DE2365705A1 - PHARMACEUTICAL VALUABLE NEW 1,2,4-OXADIAZOLYL ACETIC ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION AND USE - Google Patents

Description

GIST-BROCADES N.V., ¥ ateringseweg 1, Delft / Holland

Pharmaceutically valuable new 1,2,4-oxadiazolyl-acetic acid derivatives and methods of making them

and their use

Removal from patent ...... (patent application

P 23 64 129 Λ )

The invention relates to new 1,2,4-oxadiazolyl-acetic acid derivatives and new compounds derived therefrom, especially new, therapeutically valuable 1,2,4-oxadiazolylaeetamido-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

wherein

R _{1 is} a (lower) alkyl group (for example a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-

509883/0937

-2- 23.6S7Q5

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 (e.g. a fluoromethyl , 2-chloroethyl, methoxymethyl, 1-hydroxyethyl group), or a cycloalkyl group, optionally substituted by one or more (lower) alkyl groups, hydroxyl groups or (lower) -alkoxy groups, means, or wherein

R. an adamantyl group or a phenyl group, optionally substituted with a maximum of three substituents such as with an F, a Cl atom, hydroxy, a lower alkyl or lower-alkoxy group, means, or wherein

R. 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 ^ an aralkyl group (e.g. a benzyl group), optionally substituted in the phenyl nucleus by the aforementioned substituents, and wherein

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

Z _{1 is} a (lower) alkyl group substituted with a mononuclear 5-membered heterocyclic group as previously defined.

_{R 1} preferably 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 a hydrogen atom, a (lower) alkyl group or a phenyl group.

S09883 / 0937

_H00

COOH

II

Zp 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 an N-disubstituted one Means carbamoyl or N-monosubstituted carbamoyl group, and

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

Z ^ and / or Z ^ are preferably a hydrogen atom, a (lower) -alkoxycarbonyl group, an optionally substituted phenyl group or an N, N-di- (lower) -alkyl-carbamoyl group, where Z ^ is also a (lower) - Can be an alkyl group.

III

a group - (CH ₉ ) _M - CH

2 ^ n ~

denotes in which η denotes 0, 1, 2 or 3 and FU denotes hydrogen atom, a (lower) alkyl group and R ^ a

$ 0988-3 / 0937

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

or a salt-forming group, in which E is a hydrogen atom / (if η ^ 1}, or a denotes (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, a phenyl group, a cycloalkyl group, a or two aryl (lower) alkyl or cycloalkyl (lower) alkyl groups, the phenyl and cycloalkyl groups optionally with at most one of the aforementioned substituents may be substituted, or where R ^ and R ^ together with the carbon atom to which they are attached denote an optionally substituted cycloalkyl group, and

Ζλ is a hydrogen atom or an optionally substituted one Means aryl group.

Rp preferably denotes a (lower) alkyl group, a benzyl group, optionally substituted in the phenyl ring, a (lower) -alkyl acetate group ^ or an N, N-di- (lower) -alkylacetamidgruppe.und Z ^ is a hydrogen atom or an optionally substituted phenyl group.

The term "low" as used in the present application in connection with alkyl and alkoxy groups, means that the group in question has at most 6 carbon atoms contains. The term "cycloalkyl" as used in the application means a carbocyclic ring rait 5 to 8 carbon atoms.

The compounds of the general formulas I, II and III can be prepared by various processes known per se using the substituted oxadiazole core. The substituted 1,2,4-oxadiazole base derivatives can can be made by a wide variety of manufacturing processes, such as those described in the following references are described by F. Eloy, Fortsehr.Chem.Forsch., Volume

SG9883 / Q937

4, pp. 807-876 (1965), P.Rajagopalan, Tetrahedron Letters, No. 5, S-311-31.2 (1969), F. Eloy and R. Lenaers, Bull. Soc. Chim. BeIg ₁ 72, pp. 719-724 (1963). The substituted 1,2,4-0xadiazolyl-acetic acids are preferably prepared according to the processes described below.

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

C + C i R, C C-CH.

Ό.

xv. 'ν Vi.

This reaction is described, for example, by P.Rajagopalan in Tetrahs'dron Letters, No. 5, pp.311-312 (in which R ₁ and Z _{1 have} the definitions just given). The methylene (ie the -CHp-) group of the compound of the formula VI is then 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" The reaction between the imidates and the nitrile oxides is preferred under anhydrous conditions

S09883 / 0937

"- fa « 5 ß Εξ * i

performed by one. the two reagents with cooling mixed together, the reaction mixture stirred for about 1 hour at room temperature, then the excess Imidate removed by evaporation in vacuo. A few recrystallizations of the product give the desired pure 1,2,4-oxadiazole compound.

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

The group of 3-subst.-1, ^^
wherein, for example, R _{1 is} a lower alkyl, cycloalkyl and phenyl group substituted with chlorine, fluorine, hydroxy, lower alkyl or lower alkoxy, or a heterocyclic group such as a 2- or 3-thienyl-4- or 5-isoxazolyl - Or 4-isothiazolyl group and in which Z _{1 has} the meaning given above, can be obtained by converting nitriles of the formula. .

R ₁ -CN VII

wherein R ^ has the meaning given above, into the corresponding Amidoximes of the general formula

R. - C = N - OH VIII

¹ t

NH ₂

by methods known per se and subsequent O-acylation with, for example, acid anhydrides, ring closure of the intermediates to compounds of the general formula VI and subsequent metallization and carbonization can be produced. This manufacturing process for the connections the general formula VI is known per se, cf. for example F. Eloy, Fortschr.Chem.Forsch., Volume 4, p.814. For example, the compounds can be prepared by heating the corresponding O-acylated amidoxime until Temperatures between 120 and 170 ° C, preferably around

509883/0937

α «· y ^ / ν«, · - 7 - - ■

15O ° G are reached. Then you can distill, taking a mixture 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 methods known per se, as described, for example, in Houben-Weyl, Methods of Organic Chemistry, 4th Edition (1970), Volume 13/1, pp. 93 to 114, 173 to 174 and 296-550. The introduction of, for example, a lithium atom or sodium atom can be carried out by, 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 methoxide, naphthyl sodium, phenyl sodium in inert solvents (for example pentane, hexane, toluene, diethyl ether, tetrahydrofuran or 1 , 2-Dimethoxyethane) at very low temperatures, for example at -60 ⁰ 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 of the organometallic compound to fresh, solid carbon dioxide on which, if necessary a layer of dry diethyl ether or tetrahydrofuran is present, or by passing gaseous carbon dioxide over it 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 F. Eloy in Helv.Chim.Acta, Volume 45 (1962), pp. 441-446 (and the literature listed therein

5098 & 3/0937

236S7Ö5,

set) and from CD. Hurd, 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 made from compounds of the general formula

CH ₂ -C

CH

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 intermediates.

Path III

The 5-substituted-1, Z ^ -oxadiazol ^ -yl-acetic acid compounds, wherein Rp is a straight-chain lower alkyl (preferably a methyl) group, optionally substituted with a branched alkyl group, or a cycloalkyl, phenyl or a unsaturated heterocyclic group (for example corresponding to the formula -CH ₂ -Ra) and Z ^ denotes a hydrogen atom, can by double metallization of compounds of, for example, the general formula

S09883 / 0937

2865705

be prepared, wherein Πλ 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 conversion of the 5-acetic acid group of the corresponding Bis-acetic acids are produced with isocyanates, where Rp-substituents of the type q

-CH -C-MH-R

Z ₂

obtained where R is the group derived from the isocyanate.

