is preferably used as the reaction medium. This type of reaction appears to be suitable when using very sensitive substituted acetic acid derivatives because any reactive substituents that may be present are obviously not attacked or influenced.

According to another method, the cephalosporanic acid derivatives are grounded of the general formulas XVIII and XXIV, in which

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Q denotes a group of the formula XX and in which X is at the beginning Hydrogen means by ring expansion conversion the corresponding penicillanic acid sulfoxide derivatives, in which Q is a group of the formulas XXI and XXII, for example by heating the penicillanic acid sulfoxide derivative up to 14O ° C in the presence of a catalyst and preferably of an agent for removing water.

These preparative processes are, for example, from Belgian patents 747 118, 747 119, 747 120 and 763,104 and U.S. Patents 3,275,626, 3,591,585 and 3,632,850 known

The compounds of the general formulas XVIII and XXIV "in which Q is one of the groups of the formulas XXI ₉ XXII and XXIII, can also be prepared from the corresponding compounds" in which Q is one of the groups of the formulas XIX and XX, using suitable oxidation processes.

For example, the R-sulfoxides of the corresponding penicillins or cephalosporins can be prepared selectively by using _p in situ produced singlet oxygen, or by the R-SuIfoxyde selectively produced as intermediate products to the. 6-aminopenicillanic acid and 7-aminocephalosporanic acid and the derivatives thereof acylated.

The term "methods known per se" ₉ as used in the present application means methods which have previously been used or have been described in the literature.

The new Penicillansäure- and cephalosporanic acid derivatives XVIII and XXIV ₅ wherein Q ₈ XX, XXII and XXIII means of the general formulas, the groups of the formulas XIX, have antibiotic char acteristics _9, the effect _p that they as drugs for humans and animals, alone or mixed with other known antibiotics are valuable. Some of these new ones

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"Compounds of the general formulas XVIII and XXIV have activities which are comparable to those of the known ß-lactam-containing antibiotics. They especially have activities against gram-positive microorganisms (for example Bacillus subtilis, Staphylococcus aureus, Streptococcus haemolyticus and faecalis and Diplococcus pneumoniae) and they also show good activity against penicillin-resistant staphylococci, this applies in particular to compounds in which R 1 and R _{2 are} methyl, ethyl, methoxymethyl, mesityl, benzyl and 2,6-dichlorophenyl groups, in which Q is a group of the formulas XIX and XX and in which Z ^ and Z ^ are hydrogen atoms or methyl groups, and for the salts of these compounds.They are also active against gram-negative microorganisms, for example against Bruceila melitensis, Pasteurella multocida, Proteus rettgeri and Salmonella dublin.

The aforementioned antibiotic compounds according to the invention are preferred for the therapeutic purposes in Form of non-toxic salts like the sodium = ·, potassium or Calcium salts used. Other salts which can be used include the non-toxic, suitably crystalline Salts with organic bases such as with amines, for example trialky amines, procaine and dibenzylamine.

In the treatment of bacterial infections, the inventive antibiotic compounds for administration topically, orally or parenterally according to known methods of antibiotics administered. They are administered in unit doses that contain an effective amount of the active Ingredient together with suitable, physiologically acceptable carriers or diluents or excipients contain. The dosage units can be in the form of liquid Preparations such as solutions, suspensions, dispersions or emulsions or in solid form, such as powder, tablets and capsules are present «

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The invention therefore also relates to agents or compositions which contain an effective amount of the new penicillanic acid or cephalosporanic acid derivatives corresponding to the general formulas XVIII and EÜE ¥ or a non-toxic salt thereof together with a physiologically acceptable carrier or diluent * Such therapeutic Agents can also contain one or more therapeutically active ingredients in addition to a compound of the invention. The term ^ effective amount "as used herein means _s", based on the compounds described j a lot ₀ ,, oils sufficient to destroy the growth of susceptible microorganisms or inhibit, "when administered in a conventional manner, in other words, an amount _s which is sufficient _g -um the growth of bacteria to control ο the Wei * t or the size of the effective amount can easily by the skilled person according to standard methods for determining the relative Ik-Felio / feat of an antibacterial agent relative to sensitive I 'Microorganisms are determined using the various routes of administration available' -

Suitable carriers and. Yerdtlanungsmittel are any of the known ,, physiologically acceptable ingredients comprising serve ₉ may · the administration of the therapeutically active compound to erleichternο carrier also certain auxiliary functions have "cLISo as Yerdünnungsmittelg, flavoring or GeruchmaskierungsiBittelg binder delay agents or stabilizers act" Examples of carriers ₉ water which gelatin can contain gum arabic _{8 y} alginate _g dextran _P PolyirinjlpyrrolMIn or Matrlumcarboxymethyl _D-cellulose aqueous ethanol ₉ syrup _2, lsotonlsclie SaIzlösungen _P isotonisclie glucose ,, strength ", lactose, or other such materials commonly used in ^ the wan ptiaraazeutisehen and veterinarians antlbakterlellen means used",

The invention also provides a method to inhibit the growth of bacteria ₉ by contacting the

the occurrence of the bacteria, an effective amount of the antibacterial compounds described in the present application applies. For example, the method can be used to treat bacterial infections in animals by giving the host an effective amount of the invention antibacterial compound administered.

So that the penicillanic acid or cephalosporanic acid derivatives according to the formulas XVIII and XXIV are more suitable for absorption in the body, whereby their antibiotic activity is aged, the conversion of compounds of the formulas XVIII and XXIV, in which U is -OH, into special esters to be required. Preferred ester groups are, for example, those of the type -CH ₂ - 0 - CO - ¥, in which ¥ denotes an unsubstituted or substituted straight-chain or branched alkyl group with 1 to 8 carbon atoms, where the substituents are lower-alkoxy-, lower-alkylthio-, halogen- ( lower) alkyl, phenyl, ₃ cycloalkyl, nitro, amino, guanidino, carboxy, carbalkoxy, ₉ hydroxyl groups or haloalkenes occur.

The new penicillanic acid and. Cephalosporanic acid derivatives of formulas XVIII and XXIV can also be used as growth activators for ruminants such as cows. They are also very useful in iritro applications such as in disinfectants (for example, dairy barns) at concentrations of about 0.1 to 1 wt.% Of these agents, dissolved or suspended in a suitable inert carrier for use in the washing or spraying.

Furthermore, show some of the 3-sübst.-1,2,4-0xadiazol-5-ylacetic acids of formula I and in particular 3-benzyl-1 »2,4-oxadiazol-5-yl-acetic acid anti-inflammatory activity.

Other derivatives according to the invention which, according to known manufacturing processes, which are known per se are those of the general formulas

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■ "V

CH

XXXV

N-

CH

C -

XXXVI

N-

C - CH

Ii

Tm **.

C - CH C - N

ιι ·

XXXVII

wherein

R ^, Rp ₉ Z ^, Z ₂ > Z, iind Ζ »have the meanings given above,

Rr is a hydrogen atom, a (lower) alkyl group, denotes an aryl (lower) alkyl or a cycloalkyl (lower) alkyl group, and

Rg is a hydrogen atom, a (lower) alkyl, Phenyl group, a mononuclear 5- or 6-membered heterocyclic group Group, cycloalkyl group, an aryl (lower) alkyl or cycloalkyl (lower) alkyl group, the phenyl and cycloalkyl groups optionally with at most one of the substituents described above can be substituted, or in which

Rg denotes an amino group, optionally with (low) alkylcarbonyl, arylcarbonyl, mononuclear heterocyclic carbonyl or (low) alkoxycarbonyl groups sub-

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may be substituted, or in which

Rc and Rg together with the nitrogen atom to which they are attached, a 5- to 7-membered mononuclear heterocyclic ring such as a morpholino or piperidino ring mean.

Compounds of the classes of the last ester and amide derivatives corresponding to the formulas XII, XIII, XIV, and XXXV, XXXVI and XXXVII also show central depressive activity and can be used, for example, as anticonvulsants, muscle relaxants and tremor antagonists can be used. Continue to show Compounds of the class of the amide derivatives corresponding to the formulas XXXV, XXXVI and XXXVII activities against some species of fungi, for example against Trichophyton and Micro-

sporum strains.

The following examples illustrate the invention without restricting it.

example 1

Preparation of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid

A solution of 4.0 g (40.8 mmol) of 3,5-dimethyl-1,2,4-oxadiazole and 6.0 ml of N, N, N ·, N ^! -Tetramethylethylenediamine (TMEDA) in 100 ml of dry toluene is prepared in a 250 ml three-necked glass flask equipped with a thermometer, a gas inlet tube through which dry nitrogen is continuously introduced, and a dropping funnel with pressure compensation. The magnetically stirred solution is brought to -75 ° C with an acetone

ο The carbon dioxide bath has cooled down. Through the dropping funnel

oo a solution of approximately 40 mmoles of n-butyllithium. in 20 ml

Q η-hexane was added at a slow speed, around the Reakti - """- * onsmischung below -65 ° C to keep Subsequently, the Reako tion mixture v / urther 60 minutes at -55 to -6O stirred ⁰ C The..

co

tv> reaction mixture is then curved with a polished finish provided glass tubes into a second vessel, which contains powdered carbon dioxide and with a layer of it

is covered with dry dietary ether. After standing for a few hours, the carbon dioxide has practically disappeared from the mixture. 100 ml of water are added and then 1N hydrochloric acid is added with stirring until a pH of 8 is reached. The layers are separated, the organic layer is discarded, and the aqueous layer is shaken twice with 25 ml of dietary ether. The pH of the aqueous solution is adjusted to 2.0 with 1N hydrochloric acid. Seven extractions with approximately 25 ml parts of ethyl acetate at a pH of 2.0 result in an almost complete removal of the desired product from the aqueous layer. The extracts are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated in vacuo to a small volume until a crystalline, colorless precipitate appears. Thin-layer chromatography shows that the supernatant liquid still contains a considerable amount of the desired product and no by-products. The solvent is completely removed in vacuo. The practically colorless residue is dried to constant weight. Yield: 4.2 g (72%) ; Purity: at least 96% ₇ determined by TLC and PMR spectra

Recrystallization of the product occurs by dissolution in a small volume of chloroform, followed by slow addition of petroleum ether (bp. 80 to 11Q ⁰ C), until turbidity. The yield of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid after recrystallization is 3.6 g, melting point + 95 ° C. (slow decarboxylation begins at about 90 ° C.), pK value (loading

et

correct in water): 3 * 64.
Elemental analysis s C ₁ -HgNpO,

Calculated: C 42.26? £ H 4.26% M 19.71? » 0 33.77% Found s 42 ₉ 24 4.28 19.60 (33.88)

The partial analysis of the IR spectrum (KBr pellet _s values in cm " ¹ ): * 3450, 174O ₉ 1720, 1590, 1360, 1220. Thin-layer chromatography silicon dioxide plate, eluent a 10: 2: 1: 0" 2 mixture (expressed by volume)

from diethyl ether, ethanol, water and formic acid. Drying was done by blowing warm air over the plate. Yellow colored spots (Rf value approx. 0.7) after 5 minutes in a cylinder containing iodine crystals. Bluish spots after spraying with 15% starch solution in water. Partial interpretation of the mass spectrum: Since the compound decarboxylates easily, its molecular weight is indicated by a rather weak molecular ion peak at (M / e = 142). The decarboxylation product, namely 3,5-dimethyl-1,2,4-oxadiazole, is represented by M / e = 98. M / e 85, 59 and 57 probably mean the fragments N = CH ₂ COOH, CH ^ COOH and CH ₃ CNO and are further evidence for the assumed structure.

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

Example 2

Preparation of 3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl-

acetic acid

To a solution of 10 g of 3- (2,6-dichlorophenyl) -5-methyl-1,2,4-oxadiazole (mp. 83 to 85 ⁰ C) and 6.4 ml of TMEDA in 140 ml of dry toluene added dropwise a solution of approximately the equivalent amount of n-butyllithium in 22.2 ml of η-hexane in the course of approximately 30 minutes (the procedure is analogous to the procedure described in Example 1). The reaction temperature is -55 to -6O ⁰ C. After stirring the reaction mixture for an additional hour at about -6O ⁰ C to the mixture of powdered carbon dioxide, which is covered with dry lather Diäthy added. After standing for a few hours, water and dilute hydrochloric acid are added until a pH of 8.0 is reached; the layers are separated and the organic layer is extracted with 50 ml of water. The organic layer will

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discarded and the combined aqueous layers (approximately 300 ml) are washed twice with 100 ml of diethyl ether. Then the aqueous layer is washed three times with 100 ml parts Diethyl ether extracted at pH 2.0. The extracts are combined, washed twice with a small amount of ice water and completely evaporated in vacuo. The solid residue is first with n-heptane and then with a small volume Toluene stirred. After thorough drying in the desiccator, the end product weighs 7.6 g (6390, melting point 124.5 to 125.5 ° C.

PMR (60 Mc, CDCIz, tetramethylsilane as internal standard, £ -

Values in ppm)

CH ₂ : 4.09 (S, 2H), C ₆ H ₃ : 7.45 (almost one singlet, 3H).

Example 3

Preparation of 3- (2,4,6-trimethylphenyl) -1, 2,4-oxadiazol-5-yl-acetic acid

3- (2,4,6-Trimethylphenyl) -5-methyl-1,2,4-oxa- is used. diazole, (m.p. 20-30 ° C), as starting material. The 3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid is prepared according to the method described in Example 2. A powerful mechanical stirrer is used in the reaction using n-butyllithium. Yield 55.7%, m.p. 106 to 108 ⁰ C. IR (KBr pellet, values in cm ^"1): -. 3450, 1740, 1720, 1608, 1590 and the shoulder 1580, I365 and 1240..

PMR (60 Mc, CDCl ,, tetramethylsilane as internal standard, £ values in ppm): 2.13 (S, 6H), 2.30 (S, 3H), 4.07 (S, 2H), 6.92 (S, 2H).

Example 4

Preparation of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid

80 g (0.816 mol) 3,5-dimethyl-1,2,4-oxadiazole and 240 ml (1.6 mol) TMEDA are dissolved in 2050 ml dry toluene. The solution is cooled to -70 ° C, then one is gradually added approximately 20% solution (800 ml) of n-butyllithium in n-hexane

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(about 1.6 to 1.9 moles). The rate of addition is adjusted so that the reaction temperature varies between -60 and -65 ° C. The addition time of approximately 70 minutes is mainly consumed by the addition of the first equivalent of n-butyllithium. The reaction mixture is stirred for a further 60 minutes at -70 ⁰ C. The reaction mixture is then slowly poured into a mixture of finely powdered carbon dioxide and dry diethyl ether. After standing for about 3 hours, 1 liter of water is added to the mixture of solid and liquid. The contents of the reaction vessel are transferred to a separatory funnel. The aqueous layer is collected and since the solid is only partially dissolved, 250 ml of water is added to the mixture of salt and organic solvent. The mixture is shaken again and the aqueous layer is added to the first extract. This is repeated until all of the solid is dissolved in water. The organic layer is discarded and the alkaline aqueous layer is washed three times with diethyl ether. Concentrated phosphoric acid is then added until a pH of 2.0 is reached, and then the solution is concentrated in water at 60 ^° C. in vacuo to a volume of approximately 2 liters. During these steps, the mixture of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 1,2,4-0xadiazol-3,5-diacetic acid (contaminated with much smaller amounts of two or three were not identified By-products) already partially decarboxylated to 3,5-dimethyl-oxadiazo.l and 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid. Decarboxylation was completed by heating the acidic solution on a steam bath for 1 hour. The greater part of the desired product was extracted with three 300 ml portions of ethyl acetate. The remainder was extracted continuously with diethyl ether (16 hours). The collected organic layers were completely evaporated. The residue was dissolved in approximately 600 ml of diethyl ether, treated with activated charcoal, filtered and evaporated completely. The partially solid residue (54.6 g) was subjected to column chromatography (length 38 cm, diameter 5 , 7 cm) above silica

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subjected, with diethyl ether mainly used to remove the valeric acid. A fraction (1.6 g) with a product with a purity of over 90% and a fraction in an amount of 37.4 g with a purity of over 95% were obtained. The latter amount was recrystallized from toluene / n-heptane. Yield 34.2 g (29%) of 5-methyl-1,2,4-. oxadiazol-3-yl-acetic acid with a minimum purity of 97% ί melting point 101 to 103 ° C (final melting point) above 70 ° C sublimation, melting and resolidification. ( ⁺ calculated by TLC and PMR), pK value (determined in water): approx. 3.4.

Thin layer chromatography: same system as in example Rf value approx. 0.25 · The oxadiazol-3-yl-acetic acid is essential less sensitive to the identification system as its isomer.

Analysis of the PMR 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, 6 values in ppm, tetramethylsilane as internal standard):

2.58 (S, 3H), 3.78 (S, 2H), 10 (S, about 1H). Partial analysis of the IR spectrum (KBr pellet, values in cm); +3450, 1740 and 1720, 1595, 1430, 1415, 1395, 1380, 1225. In the same way - of course adapted to the individual case - other 1,2,4-0xadiazol-3-yl-acetic acids were produced, for example

5-Benzvl-1 ₁ 2,4-oxadiazole-3-vl-acetic acid . Mp 109-111.5 ° C. If 13 g of 3-methyl-5-behzyl-1,2,4-oxadiazole are used, 5.8 g (34%) of pure compound are obtained. During the implementation, 2 equiv. n-Butyllithium, dissolved in η-hexane, slowly. to the solution of the oxadiazole and 2 equiv. TMEDA in toluene at -75 to -80 ⁰ C given. The resulting reaction mixture is additionally stirred for 6 hours at -78 ° C. and then poured onto finely powdered carbon dioxide. The reaction product is poured into about 600 ml of water, then the pH is adjusted to about 7.0, the layers are separated, and the organic layer is washed once with water. The solution in water is purified by continuous extraction with diethyl ether at pH 8.0 for 5 hours, acidified to pH 5.2 and then in vacuo at un-

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Concentrated about 45 ° C until a volume of about 300 ml is reached. The pH is adjusted to 7.0, then it is filtered with a pump. The pH is adjusted to 1.8, then extraction is carried out continuously with dichloromethane for 16 hours. The solvent is removed and the residue is dissolved in a small amount of water, then extracted with a 1: 1 mixture of diethyl ether and ethyl acetate at pH 1.8. The finished extract is evaporated in vacuo and the residue is crystallized from diethyl ether. As stated later in the application, the primary product [a- (5) -phenyl-1,2,4-oxadiazole-3,5-diyl-bis-acetic acid] is subjected to selective decarboxylation under relatively mild conditions. It was found, however, that it can also be obtained by extraction at room temperature and subsequent purification by column chromatography ^ see also remarks in Example 39) · IR (KBr pellet, values in cm " ¹ ): +3400, 1725, 1580 , 1495, 1460, 1410, 1380, 1330, 1225, 1190, 960, 940, 840, 820, 780, 730, 710. PMR (CDCl, and a trace of dg-rDMSO, 60 Mc, TMS, S values in ppm): 3.75 (S, 2H), 4.21 (S, 2H), 7.3 (S, 5H), about 8.9 (S, 1H).

5-ethyl-1,2,4-oxadiazole-5-vl-acetic acid : m.p. 58 to 60 ° C

89.6 g of 3-methyl-5-ethyl-1,2,4-oxadiazole and receives 28 g (21%) of pure product after incomplete in situ decarboxylation of the primary product, oc- (5) -methyl-1,2,4-oxadiazol-3,5-di-yl-bis-acetic acid is a relatively stable connection. The reaction conditions were analogous to those of the conditions described above, but the addition of the solution of n-butyllithium was extended to a period of 8 hours. The reaction vessel was then closed and kept at -78 ° C. overnight. After the reaction with solid carbon dioxide the reaction mixture was neutralized as usual. After separating the layers, the organic layer became discarded, the water layer acidified to pH 2.0 and heated on a steam bath for 3.5 hours. The pH was on 8.0 adjusted, the solution in water in a vacuum to un-

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about half of its volume was concentrated. The unusual Salts were separated by filtration and the filtrate (pH 8.0) was washed with diethyl ether for 5 hours extracted continuously.

The pH was then adjusted to 5.0, followed by continuous extraction with n-heptane for 30 hours. The solution in water was acidified to pH 2.5, saturated with sodium chloride and extracted 5 times with equal volumes of acetone. These extracts were combined and activated charcoal was added, with half the volume being removed by distillation at atmospheric pressure. After filtration, the filtrate was evaporated and the residue was subjected to column chromatography on silica over n-hexane / chloroform. The pure fractions were combined and evaporated in vacuo. The remaining oil was dissolved in a small amount of ether by volume, the solution was filtered and. evaporated to dryness. The colorless oil slowly solidified on standing. IR (ibidem): ^ 350O and ^ 260O ₅ 300O ₅ -2960, 1730, 1580, 1465, 1425, 1380, 1360, 1300, 1210-1230, 119O ₉ 900, 825, 805, 725 · PMR (CDCl ₃ , 60 Mc, TMS, S values in ppm): 1 _s 40 (T, J = 7 ₉ 5 cP, 3H), 2.92 (Q, J = 7.5 cP, 2H), 3β4 (S, 2H), about 8 _S 6 (S, 1H).

Example 5

Preparation of methyl 3-methyl-1,2,4-oxadiazol-5-yl acetate

A solution with an excess of diazomethane in diethyl ether is added to a stirred, cold (approximately 2 ° C.) solution of 14 g of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in 500 ml of diethyl ether. After the initial vigorous evolution of nitrogen has ceased, the solution ₅ on the steam bath to about 250 ml concentrated "The solution is washed with 3 times 100 ml water. The washing solutions are combined, the pH is adjusted to 9> 0 and then they are extracted with diethyl ether to obtain part of the product which dissolved in water during the washing. The combined ether extracts were returned by a water

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Filtered holding paper filter and then evaporated in vacuo. The residue was kept at 8 mm for 1 hour, 14.8 g of oil were obtained. The yellow oil was distilled at 0.4-0.5 mm. The collected fraction with a boiling point from 70 to 71 ° C contained methyl-3-methyl-1,2,4-oxadiazol-5-yl

acetate, weight 12.3 gn ^ ⁵ = 1.4472.

PMR (60 Mc, CDCl ₃ ), TMS as internal standard, £ values in ppm)

2.38 (S, 3H), 3.76 (S, 3H), 3.99 (S, 2H).

IR (NaCl window, values in cm " ¹ ): 3020, 2985, 2870, 1760 and

1600.

Example 6 -

Preparation of sodium DL-6 - [(a ~ phenyl-3-methyl-1,2,4-oxadiazol-5-yl) acetamido] penicillanate

A solution of approximately 9 ml of n-butyllithium in a mixture of 4.5 η- hexane and 4.5 ml of toluene was added dropwise at -95 to -90 ⁰ C. The resulting liquid reaction mixture is then stirred at -90 ° C. for 30 minutes. A solution of 2.6 g (8.3 mmol) of trimethylsilyl-6-isocyanatopenicillanate in 10 ml of tetrahydrofuran is then slowly added dropwise, and the reaction temperature is kept slightly below -90.degree. After having stirred for a further 30 minutes at -90 ⁰ C, 1.2 ml of trimethylchlorosilane are added with a pipette. The resulting, still clear solution is stirred for a few minutes at approximately -80 ° C. and then poured into 25 ml of ice-water. A dilute sodium hydroxide solution is added until a pH of 7.0 is reached. The layers are separated, the organic layer is discarded and the aqueous layer is shaken twice with 30 ml of diethyl ether. The aqueous layer is acidified to pH 4.5 and re-extracted three times with 20 ml of diethyl ether.

Three further extractions were carried out at a pH of 5 with 20 ml of ethyl acetate each time.

. 40983Oi

The acidic organic layers were combined, washed twice with a small volume of ice-water, over anhydrous Dried magnesium sulfate, filtered and concentrated in vacuo to approximately 5 ml. A small excess of sodium c-ethyl caproate, dissolved in a small volume of acetone was added in the cold. The resulting solutions were treated with an excess of diethyl ether, resulting in precipitation of a colorless solid with it. The solid was separated off by filtration and washed several times with cold, washed dry diethyl ether. Yield 760 mg. The product was somewhat contaminated with sodium a-ethyl caproate and contained it 2 moles of water. The D / L ratio was approximately 1: 1.