The compounds of the general formulas I, II and III such as The intermediate products, namely the organometallic precursors, can also be used as starting materials for production can be used by other products which are new and which 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-OB ₁ XII

\ iο ζ ο

ο ζ,

509883/0937

where R and Z ^ have the same meanings as they are above Formula I were given and E ^ a (lower) alkyl, Cycloalkyl, benzyl, benzhydryl or phenacyl group means, or ■ «. '

E. O C-GH C C CH C-015

OZ ₃ Sh O · ^Z 2

where Zp and Z ^ have the definitions given above and Eo is a (lower) alkyl, cycloalkyl, aralkyl, phenyl, phenacyl or benzhydryl group, where the phenyl groups can optionally be substituted by halogen, optionally esterified carboxyl groups, ( lower) -alkoxy γ- (lower) -alkylthio-, (lower) -alkyl-lower- (alkoxy) - and lower- (alkoxy) -lower-alkylcarbonyl groups, or

E-O-C-CH Zr ^ P Ro ^XIV

in which Rp and Z. have the same meanings as given above for formula III and E, a lower-alkyl, cycloalkyl, aralkyl, phenyl, phenacyl or benzhydryl group, it being possible for the phenyl groups to be optionally substituted by halogen, if appropriate esterified carboxy, (lower) alkoxy, (lower) alkylthio, (lower) alkyl (lower) alkoxy, (lower) alkoxy (lower) alkylcarbonyl groups.

The conversion of compounds of the formulas I, II and III into the corresponding esters can be carried out by 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 Need to become.

The esters of formulas XII and XIV can also be made

§09883 / 0937

by using the organometallic precursors known as Intermediate products occur (as they are used to prepare the acids), and preferably those containing lithium Reacts precursors with chloroformic acid esters which contain the corresponding ester group.

(B) amides

Primary, secondary and tertiary amides can be made from reactive Intermediate products (for example the acid chlorides and anhydrides) which differ from the acids of the general formulas I, II and III derive, according to known methods or by Reaction of these acids with phosphazo intermediates, which are produced in situ from amines and phosphorus trichloride will be obtained. A wide variety of secondary amides can also be prepared by two methods, which have quite a wide application and which have a wide variety of isocyanates as reactive agents is used. -

In the first of these two processes, the α-metallized 1, 2, 4-oxadiazoles, as used in the preparation of OxadiazoIyI-acetic acids of the formulas I and II according to the general formulas

f * · C ^ - ίΤ "Τ ι ,,,, ι. ι, - Q

or

! - ■ \ _o ^/ i »

wherein

S & 9883/0937

235S7Q3

R * _f Z ^, Z ^ and Z ^ have the _{meanings given above for R 1} , Z ₁ , Z ^ and Z, or represent groups which easily fall into the groups of the definitions of R ₁ , Z ₁ , Zp and Z ^ Can be transferred and which can be influenced or react in the reaction conditions,

B denotes a metal atom Me or a group Me-Hai, the Roman number indicating the metal valency and Hal is a halogen atom, preferably a chlorine or bromine atom,

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 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 production process for the secondary amides, the 1,2,4-oxadiazolyl-acetic acids with various isocyanates in suitably selected solvents, for example 3,5-dimethyl-1,2,4-oxadiazole, and preferred implemented in the presence of special catalysts. These manufacturing processes expand the possibilities of the first method insofar that in this case species of the general formulas I, II and III are also moderate to very high result in good yields of amide, so that compounds of the formula XVII C

509883/0937

CH Z ₄

Ε —- HH-G-V ^

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

^ "^ CH-C - ^ - NH -— R

K °

XVII B: R-NH-C CH C 1 -C H-C-NH-R

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 ~ 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-OxadiazoIyI-acetic acids according to the invention by methods known per se.

503693/0937

- 14-. 2363708 ...

Are esters and amides from the starting acids and organometallic Compounds of the general formulas I, II, III, XV and XVI prepared according to the above-described, illustrated routes, so can those in these compounds existing substituents are converted into other groups (for example by removing the protective groups) Or other substituents which do not adversely affect the structure of the compounds produced can later be introduced 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 ₁ is C ^ _c _CH C-HH-Q

where Q is the group

-CH CH ^N CH _O

i I. I ²

XiX> x ^coü '

A CH ₃ ^ * CB ₃

-CH CH - C - ^. ^ -, ■ - CH-CH

! - II ⁰¹ S 1.1

^ C ₇ S CB. COU, _o j2 - N CH COU

_ ₁₅ _ 2365703

or 9

~ ch— cn m _o χχιτχ ■

I.

COU

means in which U is an amido group (for example a saccharyl, succinimido or phthalimido group) or a group 0E ^! means where E ^{1 is} a hydrogen atom, a salt-forming cation (e.g. 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 is likewise by a silyl -, a phenacyl, a benzyl, a benzhydryl, a trichloroethyl or tert-butyl group, X means a hydrogen atom, a hydroxyl group, a (lower) alkanoyloxy group (preferably an acetoxy group) or the remainder of one nucleophilic agents such as a halogen atom, an azido group or a cyano group, a carbamoylocy group, an optionally substituted mononuclear heterocyclic group containing a sulfur or nitrogen atom (e.g. a pyridinyl group), a group -SQ ^f

, . ■ rxt optionally substituted _. _ _

(v7orm Q ¹ a / diazolyl, trxazolyT, texrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl or -purinyl group) represents or in which X is a Amino group means, \ ienn Q means a group of the formula XX, R ^ has the meaning given above for formula I and also means a carboxymethyl group, Z ^ "has the meaning given above in the definition for R ^ and also a hydrogen atom, a ( lower) -alkyl group, optionally substituted by a chlorine or fluorine atom, a (lower) -alkoxy group, a cycloalkyl group, a

509883/0937

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

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

XXIV

wherein Q has the definition given _{above and R 2} and Ζλ 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 ^ a lower alkyl, an adamantyl, halomethyl, Hydroxymethyl, carboxymethyl, (lower) alkoxymethyl, benzyl or phenyl group, optionally one, two

5098 8 3/0 937

-17-. 23657QS

or can contain three substituents such as chlorine and lower-alkyl groups or which can contain a single nitro group, and more preferably R _{1 is} 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 XXIV, wherein R ^ is a methyl or ethyl group or a group -CHp-RA, wherein Rr 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 employing 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

V-; ■■■■ v \

-CH-CH C (CH -,) -. H ₀ N-CH-CH CH ₀

j. j, 32 2 j j j 2

CH-COOH_-C N C-CH ₀ X

.or . \ ν

COOH

509883/0937

23657 (35

S.

H ₀ N-CH-CH C (CH _O ) _O H ₀ N-CH - CH C (CH-J ₀

² Ii I ^{3 2 2} I i I ³

_{0 <} -CN CH-COOH,. ^ C NC

CH-COOH

XXVII. XXVIII

■ '■■■ or'

: Λ

₀ H CH CH CH ₀

ι ι ι ²

^ O NC-CH ₀ X

⁰ \ /

C.

COOI-I

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 -C -CH-COOH

N ^ O Z *

it% '

wherein R ^ and Z ^ have the _{meanings given above for R ^ and Z 1} "or a group which can easily be converted into a group corresponding to the _{definitions given for R 1} and Z ^" and which is also influenced in the reaction conditions or can react, for example

S09883 / 0937

protected amino, hydroxy and carboxy groups, or

HOOG - CH C ^ C-R *

; 2 * ^N _N O

where Rp and Z have the meanings given above for R ₂ and Z »or are groups which can easily be converted into groups corresponding to the definitions for Rp and Z and which can be influenced or react under the reaction conditions 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 be derived from other functional parts Derivatives of these acids, which are used 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 like the lower aliphatic monoesters of carbonic acid, from alkyl and aryl sulfonic acids and from more sterically 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 XXXI with the 6-aminopenicillanic acid or 7-aminocephalosporanic acid compound can be coupled using a carbodiimide reagent. Instead of the active one

Ester one can use a corresponding azolide, i.e. an amide of the corresponding acid, the amide nitrogen of which is a Part of a quasi-aromatic 5-membered ring, which contains at least 2 nitrogen atoms, for example imidazole,

509883/0937.

- ²⁰ - 236570S

Pyrazole, the thiazoles, benzimidazole, benzotriazole and their substituted derivatives. The procedures for implementation of these reactions to make a penicillin or a cephalosporin, and the methods used to make the so compounds prepared are well known for similar compounds (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 (for example 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 inventive method for preparing compounds of the general formulas XVIII and XXIV is thereby characterized in that an acid of the general formulas XXX and XXXI and the general formula

HOOC-CH (* C-CH COOH

I ^ n o "" "I xxxri

^Z 3 - ^Z 2.

where Z * and Z '$ have the meanings given above for Z ₂ and Z-, or groups which can easily be converted into groups which fall under the definitions of Zp and Z- and which are influenced by the reaction conditions or react, with a 6-isocyanatopenicillanic acid or a 7-isocyanatocephalosporanic acid compound of the formula O = C = NY, where Y is the groups of the formulas XIX and XX, and atoms or groups to protect the carboxy

509883/0937

group and optionally the hydroxy or amino group if it is present, i.e. if X in formula XX Means hydioxy or amino. The protecting group is preferred the carboxyl group or the hydroxy group, if any, 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 shown below as an example for penicillanic acid derivatives.

A-COOH +

A-CO-HH-CH CH C (CEL ₁ K + CO ₀ + E ¹¹ OH

y y. J - 2 2

- CH-COOH.

5 09 883/0937

236570

In the formula, E "means a group that protects the carboxy group 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 production of 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-Me -Hal or A-Me -A, [wherein A is a group of the general formula

C-CH ^/ 2 *

(where R * and Z ^ have the definitions given above) or

Γ \ / ■ ι, ^3Οπαν

(in which zt and z5 have the definitions given above), Me denotes a metal atom, for example lithium, sodium or magnesium, the numbers I or II indicate its valence and Hal denotes a halogen atom, preferably a chlorine or bromine atom]. The intermediate product thus obtained is then hydrolyzed to remove the metal ion and any hydrolyzable group protecting the carboxy (or hydroxy) group. The implementation is carried out in an anhydrous organic

509883/0937

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

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

In another process for the preparation of compounds of the general formulas XVIII and XXIV, an acid of the general formulas XXX, XXXI and XXXII reacted with a phosphazo compound prepared in situ, how to do it 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: 3: 1, 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 a different method, the cephalosporanic acid derivatives of the general formulas XVIII and XXIV, in which

609893/0937

Q denotes a group of the formula XX and in which X is at the beginning Hydrogen means, by ring expansion conversion from the corresponding penicillanic acid sulfoxide derivatives, in which Q denotes a group of the formulas XXI and XXII, for example by heating the penicillanic acid sulfoxide derivative up to 140 ° C in the presence of a catalyst and preferred 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, 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 means using suitable oxidation processes.

For example, the R-sulfoxides of the corresponding Penicillins or cephalosporins can be selectively produced using singlet oxygen produced in situ or by using the R-sulfoxides of 6-aminopenicillanic acid and 7-aminocephalosporanic acid, which are selectively prepared as intermediates and the derivatives thereof acylated.

The term "methods known per se" as used in the present application Registration is used means methods previously used or described in the literature.

The new penicillanic acid and cephalosporanic acid derivatives of the general formulas XVIII and XXIV, in which Q is the groups of formulas XIX, XX, XXII and XXIII means have antibiotic properties that cause them to be used as medicaments for humans and animals alone or mixed with others, known antibiotics are valuable. Some of these new ones

509883/0937

Compounds of the general formulas XVIII and XXIV have activities which are comparable to those of the known ß-lactam-containing antibiotics. They have special activities against gram-positive microorganisms (for example Bacillus subtilis, Staphylococcus aureus, Streptococcushaemolyticus and faecalis and Diplococcus pneumoniae) and they also show good activity against penicillin-resistant staphylococci, in particular this applies to compounds in which R ^ and R ^ methyl -, ethyl, methoxymethyl, mesityl, benzyl and 2,6-dichlorophenyl groups, in which Q denotes a group of the formulas XIX and XX and in which Z ₁ and Z. denote 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 of the present invention are preferred for therapeutic purposes in the form of non-toxic salts such as 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 trialkylamines, 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 powders, tablets and capsules.

09883/0937

The invention therefore also relates to agents or compositions an effective amount of the new penicillic acid or cephalosporic acid derivatives according to the general formulas XVIII and XXIV 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 contain. The term "effective amount" as used herein means, based on the compounds described, an amount sufficient to destroy or inhibit the growth of sensitive microorganisms, when given in the usual way, in other words, an amount sufficient to allow the bacteria to grow to control. The value or the size of the effective amount can easily be determined by the person skilled in the art using standard methods the relative activity of an antibacterial agent against sensitive microorganisms can be determined, using the various routes of administration available.

Suitable carriers and diluents are any of the following known, physiologically acceptable ingredients which serve to facilitate the administration of the therapeutically active compound to facilitate. Carriers can also have certain auxiliary functions as a diluent, flavor or odor masking agent, binding agent, retarding agent or stabilizers work. Examples of carriers include water, which may contain gelatin, gum arabic, Alginate, dextran, polyvinylpyrrolidine or sodium carboxymethyl cellulose, aqueous ethanol, syrup, isotonic salt solutions, isotonic glucose, starch, lactose or others those materials commonly used in pharmaceutical and veterinary antibacterial agents.

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

609833/0937

the presence 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, while maintaining their antibiotic activity, 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 -CHp- 0 - CO - -W ₁ in which ¥ denotes an unsubstituted or substituted straight-chain or branched alkyl group with 1 to 8 carbon atoms, where lower-alkoxy-, lower-alkylthio-, halogen- ( lower) -alkyl, phenyl, cycloalkyl, nitro, amino, guanidino, carboxy, carbalkoxy, hydroxyl groups or halogen atoms occur.

The new penicillanic acid and cephalosporanic acid derivatives of the formulas XVIII and XXIV can also be used as growth activators for ruminants as well as for cows. They are also very useful for in vitro 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-substituted 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

109883/09 3-7

2 3. a 5 7 O S

(a)

CH I.

C- _N. O

XXXV

(b)

N c - CH

'Il I

, N

/ Ί _Ä D

XXXVI

(O

N-

C - CH

Il

ο ^ ₃

CH-

Il

- N

XXXVII

^R 6

wherein

R ^, Rp » Iy,, Zp, Z, and Z / have the meanings given above,

R ₁ - denotes a hydrogen atom, a (lower) alkyl group, an aryl (lower) alkyl or a cycloalkyl (lower) alkyl group, and

R ^ - 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, where the phenyl and cycloalkyl groups optionally with at most one of the substituents described above can be substituted, or in which

• Rg means an amino group, optionally with (lower) alkylcarbonyl, arylcarbonyl, mononuclear heterocyclic Carbonyl or (lower) alkoxycarbonyl groups sub-

0980-3 / 0837

may be substituted, or in which

Rt- and Rr together with the nitrogen atom to which they are attached represent a 5- to 7-membered mononuclear heterocyclic ring such as a morpholino or piperidino ring.

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 K'icro-

sporum strains.

The following examples illustrate the invention without restricting it.

example 1

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

A solution of 4.0 g (40.8 inMol) of 3 »5-dimethyl-1,2,4-oxadiazole and 6.0 ml of N, N, N ¹ , N'-tetramethylethylenediamine (TMEDA) in 100 ml of dry toluene is made 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 pressure equalized dropping funnel. The magnetically stirred solution is cooled to -75 ° C. with an acetone-carbon dioxide bath. A solution of approximately 40 mmol of n-butyllithium in 20 ml of η-hexane is added through the dropping funnel at a slow rate in order to keep the reaction mixture below -65 ° C. The reaction mixture is then stirred at -55 to -60 ° C. for a further 60 minutes. The reaction mixture is then passed through a curved, ground glass tube into a second vessel which contains powdered carbon dioxide and a layer of it

50 9883/09 3 7

covered with dry diethyl ether. After a few hours left, the carbon dioxide has practically disappeared from the mixture. 100 ml of water are added and 1N hydrochloric acid is then added with stirring until a pH of 8 is reached. The layers are separates, the organic layer is discarded and the aqueous layer is shaken twice with 25 ml of diethyl ether. With 1N hydrochloric acid, the pH-fourth of the aqueous Solution set to 2.0. Seven extractions with approximately 25 ml portions of ethyl acetate at pH 2.0 give 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 does not contain any woven 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%, determined by TLC and PMR spectrum.