Analysis of the PMR spectrum of a solution of the penicillanate end product in ad> -dimethyl sulfoxide (2 microdrops of added DCO ₂ D, 60 Mc, δ "values in ppm, 2 ₉ 2-bimethylsilapentane-5-sulfonate as internal standard) s 1.46, 1.52 _? 1.56 and 1.62 (about 6h) _s 2 ₉ 34 (S, 3H), 4.22 (2 singlets, cfv? = 1.2 cP, 1H) ₅ + 5 _ΰ 5 C-quartet-like "2Ii) /. 5.67 (partially deuterated, broadened singlet) _P + 7 ^ 4 (5H), approximately 9.15.

B_e i S _n ρ i _iM e I ₁ 7

Preparation of 7 ™ [(3-Benz3rl-1,2 ₉ 4 = oxadiazol-5-yl) -acetamido] -des-aoetoxy-cephalosporanic acid

To a solution of 1 ₉ 74 g (10 mmol) 3 = 3enzyl »5-methyl-1,2,4-oacadiagol in a Mlschuag of 20 ml of dry toluene and 5 ml of dry tetrahydrofuran is added 1.5 ml (10 mmol) TMEDA. Looking at. is the Lösumg on = 100 ° G-cooled Thereafter a solution of 10 mmol of n-langefähr Butyllithitam in 5 ml ■ η-hexane dropwise feei = 100 ms is added to -105 ⁰ C and intestine is an additional hour at ⁰ +5 C = 100 stirred »A solution of 2 j 81 g (9 mmol). Tz = ⁱ imethylsilyl 7 '° isocyanato "iesacetoxy cephalosporanate ° in a mixture of 20 ml toluene and 5 ml of tetrahydrofuran is added dropwise at temperatures below -95 ⁰ C» The resulting reaction mixture is stirred for 90 minutes at -95 ⁰ C and to it during stirred for about 15 minutes,

h ! J α 'Cs α ϊ. » i IU & £

slowly increasing the temperature to -85 ° C. The reaction mixture is then poured into a well-stirred mixture of 25 ml of ice-water and 25 ml of ethyl acetate. Dilute hydrochloric acid is added at the same time to keep the pH close to 4. After stirring for a few minutes, the pH is increased to 7.0 and the layers are separated. The organic layer is discarded and the aqueous layer is extracted twice with 80 ml of ethyl acetate at pH 6.5 and 6.0, respectively, this entails the removal of by-products and the removal of a small amount of the desired product. The greater part of the desired product is removed from the aqueous layer by six extractions with 40 ml of ethyl acetate, the pH value being gradually reduced from 6.0 to 4.5. These extracts are combined, washed twice with a small volume of ice-water, treated with activated charcoal, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue is triturated with diethyl ether, filtered with a water pump, washed with cold ether and dried in vacuo. Yield 1.0 g (25%) of colorless plague. The purity of the final desacetoxy-cephalosporanic acid is estimated to be approximately 90 to 95% according to TLC and FMR. IR (KBr pellet, values in cm "* ¹ ) s £ 3500 and +2600, 3280, 1780, 1720, 1670, 1590, 1550, 1495.

PMR (60 Mc, dg-DMSO, 2,2-dimethylsilapentane-5-sulfonate, ζ " values in ppm): 2.06, (S, 3H), 3.5 (Q, ^^ 17.5 cP, 2H), 4.06 (S) and 4.10 (S) together 4H ₉ +5.1 (D, J = 4.6 cP, 1H), +5.6 (Q, J = 4.6 cP, J '^ 8.0 cP, 1H), 7.35 (S, 5H), 9.3 D, 0 cP, 0.8H).

Example 8

Preparation of N-phenyl-3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetamide

Α09830 / Ί082

(a) Preparation of an acid chloride-like, reactive intermediate of 3- (2,4,6-trimethy! phenyl) -1,2,4-oxadiazol- 5-yl-acetic acid -

A solution of 250 mg (1 mmol) 3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid, 0.005 ml of DMF and 0.11 ml of pure thionyl chloride in 5 ml of carbon tetrachloride is taken under heated to reflux for 1 hour under anhydrous conditions. Different Samples were taken at various time intervals. Carbon tetrachloride is removed by going over the samples pass dry nitrogen »Then the residues are dissolved in anhydrous chloroform and the IR spectra are determined to check the progress of the implementation »It is evident that the reaction mixture should not be refluxed for more than 10 minutes (3 to 5 minutes is sufficient). The reactive created Intermediate product is not the acid chloride as such, but a reactive intermediate product

This reactive intermediate still gives the expected amides in moderate yields when reacted with the amines. The empirically determined changes in the IR spectra are as follows: The characteristic feature of a solution of the starting acid in chloroform is a monomeric OH at 3500, a dimeric OH around 3000 to 3200, monomeric C = O (shoulder) at +1760 and dimeric C = O at 1730 cm "" ¹ . After refluxing for 3 minutes, ₉ both the OH bands and the C = 0 bands at 1760 cm " ¹ disappear completely. A sharp and intense absorption at 1740 cm remains, which is characteristic of the reactive compound. Reflux times that are greater than about 10 minutes result in a decrease in the absorption at 1740 and at least four more absorptions occur between 1660 and 1800 cm, one of these (at 1790) possibly representing the true acid chloride.

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(b) Preparation of the anilide of 3- (2,4,6-tri - .me thy! phenyl) - 1 _t 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 approximately 0.005 ml of dimethylformamide. The mixture is refluxed for 3 minutes. Then 0.3 ml of aniline is added and then the mixture is boiled for 5 minutes. The mixture is evaporated in vacuo. 35 ml of toluene and 25 ml of water and likewise dilute hydrochloric acid are added to the residue until a pH of 1.5 is reached. After separating the layers, the organic layer is washed with 20 ml of 4N hydrochloric acid and then with 25 ml of water. The organic layer is evaporated completely and the residue is dissolved in ethanol and treated with activated charcoal. The resulting colorless solution in ethanol is evaporated again and the colorless, crystalline residue is washed with n-heptane and dried in vacuo. The IR and PMR spectra confirm this structure. ΈΜ. (60 Mc, CDCl ^ + dg-DMSO, TMS as internal comparison, ^ "values in ppm): 2.16 (S, 6H), 2.31 (S, 3H), 4.18 (S, 2H) , about "5.1 (broad, about 1H), 6.91 (S) and about 6.8 to 7.8

(Multiplet) together 7H

IR (KBr _T values in cm " ¹ ): 3300, 1660, 1600, 1580, 1545, 1355 and

1240.

Example 9

Preparation of 7- £ [3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl] -acetamidoJ · -cephalosporanic acid

967 mg (3.66 mmol) of 7-aminocephalosporanic acid (7-ACA), suspended in 20 ml of ethyl acetate, are used as starting material, and a mixture is made with a major amount of N, 0-bis-trimethylsilyl-7-ACA and a minor amount * by adding amount of trimethylsilyl 7-amino-cephalosporanate forth in the usual manner successively 1.02 ml (7.32 mmol) of triethylamine and 0.92 ml (7.32 mmol) trimethylchlorosilane at 5 ⁰ C, Toggle

. 409830/1082

then stirred for a further 30 minutes at 30 ° C. To the received 0.43 ml (3.66 mmol) of quinoline are added to the reaction mixture.

In the meantime, 900 mg (3.66 mmol) of 3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid are converted into the reactive intermediate according to the procedure described in Example 8A, using 15 ml of dry carbon tetrachloride _9, 0.4 ml of thionyl chloride and approximately 0.02 ml of dimethylformamide. ' After refluxing for 5 minutes, the purple-colored solution is completely evaporated in vacuo and the residue is dissolved in 6 ml of dry ethyl acetate.

The resulting solution is quickly added to the first solution after this solution has returned to room temperature (approximately 20 ° C). The addition of the "acid chloride results in a temperature rise of about 5 ⁰ C. Then the reaction mixture for 30 minutes' stirring at 30 ° C.

The -Reaktionsmischung is poured into 175 ml of ice-water and the pH * = value is adjusted to 7 ₉ O _"9 The layers are separated, the organic layer is discarded and the v / äßrige layer is washed twice with 50 ml of diethyl ether Tellen . The aqueous layer is adjusted to pH 3.7 and then extracted four times with 25 ml portions of ethyl acetate. The extracts obtained in this way are combined, washed with a small volume of ice-water, treated with activated charcoal, filtered, dried over anhydrous magnesium sulfate and filtered again using a water pump. The complete evaporation of the almost colorless. The filtrate and thorough drying of the residue in vacuo yields 650 mg of solid product «, This product is not completely pure according to the layer chromatography, the crude product is purified by column chromatography» However, the IR spectra of the raw and pure differ. Product hardly.

330/1012

IR (KBr pellet, values in cm " ¹ ): +3500 and +2600, 3280, 1780, 1735, 1700, 1660, 1610, 1575, 1540, 1380 and / or 1355 and 1230 (very intense).

Example 10

Preparation of 7 - [(3-methyl-1,2,4-oxadiazol-5-yl) acetamido] cephalosporic acid

Dry conditions are continuously maintained by blowing dry nitrogen over the surface of the liquid Reaction mixture conducts. A solution of 10 mmol of trimethylsilyl-7-isocyanato-cephalosporanate in 19 ml of toluene quickly becomes a solution of 1.42 g (10 mmol) of crude (92-95% Purity) and possibly slightly moist 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid given in 25 ml of dry dichloromethane. The solution also contains 0.05 ml of N-vinyl imidazole (as a catalyst). One is relative of the rapid formation of carbon dioxide and of the rapidly formed precipitate quick implementation recognizable. The precipitate gradually dissolves as the reaction proceeds. The precipitation is · - .. .. the sparingly soluble mixed anhydride, which is formed by adding 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 passed through the catalyst activated. '

After stirring for 4 hours at room temperature, developed hardly any carbon dioxide. The dichloromethane was removed from the solution by concentration in vacuo. the The remaining solution was slowly poured into a well-stirred mixture of 50 ml ice water and 50 ml ethyl acetate, while simultaneously adding dilute sodium hydroxide to maintain the pH at 7.0. The layers have been separated the organic layer was discarded and the aqueous layer was washed several times with ethyl acetate starting at pH 5.5, and then at pH 5.0, 4.5.4.0.3.5 and finally

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• - 44 -

at. pH 3, ο, extracted to a separation between the desired Product and the relatively small amount of by-product, namely NjN'-dicephalosporanyl urea. the Extracts from pH 5.5 to 4.5 containing only small amounts of the desired And the pH 3.0 aqueous layer which still contained some of the product was discarded.

The extracts from 4.0 to 3.0 were combined, washed with a small volume of ice-water, dried over anhydrous magnesium sulfate, filtered and evaporated completely in vacuo. The residue was triturated with diethyl ether, filtered with a water pump and washed with diethyl ether. After being thoroughly dried in vacuo to give 2.3 g (about 58% yield) of the crystalline solid final product "Since it contained a maximum of 5 mol% urea, was the purity of the final product more than 90 wt. ^ _5, by TLC and PMR. IR (KBr pellet, values in cnf ¹ ) s +3500 and +2600, 3285, 1780, 1740, shoulders at +1720 and 1710, 1390 and / or 1350, 1230.

PMR (60 Mc, dg-DMSO, 2,2-dimethyl-silapentane-5-sulfonate as internal standard), <5 * values in ppm): 2.05 (S _f 3H), 2.34 (S, 3H ), 3.6 (broad S, 2H), 4.05 (S, 2H), 4.87 (Q, J _Aβ = 12.7 cP) and + 5.2 (D, J = 4.7 cP) together 3H, + 5 ₉ 7 _£ (Q, J = 4.7 and J «= 8.2 cP, 1H), + 9.3 (D, J ⁸ = 8.2 cP, approx. 0.8H).

Example 11

The following penicillins, cephalosporins, and desacetoxycephalosporins were prepared according to the procedure described in Example 10, using the appropriate one 1,2,4-oxadiazole acetic acid and trimethyl

silyl ester of β-isocyanatopenieillanic acid (6-IPA) or 7-aminocephalosporanic acid or 7-isocyanato-deacetoxy-cephalosporanic acid (7-IDCA) used as the starting material

409830/108 2

Ä. 6- / [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] acetamido ^ -penicillanic acid,

B. 6- [(3-Methyl-1,2,4-oxadiazol-5-yl) -acetamido] -penicillanic acid, sodium salt.H ₂ O,

C. 7- £ [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] acetamido / -cephalosporanic acid,

D. 7-C (5-methyl-1,2,4-oxadiazol-3-yl) -acetamido] -cephalosporanic acid,

E. 7 - / [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] -aeetamidoj " -desacetoxy-cephalosporanic acid,

F. 7 - [(3-Methyl-1,2,4-oxadiazol-5-yl) -acetamido] -desacetoxycephalosporanic acid,

G. 6 - [(3-Ethyl-1,2,4-oxadiazol-5-yl) acetamido] penicillanic acid, Sodium salt HgO,

Ho DL-6- [α-Methyl-0-methyl-1,2,4-oxadiazol-5-yl] -acetamido ] penicillanic acid,

I. DL-7-E cc-methyl-0-methyl-1,2 _f 4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid,

K. DL-7-C α-methyl-0-ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid,

L. 7 - [(3-Ethyl-1 ^^ - oxadiazol-S-ylI-acetainidoj-cephalosporanic acid and

M. 6- [a-Methyl-0-ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -penicillanic acid, sodium salt · H ₂ O.

With a few exceptions listed below, all reactions were carried out at room temperature (approximately 20 ° C) equimolar amounts of isocyanate and carboxylic acid and carried out with 5 to 10 mol% of catalyst N-vinyl imidazole. The isocyanates the trimethylsilyl esters of 6-APA and 7-ADCA were used as solids in over 90% pure state. Trimethylsilyl-7-isocyanato-cephalosporanate was in the form of good quality as stable solutions in toluene with a predetermined Salary used.

For each example, the reaction media, the appropriate reaction times and indications of the purity of the end products,

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the yield and the IR (KBr pellet, values in cm "") and / or the PMR spectra (60 Mc, dg-DMSO, 2,2-dimethylsilapentene-5-sulfonate as internal standard, t values in ppm ) specified. The isolation procedures were similar to those described in Example 10, but adapted to the individual compounds. The indicated yields were obtained in all cases in the first attempt. The yield figures therefore have no absolute value.

A. dichloromethane, 2 hours, isocyanate in 10 mol% excess, slightly yellowish crystals, purity at least 95%, yield

(based on the acid, 80% based on the isocyanate). IR: +3500 and +2600, 3300, 1780, + 1730, 1680, 1580, 1560, +1 540, 1430, 1380, 800 and 785.

PMR: 1.5 and 1.65 (two singlets, 6H), 4.3 (overlapping singlets, 3H), + 5.6 (multiplet, 2H), 7.7 (narrow, split Signalei 3H) and 9.25 (D, J >> 8.5 cP., 0.8H).

B. dichloromethane, 2 hours, colorless, crystalline solid, purity over 90%, yield 52%.

IR: + 3350, + 3400 to 3600, 1780, 1690 _s 1620, + 1570, 1400, 1380 sh, 1350 sh, 1330 and 1250.

PMR: 1.51 and 1.62 (2 singlets, 6H) ₉ 2 _S 55 (S, 3H), 4.07 (S, 2H), 4.2 (overlapping singlets, + 3H) ₉ 5 »45 ( Center of multiplet _S 2H) s 9.1 (D, J ^? 8.5 eP, 0 _s 8H).

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

IRs + 3500 and + 2600, 3300, 178O ₉ 1735, shoulders at + 1720 and 1700, 1680, 1580, 1560 _s + 1540, 1435 _P 1410 sh, 1380, 1350, 1230 (very intense), 795 and 785. PMR: 2.07 (S, 3H), 3.6 (broad S, 2H), 3 * 76, 4.29 (S, 2H), 4 ^ 92 (Q, J ^ = 12.7 cP) and + 5, 2 (D, J = 4.7 cP) together 3H, + 5.75 (Q. * J = 4.7 and J ¹ = 8 _g 0 cP, 1H), 7 ₃ 7 (narrow, split signals, 3H) and 9.45 (D, J ¹ = 8.0 cP, 0.8H).

D. Dichloromethane-toluene-tetrahydrofuran mixture, 7 hours, purity over 90%, yield 10%.

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

PMR: 2.05 (S, 3H), 2.58 (S, 3H), 3.6 (broad S, 2H), 3.76, 4.90 (Q, J _AB = 12.7 CP) and + 5.15 (D, J = 4.7 cP) together 3H, + 5.7 (Q, J. 4.7 and J ¹ = 8.0 cP, 1H) and 9.2 (D, J '= 8 , 0 cP, 0.8H).

E. dichloromethane, 6 hours, catalyst, N-vinylimidazole and a trace of 4-methoxypyridine-N-oxide.1H20, purity over 95%, yield over 90% (based on the acid, over 80% based on the isocyanate, which was used in 10% excess).

IR: + 3500 and + ^ 00, 3300, 1778, + 1700 (broad, intense), 1580, 1560, 1540, 1440, 1410 sh, 1380 sh, 1360, + 1240, 800 and 790 sh.

PMR: 2.08 (S, 3H), 3.5 (Q, J _Aβ ^ r17.5 cP, 2H), 4.29 (S, 2H), + 5.15 (D ₉ J = 4.5 cP , 1H), + 5.65 (Q, J = 4.5 and J »= 8.0 cP, 1H), 7.7 (narrow, split signals, 3H) and 9.4 (D, J ¹ = 8 , 0 cP, 0.9H).

F. dichloromethane, 2 hours, purity at least 95%, yield 68%.

IR: + 3500 and + 2600, 3300, 1785, 1720, 1665, 1635, 1595,

1550, 1435, 1400, 1370 (strong), 1345 and 1240.

PMR: 2.06 (S, 3H), 2.34 (S, 3H), 3.5 (Q, J _AB ^ 18 cP, 2H),

4.06 (S, 2H), + 5.1 (D, J = 4.5 cP, 1H), + 5.6 (Q, J = 4.5 and J '= 8.0 cP, 1H) and 9.3 (J * = 8.0 cP, 0.9H).

G. dichloromethane, 5 hours, colorless, crystalline solid, purity at least 90%, yield 60%.

IR: + 3450, + 3300, 1780, 1685, 1600, 1580 and 1560.

PMR: 1.25 (T, J = 7.5 cP, 3H), 1.51 and 1.61 (2 singlets, 6H),

2.7 (Q, J = 7.5 cP, 2H), 3.98, 4.03 (S) and 4.08 (S) together about 5H, 5 * 45 (center of a multiplet, 2H) and 9.1

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(D, J about 8.5 cP, 0.9H).

H. dichloromethane, 2 hours, slightly 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 / y '= 1.3 cP, 1H), 4.33 (Q, J = 7.5 cP, 1H), approx 5.2 to 5.6 (multiplet, 2H) and 9.1 (2 overlapping doublets, 0.8H).

I. Dichloromethane-toluene mixture, 9 hours, a little more colored

Solid, purity about 90%, yield 40%.

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

EMR: 1.48, 1.50 and 1.62 (2 doublets, SQ about 1.2 cP, J = 7.2 cP, 3H), 2 ₉ 06 (S, 3H) ₉ 2.35 (S, 3H) ₉ 3.6 (broad S, 2H)

4.25 (2 quartets, £ 0 approx. 1.2 CP ₉ J = 7 * 2 cP _s 1H), 4.90 (Q, J _AB = 12.6 cP) and + 5.2 (2 doublets, <i \ ? approx. 1.0 cP, J = 4.8 cP) together 3H, + 5 ₃ β5 (2 multiplets, 1H), 9.35 (2 doublets, cTvWf. 4 cP ₉ J ^! approx. 8 cP, 0, 8H),

K. dichloromethane-toluene mixture, 10 hours, colorless solid, Purity over 90%, yield 45%.

IR: + 3500, + 2600, 3300, 1785, 1745, shoulders at 1725 and 1705, 1660, 1585, 1560 and 1235 (very intense). PMR: 1.4 (T, J = 7.5 cP, 3H) ₉ 1 ₃ 55 (2 doublets, -fjimget. 1.6 cP, J β 7.2 cP, 3H), 2.06 (S, 3H ) ₅ 2.75 (Q-,. J = 7 _S 5 cP, 2H), 4.25 (2 quartets, S v> approx. 1.2 eP _s J = 7.2 cP, 1H), 3.6 (broad S, 2H), 4.90 (Q, J _AB = 12.6 cP), + '5.15 (2D, $ \? <1.0 cP, J = 4, a.cP) ₅ together' 3H, ± 5.7 (2 multiplets, 1H) and 9.35 (2 D, £ \? About 3.5 cP, J «about 8 cP, 0.8H) ₀

L. dichloromethane-toluene mixture »9 hours ^ crystalline solid, purity approx. 95%, yield 60%, IR: + 3500 and + 2600, 3300» 1780, 174O ₉ shoulders at 1720 and 1705, 1665 _S 159O ₉ 1550 and + 1240 (very intense). Pm; 1 _S 25 (T ₉ J = 7.5 cP, 3H) ₉ 2.06 (S, 3H) ₃ 2 * 75 (Q ₉ J = 7.5 cP _s 2H) ₅ 3.6 (broadly S, 2H) ₉ 4 ₅ 07 (S _p 2H), 4 _s 90 (Q,

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12.8 cP) and + 5.15 (D, J = 4.7 cP) together 3H, + 5.75 (Q, J = 4.7 cP and J ¹ = 8.0 cP, 1H) and 9, 35 (D, J ¹ = 8.0 cP,

0.8H).

M. dichloromethane, 4 hours, crystalline solid, purity

about 95%, yield 30%.

IR: + 3500, + 3350, 1785 and 1775, 1680, + 1600, 1580 and

+ 1550.

PMR: 1.25 (T, J = 7.5 cP, 3H), approx. 1.4 to 1.7 (6 lines, 9H), 2.75 (Q, J = 7.5 cP, 2H), 4.09 (2 singlets, S \> = 1.7 cP, 1H), 4 .34 (Q, J = 7.2 cP, 1H), about 5.2 to 5.6 (multi

plet, 2H) and 9.1 (2 doublets, 0.8H).

Example 12

The following substituted 1,2,4-0xadiazol-5-yl-acetic acids were made by procedures that were identical or were analogous to those used in Examples 1 and 2, adding a slight excess of 3,5-disubst.-1,2,4-oxadiazole with the 1: 1 complex of n-Butyllithium with OMEDA in a toluene / n-hexane mixture (or alternatively with n-butyllithium in a tetrahydrofuran / n-hexane mixture) reacted and then reacted the intermediate product 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-1,2j-4-oxadiazol-5-yl-acetic acid

D. a-Methyl-3-ethyl-i, 2,4-oxadiazol-5-yl-acetic acid

E. 3-Methoxymethyl-1,2,4-oxadiazol-5-y! -Acetic acid.

For each product below is the first 1,2,4-oxadiazole, the method of how to react with lithium, the solvent mixture, the reaction temperature and the approximate reaction time of the lithium conversion, the signs for the purity of the end product, the melting points in the case of solid end products and the IR spectra (KBr pellet, Values in cm) and / or the PMR spectra (60 Mc, CDCl-zfTetra-

. 409830/1082

methylsilane as an indoor standard. <Γ values in ppm). The recovery numbers are not a final value as they are from the first or second attempt.

A. 3-Benzyl-5-methyl-1,2,4-oxadiazole (6.95 g), n-butyllithium / THF-hexane to -80 ⁰ C, 80 minutes. Crude yield 4.3 g. To. Crystallization from toluene (dissolved at 60 ⁰ C) 3.6 g (4i%), mp. 106 to 109 ° C (with slow decarboxylation), purity over 96%.

IR: + 3430, 1730, 1585, + 1600 sh, 1498, 1420, 1390, 1365, 1300, 1248, 1230, 1215, 1165, 720 and 705-PMR: 3.87 (S, 2H), 4.06 (S, 2H), 7.27 (S, 5H), ^ 9.8 (S, approximately 1H),

B. 3-Ethyl-5-methyl-1,2,4-oxadiazole (22.4 g), n-butyllithium, TMEDA / toluene-hexane, -70 to -80 ° C, 2 hours, yield 16 g (50%), purity over 96%, melting point 86 to 90 ° C (with slow decarboxylation), crystallization (not required) possible by dissolving in a small amount of a 2: 1 mixture of carbon tetrachloride and chloroform at approximately 45 ° C and then slowly adding hexane.

IR: + 3440, 1730, 1715 and 1580

PMR: 1.35 (T, J = 7.5 cP _s 3H), 2 _S 8 (Q, J = 7.5 cP, 2H), 4.04

(S, 2H), ^ 10.4 (approx. 1H).

C. 3-Methyl-5-ethyl-1,2 _s 4-oxadiazole (22.4 g), n-butyllithium, TMM) A / toluene-hexane, -70 ° to -80 ⁰ C ₈ 1.5 hours Yield 7 g (22%), purity over 96% _? Mp. 64.5 Ms 65 ° C (slow decarboxylation begins at 57 ° C).

IRi + 3450, + 1730, 1600

FMR: 1.70 (D, J = 7.5 cP _s 3H), 2.41 (S, 3H) ₈ 4.16 (Q, J =

7.5 cP, 1H), ^ 9.6 (S, approx. 1H).

D. 3,5-diethyl-1,2 _s 4-oxadiazole (24.2 g), n-butyllithium, TMEDA / toluene-hexane _f -70 ° to -80 ⁰ C, 3 hours, yield 18.1 g (approx «53%) s? Purity approx. 95% (contains a small amount of valeric acid), m.p. 30 to

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IR: + 3500, + 2600, + 1740, 1580

PMR: 1.35 (T, J = 7.5 cP, 3H), 1.70 (D, J = 7.5 cP, 3H), 2.75 (Q, J = 7.5 cP, 2H), 4.6 (Q, J = 7.5 cP, 1H) and ~

(S, about 1H). - ■

.75 (.7 (S, about 1H).

E. 3-Methoxymethyl-5-methyl-1,2,4-oxadiazole (40 g), n-butyllithium, TMEDA / toluene-hexane, -75 to -8O ⁰ C, 150 minutes, yield 31.5 g (approx 58%) , purity over 96%, melting and excessive decarboxylation between about 50 and 75 ° C. IR: + 3450, 1725, 1590, 1410, 1395, 1360, 1335, 1325, 1240, 1210 sh, 1195, 1170, 1005.

PMR: 3.45 (S, 2H), 4.07 (S, 2H), 4.59 (S, 2H) and 10.65 (S, approx. 1H).

Example 13

Preparation of sodium 6 - [(5-methyl-1, '2,4-oxadiazol-3-yl) acetamido] penicillanate

1.42 g (10 mmol) of 5-methyl-15 2,4-oxadiazol-3-yl-acetic acid are added to 20 ml of dry tetrachloride. 1 ml of thionyl chloride and 2 drops of dimethylformamide are added to the suspension at room temperature. The mixture is gently boiled for 10 minutes, a clear solution being obtained and the substituted acetic acid being completely converted into its acid chloride.

At the same time, a suspension of 2.15 g (10 mmol) of 6-amino-penicillanic acid in 30 ml of dry ethyl acetate is used

* · »2.8 ml (20 mmol) triethylamine and 2.5 ml (20 mmol) trimethyl

cd chlorosilane and then treated for 30 minutes at

^ Stirred at room temperature. First adding to this mixture ° 1, 2 ml (10 mmol quinoline and then the solution of the acid -. * Chloride in carbon tetrachloride, the first addition of the dissolved acid chloride results in a temperature increase of about 10 ⁰ C. to about 30 ° C. The reaction mixture is then stirred for 30 minutes and then poured into 50 ml of ice-water, the pH is adjusted to 7.0 and the layers become

separated, the organic layer is discarded and the aqueous layer is extracted 1 time with 30 ml of diethyl ether. In order to obtain the desired penicillin, the aqueous Layer 6 times at pH 3 * 0 with a 1: 1 mixture extracted from diethyl ether and ethyl acetate. The organic layers are combined, 2 times with a small volume Washed in ice water »treated with activated charcoal, over dried anhydrous magnesium sulfate, filtered and concentrated in vacuo to a volume of approximately 20 ml. 40 ml Diethyl ether are added and then a solution of sodium oc-ethyl caproate in ethyl acetate is added, until no further precipitation occurs. The solid precipitate is collected on a suction filter, repeated washed with a 2: 1 mixture of diethyl ether and ethyl acetate and finally with diethyl ether alone. After a thorough drying in vacuo gives 2.5 g of the end product.

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

IR: (KBü pellet, values in cm " ¹ ) +3400, 1775, 1685, 1610, 1590, + 1540, 1390.

PMR: (60 Mc, d ^ -Dimethylsulfoxyd, 2,2-Dimethyl-silapentan-

5-sulfonate, £ values in ppm) 1.51 and 1.62 (2 singlets, 6H), 2.58 (S, 3H), 3.78 (S, 2H), 4.02 (S, 1H), 5.45 (center one

Multiplets, 2H), 8.9 (D, J approx. 8.5 cP, 0.9H).

Example 14

Preparation of methyl (cc-phenyl) -3-methyl-1,2,4-oxadiazol-5-yl acetate

A solution of 14 g (80 mmol) of 3-methyl-5-benzyl-1,2,4-oxadiazole and 14 ml TMEDA in 14O ml toluene is cooled to -65 ° C. A solution of approximately 75 mmol of n-butyllithium in 80 ml of a 1: 1 mixture of η-hexane and toluene is added dropwise. The rate of addition is set to a Reaction temperature set between -60 and -70 ° C. the

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Reaction mixture is stirred for a further 2.5 hours at -75 ⁰ C and then poured into finely divided solid carbon dioxide. About 3 hours later, 120 ml of water and 120 ml of diethyl ether are added. The resulting two layer system is treated with dilute hydrochloric acid until the vigorously stirred mixture reaches pH 8.0. The layers are separated, the organic layer is discarded, the aqueous layer is extracted by three extractions with 30 ml portions of diethyl ether at pH 8.0. The aqueous layer is mixed with 80 ml of ethyl acetate, ^{cooled to below 0} ° C. and acidified to 3.0 with dilute hydrochloric acid. The layers are separated and the aqueous layer is extracted again with 80 ml of ethyl acetate. The organic extracts are combined, washed once with a small volume of ice-water and shaken with anhydrous magnesium sulfate for a few minutes. The salt is filtered off in the cold and the resulting colorless solution is carefully treated 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 is distilled directly into the solution of the carboxylic acid in ethyl acetate. The reaction is continued until no further discoloration of the reaction mixture is noticed. The resulting solution is decolorized directly with a small amount of acetic acid, washed 3 times with a small volume of neutral water, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The remaining oil weighs 10 g. This crude product was only slightly contaminated with the starting material. The pure product was obtained by distillation in vacuo (boiling point 135 ° C. at 0.8 mm Hg), yield 6 g, n ²⁰ ' ³ = 1.5230

IR (KBr pellet, values in cm "" ¹ ): 1750, -1580, 1498, 1435, 1390, 1340, 1270, 1220, 1160, 1010, 740 and 650. PMR (60 Mc, CDCl ₃ , MS, C Values in ppm): 2.37. (S, 3H), 3.77 (S, 3H), 5.26 (S, 1H), approximately 7.4 (close multiplet, 5H).

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Example 15

Production of 5-methyl-1 ^^ - oxadiazol ^ -yl-acetamide

A mixture of 6.5 g of 5-methyl-1,2,4-OXaCHaZoI - ^ - Vl-acetic acid, 0.21 ml of dimethylformamide, 4.6 ml of thionyl chloride and 100 ml of carbon tetrachloride is gently boiled for 12 minutes. The resulting brownish solution is added to 100 ml of 25% ammonia over a period of 10 minutes. During the addition, the well-stirred reaction mixture is cooled with an ice-salt mixture. The reaction mixture is stirred at room temperature for 1 hour. 20 # hydrochloric acid is added until a pH of 8.0 is reached. The layers are separated. The aqueous layer is shaken 1 time with carbon tetrachloride (10 ml) and the combined organic layers are washed 1 time with 10 ml of water. The organic layer is discarded and the combined aqueous layers are evaporated in vacuo. The residue is extracted continuously with acetone for 16 hours. 7 g of a semi-solid brownish product are obtained. The greater part of this product could be dissolved in dry ethyl acetate. This solution was again evaporated to dryness and the residue was dissolved in ethanol, treated with activated charcoal and evaporated again. The solid residue was dissolved in hot acetone and then η-hexane was added until the Losiang became cloudy. After standing for several hours at room temperature and finally at 0 ^° C., the crystals were filtered off with a suction pump, washed with a cold 9: 1 mixture of η-hexane and acetone and dried in vacuo. The slightly colored final product weighed 4.8 g ($ 72) , mp 112-114 ° C. IR (KBr pellet, values in cm " ¹ ): 3380 and 3220, 1680, 1630, 1590, 1420, 1380, 1270 _s 1185 and 895.

PMR (60 Mc, dg-dimethylsulfoxide, 2,2-dimethylsilapentane-5-sulfonate, 6 values in ppm): 2.58 (S, 3H), 3.60 (S, 2H), 7.1 and 7.6 (centers of broad absorptions, approximately 2H).

Example 16

Preparation of methyl-5-methyl-1,2,4-o35addazQl-3- * yl acetate

In the same way as described in Example 10, 10 g of crude 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid were converted into the methyl ester by reaction with diazomethane. Yield 5.9 g, boiling point 70 to 72 ^° C at 0.6 to 0.7 mm, n _D = 1.4495 IR (NaCl window, values in cm " ¹ ): 3020, 2980, 2865, 1750, 1595. PMR (60 Mc, CDCl ₃ , TMS , / - values in ppm): 2.59 (S, 3H), 3.73 (S, 3H), 380 (S, 2H).

Example 17

Production of cyclohexyl-5-methyl-i, 2,4-oxadiazol-3-yl-acetate

8 g (56.3 mmol) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid were added suspended in 8 g (80 mmol) of redistilled dry cyclohexanol. Anhydrous conditions were used and added 8 g (52.2 mmol) of phosphorus oxychloride was added dropwise to the mixture over 7 minutes. During the addition it was the mixture is heated on a steam bath. Heating was continued for 45 minutes. After the reaction mixture is room temperature 75 ml of ice-water and 50 ml of diethyl ether were added. The mixture was stirred until one received clear system with 2 layers. The flask was placed in an ice-salt bath and solid potassium hydroxide became added until the pH reached 10.5. The layers were separated and the aqueous layer was added 3 times with 40 ml portions Diethyl ether extracted. The four ether extracts were combined, Washed 1 time with a small volume of ice-water and then concentrated in vacuo. The residue (10 g) was distilled in vacuo. Yield 7.9 g (62%), b.p. 120 to 121 ° C at 0.9 to 1.0 mm, njp = 1.4715

IR (NaCl window, values in cm " ¹ ): 2960 and 2880, 1740 and 1595

PMR (60 Mc, CDCl ₅ , TMS, <f values in ppm): about 1.05 to 2.2 (broad, 10H), 2.58 (S, 3H), 3.75 (S, 2H) and about 4.85 (broad, 1H).

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In the same way, for example, cyclopentyl-5-ethyl-1,2,4-oxadiazol-3-yl acetate was made in 43% yield, using 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid and cyclopentanol used as starting material: boiling point 108 ° C

0.5 mm Hg, n ^ ⁵⁰ = 1.469

IR (NaCl window, fourth in cm " ¹ ); 3000, 2915 sh, 1755, 1600,

1430, 1400, 1350, 1280, 1220 to 1240, 1185, 1060, 1000.

PMR (CDCl ₃ , 60 Mc, TMS, 5 "values in ppm): 1.39 (T, J = 7.5 cP)

and from about 1.5 to 2.2 together 11H, 2.91 (Q, J =

7.5 cP, 2H), 3.76 (S, 2H), about 5.25 (center of a multi-

pletts, 1H).

Example 18

Preparation of 7 - [(5-methyl-1,2,4-oxadiazol-3-yl) acetamido ] -3-azidomethyl-3-ceph-em-4-carboxylic acid

A mixture of 0.71 g (5 mmoles) of 5-methyl-1,2,4

yl-acetic acid, 0.5 ml thionyl chloride, 1 drop of dimethylformamide

and 10 ml of dry carbon tetrachloride became mild

Cooked for 13 minutes. Anhydrous conditions were used.

The solvent was removed in vacuo and the colored one

The residue was dissolved in 10 ml of dry ethyl acetate.

In the meantime, 1.39 ml of triethylamine and 1.26 ml of trimethylchlorosilane were successively formed into a suspension of 1.225 g (4.8 mmol) of 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid [prepared according to D. Willner, The Journal of Antibiotics, Volume 25 (No. 1), 64 (January 1972)] in 12.5 ml of ethyl acetate. The mixture was stirred for 45 minutes at room temperature, then ^{cooled to 0} ° C. and then 0.66 ml of quinoline and the prepared solution of the acid chloride in ethyl acetate were added in succession. After 5 minutes the ice bath was removed and the reaction mixture was stirred for an additional 60 minutes at room temperature. The reaction mixture was poured into a well-stirred, ice-cold mixture of 50 ml of water and 40 ml of ethyl acetate at pH 2. The pH was increased to 7 and the layers were separated. the

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organic layer was discarded and the aqueous layer was extracted 1 time with 50 ml of ethyl acetate. The aqueous layer was purified once more by extraction with 50 ml of ethyl acetate at pH 6.0 and then 6 times with 50 ml volumes of ethyl acetate successively at pH 5.0, 4.0 (2 times), 3.5 (2 times ) and 1.0 extracted. The extracts were combined, centrifuged to remove some insoluble solid material, washed twice with a small volume of ice-water, treated with activated charcoal and dried over anhydrous magnesium sulfate, filtered and evaporated completely in vacuo. The residue was triturated with diethyl ether, filtered with a suction pump and washed with diethyl ether and dried in vacuo to constant weight. Yield 1 »17 g (64%). The final product contained approximately 90% of the desired compound and approximately 10% of the corresponding Λ- cephem derivative.

IR (KBr pellet, values in cm " ¹ ): + 3450 and + 2600 3305, 2135, 1790, 1710, 1660, 1585 and 1540. PMR (dg-dimethylsulfoxide, 60 Mc, '2,2-dimethylsilapentane-5 -sulfonate, £ "values in ppm): 2.58 (S, 3H), 3.3 to 3.95 (Q, J _AB approx. 18.3 cP), 3.76 (S) and approx. 3, 8 to 4.6 (Q, J _AB = 13.1 cP) together 6H, + 5.1.5 (D, J = 4.7 cP, 1H), ■ + 5.75 (Q, J = 4.7 cP , J ^! = 8.3 cP, 1H) and 9.3 (D, J «= 8.3 cP, 0.9H).

Example 19

Preparation of the R-sulfoxide of 7 - [(5-methyl-1,2,4-oxadiazolj ^ 3-yl) acetamido] -3-azidomethyl-3-cephem-4-carboxylic acid

A solution of 730 mg (2 mmol) 7 -. (5-Methyl-1,2,4-oxadiazol-3-yl) -acetamido-3-azidomethyl-3-cephem-4-carboric acid (prepared according to the method of Example 18) in 20 ml of anhydrous tetrahydrofuran (THF) was cooled to -75 ⁰ C. To this solution was added a solution of 400 mg (2.5 mmol) of Ν, Ν-dichlorourethane (Cl ^ ^ C ^ NCO c) in 7.5 ml of anhydrous THF at -70 to -75 ⁰ C. The resulting reaction mixture was stirred for about 1 hour at -70 to -75 ⁰ C and then in a

Well-stirred mixture of 300 ml of ice-water and 200 "ml of ethyl acetate given. The layers were separated at pH 1.7 and the aqueous layer was washed three more times extracted with 200 ml volume of ethyl acetate. The four ethyl acetate layers were pooled and 2 times with 100 ml volumes; a saturated solution of sodium chloride in water. Since the original aqueous layer still contained the desired product after thin-layer chromatography, was combined them with 200 ml of water used to wash 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 and washed with a small volume of ice-water and evaporated to dryness in vacuo. The yield the first batch was 110 mg.

The ethyl acetate layer was mixed with 100 ml of water and then sodium hydrogen carbonate was added to pH 7.5. The layers were separated and the ethyl acetate layer was extracted 2 more times with 50 ml 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 twice at pH 1.7 with 100 ml volumes of ethyl acetate and once with 100 ml of ethyl acetate at pH 1.0. The aqueous layer was discarded and the combined ethyl acetate layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to low volume, the second batch separating out by the addition of η-hexane. Yield 148 mg. The IR spectra of the two layers were essentially identical. Total yield 258 mg (35%)

IR (KBr pellet, values in cm "" ¹ ): + 3450, +3300, 2550, 2130, 1790, 1720, 1680, +1655 sh, 1590, +1540, +1040. PMR (dg-DMSO, 60 Mc, c values in ppm, DSS as standard) s 2.58 (S, 3H), 3.75 (S) and 4.0 (center of approximately 0.8 ppm wide AB- Quartet, J approx. 16.5 cP) and 4.2 (center of a

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about 0.55 "wide AB-quartets, J about 13.5 cP), together 6H, 4.85 (D, J = 4.6 cP, 1H), 5.7 (Q, J = 4.6 cP and J 'approx. 8.0 cP, 1H), 9.7 (D, J ¹ approx. 8.0 cP, approx. 0.8H).

Example 20

Preparation of N - [(5-methyl) -isoxazol-3-yl] -3-methyl-1,2,4-oxadiazol-5-yl-acetamide

The method used in the following is essentially in "Hoüben- ¥ eyl, Methods of Organic Chemistry", Volume 11/2, Pages 5 and 6.

7.8 g (0.055 mol) of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid were dissolved in 80 ml of a dry solvent mixture of equal parts by volume of dioxane and toluene. 6.9 g (0.07 mol) of 5-methyl-3-amino-isoxazole, dissolved in 50 ml of the same mixture of dioxane and toluene, and 4.2 g (0.031 mol) of phosphorus trichloride ( PCI,). After the addition of PCl ^ the mixture became lukewarm and the separation of a heavy, yellowish oil was observed. Crystallization of the oil took place within a short time and the mixture was heated on a steam bath ^{at 90 ° C. for 5 minutes.} The mixture was then stirred for 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 on a steam bath for 60 minutes in order to decarboxylate the residues of oxadiazolyl-acetic acid. The suspension was cooled and extracted continuously with dichloromethane for 16 hours. The obtained 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 successively to 3 ° C, -15 ° C and finally to -70 ° C. The crystals were quickly filtered off with a suction pump, washed with dichloromethane at -70 ° C and

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lent washed with n-heptane. After drying in vacuo 10.45 g of product were obtained (85.7%, yield based on the amount of 3-methyl-1,2,4-oxadiazol-5-ylacetic acid used).

Mp 191-193 ° C

IR (KBr pellet, values in cm "" ¹ ): 3240, 3290, 1715, 1650, 1605, 1585, 1500, 1450, 1365, 1280, 1220, 1045, 940, 900, 750 and

PMR (approximately 4: 1 mixture of CDCl ₃ and dg-DMSO, 60 Mc, £ -

Values in ppm, TMS as standard): (S) and narrow D together at 2.4 (6H), 4.1 (S, 2H), 6.58 (narrow Q, 1H), 10.5 (somewhat

broad S, 1H).

Example 21 Preparation of 3-methyl-1,2,4-oxadiazol-5-yl-acetamide

The procedure used corresponds to that in "Houben-Weyl, Methods of Organic Chemistry ", Volume 11/2, pages 5 and 6, described methods.

8 grams (0.056 moles) of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid. were dissolved in 150 ml of a dry solvent mixture of equal parts by volume of dioxane and toluene at room temperature. 3.5 g of dry, gaseous ammonia are passed into the solution at room temperature, the ammonium salt of oxadiazolylacetic acid precipitating out in the form of a white, thick precipitate. While gaseous ammonia was being passed beneath the surface of the vigorously stirred mixture, a solution of 4 g (0.029 mol) of phosphorus trichloride in 50 ml of the same solvent mixture of dioxane and toluene was added over the course of 10 minutes. During the addition the mixture became lukewarm and turned yellow. The mixture was then ^{heated at approximately 90 °} C. on a steam bath for 5 minutes. The reaction mixture was heated for a further 60 minutes at room temperature and then completely evaporated in vacuo. The residue was in 75 ml

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Water-dissolved and the resulting acidic solution (pH 2.0) was heated on a steam bath for 60 minutes. The solution was cooled to room temperature, saturated with sodium chloride and extracted continuously with dichloromethane for 16 hours. The extract obtained was completely evaporated, leaving a crystalline residue which withstood attempts to recrystallize it from various solvents. The residue was therefore filtered through a short silica column with the aid of diethyl ether. The ether was removed and the residue from a 9: 1 mixture of diethyl ether and dichloromethane crystallized, the solution being gradually cooled from room temperature to -70 ° C. (the crystals were washed with very cold diethyl ether), yield 5.1 g ( 64.5%), melting point. 77 to 77.5 ° C. IR (KBr pellet, values in cm " ¹ ): 3180, +3240, 1685, +1635, 1595, 1445 sh, 1425, 1400, 1360, 1315, 1270, 1260, 1180, 1060, 890, 730 and 685.

EMR (CDClj and a trace of dg-DMSO, 60 Mc, S values in ppm, TMS as standard): 2.40 (S, 3H), 3.88 (S, 2H), + 6.6 and + 7 , 2 (centers of 2 wide ABS, about 2H).

Example 22

Preparation of 3-methyl-1,2,4-oxadiazol-5-yl-acetmorpholide

The method used is similar to that described in "Houben-Weyl, Methods of Organic Chemistry", Volume 11/2, pages 5 and 6 _% .

To a mechanically stirred solution of 7.8 g (0.055 mol) of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in a dry Mixture of 50 ml of dioxane and toluene, which was prepared at room temperature, was 12.3 g (0.014 mol) of freshly distilled "tes Morpholine added. After stirring-a few minutes a thick precipitate formed from the morpholine salt of oxadiazolyl acetic acid. To the violently stirred Suspension was added 4.2 g (0.031 mol) of phosphorus trichloride on 1 May a thick, yellow precipitate formed

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xind the temperature rose sharply. Shortly after the addition of the ^, the reaction mixture was ^{heated on a steam bath at approximately 90 °} C. for 5 minutes and then stirred at room temperature for 60 minutes. The reaction mixture was completely evaporated in vacuo. The residue was dissolved in 75 ml of water, the solution was heated on a steam bath at pH 1.5 for 60 minutes and then saturated with sodium chloride at room temperature. The solution in water was extracted continuously with dichloromethane for 16 hours. The extract obtained was evaporated and the residue was recrystallized first from carbon tetrachloride and then from toluene and then the hot solution was treated with activated charcoal. A colorless, crystalline product was obtained which was dried in vacuo; Yield 8.1 g (69.5%), mp 79 to 80.5 ⁰ C. Elemental analysis:. CQH ^, N ^ O-,

Calculated: C 51.18% H 6.16% N 19.90% 0 22.76% Found: 51.15 6.10 19.91 (22.84)

IR (KBr pellet, values in cm ~ ¹ ) s 1650, 1595, 1450, 1395, 1240,

1130, 1045, 865, 2980, 2940, 2865, 1470 sh, 1420, 1370 sh,

1350, 1310, 1290, 1280, 1180, 1080, 1030 sh, 985, 920, 900,

840 sh _s 770, 715, 680.