Recrystallization of the product occurs by dissolution in a small volume of chloroform, followed by slow addition of petroleum ether (bp. 80 to 110 ⁰ C), until turbidity. The yield of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid after recrystallization was 3.6 g, mp. + 95 ⁰ C (at approximately 90 C starts a slow decarboxylation), pK ( loading

3.

correct in water): 3.64.

Elemental analysis: Cp- H 4th ° 3 N 19th , 71% 0 33 .77% Calculated: C 42.26% 4th .26% 19th , 60 (33 .88) Found: 42.24 , 28

The partial analysis of the IR spectrum (KBr pellet, values

in cm " ¹ ): * 3450, 1740, 1720, 1590, 1360, 1220.

Thin layer chromatography: silica plate, eluent a 10: 2; 1: 0.2 mixture (expressed by volume)

509883/0937

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 1% 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 ₂ COOH and CH ₅ CNO and are further evidence of the assumed structure.

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

Example 2

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

A solution of 10 g of 3- (2,6-dichlorophenyl) -5-methyl-1,2,4-oxadiazole (melting point 83 to 85 ° C.) and 6.4 ml of TMEDA in 140 ml of dry toluene is 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 diethyl ether was added. After standing for a few hours. If water and dilute hydrochloric acid are added until a pH value of 8.0 is reached; the layers are separated and the organic layer is extracted with 50 ml of water. The organic layer will

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 stirred first with n-heptane and then with a small volume of toluene. After drying well in the desiccator, weighs the final product 7.6 g (63%), m.p. 124.5 Ms 125.5 ° C

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

Values in ppm)

CH ₂ : 4.09 (S, 2H), C ₅ 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

Using 3- (2,4,6-trimethylphenyl) -5-methyl-1,2,4-oxadiazole, (mp. 20 to 30 ⁰ C), as the 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. 106-108 ° C. IR (KBr pellet, values in cm " ¹ ): - 3450, 1740, 1720, 1608, 1590 and shoulder 1580, 1365 and 1240.

PMR (60 Mc, CDCl ₅ , 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 ⁰ C, then ge solution was added gradually an about 20% ± (800 ml) of n-butyllithium in n-hexane

509883/0 * 37

(approximately 1.6 "to 1.9 mol). 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 determined by the addition of the first equivalent n-butyl lithium consumed. the reaction mixture is stirred for a further 60 minutes at -70 ⁰ C. the reaction mixture is slowly poured into a mixture of finely powdered carbon dioxide and dry ether. After about 3 hours of standing is 1 1 water 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 becomes added to the first extract. This is repeated until all solid is dissolved in water. The organic The 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-oxadiazole 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) on silica

5098 8-3 / 0337

- 34 - 2385703

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 (2950 of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid with a minimum purity of 97% T mp. 101 to 1O3 ° C (final melting point) above 70 ⁰ C sublimation, melting and ¥ re-solidify. ( ⁺ Calculated by TLC and PMR),

pK value (determined in water): approximately 3.4. a

Thin layer chromatography: same system as in example Rf value approx. 0.25. 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, ȣ 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 - naturally adapted to the individual case - other 1,2,4-0xadiazol-3-yl-acetic acids were produced, for example

5-Benzyl-1,2,4-oxadiazol-3-vl-acetic acid , m.p. 109 to 111.5 ° C. If 13 g of 3-methyl-5-benzyl-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 add 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-

5088 * 3/0917

- 35 - 2365708 ''

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 [α- (5) -phenyl-1,2,4-oxadiazole-3,5-diyl-bis-acetic acid] is subjected to selective decarboxylation under relatively mild conditions. However, it was found that it can also be obtained by extraction at room temperature and subsequent purification by column chromatography (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 ₃ and a trace of dgTÜMSO, 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-oxadiazol-5-yl-acetic acid : m.p. 58 to 60 ° C

It uses 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, et- (5) -Methy1-1 ^^ - oxadiazol-SjS-di-yl-bis-acetic acid is a relatively stable Link. The reaction conditions were analogous to 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-

SÖ9883 / 0SS7

- 36 - 13.65705 * '

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 with sodium chloride saturated and extracted 5 times with equal volumes of acetone. These extracts were combined and activated charcoal became added, with half the volume being removed by distillation at atmospheric pressure. After filtration it was the filtrate evaporated and the residue from column chromatography subjected to silica over n-hexane / chloroform. The pure fractions were combined and evaporated in vacuo. The remaining oil was used in a small volume Ether dissolved, the solution, was filtered and. evaporated to dryness. The colorless oil slowly solidified on standing. IR (ibidem): ± 3500 and ± 2600, 3000, ± 2960, 1730, 1580, 1465, 1425, 1380, 1360, 1300, 1210-1230, 1190, 900, 825, 805, 725. PMR (CDCl ,, 60 Mc, TMS, <5 values in ppm): 1.40 (T, J = 7, 5 cP, 3H), 2.92 (Q, J = 7.5 cP, 2H), 334 (S, 2H), about 8.6 (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 (about 2 ⁰ C) solution of 14 g 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid in 500 ml of diethyl ether. After the initial vigorous evolution of nitrogen has ceased, the solution is concentrated to approximately 250 ml on the steam bath. The solution is washed 3 times with 100 ml of water. The wash solutions are combined, the pH is adjusted to 9.0 and then they are extracted with diethyl ether to obtain part of the product which dissolved in water during the wash. The combined ether extracts were returned by a water

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 at 0.4-0.5 mm distilled. The collected fraction with a boiling point of 70 to 71 ° C contained methyl-3-methyl-1,2,4-oxadiazol-5-yl-

acetate, weight 12.3 gn ^ ⁵ = 1.4472.

FMR (60 Mc, CDCl ₅ ), TMS as internal standard, ζ 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 ml of η is added to a solution of 1.74 g (10 mmol) of 3-methyl-5-benzyl-1,2,4-oxadiazole in 20 ml of tetrahydrofuran hexane and 4.5 ml of toluene was added dropwise at -95 to -90 ⁰ C. The resulting liquid reaction mixture is then stirred for 30 minutes at -90 ⁰ C. Then a solution of 2.6 g (8.3 mmol) is added trimethylsilyl-6-isocyanatopenicillanat in 10 ml of tetrahydrofuran was slowly added dropwise, the reaction temperature is maintained slightly below -90 ⁰ C. 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 more extractions were made at a pH of 5 using each carried out 20 ml of ethyl acetate.

509883/0057

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 oethylcaproate, dissolved in a small volume of acetone was added in the cold. The resulting solutions were treated with an excess of diethyl ether, which caused precipitation of a colorless solid with it. The solid was separated off by filtration and washed several times with cold, dry diethyl ether. Yield 760 mg. The product was slightly contaminated with sodium a-ethyl caproate and contained 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 a dg-dimethyl sulfoxide (2 microdrops of added DCO ^ D, 60 Mc, 6 "values in ppm, 2,2-dimethylsilapentane-5-sulfonate as internal standard): 1, 46.1.52, 1.56 and 1.62 (about 6H), 2.34 (S, 3H), 4.22 (2 singlets, <f \? = 1.2 cP, 1H), + 5, 5 (quartet-like, 2H), 5.67 (partially deuterated, broadened singlet), +7.4 (5H), about 9.15.