PMR (CDCl ₃ , 220 Mc, <i-values in ppm, TMS as standard):

2.41 (S, 3H), 3.54 (center of 3 or 4 lines, 2H), from 3.62 to 3.75 (at least 9 lines, 6H), 4.02 (S, 2H).

Example 23

Preparation of N '- (Pur-2-yl-carbonyl) -3-methyl-1,2,4-oxadiazol-5-yl-acethydrazide

The procedure used is similar to that described in "Houben-Weyl, Methods of Organic Chemistry ", Volume 11/2, pages 5 and 6, is described.

They used anhydrous conditions and under strong mechanical conditions Stirring was added to a solution of 6 g (0.042 mol) of 3-methyl-1, 2,4-oxadiazol-5-yl-acetic acid in a mixture

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from 50 ml of dry dioxane and 50 ml of toluene at room temperature in succession 5 g (0.063 mol) of pyridine and 6.3 g (0.05 mol) of fur-2-yl carbonyl hydrazide. 3.4 g (0.025 mol) of phosphorus trichloride were added all at once to the resulting clear solution. A heavy yellow oil formed that solidified immediately. The reaction mixture was then heated on the steam bath at about 90 ° C. for 5 minutes and then stirred 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 was heated on a steam bath at pH 2 for 60 minutes, a clear, yellow solution was obtained. After cooling the solution to room temperature, crystallization of a yellowish solid took place. This product was isolated by filtration with a suction pump and washed with ice-water. 7.2 g were obtained. The product was recrystallized from acetone, to gradually cooled to about -20 ⁰ C. Yield 5.1 g (about 46%) of a light yellow crystalline solid with a purity of about 95 # according to TCL and PMR, m.p. 169-171 ° C

IR (KBr pellet, values in cm " ¹ ): + 3180, 1700 and 1675, 1620, + 1590, + 1570, + 1510, 1480, 1435, 1205, 945 and 790. PMR (dg-DMSO, 60 Mc, £ values in ppm, DSS as standard): 2.36 (S, 3H), 4.04 (S, 2H), 6.65 (Q, J = 3.6 and J '= 1.7 cP, 1H ), 7.25 (a, J = 3.6 and J "= 0.7 cP, 1H), 7.9 (Q, J ¹ = 1.7 and J" = 0.7 cP, 1H), 10 .35 (S, about 1.8H).

Example 24

Preparation of N '- (ethoxycarbonyl) -5-methyl-1,2,4-oxadiazol-3-yl-acethydrazide

The procedure used is similar to that described in "Houben-Weyl, Methods of Organic Chemistry ", Volume II / 2, pages 5 and 6, is described.

Under anhydrous conditions and with strong mechanical stirring 6.7 ml (0.079 mol) of pyridine, 5.9 g (0.056 mol) of ethoxy

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carbonyl hydrazide and 2.58 ml (0.03 mol) phosphorus trichloride successively to a solution of 8.0 g (0.056 mol) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid given in a mixture of 50 ml of dioxane and 50 ml of toluene at room temperature5 the resulting The mixture is stirred at room temperature for 90 minutes and then evaporated to dryness in vacuo. The residue is dissolved in 50 ml of ice-water. The pH of the solution (0.8) is increased to 3.0 and then is extracted continuously with dichloromethane for 16 hours. The resulting solution in dichloromethane becomes complete evaporated to give 13 g of a partially crystalline solid. The solid is triturated with η-hexane and then separated off by filtration on a pump. The somewhat yellow, crystalline product weighs 12.2 g. It is crystallized from a toluene / ethanol mixture which has cooled to 5 ° C. The first batch of pure product weighs 9.4 g (73.2%), m.p. 122-123 ° C. The FiItrat of the first crystallization is completely evaporated in vacuo and the residue is in a mixture of dichloromethane and diethyl ether dissolved. When cooling this solution up -30 ° C part of the product crystallizes. The crystals are collected by filtration on a pump at low temperature filtered off and washed with cold diethyl ether. Yield 1.0g (7.8%), m.p. 121.5-123.5 ° C, overall yield 10.4 g (81%).

From the behavior during melting and from the IR and PMR

Spectra can be deduced that the compound in at least

occurs in two tautomeric forms.

IR (values in cm " ¹ ):

First batch: KBr-Pelleti 3320 and 3250 (equally intense), 3065, 2985, 2945, 1738 and I66O (equally extensive), +1640 sh, 1595, 1560, 1495, 1450 sh, 1415, 1395, 1360, 1305, 1270,

sh, 1255.

Second batch: KBr pellet: 3310 sh, 3210 (very intense), 3O6O, 2985, 1760 sh, 1735 and 1710, 1660 sh, + 1630 (very intense), 1590, 1560 sh, 15OO, 1475, 1445 sh, 1418, 1395, 1360, 1340,

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1300 sh, 1280, 1255.

IR spectra in solutions in CHCl ^ were identical: 3400, approximately 3280 (wide), 1750, 1710, 1650 sh, 1590, 1480, 1390, 1370.

PMR spectra of the compound dissolved in dg-DMSO (60 Mc, <Γ values in ppm, also with DSS as internal standard) showed the presence of tautomers: 1.18 (T, J = 7.0 cP, 3H), 2.57 (S, 3H), 3.63 (slightly broad S, 2H), about 4.05 (center of a complicated absorption that contains a main quartet, J = 7.0 cP, 2H), about 9.0 (wide S, about 0.75H), about 9.3 (wide S, about 0.15H) and 9.8 (slightly wide S, about 0.75H).

Example 25

Preparation of (4-bromo) -phenyl-3-methyl-1,2,4-oxadiazol-5-yl-acetate

Under anhydrous conditions, 6 g (0.042 mol) of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid, 7.3 g (0.043 mol) of 4-bromophenol and 3.6 ml (0.042 mol) of pyridine are dissolved in dissolved a mixture of 25 ml of dioxane and 25 ml of toluene. 2 ml (0.024 mol) of phosphorus trichloride are added, the stirred mixture becoming lukewarm. The mixture is stirred at room temperature overnight. The supernatant liquid is separated from the precipitate. The precipitate is washed twice with 10 ml portions of a 1: 1 mixture of dioxane and toluene. The washing solutions are added to the decanted solution, then the solvent is completely removed in vacuo. The slightly moist, crystalline residue weighs 12.3 g. It is dissolved in 150 ml of diethyl ether. The solution is washed 3 times with a total of 75 ml of water and then evaporated completely. The residue weighs 10.8 g. It is dissolved in a boiling mixture of diethyl ether and n-pentane, then the solution is gradually abgdcühlt to -18 ⁰ C. The precipitated crystals are separated off by filtration, washed with a cold mixture of diethyl ether and pentane of about 1 si and finally dried in vacuo.

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Yield 8.0g (64.5%). The finished product melts at

73 to 74 ° C.

IR (KBr pellet, values in cm " ¹ ): 1745, 1585, 1480, 1440, 1400,

1370, 1335, 1290, 1210, 1180 sh, 1165, 840, 770, 705, 680.

PMR (CDCl ^, 60 Mc, S values in ppm, TMS as internal standard): 2.41 (S, 3H), 4.16 (S, 2H), about 6.85 to 7.65 (typical

AA ¹ BB 'cleaved signals, 4H).

Example 26

Preparation of sec “-butyl-3-methyl-1,2,4-oxadiazol-5-yl acetate

Essentially as described in Example 17, 12 g of phosphorus oxychloride are slowly added 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 rate of addition is adjusted so that the reaction temperature is 65 ± 5 ° C. The resulting reaction mixture is then stirred for 90 minutes at 65 ° C. and then treated in the same way as described in Example 17. The product is distilled at 68 ° C. and 1.5 mm Hg, yield 6.1 g (35%). The purity of the finished product was approximately 95% , njj = 1 ^ 438

IR (NaCl window, values in cm " ¹ ): 3000, 2960, 2900, 1745, 1600. PMR (60 Mc, CDCl ₃ J TMS, S values in ppm): 0.9 (triplet-like, J = 7, 0 cP, 3H), 1.25 (D, J = 6.3 cP "3H), about 1.55 (quintet-like, 2H) ₉ 2.40 (S, 3H), 3 * 93 (S, 2H), 4.93 (regular sextet * J = 6.2 cP ₉ 1H).

Example 27

Preparation of benzyl 3-methyl-1,2,4-oxadiazol-5-yl acetate

Essentially as described in Example 17, 8 g of phosphorus oxychloride are slowly added 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 were added. The rate of addition is set to a Reaction temperature set from 40 to 45 ° C. The resulting reaction mixture is heated for a further 5 hours at 40.degree stirred and then treated in the usual way. The

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The yellow oil is kept over silica using η-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 chromatographed as the eluent. The colorless oil finally obtained weighs 6.1 g, (47%), the purity is approximately 95% according to TLC and PMR,

njp = 1.518

IR (NaCl window, values in cm " ¹ ): 1745, 1590, 1500, 1395, 1355,

1200, 750, 700

PMR (60 Mc, CDCI ,, TMS, <f values in ppm): 2.35 (S, 3H), 3.93

(S, 2H), 5.17 (S, 2H), 4.3 (5H).

Example 28

Preparation of N- (2-chlorophenyl) -3-methyl-1,2,4-oxadiazol-5-yl-acetamide

Essentially as described in Example 20, 1.65 ml of dry pyridine and 1.33 ml of 2-chloroaniline are successively formed into a solution of 2.0 g of 3-methyl-1,2,4-oxadiazol-5-ylacetic acid in a mixture of 13 ml of dioxane and 13 ml of toluene were added. The precipitation of a viscous oil is observed. The reaction mixture is then stirred for 90 minutes at room temperature and then evaporated to dryness. The residue is stirred well with 10 ml of ice-water and then dichloromethane is added. The pH of the resulting, clear two-layer system is approximately 0.8. The pH is increased to 3 »P and the layers are separated. The water layer is extracted 4 times with 25 ml volumes of dichloromethane. The five extracts are combined, washed 1 time with a small volume of ice-water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue is crystallized from carbon tetrachloride, yield 2.7 g (77%) of pure product, melting point 118.5 to 119.5 ° C.

IR (KBr pellet, values in cm " ¹ ): 3260, 1660, 1590, 1535, 1480, 1440, 1295, 890, 870, 750, 680.
PMR (60 Mc, CDCl ₃ , TMS, S values in ppm): 2.45 (S, 3H), 4.08

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(S, 2H), about 6.85 to 7.5 (multiplet, 3H), 8.32 (Q, J = 7.5 cP and J ^f = 2.2 cP, 1H), about 9.6 (broad S, about 1H).

Example 29

Production of N-monosubst .- ^ - subst.-i, 2,4-0xadiazol-5-ylacetamides and N-monosubst.-5-substituted-1,2,4-0xadiazol-3-yl-acetamides by appropriately catalyzed reactions of 3 (5) -subst.-1,2,4-0xadiazol-5 (3) -ylacetic acids with isocyanates

As an explanation of the wide applicability of the reaction, the following are the reactions and products for the following 'Examples listed:

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

B. N-propen-3-yl-ot- (3-ethyl-1,2,4-oxadiazol-5-yl) propionamide

C. cc- (3-Ethyl-1,2,4-oxadiazol-5-yl) propion- (4-chloro) anilide

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

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.

The reactions of isocyanates were 1,2,4-0xadiazol-5-yl-acetic acids at room temperature (about 20 ⁰ C) using solvents such as dichloromethane, toluene, chlorobenzene, 3,5-dimethyl-1,2,4- oxadiazole, etc. carried out. The reactions with the 1,2,4-0xadiazol-3-yl-acetic acids were carried out in the same manner, but terminated by heating the reaction mixtures to about 60 to 100 ° C. for about 15 to 30 minutes. Unless otherwise stated, all reactions were catalyzed in the presence of 2 to 5 mol% of N-vinyl imidazole. The isocyanates used below were technical crude samples. For this reason and for other reasons such as the volatility of some isocyanates and possible moisture in the 1,2,4-oxadiazole acetic acids used, the isocyanates were used in a 10 to 20 mol% excess.

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A detailed description will be given in Example A. 'For the other examples are the starting materials, the reaction media, the approximate reaction time, the Information on the purity and / or purification of the end products and the melting points and IR and / or PMR spectra of the End products listed. The isolation processes including the separation of the desired amides from the by-products of the Implementation (generally only relatively small amounts of 1,3-disubstituted ureas and 1,2,4-oxadiazole-acetic acid) and the catalyst were more or less similar to the isolation procedure described in Example A, however they were of course adapted to the individual cases. The yields were obtained in the first attempt. The yield values therefore have no absolute value.

A. Using anhydrous conditions, 17 mmol of approximately 90% pure α- (3-ethyl-1,2,4-oxadiazol-5-yl) propionic acid was obtained (= ^ Ethyl-tf-rnetfryl-i, 2,4 ~ oxadiazol ~ 5-yl-acetic acid) dissolved in 40 ml of toluene. Approximately 20.5 mmol of n-propyl isocyanate and about 60 mg catalyst (a saturated solution of 4-methoxypyridine-1-oxide.1HpO in N-vinylimidazole) were added to the solution. During a slow stream of nitrogen was passed continuously over the surface, · the reaction mixture was for 5 »5 hours at room temperature touched. The reaction mixture was evaporated in vacuo and the residue was dissolved in 100 ml of a 1: 1 mixture dissolved from ethyl acetate and diethyl ether. This solution was extracted 4 times at pH 2.0 with 10 ml of water. The combined acid wash solutions were extracted once with 10 ml of ethyl acetate and discarded. The two organic Layers were combined and extracted 3 times at pH 7.0 with 10 ml of water. The combined washing solutions were used 1 time extracted with 10 ml of ethyl acetate and discarded. The combined organic layers were treated with activated charcoal, dried over anhydrous magnesium sulfate, filtered and completely evaporated in vacuo. The residue was stirred with 20 ml of η-hexane, then diethyl ether was slowly added.

ben until the solid was almost completely dissolved. After filtration, the solution was gradually cooled to -18 ° C. The crystalline precipitate was separated off by filtration, washed with η-hexane and with cold diethyl ether. Yield 1.7g (approx 50%). The purity of the final product was approximately 95% according to TCL and PMR, m.p. 52 to 53 ° C. PMR (60 Mc, .CDCl-x, TMS, 5 values in ppm): 0.95 (triplet similar, J approx. 7.0 cP, 3H), complex 8H absorption range from 1.2 to 1.75, consisting of a CH, triplet at 1.35 (J ¹ approx. 7.5 cP) a partially hidden Q ^ multiplet and a CH ^ doublet at 1.67 (J "= 7.2 cP), 2, 78 (Q, J ¹ approx. 7.5 cP, 2H), 3.25 (quartet-like, mean J approx. 6.5 cP, 2H), 3.93 (Q, J "= 7.2 cP, 1H) , about 6.8 (broad S, about 0.8H).

B. a- (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 after column chromatography 2.7 g (64%) of pure product, mp. 70-71 ⁰ C. IR (KBr -Pellet, values in cm " ¹ ): 3280, 3070, 2980, 2940, 1650, 1580, 1550, 1240, 990, 940, 890, 750, 685 = PMR (60 Mc, CCl ₄ , TMS, S values in ppm): 1.35 (T, J = 7.5 cP, 3H), 1.61 (D, J ^! = 7.2 cP, 3H), 2.72 (Q, J = 7.5 cP, 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-oxadiazol-5-yl) propionic acid (11.8 mmoles of approximately 90% purity), 4-chlorophenyl isocyanate (14 mmoles), dichloromethane, approximately 50 mg of a saturated solution of 4-methoxypyridine-1-oxide.1H ₂ O in N-vinylimidazole (catalyst), 4 hours, yield 1.85 g (approx. 60%) of an at least 95% pure product according to TLC and PMR, mp. 130 to 131 ° C (after crystallization from benzene).

IR (KBr pellet, values in cm " ¹ ): 3260, 3190, 1675 sh, 1655, 1585, 1540, 1490, 1400, 1250, 840, 765.

IR (chloroform, values in cm " ¹ ); about 3400, about 3300,

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Ϊ69Ο, 1600, 1580, 1510 to 1550, 1495, 1395. (The compound shows monomeric / dimeric features) PMR (60 Mc, CDCl ₃ , TMS, € values in ppm): 1.37 (T, J = 7, 5 cP, 3H), 1.74 (D, J = 7.2 cP, 3H), 2.82 (Q, J = 7.5 cP, 2H), 4.07 (Q, J = 7.2 cP , 1H), 7.38 (center of an AA'BB ¹ split pattern, 4H), about 9.0 (broad S, about 0.9H),

D. 3-Benzyl-1,2,4-oxadiazol-5-yl-acetic acid (10mmoI), Allyl isocyanate, toluene, 3.5 hours, yield 1.54 g (60? 0 pure product, crystallized from chloroform, m.p. 107.5 bis 108.5 ° C.

IR (KBr pellet, values in cm "" ¹ ): 3290, 3100, 1655 and 1640 sh, 1590, 1570, 1495, 1370, 1240, 1165, 1000, 735, 700. PMR (60 Mc, CDCl ,, TMS , £ values in ppm): 6H absorption range from about 3.75 "to about 4.15, consisting of a CHp singlet at 3.83, a C ^ singlet at 4.0.6 and a CHp multiplet, about 4 .85 to about 5.35 (extended multiplet, 2H), about 5.5 to 6.1 (extended multiplet, 1H), about 7.3 (C ₆ H ₅ ), and about 7.1 (broad S) together about 5.8H.

E. 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid (9.1 mmol), 4-chlorophenyl isocyanate (11 mmol), chlorobenzene, approximately 40 mg of a saturated solution of 4-methoxypyridine-1-oxide .1HpO in N-vinylimidazole, 4 hours at room temperature and 15 minutes at about 70 ⁰ C, yield 1.56 g (60%) of almost pure product, mp. 139 to 141 ° C.

IR (KBr pellet _f values in cm " ¹ ): 3255, 3195, 3130, 3075, 2950, 1660, 1610, 1590, 1545, 1495, 1400, 1450, 1260, 975, 895, 840, 760, 710, 690

PMR (60 Mc, CDCl ,, TMS, f values in ppm): 2.66 (S, 3H), 3.85 (S, 2H), 7.35 (center of an AA ¹ BB ¹ split pattern, 4H) , about 8.6 (broad S, about 0.8H).

F. 3-Methoxymethyl-1,2,4-oxadiazol-5-yl-acetic acid (6.5 ml), 4-chlorophenyl isocyanate (7.5 mmol), 3.5 hours, Yield 1.4 g of almost pure product. After crystallization from

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Toluene 1.15 g (63%), m.p. 114.5-115.5 ° C. PMR (60 Mc, CDCl ₃ , TMS, £ "values in ppm): 3.49 (S, 3H), 4.06 (S, 2H), 4.61 (S, 2H), 7.35 (center of an AA ¹ BB ¹ split pattern, 4H), about 8.95 (broad S, about 0.8H).

Example 30

Preparation of N, N'-bis (propen-3-yl) -1,2,4-oxadiazol-3,5-ylbisacetamide

To a solution of 2 g of almost pure 1,2,4-0xadiazol-3,5-ylbis-acetic acid (10.7 mmol) in 15 ml of 3,5-dimethyl-1,2,4-oxadiazole, one adds 40 mg of N-vinylimidazole and then becomes a solution of approximately 12 mmol of allyl isocyanate in 10 ml Toluene introduced drop by drop, but quickly. Use anhydrous conditions. The reaction mixture is during Stirred for 2 hours at room temperature. Because a thin layer chromatogram indicated only a partial conversion of the starting material into the three compounds, but mainly into the bisamide, a solution of allyl isocyanate (approximately 10.5 mmol) in approximately 10 ml of toluene was added again. After stirring for a further 4 hours, the reaction mixture is mixed with 40 ml of ice water. The pH is set to 7.0. A solid precipitate (apparently a mixture of mostly bisamide and a small amount of 1,3-bisallyl urea) is obtained by filtration separated at a pump. The two layers of the filtrate are separated and the organic layer is discarded. The remaining water layer, which the urine derives off, containing the unconverted starting material and the three reaction products is acidified to pH 2.0 and then Extracted 15 times with 20 ml volumes of ethyl acetate. This will be the urea and the bisamide are completely extracted, but the other two reaction products are only partially extracted. The precipitation is added to the combined extracts and the resulting solution is completely evaporated in vacuo. The residue is column chromatography over silica gel subjected, with diethyl ether, Mi-

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loop of diethyl ether with increasing amounts of a 5: 4 mixture of ethyl acetate and acetone is used and this mixture contains very small but increasing amounts of formic acid. A satisfactory separation of the urea and the bisamide is achieved, the separation of the bisamide from the two acidic monoamides (in the order of elution N- (propen-3- ⁱ -yl) -1,2,4-oxadiazol-5-yl- acetamid-3-ylacetic acid and N- (propen-3-yl) -1,2,4-oxadiazol-3-yl-acetamid-5-yl-acetic acid) were less satisfactory, however.

After crystallization from ethyl acetate, 1.3 g (48%) bisamide (title compound), mp 170 to 172 ° C and 0.34 g (14%) N- (propen-3-yl) -1 were obtained in an essentially pure state , 2,4-oxadiazol-5-yl-acetamid-3-yl "-acetic acid, melting point 97 to 98 ° C., obtained. IR bisamide (KBr pellet, values in cm" ¹ ): 3300, 3185, 2930, 1645, 1590, 1565, 1415, 1380, 1245, 990, 935, 755, 710 PMR bisamide (60 Mc, dg-DMSO, DSS, «5" values in ppm): 8H absorption range from about 3.5 to 4, 05, consisting of a CH ₂ singlet at 3.67, a CH ₂ singlet at 3.95 and. A multiplet (two N-CH ₂ groups), approximately. 4.9 to 5.4 (extended multiplet, 4h), about 5.5 to 6.2 (extended multiplet, 2H), about 8.4 (about 1.8H) PMR by-product (ibidem): 6H absorption range of about 3.6 to 4.1, consisting of one CHp singlet at 3.61, a CH ₂ singlet at 3.97, and a CH ₂ multiplet, about 4.95 to 5.4 (multiplet, 2H), about 5.55 to 6.25 (multiplet, 1H ), about 8.5 (about 0 , 8H).

In an analogous manner, for example, were prepared: 3cc- (4-fluorophenylcarbamyl) -benzyl-1,2,4-oxadiazol ~ 5-yl-acet-

(4-fluoro) anilide -

whereby one of 3 - («- carboxy) -benzyl-1,2,4-oxadiazol-5-yl-acetic acid and 2 equiv. 4 «fluorophenyl isocyanate went out to obtain the compound in 45% yield (crystallized with about 1 mol of water), mp. 85 to 87 ° C (subl.). IR (KBr pellet, values in cm " ¹ ) i 3400-3500, approximately 3200-3300, 315O _? 3075 * 1670, 1620-1640, 1585, 1560, 1550 sh, I510, 1415,

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1235 sh, 1225, 1165, 845-

PMR (approximately 7: 1 mixture of CDCIU and d ^ -DMSO, 60 Mc, TMS, ζ values in ppm): 4.06 (S, 2H), 5.35 (S, 1H), 6.95 ( Center of sextet-like absorption, apparent J values of 8.5 and 1.3 cP, 4H), from about 7.2 to 7.7 (multiplets, 9H), 9.85 (common singlet) and 10.05 (ibidem ),

together about 1.6H, and

ac et
1,2,4-0xadiazol-315-diyl-bis-44-chloro) -anilide , whereby 1.5 g (8 mmol) 1,2,4-0xadiazol-3,5-diyl-bis-acetic acid and approx 14 mmoles of 4-chlorophenyl isocyanate used as starting material and a yield of 1.1 g (35%) of the bisanilide and 0.8 g (34%) of 1,2,4-0xadiazol-3-yl-acetic acid-5-yl - (4-chloro) acetanilide received. The bisanilide melted with decomposition at 240 to 247 ° C (discoloration at 220 ° C). The second product

melted at 182 to 184 ⁰ C..

acet

1,2,4-0xadiazole-3,5-diyl-bis - / (4-chloro) anilide: IR (KBr pellet, values in cm " ¹ ) i 3280, 3130, 3065, 1670, 1600, 1550, 1500, 1415, 1390, 1355, 1325, 1295, 1265, 1235, 1190, 1110, 905, 855, 830, 770, 720, 700.

PMR (dg-DMSO, 60 Mc, DSS, Γ values in ppm); 3.95 (S, 2H), 4.23 (S, 2H), about 7.5 (center of a typical AA ¹ BB 'split pattern, 8H), 10.5 (slightly broad S) and 10.6 (ibidem ) together about 1.8H.

1,2,4-Oxadiazol-3-yl-acetic acid-5-yl- (4-chloro) -acetanilide: IR (KBr pellet, values in cm " ¹ ): + 3500, + 2550 to + 2650, 3265, 3120, 3040, 2950, 1710, 1665, 1595, 1540, 1500, 1435, 1380, 1250, 1195, 1100, 850, 755.

PMR (dg-DMSO, 60 Mc, DSS, 6 values in ppm): 3.83 (S, 2H), 4.22 (S, 2H), approximately 7.5 (center of an AA ¹ BB ¹ split pattern, 4H), 10.6 (slightly broad S, about 0.9H).

Example 31

Preparation of 7- [5- (N-propen-3-yl) - * carbamoylmethyl-1 "2,4-oxadiazol-3-yl-acetamidoJ-cephalosporanic acid

_{0 P} 3 ml were added to a suspension of 390 mg (1 ^ 45 mmol) of 7-amino-cephalosporanic acid in 8 ml of dry dichloromethane

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(2.18 mmol) triethylamine. Man. used anhydrous conditions and stirred the mixture for about 5 minutes. Then 0.067 ml (0.77 mmol) of PCl ^ was added. The emerging The suspension was stirred for about 5 minutes and then 327 mg (1.5 mmol) of 5- (N-propen-3-yl) -carbamoylmethyl-1,2,4-oxadiazol-3-yl-acetic acid, suspended in 4 ml of dichloromethane, initiated. The resulting yellow reaction mixture was stirred at room temperature for 16 hours and then poured into 19 ml of ice water, wherein at the same time a dilute sodium hydroxide solution was added.

The layers were separated at pH 6.5. The organic layer was discarded and the water layer was extracted at pH 6.5f 5.0 and 4.0 with 25 ml volumes of ethyl acetate. The extracts were discarded. The remaining water layer was extracted further 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 water, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to approximately 10 ml. The desired product turned out to be almost pure. Yield 250 mg. IR (KBr pellet, values in cm " ¹ ): + 3550, + 2600, 3290, 3090, 3050, 2950, 1780, 1740, 1720, 1660, 1585, 1545, 1420, 1385, 1355, 1240.
PMR (60 Mc, approximately 4: 1 mixture of dg-DMSO and DCO ₂ D, DSS, ο values in ppm): 2.06 (S, 3H), 8H absorption range from about 3.45 to about 4.15 , consisting of the S-CH ₂ absorption at about 3.6, a CH ₂ singlet at 3.84, a CH ₂ singlet at 3.97 and an N-CH ₂ multiplet, a 5H absorption range of about 4 , 6 to 5.4, consisting of an AB quartet at 4.63, 4.85, 4.97 and 5.20 (J _Aß about 12.8 cP), a doublet at 5.12 (J = 4 , 8 cP) and a CH ₂ multiplet, a 2H absorption range from 5.55 to 6.1, consisting of a multiplet and a doublet at 5.76 (J = 4.8 cP). The spectrum in dg-DMSO alone shows a triplet-like NH absorption at 8.45 and an NH doublet (J = 8.0 cP) at 9.25.

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Example 32

Production of 7 ~ [5 = benzyl-1,2 <, 4- = oxadiazol-3-yl-acetamido Ίο ephalosporanic acid

In the same way as described in Example 13, 1048 mg (4 mmol) of 5-benzyl-i ^^ - oxadiazol-S-yl-acetic acid are converted into the acid chloride, using 12 ml of dry carbon tetrachloride, 0.4 ml of thionyl chloride and 2 » Drops of dimethylformamide used. The solution is boiled a little for 15 minutes, then the carbon tetrachloride is removed in vacuo and the discolored residue is dissolved in 5 ml of dry ethyl acetate.

At the same time a suspension of 1.088 g (4 mmol) 7-Aminocephalosporanic acid in 25 ml of dry ethyl acetate with 1.14 ml (8 mmol) of triethylamine and 1.04 ml of trimethylchlorosilane (8 mmol) treated. After stirring for 30 minutes at room temperature, 0.47 ml (4 mmol) of quinoline and (dropwise) the Solution of the acid chloride added. The reaction mixture is stirred for a further 30 minutes and then as usual treated. In the isolation procedure, the desired compound was obtained by extraction with ethyl acetate at decreasing pH values of 6.0 Ms 4.5 obtained. Yield 1.35 g (70%) of practically pure product.

IR (KBr pellet, values in cm " ¹ ): 3275, 3075, 2975, + 3550 and + 2600, 1790, 1735, + 1700 sh, 1675, 1640 sh, 1580, 1555, 1420, 1390, 1285, 1250, 1220, 750, 715. PMR (60 Mc, dg-DMSO ", DSS, £ values in ppm): 2.06 (S, 3H), +3.4 (broadened S, 2H), 3.79 (S. , 2H), 4.34 (S, 2H), 4.60 to 5.17 (AB, J = 12.4 cP) and + 5.1 (D, J = 4.8 cP) together 3H, + 5 , 7 (Q, J = 4.8 and J ^! Approx. 8.2 cP, 1H), 7.35 (5H), + 9.2 (D, J ¹ approx. 8.2 cP, approx. 0.8H ).

Example 33

Production of amides by reacting 1,2,4-oxadiazole acetic acids with primary and secondary amines, in the presence of

Phosphorus trichloride ■

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It was found that the method described in Example 23, in which the amine, the 1,2,4-oxadiazole acetic acid and Phosphorus trichloride in 2.5: 1: 0.58 molar ratios is used for the preparation of amides in the case of secondary Amines and primary amines have a wide field of application. This procedure is a little more difficult, especially with amines Naturally suitable, for example for those for whom the production of isocyanates is difficult (e.g. 4-aminopyridine, 2-aminothiazole). With regard to the examples listed, the reaction conditions were the same as described in Example 23, however, the isolation procedures were adapted to the individual cases. It was found to be 60 minutes long Warm the solution of the residue from the reaction in acid water as described in Example 23 in general is not required and should be omitted if complex amides occur. The ones listed below Examples are illustrative only and the yields listed are not final as they are on the first try were obtained.

A. N- (Thiazol-2-yl) -3-ethyl-i, 2,4-oxadiazol-5-yl-acetamide

B. N- (4-pyridyl) -3-methyl-1,2,4-oxadiazol-5-yl-acetamide, hydrogen chloride acid salt

C. N-Methyl-N-phenyl-3-ethyl-1,2,4-oxadiazol-5-yl-acetamide

D. N, N-di (n) -butyl-3-methyl-1,2,4-oxadiazol-5-yl-acetamide.

A. Yield? 6%, melting point 170.5 to 171.5 ° C. (subl.), Was isolated by extraction with ethyl acetate and from ethyl acetate

crystallized.

IR (KBr pellet, values in cm "" ¹ ): 3300, 3200, 3090, 2980, 2940, + 2880, + 2760, 1680, 1600 (very intensive), + 1570 sh, + 1530 sh, + 1530 sh, 1420, 1385 sh, 1370, 1350, 1300, 1280, 1260,

1200, 1180, 1160, 965, 890, + 830, 790, 750.

PMR (approximately 6: 1 mixture of CDCl, and dg-DMSO, 60 Mc, TMS,

S values in ppm): 1.3 (T, J = 7.5 cP, 3H), 2.75 (Q, J = 7.5 cP, 2H), 4.2 (S, 2H), + 6 .9 (D, J = 3.5 cP, 1H), 7.4 (D, J = 3.5 cP,

1H), under 9 (very broad, about 1H).

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B. Yield hO% _t mp. 211 to 212 ° C., purification from a solution in water by washing with dichloromethane at pH 2.0. It was extracted from water with dichloromethane at pH 6.0. Since the free base did not solidify easily, the residue was dissolved in acetone and then 4N HCl was added. The isolated HCl salt was pure but somewhat moist. IR (KBr pellet, values in cm " ¹ ): + 3220, + 3100 sh, + 3020 sh, + 2950 to 2500, 1720, 1630, 1595, 1535, 1500 sh, 1420, 1400, 1380, 1355, 1335, 1310, 1280, 1200, 1165, 840. PMR (dg-DMSO, 60 Mc, DSS, S values in ppm): 2.38 (S, 3H), 4.48 (S, 2H), 8.1 to 8.85 (AA ¹ BB ¹ split pattern, 4H), 12.6 (NH, slightly broad S, about 0.9H).

C. Yield 5836, m.p. 53 ° C. As the crude product obtained did not solidify easily, column chromatography on silica using n-hexane, n-hexane / toluene mixtures, toluene and finally a 3: 1 mixture from toluene and diethyl ether as eluents. The compound was then made from toluene / Heptane crystallizes.

IR (KBr pellet, values in cm " ¹ ): 3000, 2950, 1660, 1505, 1420, 1400, 1375, 1315, 1270, 1180, -1135, 785, 720. FMR (CDCl ₃ , 60 Mc, TMS, if values in ppm): 1.21 (T, J = 7.5 cP, 3H), 2.73 (Q, J = 7.5 cP, 2H), 3.33 (S, 3H), 3, 76 (S, 2H), 7.1 to 7.6 (multiplet, 5H).

D. Yield 66%, oil; almost pure crude product (yield over 8Ο5δ), which was purified by column chromatography over silica in the same way as described for C., IR (NaCl window, values in cm " ¹ ): 2965, 2885, 1655, 1595,

1440 to 1480, 1400, I36O, 1305, 1230, 745.

PMR (CDCl ₃ , 60 Mc, S values in ppm, TMS): from about 0.7 to about 1.9 (complex split pattern, 14h), 2.37 (S, 3H), about 3.1 to 3 .5 (multiplet, 4H), 3.96 (S, 2H).

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Example 34

Preparation of 7- [5-ethyl-1,2,4-oxadiazol-3-yl-acetamido] -cephalo sporic acid

Using anhydrous conditions, a mixture of 3.1 g (20 mmol) of 5-ethyl-1 ^^ - oxadiazole ^ -yl acetic acid, 2.2 ml of thionyl chloride, 2 microdrops of dimethylformamide and 60 ml carbon tetrachloride moderately cooked for about 20 minutes. According to the IR spectrum was then a complete conversion of the carboxylic acid into the acid chloride takes place. The resulting solution was in vacuo evaporated and the residue was dissolved in 20 ml of ethyl acetate, In the meantime, 5.6 ml of triethylamine were added at 10 ° C a suspension of 5.44 g (20 mmol) of crude 7-aminocephalosporanic acid given in 50 ml of ethyl acetate. 5.1 ml of trimethylchlorosilane were then added. The mix was stirred for 60 minutes at room temperature. Then 2.36 ml of quinoline and the solution of the acid chloride added dropwise. The reaction mixture was additionally stirred for 30 minutes at room temperature. The content the flask was poured into 75 ml of ice water. The pH was adjusted to 7.0 and the layers were separated and the organic layer was discarded. The desired compound was obtained from the water layer through a number of Extractions with 100 ml volumes of ethyl acetate at pH values that were gradually lowered from pH 5.0 to 2.0, extracted. The. combined extracts were washed twice with small volumes of ice water, once at pH 1.0 and once at pH 2.0. The extract was treated with activated charcoal, dried over anhydrous magnesium sulfate and filtered and in vacuo about 25 ml concentrated. The resulting crystalline precipitate was filtered on the pump with dry ethyl acetate and carbon tetrachloride and dried to constant weight. Yield 5.9 g (approx 70%). This product was 90 to 95% pure.

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The combined filtrates were evaporated in vacuo, whereby 1 »3 g of a slightly yellow material was obtained which through repeated trituration with diethyl ether was purified, wherein 0.65 g of additional product was obtained. According to the thin-layer chromatogram and the IR spectrum, this had second batch roughly the same purity.

IR (KBr pellet, values in cm " ¹ ): + 3550 and + 2600, 3290, 3060, 2995, 2955, 1790, 1750, 1725, 1670, 1645 sh, 1580, 1555 ·, 1420, 1385, 1230, 1210 sh, 750, 720.

PMR Cd ₆ -DMSO, 60 Mc, S values in ppm, DSS): 1.30 (T, J = 7.5 cP, 3H), 2.05 (S, 3H) ₉ 2.95 (Q, J = 7.5 cP, 2H), 3.6 (broadened S, 2H), 3.77 (S, 2H), 4.60 to about 5.25 (AB-Q, J = 12.8 cP) and about 5.15 (D ₉ J = 4.8 cP) together 3H, about 5.25 (Q, J = 4.8 cP and J «= 8.0 cP, 1H), 9.2 (D, J« = 8.0 cP, approximately 0.8H).

According to the usual procedure, a solution of 5.7 g of the first batch in 250 ml of acetone was made with a solution equivalent amounts of sodium α-ethyl caproate dissolved in 12.5 ml Ethyl acetate. 5.3 g of the somewhat purer sodium salt of cephalosporin were obtained.

Example 35

Preparation of 7- [3-carboxymethyl-1,2,4-oxadiazol-5-ylacetamido] -cephalosporanic acid

2.79 g (15 mmol) of possibly slightly moist 1,2,4-oxadiazole-3,5-bis-acetic acid were dissolved in 20 ml of 3,5-dimethyl-1,2,4-oxadiazole. Using anhydrous conditions were 0.05 ml of N-vinylimidazole (as a catalyst) and a Solution of 18 mmol trimethylsilyl-7-isocyanatocephalosporanate admitted. As a result, a small amount of a solid was precipitated, which dissolved in the course of the reaction. The reaction mixture was stirred overnight at room temperature and then in a stirred mixture of 50 ml of diethyl ether and poured 25 ml of ice water. The pH was raised to 7.0 and the layers were separated. The organic layer

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was discarded and the water layer was extracted several times with 50 ml volumes of ethyl acetate at pH 5.0, 4.5 and 4.0. The extracts were discarded and the remaining water layer was extracted again 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 pump filtered to remove a small amount of precipitate (approximately 300 mg) which was discarded. The clear filtrate was partially decolorized by activated charcoal and then evaporated in vacuo. The residue was dissolved in 200 ml of dry acetone. A concentrated solution of sodium oc-ethyl caproate was slowly added until no further precipitate of solid material formed. The flask was kept at approximately 3 ^° C. overnight. The solid was collected by filtration. It was washed with dry acetone and dried in vacuo to constant weight. The product weighed 6.2 g. It contained approximately 65% of the desired monosodium salt according to the PMR spectrum. 6.0 g of this product was dissolved in a stirred mixture of 50 ml of ethyl acetate and 50 ml of ice water. The pH of the mixture was 3.5. The layers were separated. The colored organic layer containing a small amount of the desired product was discarded. Between pH 3.4 and pH 2.7, the remaining water layer was extracted 8 times with 50 ml volumes of ethyl acetate. The extracts were combined, treated with activated charcoal, dried over anhydrous magnesium sulfate and completely evaporated in vacuo. The residue was repeatedly stirred with diethyl ether, filtered and in vacuo until. dried to constant weight. Yield 4.0g. The purity of the product was at least 8596. It contained no major amount of by-product but small amounts of approximately three impurities. This product could also be converted into the monosodium salt.

PMR (d ₆ -DMSO, 60 Mc, DSS, S values in ppm): 2.05 (S, 3H), 3.6 (somewhat broadened S, 2H), 3.81 (S, 2H), 4, 09 (S, 2H), from 4.59 to about 5.2 (AB-Q, J = 12.8 cP) and about 5.15 (D, J = 4.8 cP) together 3H, about 5.7 (Q, J = 4.8 cP and

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J »approx. 8.1 cP, 1H), 9.35 (D, J «approx. 8.1 cP, approx 0.9H).

IR of the monosodium salt (KBr pellet, values in cm): approx 3500 and about 2500, about 3300, + 1770, + 1740, + 1720, 1690, + 1610, + 1590, about 1550, 1420, + 1390, + 1360, about 1270, 1240.

Example 36

Preparation of n-heptyl-3-methyl-1,2,4-oxadiazol-5-yl acetate

Anhydrous conditions were used and a stream of gaseous hydrochloric acid was passed through 25 ml of n-heptanol. As soon as the saturated solution had reached room temperature, 5.7 g (0.04 mol) of 3-methyl-1,2,4-oxadiazol-5-ylacetic acid were passed in. The introduction of a slow stream of hydrochloric acid was continued for 2 hours. The reaction mixture was additionally stirred for 60 hours at room temperature, during which the conversion of the carboxylic acid was essentially completed. The reaction mixture was mixed well with 75 ml of cold water. The layers were separated, the organic layer was washed 3 times with 10 ml volumes of a saturated solution of sodium bicarbonate in water and washed 2 times with 10 ml of cold water. All layers were combined and extracted twice with 20 ml volumes of ethyl acetate. The combined ethyl acetate extracts were washed 1 time with 10 ml of ice water. The water layers were discarded and the two organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was distilled and fractionated under reduced pressure ^and 6.8 g of the desired product with a purity of about 95 mole 5a (the impurities are mainly gerin- 'ge amounts of n-heptanol) was obtained, bp. 108 ° C at 0.25 mm Hg, n ^ ° = 1.450.

IR (NaCl window, values in cm " ¹ ): 2940, 2860, 1745, 1590, 1465, 1440 sh, 1395, 1350, 1290, + 1250, 1200, 740.

PMR (CDCl ₃ , 60 Mc, TMS, ζ values in ppm): 0.88 distorted

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Triplet, 3H), from about 1.0 to 1.9 (broad absorption range, 1OH), 2.38 (S, 3H), 3.93 (S, 2H), 4.17 (T, J = 6.4 cP, 2H).

The process described above is the very sensitive but reactive one for the preparation of primary alkyl esters 1,2,4-0xadiazol-5-yl-acetic acids generally applicable, yields of over 50% are obtained. For example, results in the esterification of the same oxadiazole acetic acid with a 2: 1 technical mixture of 3-methylbutanol-1 and (dl) -2-methylbutanol-1 in 54% yield a mixture of both esters in exactly the same ratio as in the one used Mixture of the alkanols is present.

Example 37

Preparation of 7- [3-methoxymethyl-1,2,4-oxadiazol-5-yl-acetamido] -cephalosporanic acid

To a suspension of 6 g (22 mmol) of 7-amino-cephalosporanic acid 4.60 ml (33 mmol) of triethylamine in 100 ml of dry dichloromethane were added under anhydrous conditions. The mixture is stirred for about 5 minutes, after which 0.96 ml (11.1 mmol) PCI is added. The emerging The mixture is stirred for about 5 minutes and then 4.0 g (21.5 mmol) of 3-methoxymethyl-1,2,4-oxadiazol-5-yl-acetic acid, partially dissolved in 60 ml of dry dichloromethane was added. The resulting reaction mixture is stirred for 18.5 hours at room temperature. About 200 ml of ice water are added, followed by 4N NaOH added quickly until a pH of 7.2 is reached. The layers are separated. The water layer is used 2 times Dichloromethane and shaken 1 time with 100 ml of ethyl acetate, then the organic layers are discarded. The water layer is acidified to pH 2.0 and extracted repeatedly with ethyl acetate. These extracts are combined by a filter aid (Gelite) filtered and completely evaporated in vacuo. The residue is dissolved in 75 ml of acetone with

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Treated activated charcoal, filtered through the filter aid and again evaporated to dryness in vacuo. The somewhat brown, crystalline residue is stirred up several times with dry dichloromethane, filtered on a pump and washed with dichloromethane and diethyl ether. After drying in vacuo, 3.5 g (37%) of essentially pure, almost colorless product are obtained.

IR (KBr pellet, values in cm " ¹ ): + 3550 and + 2550, 3285, 1780, 1740, 1715, 1660, 1630 sh, 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) ϊ 2.06 (S, 3H), 3.70 (S, 3H), 3.6 (somewhat broadened S, 2H), 4.12 (S, 2H), a 5H absorption region consisting of a CH ₂ singlet (at 4.56), an AB-Q at about 4.6 to 5.2 (J _AB about 12.8 cP), and a Doublet at about 5.15 (J = 4.7 cP), about 5.7 (Q, J = 4.7 cP and J ¹ approx. 8.2 cP, 1H) and 9.35 (D, J ¹ approx 8.2 cP, approx 0.9H).

Example 38

Preparation of 7- [3-methyl-oc-carbomethoxy-1,2,4-oxadiazol-5-yl-acetamido] -cephalosporanic acid

Using anhydrous conditions, a solution of 1.09 g (7 mmol) is methyl-3-methyl-1,2,4-oxadiazol-5-yl acetate in 15 ml of tetrahydrofuran at -100 ⁰ C cooled. Subsequently, 3.3 ml of a 2.34 solution η (7.7 mmol) of n-butyllithium in η-hexane was added dropwise, keeping the reaction temperature below -90 ⁰ C. The resulting solution is stirred at -90 ° C. for 60 minutes. A solution of 7 mmol of trimethylsilyl 7-isocyanato-cephalosporanate in 9 ml of toluene is added dropwise at -90 ° C to -95 ° C. The resulting reaction mixture is stirred for a further 45 minutes at temperatures which gradually rise to -75 ° C. With the simultaneous addition of 4N HCl, the reaction mixture is poured into a mixture of 25 ml of ice water and 25 ml of diethyl ether. After the mixture has reached a

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reaches a constant pH of 4.0, the pH is increased to 7.0. The layers are separated and the organic layer is discarded. The water layer is extracted with 25 ml of ethyl acetate at pH 6.0 and the extract is discarded. The desired cephalosporin (an approximately 1: 1 mixture of the D-form or L-form) is obtained by extracting the water layer several times with ethyl acetate at pH 4.5 to 4.0. Yield 1.1g (approx 34%). The end product is contaminated with less than 5 mol- # Ν, Ν'-dicephalosporanyl urea. IR (KBr pellet, values in cm " ¹ ): + 3500 and + 2600, approximately 3150 to 3270, 2950, 1785, 1740, 1710 sh, 1670, 1625, 1520 to 1560, 1440, 1425 sh, / 1390, 1360 , 1300, 1240 (with shoulders), 1170, 1120, 1080, 1050, 805, 725

PMR (approx. 3: 1 mixture of dg-DMSO and DCO ₂ D, 60 Mc, DSS, S values in ppm): 2.07 (S, 3H), 2.33 (S, 3H), approx. 3, 6 (center of an unresolved AB-Q, 2H), 3.60 (S, 3H), from about 4.65 to 5.25 (AB-Q, J approx. 13 cP) and 5.17 (center of a doublet, J approx. 4.7 cP) together 3H, 5.78 (center of a doublet, J approx. 4.5 cP, approx. 0.5H), 6.00 (center of a doublet, J approx. 4.7 cP, approx 0.5H).

Due to an exchange _{phenomenon, C a} -H and NH are not recognizable in this spectrum. These signals appear in the more complex spectrum in dg-DMSO alone, at 5.5 ppm (slightly broad S, approximately 1H) and at 9.55 ppm (doublets, approximately 0.8H).

Analogous processes are used to produce:

7- [3-methyl-a- (morpholinocarbonyl) -1,2,4-oxadiazol-5-yl-acet-

amidoi-cephalosporanic acid

where one 3-methyl-1 ^^ - oxadiazol-S-yl-acetmorpholide etc.

used as starting material (extraction of the desired cephalosporin at pH 4.0 to 2.5 with ethyl acetate), yield

about 75%

IR (ibidem): + 3500 and + 2600, approximately 3230 to 3330,

+ 3050, + 2980, + 2940, + 2870, 1785, + 1735, + 1700, 1640 until 1660, 1585, 1530 until 15.55, 1450, 1390, + 1240 (with school

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tern, 1165, 1125, 1080, 1045, 720.