Example 7

Preparation of 7 - [(3-benzyl-1,2,4-oxadiazol-5-yl) -acetamido] -des-acetoxy-cephalosporanic acid

1.5 ml (10 mmol) are added to a solution of 1.74 g (10 mmol) of 3-benzyl-5-methyl-1,2,4-oxadiazole in a mixture of 20 ml of dry toluene and 5 ml of dry tetrahydrofuran TMEDA. The solution is then cooled to -100 ⁰ C. Then a solution of approximately 10 mmol of n-butyllithium in 5 ml of η-hexane is added dropwise at -100 to -105 ° C and then stirred for a further hour at -100 + 5 ° C. A solution of 2.81 g (9 mmol) of trimethylsilyl 7-isocya'nato-desacetoxycephalosporanat 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 C and then stirred for about 15 minutes,

SÖ3883 / Ö931

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 a colorless solid. The purity of the final desacetoxycephalosporanic acid is estimated to be approximately 90 to 95% by TLC and PMR. IR (KBr pellet, values in cm " ¹ ): +3500 and +2600, 3280, 1780, 1720, 1670, 1590, 1550, 1495.

PMR (60 Mc, dg-DMSO, 2,2-dimethylsilapentane-5-sulfonate, <T values in ppm): 2.06 (S, 3H), 3.5 (Q, J _AB ^ 17.5 cP, 2H), 4.06 (S) and 4.10 (S) together 4H, +5.1 (D, J = 4.6cP, 1H), +5.6 (Q, J = 4.6cP, J '^ 8.0 cP, 1H), 7.35 (S, 5H), 9.3 D, J' ^ 8.0 cP, 0.8H).

Example 8

Preparation of N-phenyl-3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-y! -Acetamide

S.03883 / Ö937

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

A solution of 250 mg (1 mmol) 3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid, 0.005 ml 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 different time intervals. Carbon tetrachloride is removed by bubbling dry nitrogen over the samples. Then be the residues are dissolved in anhydrous chloroform and the IR spectra are determined to monitor the progress of the reaction to check * 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 The 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 at around 3000 to 3200, monomeric C = O (shoulder) at +1760 and dimeric C = O at 1730 cm " ^1. After 3 minutes refluxed, both the OH and C = 0 bands disappear completely at 1760 cm, leaving a sharp and intense absorption at 1740 cm characteristic of the reactive compound 10 minutes results in a decrease of the absorption at 1740 and there are at least four further absorptions between 1660 and 1800 cm, one of these (at 1790) possibly represents the true acid chloride.

(b) Preparation of the anilide of 3- (2,4,6-tri-.methylphenyl) -1,2,4-oxadiazol-5-yl-acetic acid

As stated above, 1 mmol of the starting compound is used 0.11 ml of thionyl chloride in 5 ml of carbon tetrachloride in the presence treated by approximately 0.005 ml of dimethylformamide. The mixture is refluxed for 3 minutes. Afterward 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 value is reached of 1.5 is reached. After separating the layers, the organic layer is washed with 20 ml of 4N hydrochloric acid and then washed with 25 ml of water. The organic layer is evaporated completely and the residue is dissolved in ethanol dissolved 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 in vacuo dried. The IR and PMR spectra confirm this structure.

PMR (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 (KBry 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-oxadiazole-

5-yl! -Acetamido Λ -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 represents a mixture with a major amount of N, 0-Bls-trimethylsilyl-7-ACA and a minor amount of trimethylsilyl 7-aminocephalosporanate in the usual way by successively adding 1.02 ml (7.32 mmol) of triethylamine and 0.92 ml. (7.32 mmol) trimethylchlorosilane is added at 5 ° C,

509883/09 ^ 7

then stirred for a further 30 minutes at 30 ° C. To the received 0.43 nil (3.66 mmol) of quinoline is 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 used converted into the reactive intermediate according to the method described in Example 8A, using 15 ml of dry carbon tetrachloride, 0.4 ml of thionyl chloride and approximately 0.02 ml of dimethylformamide were used. After refluxing for 5 minutes heated, the purple-colored solution is evaporated completely in vacuo and the residue dissolved in 6 ml of dry ethyl acetate.

The resulting solution is quickly added to the first solution after this solution has regained room temperature (approximately 20 ^° C.). The addition of the "acid chloride" results in a temperature increase of approximately 5 ° C. The reaction mixture is then stirred at 30 ° C. for 30 minutes.

The reaction mixture is poured into 175 ml of ice-water and the pH is adjusted to 7.0. The layers are separated, the organic layer is discarded and the aqueous layer is discarded Layer is washed twice with 50 ml portions of diethyl ether. The aqueous layer is adjusted to pH 3.7 and then extracted four times with 25 ml portions of ethyl acetate. The extracts thus obtained are combined, with a small one Washed volume of ice-water, treated with activated charcoal, filtered, dried over anhydrous magnesium sulfate and filtered again using a water aspirator. Complete evaporation of the almost colorless filtrate and Thorough drying of the residue in vacuo gives 650 mg of solid product. This product is according to thin-layer chromatography not completely pure, the crude product is purified by column chromatography. However, they differ the IR spectra of the raw and pure product hardly.

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] -cephalosporanic acid

Continuously dry conditions are maintained, by bubbling dry nitrogen over the surface of the liquid reaction mixture. 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 (92-9556 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 of the rapid formation of carbon dioxide and the rapid formation of precipitate is relative quick implementation recognizable. The precipitate gradually dissolves during the further course of implementation. The precipitate is ■ - .. .. the sparingly soluble mixed anhydride, which is formed by adding the carboxylic acid to the isocyanato. Decomposition of the labile, mixed anhydride mainly to the soluble trimethylsilyl ester of the desired Cephalosporins and carbon dioxide are activated by the catalyst.

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 added to a well-stirred mixture of 50 ml of ice-water and 50 ml of 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

S09ÖÖ3 / 0937

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 of pH 5.5 to 4.5 containing only small amounts of the desired product and the aqueous layer of pH 3.0, 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 drying well in vacuo, 2.3 g (approximately 58% yield) of the crystalline, solid end product were obtained. Since it contained a maximum of 5 mol% urea, the purity of the end product was over 90% by weight, according to TLC and PMR. IR (KBr pellet, values in cm " ¹ ): +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), S fourth in ppm): 2.05 (S, 3H), 2.34 (S, 3H), 3.6 (broad S, 2H), 4.05 (S, 2H), 4.87 (Q, J _AB = 12.7 cP) and + 5.2 (D, J = 4.7 cP) together 3H , + 5.7 (Q, J = 4.7 and J «= 8.2 cP, 1H), + 9.3 (D, J ^f = 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 1,2,4-oxadiazole acetic acid and the trimethylsilyl ester 6-isocyanatopenicillanic acid (6-IPA) or 7-aminocephalosporanic acid or t-isocyanato-deacetoxy-cephalosporanic acid (7-IDCA) used as starting material:

609883/0037.

A. S- f [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] -acetamido_f -penicillanic acid,

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

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

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

E. 7-1 [3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yl] ~ acetamido} - -desacetoxycephalosporanic 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. H ^ O,

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

I. DL-7- [cc -methyl-0-methyl-i, 2,4-oxadiazol-5-yl] -acetamido ] -cephalosporanic acid,

K. DL-7-E a-Methyl-0-ethyl-i, 2,4-oxadiazol-5-yl) -acetamido ] -cephalosporanic acid,

L, 7 - [(3-ethyl-1,2,4-oxadiazol-5-yl) acetamido "J-cephalosporanic acid and

M, - 6- [a-methyl-0-ethyl-1,2,4-oxadiazol-5-yl) acetamido] penicillanic acid, Sodium salt. HpO.

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

For each example, the reaction media are appropriate Reaction times as well as indications of the purity of the end products,

509063/0937

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, C values in ppm) The isolation procedures were similar to those described in Example 10, but adapted to the individual compounds The yields given were obtained in all cases in the first experiment and the yield figures are therefore not an absolute value.

A. dichloromethane, 2 hours, isocyanate in 10 mol% excess, slightly yellowish crystals, purity at least 95%, yield 90% (based on the acid, 80% based on the isocyanate). IR: +3500 and +2600, 3300, 1780, + 173O, 1680, 1580, 1560, +1 540, 1430, 1380, 800 and 785.

PMRi 1.5 and 1.65 (two singlets, 6H), 4.3 (overlapping singlets, 3H), +5.6 (multiplet, 2H), 7.7 (narrow, split signals, 3H) and 9, 25 (D, JA ³ 8.5 cP., 0.8H).

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

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

PMR: 1.51 and 1.62 (2 singlets, 6H), 2.35 (S, 3H), 4.07 (S, 2H), 4.2 (overlapping singlets, + 3H), 5.45 (center of the multiplet, 2H), 9.1 (D, J J = * 8.5 cP, 0.8H).

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

IR: + 3500 and + 2600, 3300, 1780, 1735, shoulders at + 1720 and 1700, 1680, 1580, 1560, + 1540, 1435, 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 _AB = 12.7 cP) and + 5 , 2 (D, J = 4.7 cP) together 3H, + 5.75 (Q, J = 4.7 and J ¹ = 8.0 cP, 1H), 7.7 (narrow, split signals, 3H) and 9.45 (D, J ¹ = 8.0 cP, 0.8H).

S098Ö3 / 0931

! 65705

D. dichloroethane-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 * = 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.1H ₂ 0, 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 + 2600, 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, «1 ^^ 17.5 cP, 2H), 4.29 (S, 2H), + 5.15 (D, J = 4.5 cP, 1H), + 5.65 (Q, J = 4.5 and J «= 8.0 cP, 1Ή), 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

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

H. dichloromethane, 2 hours, some colored solid, purity approximately 90%, yield 15%.

PMR: about 1.4 to 1.7 (6 lines, 9H), 2.34 (S, 3H), 4.08 (2 singlets / 9 = 1.3 cP, 1H), 4.33 (Q, J = 7.5 cP, IH), 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).

PMR: 1.48, 1.50 and 1.62 (2 doublets, <5 ~ Q approx. 1.2 cP, J = 7.2 cP, 3H), 2.06 (S, 3H), 2.35 (S, '3H), 3.6 (broad S, 2H) 4.25 (2 quartets, £ \> about 1.2 cP, J = 7.2 cP, 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,. + 5.65 (2 multiplets, 1H), 9 , 35

(2 doublets, cTvWf. 4 cP, J ¹ 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), 1.55 (2 doublets, S v> approx. 1.6 cP, J = 7.2 cP, 3H), 2.06 (S. , 3H), 2.75 (Q., J = 7.5 cP, 2H), 4.25 (2 quartets, S \> approx. 1.2 cP, J = 7.2 cP, 1H), 3, 6 (broad'S, 2H), 4.90 (Q, J " _Aβ = 12.6 cP), + 5.15 (2D, t ^ * \? <1.0 cP, J = 4.8-cP), together '3K, + 5.7 (2 multiplets, 1H) and 9.35 (2 D, S? about 3.5 cP, <F x about 8 cP, 0.8H).

L. dichloromethane-toluene mixture, 9 hours, more crystalline

Solid, purity about 95%, yield 60%.

IR: + 3500 and + 2600, 3300, 1780, 1740, shoulders at 1720

and 1705, 1665, 1590, 1550 and + 1240 (very intense).

PMR: 1.25 (T, J = 7.5 cP, 3H), 2.06 (S, 3H), 2.75 (Q, J = 7.5 cP, 2H), 3.6 (broadly S, 2H), 4.07 (S, 2H), 4.90 (Q, J _Aβ =

6098Ä3 / 0Ö37

~ ⁴⁹ ~ g 9 6 5 7 Θ ζ

12.8 cP) lind + 5.15 (D, J = 4.7 cP) together 3H, + 5.75 (Q, J = 4.7 cP and J ^f = 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 prepared by procedures identical or analogous to those described in Examples 1 and 2 were used by adding a slight excess of 3,5-disubst.-1,2,4-oxadiazole with the 1: 1 complex of n-Butyllithium with TMEDA 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-oxadlazol-5-yl-acetic acid

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

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

D. a-Methyl-3-ethyl-1,2,4-oxadiazol-5-yl-acetic acid

E. 3-Methoxymethyl-1,2,4-oxadiazol-5-yl-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 of 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 ^ tTetra-"

09883/0937

methylsilane as internal 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 -8O ⁰ C, 80 minutes. Crude yield 4.3 g after crystallization from toluene (dissolved at 6O ⁰ C) 3.6 g (4i%), mp. 106 to 109 ⁰ C (with slow decarboxylation), purity over 96%.

IR: + 3430, 1730, 1585, + 160 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-Ä * thyl-5-methyl-1,2,4-oxadiazole (22.4 g), n-butyllithium, TMEDA / toluene-hexane to -70 to -8O ⁰ C, 2 hours, yield 16 g (50%), purity 96%, mp 86 to 9O ⁰ C (with slow decarboxylation), crystallization (not required) possible by dissolving in a small amount of a. 2: 1 mixture of carbon tetrachloride and chloroform at about 45 C and subsequent slow addition of hexane.

IR: + 3440, 1730, 1715 and 1580

PMR: 1.35 (T, J = 7.5 cP, 3H), 2.8 (Q, J = 7.5 cP, 2H), 4.04

(S, 2H), "-ΊΟ, 4 (approx. 1H).

C. 3-Methyl-5-ethyl-1,2,4-oxadiazole (22.4 g), n-butyllithium, TMEDA / toluene-hexane, -70 ° to -80 ⁰ C, 1.5 hours Yield 7 g (22%), purity over 96%, melting point 64.5 to 65 ° C (slow decarboxylation begins at 57 ° C).

IR: + 3450, + 1730, 1600

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

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

D. 3,5-diethyl ~ 1,2,4-oxadiazole (24.2 g), n-butyllithium, TMEDA / toluene-hexane, -70 ° to -80 ⁰ C, 3 hours, yield 18.1 g (approx .53%), purity approx. 95% (contains a small amount of valeric acid) ₉ m.p. ₀ 30 to 32 ° C.

5Ö98S3 / Ö93?

IR: +3500, + 2600, + 1740, 1580 PMR: 135 (T J 75 cP 3H) 1

R: +3500, + 2600, + 1740, 1580

MR: 1.35 (T, J = 7.5 cP, 3H), 1.70 (D, J = 7.5 cP, 3H), , 75 (Q, J = 7.5 cP, 2H), 4.6 (Q, J = 7.5. CP, 1H) and ^ 9, S, about iH).

PMR:

E. 3-methoxymethyl-5-methyl-1,2,4-oxadiazole (40 g), n-butyllithium, TMEDA / toluene-hexane, Ms -75 -80 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-1,2,4-oxadiazol-3 * -ylacetic acid become added to 20 ml of dry carbon tetrachloride. To the 1 ml of thionyl chloride and 2 drops of dimethylformamide are added to the suspension at room temperature. The mixture becomes moderate boiled for 10 minutes, a clear solution being obtained and the substituted acetic acid in its acid chloride is fully transferred.

At the same time, a suspension of 2.15 g (10 mmol) of 6-amino-penicillanic acid in 30 ml of dry ethyl acetate is treated with 2.8 ml (20 mmol) of triethylamine and 2.5 ml (20 mmol) of trimethylchlorosilane and then for 30 Stirred minutes at room temperature. Are added to this mixture 1. First, 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 while Stirred for 30 minutes and then poured into 50 ml of ice-water. The pH value is adjusted to 7.0 and the layers become

S09883 / Ö937

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, dried over anhydrous magnesium sulfate, filtered and im Concentrated vacuum to a volume of approximately 20 ml. 40 ml of diethyl ether are added and then one Solution of sodium oc-ethylcaproate in ethyl acetate added, until no further precipitation occurs. The solid precipitation is collected on a suction filter, repeated with a 2: 1 mixture of diethyl ether and ethyl acetate and finally washed with diethyl ether alone. After thorough drying in vacuo, 2.5 g of the end product are obtained.