PMR (approximately 4: 1 mixture of dg-DMSO and DCO ₂ D, 60 Mc, DSS,

S 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 approx. 13 cP) and 5.15 (D, J approx. 4.6 cP) together 3H, 5.60 (D, £ \ 2 = 0.7 cP, approx. 0.2H), 5.78 (center of 2 doublets , J about 4.6 cP

and J v> approx. 1.2 cP, 1H).

The complex spectrum of the compound in dg-DMSO alone shows

one full C _a ~ H singlet at 5.6 ppm and two superimposed

NH doublets at 9.4 ppm (J ¹ about 7.5 to 8.0 cP).

Example 39

Production of 1,2,4-0xadiazol-3,5-diyl-bis-acetic acid

Using anhydrous conditions, a solution of approximately 1 mole of n-butyllithium in η-hexane is added dropwise added to a solution of 50 g (0.51 mol) of 3,5-dimethyl-1,2,4-oxadiazole and 150 ml (1 mol) of TMEDA in 1400 ml of toluene. Around To keep the reaction temperature between -71 and -76 ° C, the addition time is extended to 105 minutes. The reaction mixture is additionally stirred at -78 ° C. for 90 minutes. The reaction mixture is poured into a mixture of finely divided carbon dioxide and a small volume of diethyl ether. After keeping for a few hours, the precipitate formed is filtered through a glass filter separated under a layer of dry air. The filter cake is washed with diethyl acetate and diethyl ether. . The solid is with a mixture of 250 ml of ice water and 10 ml of diethyl ether suspended. Concentrated phosphoric acid slowly and carefully becomes the stirred suspension added until a clear, brown solution with a pH of 2.0 is reached. The solution is saturated with sodium chloride. externally cooled with ice and continuously with dichloromethane extracted. At the beginning of the extraction, the water layer is heavier. The extraction is finished after about 2 hours, then the two layers are equally heavy. The organic extract, which contains a lot of valeric acid, a lot of 3-methyl-1,2,4-oxadiazole

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5-yl-acetic acid, which contains a relatively small amount of stored product and also a considerable part of the desired bisacetic acid derivative, is evaporated in vacuo. The residue (58 g), which is partially solidified, is stirred 3 times with 50 ml volumes of η-hexane containing 2 Vo 1% diethyl ether in order to remove the valeric acid present, which results in a slight loss of oxadiazole acetic acids results. The acid residue (product 1) is temporarily stored in a refrigerator. The remaining water layer is poured onto crushed ice and extracted continuously with diethyl ether until practically all of the 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid has been removed from the water layer. However, a small amount of rearranged product and a considerable amount of the bisacetic acid derivative were still present in the ether extract.

The remaining amount of the bisacetic acid derivative was completely removed from the cooled water layer by continuous extraction with ethyl acetate under reduced pressure (ethyl acetate, b.p. at 35 to 40 ° C). The extract obtained and the ether extract were combined and evaporated in vacuo. The remaining solid material (Product 2) was combined with Product 1 and dissolved in approximately 250 ml of water. To this solution were added a few drops of concentrated phosphoric acid (up to pH 2.0) and a small amount of sodium chloride. The solution was cooled with an ice bath for 18 hours, continuously extracting with dichloromethane (difficult as the water layer). The practically pure extract of 3-methyl-1,2,4-oxadiazol-5-ylacetic acid was evaporated in vacuo. The slightly yellow, crystalline residue (product 4) weighed 27.5 g (approximately 37% of the 3 »5-dimethyl-1,2,4-oxadiazole used). Recrystallization of the residue gave 24.0 g of almost pure material.

The remaining water layer from which the 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid was completely removed, it was extracted continuously with ethyl acetate as described above. Of the

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Will extract treated with activated carbon and completely The almost colorless ,, crystalline residue evaporated weighing 23 g (product 5) ο To the rearranged by-product to remove ₉ is this residue for several hours in a mixture of 60 ml of dichloromethane and 40 ml of ether was stirred "The undissolved _s ^ colorless crystalline Mass © is separated by filtration, washed with dichloromethane and n = hexane and dried to constant weight _g yield 18 _S 9 g (20%) of pure 1,2,4-0xadlazol-3p5-dlyl-bisacetic acid _{i >} mp = 109 Ms 111 ° C (a partial decarboxylation starts at about 100 ⁰ C). IR (KBR pellet values in cm) s very intensive absorptions at + 2900 Ms 320O ₉ 1700 to 1720, 1430 to 1240 g a number of other ₀ less intensive absorptions at + 3400 _s 2500 to 2700, 1595p 1410 sh _P 1375 _S. 1320, 1290 _P 120O ₅ 117O ₀ 945 ₉ 92O ₉ + 890 _s 850 ₉ 730 ₉ occurred.

PMR (about 1 s1 = mixture of CDCIj and dg ~ DMSO _P 60 Me _s «4 ~ values in ppm) g 3J5 (S ₅ 2H) ₂ 4 ₂ 02 (S ₅ 2H) ₅ , about 9 (broad S ₅

Stability of 1 ₉ 2 ₅ 4 ~ 0xadiazol ~ 3!> 5- diyl = ~ bisessigsäures A small sample was dissolved in a little diethyl ether moist "The solution was heated during reflux for 24 hours" by thin layer chromatography, it was found that less than 5% _P the 5 = methyl ~ 1 _S 2 _p 4 ~ oxadiazol = 3-yl = acetic acid were degraded.

Remarks on the reaction conditions and _{isolation methods in the preparation of 1 s} 2 _S) 4-0xadiazol- = 3s5-diyl = bisacetic acid

The method described above is only an explanation of the Rßaktionsbedingungen and isolation procedures "was found ₅ that in the second reaction with lithium ₉ in a lateral position to Cj of the oxadiazole ring in many cases (when no additional activating Substltuenten such as phenyl are present) stattfindetρ slower runs as the often very fast and complete first conversion with lithium laterally to C, -. In the example given above, the second reaction with lithium did not proceed further than at most 30 to 35% _ΰ da no more

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when insignificant amounts of rearranged products were found and the loss of bisacetic acid was low, and mainly or essentially only due to the non-optimal cleaning of the product 5 (see above) was because the decarboxylation product (5-methyl-1,2,4-oxadiazol-3-y! -acetic acid) was not isolated and neither was its presence by thin layer chromatography was displayed. The remainder of the product, which is represented by the isolated crude reaction products (approximately 60%), shows an exact decarboxylation (under the isolation conditions used) of the product of the simple lithium conversion, namely from J-methyl-ijZ ^ -oxadiazol-S-yl-acetic acid which is considerably less stable than bisacetic acid. ·

As shown in Example 4, the level of dilithium conversion can be increased. If one wishes to carry out a dilithium conversion in the present example, this can be achieved by selecting one of two alternatives. The second equivalent of n-butyllithium can be added first, as can an additional short stirring time at slightly higher temperatures (approximately -60 to -65 ° C.). On the other hand, this process results in a somewhat more pronounced formation of the rearranged product (s), which in the present case would not interfere with satisfactory isolations of the bisacetic acid. Second, the additional stirring time at low temperature can be greatly extended. In general, it depends on the nature of the substituents of the 1,2,4-oxadiazole used as starting material, which yield-increasing process is possible or more favorable. Relatively low reaction temperatures (approximately -75 to -80 ⁰ C) during the addition of the reagent and during extended further stirring are essential if there is a risk that migrated products are made stronger. This situation can prevail in cases in which both lithium conversions are relatively slow, thus generally when the introduction of the lithium is lateral to Cc

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is slowed down. This occurs when the Cj substituent is not methyl, but a longer alkyl chain (e.g. ethyl).

The double reaction with lithium often requires the use of a more powerful reagent. Therefore often, but not generally my, the very strong complex of n-BuLi: TMSDA is the reagent of choice. Other reagents that differ in their nature differ slightly and / or which are less reactive, sometimes give better results, for example when the lithium conversion lateral to C * is relatively easier. Such a situation exists when the C1 substituent is benzyl. here the use of diisopropyl-lithium amide results in an almost quantitative isolation of the almost pure dilithium salt of corresponding bisacetic acid.

An effective isolation method is for successful manufacture equally important. Even if good conversions are realized, the insulation is correspondingly good Yields are often difficult because these bisacetic acids are relatively strong acids and are very soluble in water. Although these connections are relatively stable, they can still be called sensitive connections. That therefore, suitable isolation methods will vary according to the nature of the substitution and the composition of the reaction mixture. As explained in this example and in example 4 there are two ways of treating the crude reaction mixture with carbon dioxide after the reaction. The reaction mixture can be mixed with water as a whole. However, this generally requires a lot of water before the reaction mixture dissolves and afterwards a number of steps are also required which are skipped can, if one can first isolate the double lithium salt of bisacetic acid by filtration, because then it is only the amount of water required to dissolve the double lithium salt »Depending on the individual Case (the nature of the bisacetic acid and the relative extent

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rer formation, the nature of the by-products (by-product) and the relative amount (s) of their formation as well as the nature of the reaction medium) it is often advantageous or necessary to subject the solutions of the reaction products in water to a number of purification steps, before the actual extraction of the bisacetic acid is carried out "such methods may concentration as in vacuo at pH values of about 8 or 5» 5 or continuous extractions with n-pentane at pH 5 »0 seinj the by-products or ingredients such as valeric acid _s UIEDA and to remove diisopropylamine.

Be considered one of these factors _g so, a number of Bisessig- · acids made us isolated "some values are shown for two examples in the following. It also explains the possibility of _s having an extra substitute in one of the two possible positions »

cc- (3) -Phenyl-1,2,4-oxadiazole-3 _s 5-diyl-bisacetic acid

If 3-benzyl.5-methyl-1,2,4-gxadiazole is used as the starting material and n-BuLi / TMEDA as the reagent, the compound is obtained in a yield of approximately 50%? wherein wirdj noted that the compound with about 5 moles O ₃ crystallizes diethyl ether. In this state the product is a solid at room temperature.

PMR (CDCl ₃ with a trace of dg-DMSO, 60 Mc ₅ TMS ₉ £ values in ppm) i 3.9 (S, 2H), 5.3 (S, 1H), approximately 7.35 (center of a multiplet, covering about 0.5 ppm, 5H), about 10.5 (slightly broad S, 2H).

Additional chemical evidence of this structure is provided by conversion into the dimethyl ester and into the bis (4-fluoro) ~ obtained anilide.

^a - (5) -Carbomethoxy-1,2,4-oxadiazole-3,5-diyl-bisacetic acid

If methyl-3-methyl-1,2,4-oxadiazol-5 ~ yl acetate is used as Starting material and n-BuLi / TMEDA as reagent, so will the almost

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pure compound isolated in approximately 25% yield. The product is a somewhat yellow, hygroscopic, crystalline solid.

IR (KBr pellet, values in cm " ¹ ): +3500, 2950 to 3130 (intensive), 1710 to 1745 (very intensive), 1600, 1450, 1245 (intensive), 1420, 1390, '1330, 1300, 1210 , 1180, 860, 745. PMR (approximately 5: 2 mixture of CDCl, and dg-DMSO, 60 Mc, TMS, S values in ppm): 3.65 (S, 3H, 3.95 (S, 2H ), about 7.1 (asymmetrical, broadened S, about 3H).

Possibly as a result of the presence of a small amount of water present in the compound and / or in the dg-DMSO, the naturally quite acidic Cc-C _a -H will not be separately visible, presumably it will be exchanged so that it will be Signal occurs along with the COOH signals at low field.

Additional chemical proof of its structure is obtained by converting the bisacetic acid into bis (4-chloro) anilide.

Example 40

Preparation of 3-hydroxymethyl-1,2,4-oxadiazol-5-yl-acetic acid

Using anhydrous conditions, a solution of approximately 1.2 moles of n-butyllithium in η-hexane becomes an effectively cooled solution of 66 g (0.58 moles) of 3-hydroxymethyl-5-methyl-1,2 over a 3 hour period , 4-oxadiazole and 87 ml of Ν, Ν, Ν ', N ¹ -tetramethylethylene diamine in 1200 ml of tetrahydrofuran. During the addition, the reaction temperature can not rise above about -70 ⁰ C. The reaction mixture is additionally stirred for 1 hour at -70 ^0C. While cooling dry, gaseous carbon dioxide is passed over the surface of the stirred reaction mixture for 10 hours at -70 ⁰ C. The temperature can then gradually rise to -5 ° C. The educated lower

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shock is separated by filtration on the pump and washed with dry ethyl acetate and with η-hexane. The precipitate is slowly dissolved by adding small portions to a stirred, ice-cold mixture of 500 ml of water and 500 ml of diethyl ether. Concentrated phosphoric acid is added to pH 4.0. The layers are separated and the organic layer is discarded. The water layer is further acidified to pH 2.0 and then evaporated in vacuo. Remnants of the water in the residue are removed in vacuo with the aid of benzene. The residue is dried in vacuo over phosphorus pentoxide for 16 hours. That
syrupy product "is stirred with 5-00 ml of acetone at about 35 ° C. The acetone is discarded. This is done several times, the residue becoming a solid mass. The solid mass
is placed on a filter and stirred several times with 500 ml parts of acetone until, after thin layer chromatography, the filtrate does not contain any further desired compound. All of the filtrates are pooled, approximately in total
4000 ml, and in a vacuum to a volume of approximately 300 ml
concentrated. 600 ml of ethyl acetate are added and the
resulting solution is _o ml concentrated again in vacuo to a final volume of 250 The resulting crystalline precipitate is filtered at the pump, washed with dry ethyl acetate and with carbon tetrachloride. After drying in vacuo, 41 g are obtained. Melting and decomposition
take place between 96 and 98 ° C. The filtrate is evaporated in vacuo. The oily residue is repeatedly stirred with small volumes of dichloromethane. The resulting solid is transferred to a filter and washed with ethyl acetate and carbon tetrachloride. After drying, the second batch weighs 14.1 g. It melts with strong decomposition at 92 to 96 ^° C. According to the thin-layer chromatograms, IR and PMR spectra, the two batches are essentially identical. Overall yield 45.1 g (approx. 55%) with a purity of approx. 965ο.

IR (KBr pellet, fourth in cm "* ¹ ): 3440, 1745, 1720, 160, 1430, 1390, 1320, 1240, 1220 sh, 1180, 1070, 1040, 780, 735, 650.

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PMR (approximately 6: 1 mixture of CDCl, and dg-DMSO, 60 Mc, TMS, £ values in ppm) 3.95 (S, 2H), 4.66 (S, 2H), approximately 7.5 (broadened S, about 2H).

Example 41

Production of sodium 7- (5-ethyl-1 ^^ - © xadiazol-S-yl-acetamido) -3- (5-methyl ° = 1,3,4-thiadiazol-2-yl-mercaptomethyl) -3 -

The same conditions as described in the example were used = starting from 1.55 g (10 mmol) of 5-ethyl-1,2,4-oxadiazQl-3-yl ~ acetic acid and 3 _S 44 g (10 mmol) of 7- amino-3- (5-methyl-1 _$ 3, 4-thiadiazol «2» ~ yl mercaptomethyl) -3-cephein-4-carboxylic acid having "a purity of about 92% is obtained 2.58 g of nearly pure desired Product »

In the isolation procedure the compound was removed from water by a number of extractions with ethyl acetate between pH 5.0 and pH 3 »5. The combined extracts were _{washed with water at pH 19} 0 and 2.5, decolorized with activated charcoal and completely evaporated in vacuo. The residue weighed 3.2 g (approximately 65%) <= It was dissolved in a mixture of 65 ml of acetone and 250 ml of ethanol "A concentrated solution of 6 mmol of sodium-ß £ = ethylhexanoate in ethyl acetate was added and the resulting solution was concentrated in vacuo to a volume of 50 ml. 100 ml of diethyl ether were slowly added to the well-stirred solution. The precipitate formed was collected by filtration, washed with ether and dried in vacuo.

IR (KBr pellet, values in enf ¹ ): + 3450 (H ₂ O), 3280, 3050, 2985, 2940, 1765, 1680, 1610, 1580, 1550, 1415 sh, 1390, 1370, PMR (dg-DMSO , 60 Mc, DSS, £ values in ppm): 1.28 (T, J = 7.5 cP ₉ 3H), 2.69 (S) and 2.93 (Q, J = 7.5 cP) together 5H, about 3.6 (2H), 3.77 (S, 2H), from about 4 _S 25 to 4.7 (AB-Q, J approx. 13 cP, 2H), 5.0 (D, J approx 4.9 cP _r 1H), 5.55 (Q ₉ J approx. 4.9 cP, J ¹ approx. 8.2 CP ₉ 1H) ₈ 9 ^ 2 (D ₉ J ¹ approx. 8.2 cP, about 1H).

409830/1082

Example 42

Some of the penicillins and cephalosporins made according to the respective examples were shown on their antibiotic activity in vitro using an agar serial dilution test and / or in some cases tested with a serial micro-dilution test, these tests being as follows were carried out.

A. Serial Agar Dilution Test

A stock solution of the compound at a concentration of 2000 / µg / ml in a sterile suitable vehicle is prepared. Twofold dilutions are made with sterile. 1/20 mol phosphate buffer pH 6.5 (KH ₂ PO ^ -NaOH) carried out. 1 ml portions of each dilution are added to 19 ml brain heart infusion agar in sterile petri dishes. The hardened surface is inoculated with the test organisms and incubated at 37 ° C. for 24 hours.

B * serial micro-dilution test

2 drops of a stock solution of the compound to be examined (Antibiotic) in a known concentration are placed in the first hole of a test plate with nine numbered holes with a given sterile Pasteur pipette. After getting this pipette

Rinsed 3 times with physiological NaCl solution

2 drops of the stock solution of the test organisms in a culture medium in all holes except for hole 8. In the first hole was the solution of the compound to be examined half diluted, then the liquid in the first hole was stirred and 2 drops of this mixture were added to the second Hole given and so up to hole 8. In this way, geometrical dilutions of the compound to be investigated are obtained in solution Progression. The hole 9 does not contain any antibiotic and is used for the growth of the test organisms in the pure medium to control.

The test plates are ^{incubated at 30 or 37 °} C. for approximately 18 hours. The minimum inhibitory concentration (MIC) of the

A09830 / 1082

tested compound, i.e. the lowest amount of antibiotic, which completely inhibits the growth of the test organisms is expressed in / µg / ml in both cases.

The MIC values of the compounds examined and of benzylpenicillin, Fhenoxymethylpenicillin, ampicillin, cephalexin, cephalotin, benzylcephalosporin, benzyldesaeetoxy-cephalosporin as comparison compounds are listed in the following tables. The MIC values obtained by serial micro-dilution experiment are set in brackets.

409830/1082

Examined
link

6633 Staph.aureus A 321

A355 ') A2000 A2001

Strep, haem. A 266 Strep, faec. L 80 Dipl.pneum. L 54 Haem.infi. A 1030 frucmelit. A 488 Past.Multo. A 723 adhesive pneum. A 809 SaIm.dubl. P 43 Saim.typh. R 127 Esch.coli U 20
Shig.Equir. T 3 ', pseud.aerug. H 10 2396

Wyeth A 1058 Prot.rettg. A 821 mirab. H 3 ' I 93

A1200 morg. 2241

benzyl desacetoxy ceph. (K-SaIz)

0.5

25 U.

> 100

100 '25 100> 100

mm

> 100

100

> 100

> 100

> 100

> 100

> 100

50

> 100

_e £ alexine (acid)

0.5 1.5 12.5 12.5

0.25

100

(125)

12.5

1.5

> 1Ö0

> 100

> 100

12.5

25th

12.5,

> 100

enicillin G

(0.006)

(0.03) (10)

Penicillin V

Ampicillin Cephalosporin Cephalotin G (K-SaIz) (Acid) 0.03 0.09 0.12 y 0.12 1.5 0.5; 6th 1.5 (1.8) 0.5 ". 1.5 ■ 1.5 0.5; 1 (0.9) -. <0.015 0.03 0.06 'j 1.0 25th 25! 0.06 0.06 " 0.5 I. <125 (0.5) (125) - 1.0 2 6th 0.25 1 0.7 25 " 1 0.7 (0.37) 1.5 β V. 5
^ V 3 50 3 1.0 25th 1.5 125 > 100. > 100 · ' 12.5 > 100 > 100 * Ί00 > 100 > 100 3 25th 12.5 0.9. 25th 12.5 0.15 2 0.6 12.5: > 100. > 100

·) -Penicillanase-producing strain

Investigated connection ■

to
■ w
α »
ο

Connection A

BacSubt.ATCC 6633 Staph.aureus A 321

A355)

, 'A2000

A2001

Strep, haem. A $ 26 ■ Strep "faee. L BO PipIUpnem. L 54 Haenwinfl. A 1030 fruc.melit. A 488 Past.MuIto. A 723 Heb.pnewn .. A 809 Salm.dublc P 43 Saln.typh · R 127 Eseh.coli U 20 Shig.Equir * T 3, Pseud »aerug® H 10 2396

Wyeth A 1058 Prot.rettg · A 821 jnirab »

tomorrow

H 3 L 93 A1200 2241

Connection B

Connection C connection D

·) Penicillinase-producing strain

0.25 0.25

O.75 (Ob) 0.25 (0.3) (t)

0.5 12.5 0 = 5 (125)

1
12 "5

> 100 25

> 100> 100> 100 50

> 100 25

> 100> 100

Connection E

Example <
6th

0.12 I, 0.5

' 0.5 (0.6) j _k 0.75 (1.0

0.75 (0.6

J 50 ";

0.75 (30)

mm

"i.5 ·

3 '

12.5

12.5

> 100> 100> 100

1.5

25th

12.5

25. ".> 100

> 100

> 100

> 100

> 100

> 100

> 100

> 100

> 100

100

> 100

> 100

Example,
7th

Ex.

Connection A: 6 Connection B: 7 Connection C: 7 Connection D: 7 Connection It 7-

0.06 0.12

1 (0.15) 1

(0.11) 0.03 6

0.25 (125) 100 50 '50> 10Ö

> 100> 100 > 100

> 'ioo

> 100> 100> 100> 100 > 100> 100

\ (3-methoxymethyl-i, 2,4-oxadiazol-5-yl) acetamido] -penicillansäure, a-phenyl (3-niethyl-1 ₉ 2,4-oxadiazol-5-yl) cephalosporanic -acetamidoJ

> -Benzyl-1,2,4-oxadiazol-3-yl) -acetamido] -cephalosporanic acid , J-methyl-1,2,4-oxadiazol-5-yl) acetamido] cephalosporanic acid [^ .- Forpholino- (3-methyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid

23641

a CM
τ- CM CM 1Λ
CM ΙΛ ^ - » Pl t- ΙΛ ca n Ο CM t ^ O CM
Τ ™ • Ην- τ- ΙΛ ΙΛ (D τ ™ pq τ- CO τ— τ-

coir! • Η ν- PQ ^

CQ Ü • Η ν-Φ ν-

coffee shop

φ ■ PQ

P, • Η ^ ω τ PQ

caQ • Η Φ PQ

CQO • Η Φ PQ

PiPQ ca • Η Φ PQ

P. IQ << • Η ν-φ.

• HO

ΙΛ · ΙΛΟΟΟ ΙΛΙΛ O

τ— ΙΛ » " ΟΟΟ ο. O

" CMU ^ OCMt-tt- CM CVl ΙΛ τ- VOt-VDt-CM"? \ T- _A ^ Λ ^ "~ * ~ ^W Λ

νοίΛΙΛ ΙΛ ρ «. ΙΛ O ΟΟΟΙΛΟ OO

OCM. ΙΛ CM . · CM «Λ ο OO OOO « O OO

• »CM. »Η..ΟΟθΓ-ΙΛτ-τ-T-CMT- τ-τ-

ΟΟτ-νοηΟνοΟν ^ Οτ-τ-ίΛτ- ^ CJ ΛΛΛ ^ Α ^ ΑΛ

η cm ο ^ -ίπ ιλ O τ- η ιλ ^^.