The structure and the good purity state are confirmed by IR and PMR spectra confirmed. According to the PMR spectrum

the end product contains 1 mole of water / mole of penicillin.

IR: (KBβ pellet, values in cm " ¹ ) + 3400, 1775, 1685, 1610,

1590, + 1540, 1390.

PMR: (60 Mc, dg-dimethyl sulfoxide, 2,2-dimethyl-silapentane

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

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

Example 14

Preparation of methyl (a-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 of TMEDA in 140 ml of 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 adjusted to a reaction temperature from -60 to -70 ⁰ C. the

509803/0937

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 ⁰ C and treated with dilute hydrochloric acid, acidified to pH 3.0. 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 | ⁰ ' 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 , TMS, £ values in ppm): 2.37 (S, 3H), 3.77 (S, 3Ji), 5.26 (S, 1H), about 7., 4 (close multiplet, 5H).

SÖ9S83 / Ö93?

Example 15

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

A mixture of 6.5 g of 5-methyl-1,2,4-oxadiazol-3-yl-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 solution 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 end product weighed 4.8 g (72%), pp. 112 to 114 ^° C. IR (KBr pellet, values in cm " ¹ ): 3380 and 3220, 1680, 1630, 1590, 1420, 1380, 1270 , 1185 and 895.

PMR (60 Mc, d ^ -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).

50988370937

Example 16 .

Preparation of methyl 5-methyl-1,2,4-oxadiazol-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 ⁰ 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 ,, TMS, S 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 mmoles) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid were suspended in 8 g (80 mmoles) of redistilled dry cyclohexanol. Using anhydrous conditions, 8 g (52.2 mmol) of phosphorus oxychloride was added dropwise to the mixture over 7 minutes. During the addition, the mixture was heated on a steam bath. Heating was continued for 45 minutes. After the reaction mixture had reached room temperature, 75 ml of ice-water and 50 ml of diethyl ether were added. The mixture was stirred until a clear 2-layer system was obtained. The flask was placed in an ice-salt bath and solid potassium hydroxide was added until the pH reached 10.5. The layers were separated and the aqueous layer was extracted 3 times with 40 ml portions of diethyl ether. 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%), bp. 120 mm to 12T ⁰ C at 0.9 to 1.0, NJP = 1.4715

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

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

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In the same way, "for example, cyclopentyl-5-ethyl-1,2,4-oxadiazol-3-yl acetate produced in 43% yield, taking 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid and cyclo-

Pentanol used as starting material: b.p. 108 ° C at 0.5 mm Hg, n ^ ⁵⁰ = 1.469

IR (NaCl window, values in cm " ¹ ): 3000, 2915 sh, 1755, 1600,

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

PMR (CDCl ₃ , 60 Mc, TMS, ^ 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 mmol) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid, 0.5 ml of 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 added to 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

5Ö9883 / Ö931 ¹

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? O). The final product contained approximately 90% of the desired compound and approximately 10% of the corresponding / \ -cephem derivative.

IR (KBr pellet, fourth in cnf ¹ ): + 3450 and + 2600 3305, 2135, 1790, 1710, 1660, 1585 and 1540. PMR (dg-dimethylsulfoxide, 60 Mc, 2,2-dimethylsilapentane-5-sulfonate, S fourth 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, + 5.15 (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-oxadiazol-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-carboxylic acid (prepared according to the method of Example 18 ) in 20 ml of anhydrous tetrahydrofuran (THF) was cooled to -75 ⁰ C. A solution of 400 mg (2.5 mmol) of N, N-dichloro urethane (Cl ₂ NCO ₂ C ₂ H ₅ ) in 7.5 ml of anhydrous THF was added to this isolution at -70 to -75 ° C. The resulting reaction mixture was stirred for about 1 hour at -70 to -75 ° Q and then poured into a

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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 combined and 2 times with 100 ml volumes

a saturated solution of sodium chloride in water. Since the original aqueous layer after the 'thin layer chromatography Still contained the desired product, it was combined with 200 ml of water, which is used to wash the organic layer. The combined aqueous layers were acidified to pH 1.7 and then 2 sharks extracted with 100 ml volume of n-butanol. The butanol extracts were combined and with a small volume of ice-water washed and evaporated to dryness in vacuo. The first batch yield 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. Overall 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, £ * values in .ppm, DSS as standard): 2.58 (S, 3H), 3.75 (S) and 4.0 (center of about 0.8 ppm wide AB-quartet, J about 16, 5 cP) and 4.2 (center of a

509383 / Ö93?

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 ¹ 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-diethyl-1,2,4-oxadiazol-5-yl-acetamide

The method used in the following is essentially described in "Houben-Weyl, 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-aminoisoxazole, 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 a heavy, yellowish oil was observed to separate out. Within a short time a crystallization took place of the oil and the mixture was heated for 5 minutes at 9O ⁰ C on a steam bath. 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 to decarboxylate the residues of oxadiazolyl acetic acid. The suspension was cooled and extracted continuously with dichloromethane for 16 hours. The extract obtained 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 added slowly to room temperature "and filtered successively at 3 ° C, -15 ° C and finally cooled to 70 ⁰ C. The crystals were quickly with a suction pump, with dichloromethane of -70 ⁰ C and locking

503883/0937

lent rait washed 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

650

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

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, • the method described.

8 g (0.056 mol) 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

8Ο98β3 / Ο937 '

Dissolved water 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 column of silica 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 ⁰ to 77.5 C. IR (KBr pellet, values in cm ^"1): 3180 sh, +3240, 1685, +1635, 1595, 1445, 1425, 1400, 1360, 1315, 1270, 1260, 1180, 1060 , 890, 730 and 685.

PMR (CDCl ^ 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, approximately 2H).

Example 22

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

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

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 at room temperature was prepared, 12.3 g (0.014 mol) of freshly distilled morpholine were added. After stirring for 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 in one portion, during which a thick, yellow precipitate formed

509883 / 093.7

and the temperature rose sharply. Shortly after the addition of the PC1 _: 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 _1, N ^ O,

Calculated: C 51.1896- 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 ): I650, 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, 770, 715, 680.

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

2.41 (S, 3H), 3.54 (center of 3 or 4 lines, 2H), of

3.62 to 3.75 (at least 9 lines, 6H), 4.02 (S, 2H).

Example 23

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

The process ended is similar to that 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-ylacetic acid in a mixture

£ 09883/093?

- ⁶ 3 - "236570S

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 approximately 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 (approx. 6%) of a light yellow crystalline solid with a purity of approx. 95% according to TCL and PMR, m.p. 169 to 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, 9 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 (Q, 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.

6.7 ml (0.079 mol) of pyridine, 5.9 g (0.056 mol) of ethoxy-

609883/0037

carbonyl hydrazide and 2.58 ml (0.03 mol) of phosphorus trichloride successively to a solution of 8.0 g (0.056 mol) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid in a mixture of 50 ml of dioxane and 50 ml of toluene "are added at room temperature. The resulting 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 extracted continuously for 16 hours with dichloromethane. The resulting solution in dichloromethane is evaporated completely, giving 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 to 123 ° C. The filtrate from the first crystallization is completely evaporated in vacuo and the residue is dissolved in a mixture of dichloromethane and diethyl ether. On cooling this solution to -30 ⁰ C crystallizes some of the product. The crystals are filtered off by filtration on a pump at low temperature and washed with cold diethyl ether. Yield 1.0 g (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 one can deduce that the connection in at least

occurs in two tautomeric forms.

IR (values in cm " ¹ ):

First batch: KBr pellet: 3320 and 3250 (uniformly intense), 3065, 2985, 2945, 1738 and 166O (uniformly extensive), +1640 sh, 1595, 1560, 1495, 1450 sh, 1415, 1395, 1360, 1305, 1270,

sh, 1255.