. .W. ο O O η τ-

Ο ΙΛ 00 »Λ00Ο00000

O _- CM ΟΟΟΟΟ »ΟΟΟΟΟΟΟΟ

Ot- O

ΙΛ v "* VO τ-

.Q Q CM ._ τ- O τ -_._ O O O τ- τ- CM

»-» ■ * - «% ν» W ■ »V ^>« / ^^ · * ~ "» W ^ i T - * -, ¥ - ^ - 1— 1— \ -

VO VO ΙΛΙΛτ- VO _Λ ^ WVO ν-τ-τ- _ΛΛ τ- _{ΛΛΛΛΛΑΛ}

CM £>. ΙΛ.

• «. CM ^ -ο

On «ΙΛΙΛ ιλ ΟΟΟΟΟΟΟΟΟΟΟΟ

ΙΛ v _ <^ _ y OCM · CM O-ΟΟΟΟΟΟΟΟΟΟΟΟ

. ΙΛ ΙΛν ^ CM τ-Ο ΙΛΟτ-τ-τ-τ-τ-τ-τ-τ-τ-τ-τ-τ-

T-OC ^ t ^ T-Οτ- Ι ^ -Ί ^ ίΝτ-Λ-ΛΛλΛΛΛΛΛΛΛΛ,

OO i

CM VO

^ -> · · * —S ΙΛίΛΙΛ ΟΟΟ ΙΛΟ

ΙΛ νΟτ-Ο'ΛΟ'ΛΟ ... ΙΛΟΟΟ · Ο

• "^ r - '^ w · 0 · 0 \ 0 CMCMCM.TTTO CMt-

Οτ-νοηηθτ-τ- ^ - "T- VOVOt-ttt-λ _{Α A} ^ TVOVOt- _A

ON CO ΙΛ VO τ- CM P ₁

ΟΟΟ

M ctf ^^^ n VO ^ ->. ΙΛΟΟΟ ΟΟΟ O OO

τ-τ-ΐΛΐΛ! ΛΟ «Λθη · O O O ΟΟΟ ΟΟΟΟ

OO OOOO τ- OWVO VO τ- λ Λ Λ ^w ^ N ^ A / k «" »^ * - yv A ^

ΙΛΙΛ Ο ^ ΛίΛ ΟΟΟ OO

CVl CM ΟΟ · * ΟΟΟ OO

_{,, UL,.} · Γ- »r-CMCV10 ΐ-τ-τ-ΟΟ τ- r

Οοηιηηο «Ο ·> -Ί τ- _Λ τ-τ-ΐΛη _{Λ Λ Λ} ιαιλμ _{λ λ}

νονό ΟΟΟΟΟΟΟΟΟ.Ο

OO O O OO O ΟΟΟΟΟΟ O

.. · ΙΛ O τ-τ- rlrtrrrrrr r

OOnnlr «nrP) Pl _A nln« AAAAAA ¹ A

-, vi O \ pl

cicQSSSS_ S "« a 8 * 8 8 2 «

ο O τ- τ- τ- ο ιλ ι V.XVO τ- 1 ηη «ΐ (θ _{Λ Λ Λ} ητ-τ-νο

t> -CO <Τ \ O ν-OJ ΝΛ-ί IAVOO-CO ONOv-OJ .

v-T-v-v-v-v-v-v-v-v-OJCMOJOJOJ

409830/1082

Examined connection -

co 00 CO O

CD 00

Example 11K

Ex, 11L

Ex, 11M

Bac.Subt.ATCC 6633 0.25 0.12 0.06 Staph.aureus A 321 1.5 0.25 0.12 A 355 ') 1.5 (0.9]
1.5 (1.2; 1 .. 12.5 A2000 1 (0.9) 1 6th A2001 0.06 1 6th Strep.haem. A 266 100 0.25 0.5 ' Strep.faec. L 80 1 50 • 6 Dipl.pneum. L 54 (125) 1 • 0.5 Haem.infl. A T030 12.5 0 * 125) (3.7) Bruc.rr.elit. A 488 1.5 6th 0.5 Past.multo. A 723 6th 2 1 ICleb.pneum. A 809 100 1.5 > 100 Salm.dubl »- P 43 > 100 3 50 Salm.typh. R 127 > 100 6th > 100 Esch.coli U 20 25th 6th > 100 Shig. equir. T 3 > 100 3 50 Pseud.aerug. H 10 > 100 > 100 > 100 "2396 > 1Q0 > 100 > 100 Wyeth A1.O58 12.5 > 100 > 100 Prot.rettg. A 821 > 100 1 3 from me. H 3 12.5 50 > 100 L 93 > 100 3 25th A 1200 > 100 25th > 100 tomorrow 2241 > 100 > 100

, κ: cc

CD OO CO O

Investigated connection

Example 13

Example 18

Example 19

Example 31

Example example
37 38

0.03 1 0.5 1 • 0.12 6th Bac ". SubtV ATCC 6633 0.12 1 6th 1.5 0.5 25th Staph.aureus A 321 10 1.5 (1.2) 12.5 (15) 6 (1.9)
3 (1.2) 1.5 (0.9) 25 (23)
25 (23) : A 355 «) 1.5 1.5 (1.2) 6 h)
6 (6) ■ 3 (1.2) 1.5 (0.6) 25 (15) A2000 1.5 1 (0.9) 0.5 (2.5) 0.75 (0.45) _ A2001 0.03 0.25 •> 100 25th 0.12 > 100 Strep.haem. A 266 6th > 100 3 1.5 50 12.5 Strep, faec. L 80 1.0 3 (23) Ζ > 1? 5) 0.75 (125) Dipl.pneum. L 54 (125) (6). 6 · • - (125.23) Haem.infl. A 1030 3 6th 25th 1i5 _, ■ 12.5 Bruc.meXit. A 488 1 10 50 '6 1 50 Past, multo. A 723 > 100. 6th 25th 6th 3 100 · Adhesive pneum. A 809 3 6th 100. 12.5 3 100 Salm.dubl. P 43 25th 12.5 100 ' 12.5 12.5 > 100 Salm.typh. R 127 50 12.5 '· ■' 6th 12.5 12.5 ■ 50 · Esch.coli U 20 3 3 > 100 > 100 3, 6 ■> ioo Shig. equir. T- 3 > 100 > 100 ,> 100 > 100 > 100 > 100 Pseud.aerug. H 10 • - > 100 > 100 > 100 > 100 > 100 2396 > 100 > 100 6th 12.5 > 100 25th Wyeth A 1058 6th 12.5 50 25th 3, 12.5 100 Prot. Rescue A.821 100 25th 25th . 6th 25th 50 from me. H 3 3 6th > 100 25th 6, 12.5 > 100 L 93 25th 25th > 100 > 100 50, 100 > 100 A 1200 ioo > 100 > 100 tomorrow 2241

Example 43

First in vivo tests of the penicillanic acid and cephalosporanic acid derivatives produced gave the following results:

(a) Compound sodium 7 - [(3-methy1-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanate (prepared as in Example 10) ', the acute toxicity was determined in Swiss mice by a intended for intraperitoneal administration. The LDc _n values are> 6000 mg / kg (Cephalotin LD ₅₀ > 600 mg / kg).

In a protection experiment, the following were found for this compound

Connect
manure Appoint
reaching " ED ₅₀ (mg / kg, Kiebsiella
pneumoniae Escherichia
coli Verb. To
Ex. 10
Cephalotin sc
ip
sc
ip Stapho
aureus
pen.resi
st ent "Proteus
rettgeri 2.3
0.8 120.0
> 300 31.0
37.6 1.25
4.34

The blood values or »= levels of the above-mentioned to be examined Compound and of cephalotin were after intramuscular administration of 50 mg / kg of these compounds in aq. ger solution determined in rabbits. After half an hour, the compound of Example 10 showed a value of 38.3 / ug / znl, the value for cephalotin was 33 ^ 9 / Ug / ml.

35.9% of the administered compound (according to Example 10) was recovered in the urine, while in the case of cephalotin 22.2% was recovered within 6 hours.

(b) The ED (- _n value of sodium -? - [(3-methoxymethyl-1,2,4-oxadiazol-5-yl) acetamido] cephalosporanate (prepared as described in Example 37) is 1.2 mg / kg in a protective test against a penicillin-resistant Staphylococcus

409830/1082

aureus strain after subcutaneous administration, while for cephalotin a value of 1.3 mg / kg was found. The compound according to Example 37 gives good results in tests with mice Blood levels and very strong urine activity against pathogenic germs. The compound can preferably be used parenterally will.

(c) The EDcQ of sodium 7 - [(3-ethyl-1,2,4-oxadiazol-5-yl) acetamido] cephalosporanate (prepared as described in Examples 11L and 34) is 4.4 mg / kg for one Protection attempt against a penicillin-resistant strain of Staphylococcus aureus after subcutaneous administration while a value of 1.3 mg / kg was found for cephalotin.

(d) In mice, there are relatively high blood levels and interesting activities against Proteus strains, Salmonella strains and penicillin-resistant Staphylococcus strains in urine after parenteral administration of the following compounds observed:

Sodium 6 - [(3-ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -penicilla-

Sodium 6 - [(5-methyl-1,2,4-oxadiazol-3-yl) -acetamido] -penicil-

lanat

Sodium 6- [α-methyl- (3-methyl-1,2,4-oxadiazol-5-yl) acetamido] -

penicillanate

7- [£ 3- (2,6-dichlorophenyl) -1 ^^ - oxadiazol-S-yli-acetamido] -

cephalosporanic acid

Example 44

Syrups were prepared from the penicillins and cephalosporins described in accordance with the preceding examples, the following ingredients being mixed: Active compound 1.5 to 6 g of sodium carboxymethyl cellulose 0.06 to 0.600 g of sodium saccharinate 0.1 to 1 g of methyl p-hydroxybenzoate 0, 06 g
Strawberry flavor 0.1 to 5 g

Amaranth 0.010 g

Sucrose 30 g 409830/1082

Water, added to a volume of 60 ml

These prepared syrups can be used for oral administration.

Example 45

Capsules containing, as the active ingredient, a penicillin or cephalosporin derivative, prepared according to the preceding Examples containing were prepared in the usual manner. The components of the capsules are listed below :

Active compound 150 to 500 mg Potassium bicarbonate 100 to 300 mg

Magnesium stearate 2 to 10 mg

Lactose for one capsule

These capsules can be used for oral administration.

Example 46

Tablets containing, as active ingredients, a penicillin or cephalosporin derivative, prepared according to the preceding Examples containing were prepared in the usual manner. The ingredients of the tablets are listed below Σ

Active compound 125 to 500 mg polyvinylpyrrolidone 5 to 30 mg amylum pellagra 100 to 300 mg

Magnesium stearate 1 to 20 mg

Lactose for one tablet

These tablets can be used for oral administration.

Example 47

From the penicillin and cephalosporin derivatives produced according to the preceding examples, a dry one becomes Powder for injection made in the usual way. An amount of 100 to 2000 mg sterile sodium salt of the appropriate Compound is aseptically placed in an ampoule designed for in-

A09830 / 1082

injectable agent is suitable under a nitrogen atmosphere
filled. The ampoule is closed with rubber plates, these are held in place by aluminum connecting rings so that the exchange of gas or the penetration of microorganisms is avoided. Before use, the powder is dissolved in a suitable amount of sterile and pyrogen-free water.

409830/1082

Claims (26)

Patent to s ρ r ü c h e Substo-1 _S 2s, 4-0xadiazol-yl-acetic acids of the general formulas y ^r ' in which the symbol R _{1 is} a (lower) alkyl group such as a methyl, ethyl, propyl, isopropyl-j, butyl, ₉ sec-butyl, isobutyl, t-butyl group, optionally substituted in the primary or secondary position in relation to the carbon atom in the ring with a fluorine atom _s a chlorine atom, a hydroxy group or a (lower) alkoxy group such as a fluoromethyl, 2-chloroethyl-p methoxymethyl, 1-hydroxyethyl group, or a cycloalkyl group optionally substituted with one or more (low ) -Alkyl groups, hydroxy groups or (lower) -AlkO3cygruppen, or where R ^ is an adamantyl group, or Phenylgruppej optionally substituted with not more than three substituents such as a fluorine atom, a Chloratoia, a hydroxy _»s of a (lower) alkyl or · = a (low) - Älkoxygruppe _{9 s} or means wherein R _{1 is} a mononuclear heterocyclic 5-membered group _9, for example a furyl- _S thienyl- ^ Xsoxazolyl-j, isothiazolyl- ₃ oxadiazolyl group, optionally substituted with (lower) «alkyl groups ₉ , or in which R ₁ denotes an aralkyl group such as a benzyl group, optionally substituted in the phenyl nuclei, as described above ;, denotes j, and in which Z ₁ denotes a hydrogen atom, a (lower) alkyl, an aralkyl, a cycloalkyl or a phenyl group, the cycloalkyl or phenyl group optionally with 409830/1082 the aforementioned substituents may be substituted, or where Z ^ is a (lower) alkyl group substituted with a mononuclear 5-membered heterocyclic group, as mentioned above, means or / V ₅ HOOC CH C "\ P CH COQH II Zp is a hydrogen atom, a (lower) -alkyl-, Phenyl, cycloalkyl, aryl (lower) alkyl group, a carboxy group, esterified with a (lower) alkyl, phenyl, Cycloalkyl or aralkyl radical, or an N-disubstituted one Denotes carbamoyl or N-monosubstituted carbamoyl group, and Ζ-, a hydrogen atom or a phenyl group, optionally substituted with at most three of the aforementioned substituents, or an N-disubstituted carbamoyl or carboxyl group, esterified with a (lower) alkyl, phenyl, cycloalkyl or aralkyl radical, or HOOC CH C ^ ^ C : R ₂ III Z ₄ \ l ^/ wherein R _{0 is} a group of the formula _ 3 - (CH ₂ ) _n - C < means in which η means 0, 1, 2 or 3 and FU a hydrogen atom or a (low) - Alkyl group means and 409830/1082 R. a hydrogen atom, a (lower) -alkyl-, Means cycloalkyl, phenyl or aralkyl group or in which R. denotes a -COOE group, in which E denotes a hydrogen atom or a salt-forming radical (if η _y denotes y), or a (lower) -alkyl, benzyl or phenyl ester radical, or in which R, a carbamoyl 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 can optionally be substituted by at most one of the aforementioned substituents, or in which R ^ and R ^ together with the carbon atom that they are bonded mean an optionally substituted cycloalkyl group and in which Zi is a hydrogen atom or optionally one substituted aryl group means and the salts and esters thereof. 2. Compounds according to claim 1, characterized in that that R ^ is a (lower) alkyl group such as a methyl or ethyl group, optionally substituted by a fluorine atom, a chlorine atom, a hydroxyl group or a (lower) alkoxy group, or represents a substituted phenyl group or a benzyl group. 3. Compounds according to claim 2, characterized in that Z _{1 is} a hydrogen atom, a lower-alkyl group or a phenyl group. 4. Compounds according to claim 1, characterized in that Zp is a hydrogen atom, a (lower) alkoxycarbonyl group, an optionally substituted phenyl group, a 409830/108 2 N, N-di- (lower) -alkyl-carbamoyl group or a (lower) -alkyl group means. 5 connections according to claim 1, characterized in that that Ζ-, a hydrogen atom, a (low) -alkoxycarbonyl group, denotes an optionally substituted phenyl group or an N, N-di- (lower) -alkyl-carbamoyl group. 6. Compounds according to claim 1, characterized in that that Rp is a (lower) alkyl group, a benzyl group, optionally substituted in the phenyl ring, a (lower) alkyl acetate group or an N, N-di (lower) alkylacetamido group. , 7 connections according to claim 1, characterized in that that Z ^ is a hydrogen atom or an optionally substituted one Means phenyl group. 8. Compounds according to any one of claims 1 to 7, namely 3-methyl-1,2,4-oxadiazol-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-oxadiazol-3-yl-acetic acid, 3-ethyl-1 ^^ - oxadiazol-S-yl-acetic acid, 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid, 5-benzyl-1,2,4-oxadiazol-3-yl-acetic acid, α-methyl-3-diethyl-1,2,4-oxadiazol-5-yl-acetic acid, <x-methyl-3-ethyl-1 ^^ - oxadiazol-S-yl-acetic acid, tt- (5) -Methyl-1,2,4-oxadiazole-3,5-diyl-bis-acetic acid, a- (5) -Phenyl-1,2,4-oxadiazole-3,5-diyl-bis-acetic acid, 1,2,4-0xadiazol-3,5-yl-bis-acetic acid, 3-benzyl-1,2,4-oxadiazol-5-yl-acetic acid, α- (5) -phenyl-3-methyl-i, 2,4-oxadiazol-5-yl-acetic acid, 3-methoxymethyl-1,2,4-oxadiazol-5-yl-acetic acid, 409830/1082 35 _T Ethyl-δ <: - methyl-1 _J 2 _i 4-oxadiazol-5-yl-acetic acid, α- (3-ethyl-1,2,4-oxadiazol-5-yl) propionic acid, 3- (oc -Carboxy) -benzyl-1 ^^ - oxadiazol ^ -yl-acetic acid, 5- (N-propen-3-yl) "carbaraoylmethyl-1,2,4-oxadiazol-3-yl-acetic acid acid, α- (3) -Phenyl-1,2,4-oxadiazole-3,5-diyl-bis-acetic acid, α- (5) -Carbomethoxy-1,2,4-oxadiazole-3 »5-diyl-bis-acetic acid 3-hydroxymethyl-1,2,4-oxadiazol-5-yl-acetic acid and the salts and esters thereof. 9. Ester derivatives of substituted 1,2,4-oxadiazol-yl-acetic acids according to claim 1 of the general formulas R ₁ and Z * have the meanings given above for formula (I) and E ₁ denotes a (lower) alkyl, cycloalkyl, benzyl, benzhydryl or phenacyl radical, or C __CH_ C ^ C- CH-C-OE ₀ XIII ₂ . .% - / Ll Zp and Z, have the definitions given above and Ep denotes a (lower) alkyl, ₉ cycloalkyl, aralkyl, phenyl, phenacyl or benzhydryl radical, where the phenyl radicals can optionally be substituted with halogen, optionally esterified carboxy, (lower) alkoxy, (lower) alkylthio, (lower) -alkyl-lower- (alkoxy) 40983Q / 1Q82 and lower- (alkoxy) -lower-alkylcarbonyl, or ^XIV wherein R ₂ and Z ^ have the meanings given for formula (III) and E, a lower alkyl, cycloalkyl, aralkyl, Denotes phenyl, phenacyl or benzhydryl group, it being possible for the phenyl groups to be optionally substituted by Halogen, optionally esterified carboxy, (lower) -alkoxy, (lower) -alkylthio, (lower) -alkyl- (lower) -alkoxy, (lower) alkoxy (lower) alkylcarbonyl. 10. Ester derivatives according to claim 9, namely methyl-3-methyl-1,2,4-oxadiazol-5-yl acetate, Methyl- (cc-phenyl) -3-methyl-1 ^^ - oxadiazol-S-yl Methyl 5-methyl-1,2,4-oxadiazol-3-yl acetate, Cyclohexyl-5-methyl-i, 2,4 ~ oxadiazol ~ 3-yl acetate, Cyclopentyl-5-ethyl-1,2,4-oxadiazol-3-yl-acetate, (4-bromo) -phenyl-3-methyl-1,2,4-oxadiazol-5-yl-acetate, sec-butyl-3-methyl-i, 2,4-oxadiazol-5-yl acetate, Benzyl-3-methyl-1 ^^ - oxadiazol-iü-yl-acetate and n-Heptyl-3-methyl-1,2,4-oxadiazol-5-yl-acetate. 11. Penicillanic acid and cephalosporanic acid derivatives according to the general formulas C-CH-C-NH-Q N L- (T Z "0 wherein Q is groups 409830/1082 CH CIi ■ Η- λαλ — CH— approx a- CH-CH .CH — COU XIX CH, -CH- COU XXI COU 9 CH-CH ^y XX or XXII CH - COU , * - CH—
'JC N.,. OU 2 .. C CH ₂ - X XXIII means in which U is an amido group, for example a saccharyl, succinimido or phthalimido group or a group OE ¹ in which E "is a hydrogen atom, a salt-forming cation, an ester radical such as a (lower) alkyl group which is optionally substituted by a (lower) alkanoyloxy group, which can also be substituted, a silyl- ₉ phenacyl-, benzyl-, benzhydryl- , Trichloroethyl or tert-butyl group means ₉ X is a hydrogen atom, a hydroxyl group, a (lower) alkanoyloxy group (preferably acetoxy) or the residue of a nucleophilic agent such as a halogen atom, an azido 409830/1082 group, a cyano group, a carbamoyloxy group, an optionally substituted mononuclear heterocyclic group containing a sulfur or nitrogen atom (such as pyridinyl), represents a group -S-Q 'in which - ^ optionally substituted Q ¹ a / DiazoIyI-, Triazolyl-, TetrazoIyI-, Means thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl or purinyl group,
or where X denotes an amino group in which Q denotes a group of the formula XX, R ^ 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 by a fluorine atom or a chlorine atom , a hydroxy group or a (lower) alkoxy group such as a fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl group, or a cycloalkyl group, optionally substituted with one or more (lower) alkyl _{groups f} hydroxy groups or (lower) alkoxy groups means or wherein R _- . an adamantyl group or a phenyl group, optionally substituted by at most three substituents such as a fluorine atom, a chlorine atom, a hydroxy, a lower (alkyl) or a (lower) alkoxy group, or in which R ^ a mononuclear heterocyclic 5-membered Group such as a furyl, thienyl, isoxazolyl, isothiazolyl, Oxadiazolyl group, optionally substituted with (lower) - ' Alkyl groups, means or wherein R ^ an aralkyl group such as a benzyl group, optionally substituted in the phenyl nucleus as described above, or denotes a carboxymethyl group, and in what Z ^ "in addition to the definitions listed above for R ^ a hydrogen atom, a (lower) -alkyl group, optionally substituted with a chlorine or fluorine atom, 409830/1082 a (lower) alkoxy group, a cycloalkyl group, a Phenyl group, which itself can optionally be substituted with a maximum of three of the aforementioned substituents, means or wherein Z ^ "is a carboxy group esterified with a (lower) -alkyl-, phenyl-, cycloalkyl- or aralkylre *? +., means, where the phenyl groups are optionally substituted by at most one of the aforementioned substituents canj or wherein Z ^ "is a carbamoyl group, optionally substituted on the N. with one or two (lower) alkyl groups, a phenyl group, a mononuclear 5-membered heterocyclic Group, a cycloalkyl group, one or two aryl (lower) alkyl ethers Cycloalkyl (lower) alkyl groups, the phenyl or cycloalkyl groups optionally may be substituted with at most one of the aforementioned substituents, or in which Z ^ "means a carbamoyl group whose nitrogen atom is a member of a heterocyclic ring such as morpholino, and wherein Z <j "means a hydrogen atom in combination, if R * means an acetic acid residue, NH- C CH C _v ^ CR ₀ XXIV N 0 ft Z N0 wherein Q has the definition given above and R _{2 is} a group of the formula - CH means in which 409830/1082 η means 0, 1, 2 or 3, and R, a hydrogen atom or a (lower) alkyl group means and R / a hydrogen atom, a (lower) -alkyl-, Cycloalkyl, phenyl or aralkyl group means or R. denotes a —COOE group ₉ in which E denotes a hydrogen atom or a salt-forming radical (if η> 1) or a (lower) -alkyl, benzyl or phenyl ester radical, or R ^ is a carbamoyl group, optionally N-substituted with one or two (lower) -alkyl or alkenyl groups, a phenyl group, a cycloalkyl group, a or two aryl (lower) alkyl or cycloalkyl (lower) alkyl groups, the phenyl and cycloalkyl groups may optionally be substituted by at most one of the aforementioned substituents, or in which R, and R. together with the carbon atom to which they are attached represent an optionally substituted cycloalkyl group,
and in what Z. denotes a hydrogen atom or an optionally substituted aryl group, and the salts and esters thereof. 12. penicillanic acid and cephalosporanic acid derivatives according to claim 11, characterized in that R ^ (in formula XVIII) is a lower-alkyl group, an adamantyl, halomethyl, hydroxymethyl, carboxymethyl, (lower) alkoxymethyl, benzyl or phenyl group, optionally with one, two or three substituents such as chlorine or lower-alkyl groups or a single nitro group, and in which in particular R ^ is methyl, ethyl, methoxymethyl, 2 s 6-dichlorophenyl, 2,4,6 -Trimethylphenyl or a carboxymethyl group, and the pharmaceutically acceptable salts and esters thereof. 409830/1082 13. Penicillanic acid and cephalosporanic acid derivatives nach'Anspruch 11, characterized in that Z ^ "(in formula XVIIl) a hydrogen atom, a lower-alkyl group, represents an optionally substituted phenyl group, an esterified carboxy group or a carbamoyl group and the pharmaceutically acceptable salts and esters thereof. 14. penicillanic acid and cephalosporanic acid derivatives according to claim 11, characterized in that R ^ (in formula XXIV) denotes a methyl or ethyl group or a group -CH ₂ -Ra, wherein R ^ is a branched alkyl, cycloalkyl, phenyl -, a (lower) alkoxycarbonyl, an N-monosubstituted carbamoyl group or an unsaturated heterocyclic group, and the pharmaceutically acceptable salts and esters thereof. 15. penicillanic acid and cephalosporanic acid derivatives according to claim 11, characterized in that Z. is a hydrogen means atom or a phenyl group. 16. Penicillanic acid and cephalosporanic acid derivatives according to one of claims 11 to 15, namely 6- [(cc-phenyl-3-methyl-1,2, A-oxadiazol-5-yl) acetamido] penicillanic acid, 7 - [(3-Benzyl-1,2,4-oxadiazol-5-yl) -acetamido] -desacetoxycephalosporanic acid, 7- {[3- (2,4,6-trimethylphenyl) -1,2 ^ 4-oxadiazol-5-yl] acetamido? -cephalosporanic acid, 7 - [(3-Methyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid , 6- {_ [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] -acetamidoJ · - penicillanic acid, 6- [(3-methyl-1,2,4-oxadiazol-5-yl) acetamido] penicillanic acid, 7- £ [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] -acetamidof- cephalosporanic acid, 7 - [(5-methyl-1,2,4-oxadiazol-3-yl) -acetamido] -cephalosporan- - acid, 409830/1082 ^'11? "2364-29 7- Γ [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] acetamido} * " desacetoxy-cephalosporanic acid, 7 - [(3-methyl-1,2,4-oxadiazol-5-yl) -acetamido] -desacetoxycephalosporanic acid, 6 - [(3-ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -penicillanic acid, 6 - [(a-Methyl-3-methyl-i, 2,4-oxadiazol-5-yl) -acetamido] -penicillanic acid, 7 - [(a-Methyl-3-methyl-1,2,4-oxadiazol-5-yl) -acetamido] -cepha-iosporanic acid, 7 - [(ct-methyl-3-ethyl-i, 2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid, 7 - [(3-ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid, 6 - [(a-methyl-3-ethyl-i, 2,4-oxadiazol-5-yl) acetamido] penicillanic acid, 6 - [(5-methyl-1,2,4-oxadiazol-3-yl) acetamido] penicillanic acid, 7 - [(5-methyl-1,2,4-oxadiazol-3-yl) -acetamido] -3-azido-methyl-3-cephem-4-carboxylic acid, 7 - [(5-methyl-1,2,4-oxadiazol-3-yl) -acetamido] -3-azidomethyl-3-cephem-4-carboxylic acid-R-sulfoxide, 7- [5- (N-propen-3-yl) -carbamoylmethyl-1,2,4-oxadiazol-3-ylacetamido] -cephalosporanic acid, 7- [5-Benzyl-1,2,4-oxadiazol-3-yl-acetamido] -cephalosporanic acid, 7- (5-ethyl-1,2,4-oxadiazol-3-yl-acetamido) -cephalosporanic acid, 7- (3-Carboxymethyl-i, 2,4-oxadiazol-5-yl-acetamido) -cephalosporanic acid , 7- (3-methoxymethyl-i, 2,4-oxadiazol-5-yl-acetamido) -cephalosporanic acid, 7- (3-methyl-a-carbomethoxy-1,2,4-oxadiazol-5-yl-acetamido) -cephalosporanic acid, 7- [3-methyl-a- (morpholinocarbonyl) -1 [ _t 2,4-oxadiazol-5-yl-acetamido] -cephalosporanic acid, 7- (5-ethyl-1,2,4-oxadiazol-3-yl-acetamido) ~ 3- (5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl) -3-cephem-4- carboxylic acid and the alkali metal, alkaline earth metal and amine salts and the pharmaceutically acceptable esters thereof. 17. Amide derivatives of substituted 1,2,4-oxadiazol-yl-acetic acids according to the formulas 409830/1082 H ₁ C- ^ ™ CH_C-r ^ ⁵ XXXV -A "V -CH- C. ^ / CR ₂ XXXVI ⁿ \, _; s * ⁵ ^ p - CH - ^{c - N} _v XXXVII R. "ο. ·· ^> * er 'Lo \ il wherein R ^, Rp, Z ^, Zp ₉ Z-, and Z. have the definitions given in claim 1 above, Rc is a hydrogen atom, a (lower) alkyl group, an aryl (lower) alkyl or a cycloalkyl (lower) alkyl group means and Rg is a hydrogen atom or a (lower) alkyl, Phenyl group, a xaononuclear 5- or 6-membered heterocyclic, Cycloalkyl, Aryl ™ (lower) alkyl or cycloalkyl (lower) alkyl group means, where the phenyl and cycloalkyl groups optionally with at most one of the above mentioned substituents can be substituted, or wherein Rg is an amino group, optionally substituted with a (lower) alkyl carbonyl, aryl carbonyl, mononuclear heterocyclic carbonyl or (lower) alkoxycarbonyl group, or wherein Rc and Rg together with the nitrogen atom to which they are bound ;, a 5- to 7-membered mononuclear mean heterocyclic ring such as morpholino or piperidino. 409830/1082 18. Amide derivatives according to claim 17> namely 3-methyl-1 ^^ - oxadiazol ^ -yl-acetmorpholide, N- (Thiazol-2-yl) -3-ethyl-1,2,4-oxadiazol-5-yl-acetamide, Hydrochloric acid salt of N- (4-pyridyl) -3-methyl-1,2,4-oxadiazol-5-yl-acetamide, N-methyl-N-phenyl-3-ethyl-1,2,4-oxadiazol-5-yl-acetamide, N, N-Di- (n) -butyl-3-methyl-1 ^^ - oxadiazol-S-yl-acetamide, N, N'-bis (propen-3-yl) -1,2,4-oxadiazol-3,5-yl-bis-acetamide, N- (propen-3-yl) -1> 2,4-oxadiazol-5-yl-acetamid-3-yl-acetic acid, 3-a- (4-fluorophenylcarbamyl) -benzyl-1,2,4-oxadiazol-5-yl-acet- (4-fluoro) -anilide, 1 ^^ - Oxadiazol-S ^ -diyl-bis- acet- (4-chloro) -anilide, 1,2,4-0xadiazol-3-yl-acetic acid-5-yl- (4-chloro) ~ acetanilide, N -Propyl-cc- (3-ethyl-1,2,4-oxadiazol-5-yl) -propionamide, N-propen-3-yl-cc- (3-ethyl-1,2,4-oxadiazole-5- yl) propionamide, € £ - (3-ethyl-1,2,4-oxadiazol-5 ~ yl) propion- (4-chloro) anilide, N- (propen-3-yl) -3-benzyl- 1 ^^ - oxadiazol-S-yl-acetamide, 5-methyl-1,2,4-oxadiazol-3-yl-acet- (4-chloro) -anilide, 3-methoxymethyl-1,2,4-oxadiazole- 5-yl-acet- (4-chloro) -anilide, N- (2 ~ chlorophenyl) -3-methyl-1 ^^ - oxadiazol-S-yl-acetamide, N ¹ - (ethoxycarbonyl) -5-methyl-1 , 2,4-oxadiazol-3-yl-acethydrazide, N * - (Fur-2-yl-carbonyl) -3-methyl-1,2,4-oxadiazol-5-yl-acethydrazide, 3-methyl-1 ^^ - oxadiazol-S-yl-acetmorpholide, 3-methyl-1,2 ^ -oxadiazol-S-yl-acetamide, N - [(5-methyl) -isoxazol-3-yl] -3-methyl-1,2,4-oxadiazol-5-ylacetamide, 5-methyl-1,2,4-oxadiazol-3-yl-acetamide and N-phenyl-3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetamide. 19 Process for the production of substituted 1,2,4-0xadiazole 5-yl-acetic acid derivatives according to known processes, characterized in that compounds of the general formula CH COOH ° K 409830/1082 be made, in which the symbol R _{1 is} a (lower) alkyl group such as a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, t-butyl group, optionally in the primary or secondary position with a fluorine atom or a chlorine atom , a hydroxy group or a (lower) alkoxy group such as fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethyl substituted, or a cycloalkyl group, optionally substituted by one or more (lower) alkyl groups, hydroxy groups or (lower) alkoxy groups, or wherein R ₁ denotes a tert-(lower) -alkyl or adamantyl group or a phenyl group, optionally substituted by at most three of the aforementioned substituents, or in which R _{1 is} a mononuclear heterocyclic 5-membered group, for example a furyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl group, optionally substituted by (lower) alkyl groups, or in which R _{1 is} an aralkyl group such as a benzyl group, optionally substituted in the phenyl nucleus as mentioned above,
and in what Z ₁ denotes an Y / hydrogen atom, a (lower) alkyl, an aralkyl, a cycloalkyl or a phenyl group, the cycloalkyl or phenyl group optionally being substituted by substituents as mentioned above, or in which Z _{1 is} a (lower) alkyl group substituted with a mononuclear 5-membered heterocyclic group as previously defined, and the salts and esters of these acids. 20. Process for the preparation of substituted 1,2,4-oxadiazole-3,5-di- (yl) -acetic acid derivatives, characterized in that the nitrile used as starting material in the corresponding amidoxime transferred, an 0-acylation with 40 9 8 30/1082 an acylating agent such as an acid anhydride carries out and carries out a ring closure reaction with the intermediate product thus obtained, then a followed by double metallization and then double carbonization, characterized in that that compounds of the general formula HOOC CH C "^ C - CH - COOH - II I Z ₃ ^ N ~ 0. Z ₂ . are made in which Z _{2 is} a hydrogen atom, a (lower) alkyl, phenyl, cycloalkyl, aryl (lower) alkyl group, a carboxy group esterified with a (lower) alkyl, phenyl, cycloalkyl or aralkyl radical or an N -disubstituted carbamoyl or N-monosubstituted carbamoyl group, and wherein Ζ, a hydrogen atom or a phenyl group, optionally substituted by at most three substituents such as a fluorine atom, a chlorine atom, a hydroxy, a lower (alkyl) or a lower (alkoxy) group, or an N-disubstituted carbamoyl or Carboxyl group, esterified with a (lower) -alkyl, phenyl, cycloalkyl or aralkyl radical, means
and the salts and esters of these acids. 21. Process for the preparation of 5-substituted-1,2,4-oxadiazol-3-yl-acetic acid derivatives, characterized in that the 5-substituent of the correspondingly substituted 1,2,4-0xadiazol-3 »5-di (yl) acetic acid derivatives selectively decarboxylated, characterized in that compounds of the general formula 40983 07 1082 HOOC CH C ^ CR _n III are made in which R _{2 is} a group of the formula - (CH ₂ V _n - CH means in which η means 0, 1, 2 or 3, FU- a hydrogen atom or a (lower) alkyl group means, and R ^ a hydrogen atom, a (lower) -alkyl-, Means cycloalkyl, phenyl or aralkyl group or in which R ^ is a -COOE- group, where E is a Hydrogen atom or a salt-forming radical (if η ^ 1), or a (lower) alkyl, benzyl or phenyl ester group means, or wherein R. a carbamoyl 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, means, where the phenyl and cycloalkyl groups optionally with at most one of the aforementioned Substituents can be substituted, or wherein R, and Rr together with the carbon atom to which they are attached are optionally substituted
Mean cycloalkyl group,
and in what Z ^ denotes a hydrogen atom or an optionally substituted aryl group,
and the salts and esters thereof. 409830/1082 22. Process for the preparation of amide derivatives according to claims 11 to 18, characterized in that one (a) an amine with an active ester, acid halide, Acid anhydride including a mixed anhydride made from stronger acids, acid azide, active Thioester or azolide, which is different from an acid of the general formula "ρ * C ^ ^^ C -— CH COOH 1 p derive, wherein FLj "and Z have the _{meanings given above for R ^ and Z 1} " or mean groups which easily fall into those belonging to the definitions of R ,. and Z ^ "correspond to, can be converted and which can be influenced or react under the reaction conditions used (for example protected amino, hydroxyl and carboxy groups), or which are derived from a carboxylic acid of the general formula Hooo-OH derive, in which Rp and Zr ' have the definitions given above for Rp and Z, or can easily be converted into such substituents as were given in the definitions for R £ and Zr and which can be influenced or react under the reaction conditions , or reacts with the acid of the formulas XXX or XXXI as such in the presence of a carbodiimide reagent or similar reagents, (b) an isocyanate with either (1) an acid of the general formulas XXX, XXXI and 4098 30/1082 HOOC CIi C ^ C CH-- COOH XXXII \ ⁷ where Zp and Z ^ have the definitions given above for Zp and Z-, with the proviso that those substituents for the definitions of R ^, f ^, ^Z V '> ^z a> ^z ? ^{VUCl <3i Z} 3' ^ ^{ie un} ' ^fcer the reaction conditions can be influenced or react, are protected, in an inert organic solvent medium and preferably in the presence of an organic base,
or with (2) an organic metal compound of the formula A-Me ¹ , A-Me ^{i: E} -Hal _f A-Me ^{i: C} -A, in which A is a group of the formulas R * c ^ C CH- XXXIII wherein R ₁ and Z ^ have the definitions given above, or mean ^, where Zp and Z- have the definitions given above, means, Me means a metal atom such as a lithium, sodium or magnesium atom, the digits I or II indicate its value and Hai means a halogen atom, preferably a chlorine or bromine atom,
in an anhydrous organic solvent medium 409830/1082 Implements conditions that favor a Grignard, Reformatzky, or similar type of implementation, and then removes the metal residue from the products thus obtained, (3) an acid of the general formulas XXX, XXXI and XXXII with a phosphazo intermediate produced in situ, as obtained in the reaction of phosphorus trichloride and the corresponding amine, under anhydrous Reacts conditions and then separates and / or isolates the compound thus obtained and the optionally existing protective groups removed. 23. Process for the preparation of 6-substituted-aminopenicillanic acid and 7-substituted-aminocephalosporanic acid derivatives, characterized in that one (a) a salt, an ester or an amide of a 6-aminopenicillanic acid or 7-aminocephalosporanic acid compound of the formulas X (CH ^ 32-, Η ,, Ν - CH CH. C. CH-COOH. _{0 <s} C N ^ J3 XXV. · "- _.: COOH XXVI HJ - CH CH C (CH,) ;,, H-N - CH-CH Ii III o ^ - t • 0 CIi CH
II —N- I 1
-CH ^ CH
Γ ² or 1
^ C-CH ₂ X , N - 0- - CH-COOH XXVII CH-COOH XXVIII XXIX 409830/1082 X is a hydrogen atom, a hydroxy group, a (lower) alkanoyloxy group (preferably acetoxy) or the residue of a nucleophilic reagent such as a halogen atom, an azido group, a cyano group, a carbamoyloxy group, an optionally substituted raononuclear heterocyclic group which contains a sulfur or nitrogen atom such as pyridinyl, denotes a group -SQ ", in which Q ¹ denotes a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, Qxazolyl-j, Qxadiazolyl, benzimidazolyl, benzoxazolinyl, triazolopyridinyl or purazolopyridinyl group , or where X is an amino group when Q is a group of Formula XX denotes, where the substituent X is preferably protected if it is a hydroxy or an amino group means, with an active ester, acid halide, acid anhydride including the mixed anhydrides made from stronger acids, an acid azide, an active thioester or an azolide, which is different from an acid of the general formula CH COOH XXX ■ derive, in which R ^ and Z ^ have the _{meanings given above for R 1} and Z "or are groups which can easily be converted into those which fall under the definitions of R ^ and Z ^" and which are used in the reaction - "Conditions can be influenced or react (such as protected amino, hydroxy and carboxy groups) or HOOC CH— C Γ ^ P R * 409830/1 082 wherein R ₂ and Z. have the definitions given above for Rp and Z. or are groups which can easily be converted into those which come under the definitions of R ₂ and Z, derive or with acids of the formulas XXX or XXXI as such or in the presence of, for example, a carbodiimide reagent or similar reagents, (b) an ester or amide of 6-isocyanatopenicillanic acid or 7-isocyanatocephalosporanic acid derivatives, which optionally contain other protected active groups, with either (1) an acid of the general formulas XXX, XXXI and XXXII, wherein Z ₂ and Z, have the meanings given above, with the proviso that those substituents of the defi nitions of Z ₂ and Z-, the. under the ver applied reaction conditions can be influenced or react, are protected, in an inert organic Solvent medium and preferably in the presence of an organic base or with (2) an organometallic compound of the formulas A-Me ¹ , A-Me ^{i: L} -Hal or A-Me ^{I: C} -A _f in which A is a group of formulas CH Ί XXXIII in which or and Z ^ have the definitions given above, wherein XXXIV and Z, which have the definitions given above, 409830/1082 means, Me means a metal atom such as a lithium, sodium or magnesium atom, the digits I or II indicate its value and Hai means a halogen atom, preferably a chlorine or bromine atom, reacts in an anhydrous organic solvent under conditions that favor a Grignard, Reformatzky or an analogous type of reaction, and then removes the metal residues from the products thus obtained _} (3) one reacts an acid of the general formulas XXX, XXXI and XXXII with a phosphazo intermediate prepared in situ, which is obtained by reacting phosphorus trichloride and an amine salt of a compound corresponding to the formulas XXV, XXVI ₉ XXVII ₉ XXVIII and XXIX in the presence of a receives exactly predetermined excess of amine used under anhydrous conditions, (4) a penicillanic acid sulfoxide according to the general formulas XXVIII and XXIV, in which Q is the group of the formulas XXI and XXII means heated up to 140 ° C. in the presence of a suitable catalyst, if appropriate the compounds obtained in this way are further substituted or existing substituents are converted into others and then the compound obtained separates and / or isolated and the protective groups which may be present are removed in order to obtain the to produce corresponding penicillanic or cephalosporanic acids, and optionally these acids obtained in their salts or esters converted to compounds the general formulas R ₁ C ^ ^ C-CH -C -NH-Q XVIII Γ / ! ti ^σ Z ₁ "0 409830/1082 236A1 -NH- C.-CH IS 4th manufacture in which Q the group O' CH— CH ' - N XIX CH, CH - COU htf - CH CH C-CH ₂ X COU XX XXIV λ «- rCH ■■ CH K CH-CC IH-COU XXI λλ— CH CH ' • N XXII CH - COU CH or , C N GH, J-CH ₂ -X t COU XXIII means in which U is an avo group, for example a saccharyl, succinimido or phthaliraido group, or a group OE ¹ , where E 'is a hydrogen atom or a salt-forming cation, an ester group such as. a (lower) alkyl group, optionally substituted with a (lower) alkanoyloxy group, which can also be substituted, a silyl, ■ 409830/1082 Phenacyl, benzyl, benzhydryl, trichloroethyl or tert-butyl group means, X is 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 azido group, a cyano group, a carbamoyloxy group, an optionally substituted mononuclear heterocyclic group which contains a sulfur or nitrogen atom , as a pyridinyl group means, a group -SQ ¹ , wherein Q ^{1 is} a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl or Purinyl group means
or where X is an amino group when Q is a group of the formula XX, Rm is a (lower) alkyl group such as a methyl, ethyl, propyl, isopropyl, _S butyl, sec * -butyl, isobutyl, t-butyl group, optionally in the primary or secondary position with a fluorine atom, a chlorine atom, a hydroxy group or a (lower) alkoxy group such as a fluoromethyl 2-chloroethyl, methoxymethyl, 1-hydroxyethyl group, or a cycloalkyl group, optionally substituted by one or more (lower) alkyl groups, hydroxy groups or (lower) alkoxy groups, or where R. a tert .- (lower) -alkyl or adamantyl group or a phenyl group _} optionally substituted with at most three of the aforementioned substituents, or in which R _{1 is} a mononuclear heterocyclic 5-membered group, for example a furyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl group, optionally substituted by (lower) alkyl groups, or in which R ₁ is an aralkyl group such as a benzyl group, optionally substituted in the phenyl as described above _s or represents a carboxymethyl group, Λ09830 / 1082 Z ₁ "in addition to the _{definitions given above for R 1} , a hydrogen atom, a (lower) -alkyl group, optionally substituted by a chlorine atom or a fluorine atom, a (lower) -alkoxy group, a cycloalkyl group, a phenyl group, which itself optionally has at most three of the aforementioned substituents may be substituted, means, or wherein Z ₁ "denotes a carboxy group, esterified with a (lower) alkyl, phenyl, cycloalkyl or aralkyl radical, it being possible for the phenyl groups to be optionally substituted by at most one of the aforementioned substituents, or in which Z ₁ "is a carbamoyl group, optionally substituted on the N by one or two (lower) alkyl groups, a phenyl, a mononuclear 5-membered heterocyclic group, a cycloalkyl group, one or two aryl (lower) alkyl or cycloalkyl ( lower) -alkyl groups, where the phenyl and cycloalkyl groups may optionally be substituted with at most one of the aforementioned substituents, or in which Z ₁ "represents a carbamoyl group whose nitrogen atom is a member of a heterocyclic ring such as morpholino, and wherein Z ₁ "denotes a hydrogen atom when R ₁ denotes an acetic acid radical, in which R _{0 is} a group of the formula means in which η 0 _{f means} 1, 2 or 3, R ^ is a hydrogen atom or a (lower) alkyl group means, R ^ a hydrogen atom, a (lower) -alkyl-, Means cycloalkyl, phenyl or aralkyl group, or in which R ^ is a -COOE- group, where E is a Hydrogen atom, (if η ^ -1), or a (lower) -alkyl-, 409830/108 2 Benzyl or phenyl ester group means ,, or wherein R ^ a carbamoyl group, optionally N-substituted by one or two (lower) alkyl or alkenyl groups, a phenyl group, a Cyeloalkylgruppe, one or two '_ aryl (lower) alkyl or cycloalkyl (lower) - alkyl groups • ₉ denotes, where the phenyl and cycloalkyl groups' may optionally be substituted with at most one of the aforementioned substituents, or in which R ^ and R ^ together with the carbon atom to which they are attached ₃ denote an optionally substituted cyeloalkyl group,
and in what Z ^ is a hydrogen atom or an optionally substituted one Means aryl group. 24. Pharmaceutical composition, characterized in that it contains an effective amount of one or more Compounds according to claims 1 to 18 together with pharmaceutically acceptable carriers or diluents contains. 25 «Antibacterial composition _9, characterized in that it contains an effective amount of one or more penicillanic acid or cephalosporanic acid derivatives according to claims 11 to 16 together with a physiologically acceptable carrier or diluent. 26. Antibacterial composition according to claim 25, corresponding to Examples 44 to 47w 27 « Jevßrnired to fight bacterial infections in warm-blooded animals _g dp by Jgekennzei ^ anei ^ that the warm-blooded Tie # en eißii bactericidal w ^ i * "keade Jtenge © iaer connection of the ÄSBOTChe 11 bis | i6i # erabrei # it. -ββ. <? "? ·. Disinfectants, characterized in that it is an effective amount of one or more penicillanic acid or cephalosporanic acid derivatives according to the Claims 11 to 16 together with a suitably inert carrier and applied by washing or spraying. 409830/1082