Second batch: KBr pellet: 3310 sh, 3210 (very intense), 3060, 2985, 1760 sh, 1735 and 1710, .1660 sh> + I630 (very intense), 1590, 1560 sh, 1500, 1475, 1445 sh, 1418, 1395, 1360, 1340,

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1300 sh, 1280, 1255.

IR spectra in solutions in CHC1 * * 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 ^^ - oxadiazol-S-yl-acetic acid, 7.3 g (0.043 mol) of 4-bromophenol and 3.6 ml (0.042 mol) of pyridine are mixed in dissolved from 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 abgäcühlt to -18 ⁰ C. The precipitated crystals are separated off by filtration, washed with a cold mixture of diethyl ether and pentane of approximately 1: 1 and finally dried in vacuo.

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

73 to 74 ⁰ 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

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

Substantially as described in Example 17, 12g are obtained Phosphorus oxychloride slowly to a mixture of 12 g of 3-methyl-1 ^^ - oxadiazol-S-yl-acetic acid and 8.9 g dry sec-butanol given. The rate of addition is adjusted so that the reaction temperature is 65 ± 5 ° C. The emerging The reaction mixture is then stirred at 65 ° C. for 90 minutes and then treated in the same way as described in Example 17. The product is at 68 ° C and 1.5 mm Hg distilled, yield 6.1 g (35%). The purity of the finished product was approximately 95%, n ^ = 1.438

IR (NaCl window, values in cm " ¹ ): 3000, 2960, 2900, 1745, 1600. PMR (60 Mc, CDCl *, TMS, 6 values in ppm): 0.9 (triplet-like, J = 7, 0 cP, 3H) j 1.25 (D, J = 6.3 cP, 3H), about 1.55 (quintet-like, 2H), 2.40 (S, 3H), 3.93 (S, 2H), 4.93 (regular sextet, J = 6.2 cP, 1H).

Example 27

Preparation of benzyl 3-methyl-1,2j4-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. The rate of addition is set to a reaction temperature of 40 to 45 ° C. The resulting reaction mixture is stirred for a further 5 hours at 4O ⁰ C and then treated in the usual manner. The

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The yellow oil is kept over silica using η-hexane and 3: 1-hexane / toluene, 1: 1 ~ toluene / hexane, 3ϊ1-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 cnf ¹ ): 1745, 1590, 1500, 1395, 1355,

1200, 750, 700

PMR (60 Mc, CDCl ₃ , 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 added to a solution of 2.0 g of 3-methyl-1,2,4-oxadiazol-5-ylacetic acid in one Mixture of 13 ml of dioxane and 13 ml of toluene 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 3.0 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, mp. 118.5 to 119.5 ⁰ C.

. IR (KBr pellet, values in cm ^"1): 3260, 1660, 1590, ¹ 535, 1480, 1440, 1295, 890, 870, 750, 680.
PMR (60 Mc, CDCl ₃ , TMS, S. values in ppm): 2.45 (S, 3H), 4.08

60908370937

- ⁶⁸ ~ 2365703

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

Example 29

Production of N-monosubst.-3-subst. ~ 1,2,4-0xadiazol-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-oxadiazole-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-cc- (3-ethyl-1 ₉ 2,4-oxadiazol-5-yl) -propionamide

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

C. oc- (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.

Acids The reactions of isocyanates with 1 ^^ were carried out at room temperature (about 20 ⁰ C) using solvents such as dichloromethane, toluene, chlorobenzene, 3,5-dimethyl-1,2,4-oxadiazole, etc.. The reactions with the 1,2,4-0xadiazol-3-yl-acetic acids were carried out in the same way, 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-imidazo1. The isocyanates used in the following were technical raw samples. For this reason and for other reasons such as the volatility of some isocyanates and possible moisture in the 1,2,4-0xadiazole acetic acids used, the isocyanates were used in a 10 to 20 molar excess.

509883/0937

A detailed description is given in Example A. "For the other examples, the starting products, the reaction media, the approximate reaction time, the information on the purity and / or the purification of the end products and the melting points and IR and / or PMR spectra of the end products are listed. The isolation procedures 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 do not have an absolute fourth.

A. Using anhydrous conditions 17 mmol of approximately 90% pure ce- (3-ethyl-1,2,4-oxadiazol-5-yl) propionic acid (- ^ -Aftiyl-ß-metfcßrl-i ,, 2,4-oxadiazol-5-yl-acetic acid) dissolved in 40 ml of toluene. About 20.5 mmol of n-propyl isocyanate and about 60 mg of catalyst (a saturated Solution of 4-methoxy ~ pyridine-1 ~ oxide.1H20 in N-vinylimidazole) were added to the solution. While a slow nitrogen stream 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 evaporated completely in vacuo. The residue was with 20 ml of η-hexane was stirred, then diethyl ether was slowly added

-809883/09: 37

ben until the solid was almost completely dissolved. After filtration, the solution was gradually cooled to -18 ⁰ 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 ₃ , TMS, 6 values in ppm): 0.95 (triplet-like, J approx. 7.0 cP, 3H), complex 8H, absorption range from 1.2 to 1.75, consisting of one CH ^ Triplet at 1.35 (J ¹ approx. 7.5 cP) a partially hidden CHp multiplet and a CH ₃ doublet at 1.67 (J "= 7.2 cP), 2.78 (Q, J 'about 7.5 cP, 2H), 3.25 (quartet-like, mean J about 6.5 cP, 2H), 3.93 (Q, J "= 7.2 cP, 1H), about 6.8 (broad S, about 0.8H).

B. oc- (3-Ethyl-1,2,4-oxadiazol-5-yl) propionic acid

(20 mmol of approximately 90% purity), allyl isocyanate (approximately 24 mmol), toluene, 3.5 hours, yield after column chromatography 2.7 g (64%) of pure product, m.p. 70 to 71 ° 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 ^, TMS, £ Values in ppm): 1.35 (T, J = 7.5 cP, 3H), 1.61 (D, J ¹ = 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. oc- (3-Ethyl-1,2,4-oxadiazol-5-yl) propionic acid (11.8 mmol of approximately 90% purity), 4-chlorophenyl isocyanate (14 mmol), dichloromethane, approximately 50 mg of a saturated Solution of 4-meth.oxypyridine-i-oxide.IH2O in N-vinylimidazole (Catalyst), 4 hours, yield 1.85 g (about 60%)

an at least 95% pure product according to TLC and PMR, mp.

130 to 131 ^O 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): about 3400, about 3300,

509883/093?

1690, 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 AA ¹ 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%) of 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 ₃ , TMS, £ values in ppm): 6H absorption range from about 3.75 to about 4.15, consisting of a CHp singlet at 3.83, a CH ₂ singlet at 4.06 and a CH ₂ multiplet, about 4, 85 to about 5.35 (extended multiplet, 2H), about 5.5 to 6.1 (extended multiple.tt, IH), about 7.3 (CgH 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. 1H ₂ 0 in N-vinylimidazole, 4 hours at room temperature and. 15 minutes at about 70 ° C, yield 1.56 g (60Si) almost pure product, mp. 139 to 141 ⁰ C.

IR (KBr pellet, 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 ₃ , TMS, / 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 mmol), 4-chlorophenyl isocyanate (7.5 mmol), 3.5 hours, Yield 1.4 g of almost pure product. After crystallization from

509883/0937

Toluene 1.15 g (63%), mp 114.5 to 115.5 ⁰ C. PMR (60 Mc, CDCl _3, TMS, ^ T-throwing 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 contains the urea derivative, 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 makes the urea and bisamide complete, the other two However, reaction products are only partially extracted. The precipitate is added to the combined extracts and the resulting solution is completely evaporated in vacuo. The residue is column chromatographed over silica gel subjected, with diethyl ether, Mi-

509883/093?

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

After crystallization from ethyl acetate, 1.3 g (48%) bisamide (title compound), melting point 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., was 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, d ^ -DMSO, DSS, <f values in ppm): 8H absorption range from approximately 3.5 to 4.05, consisting of a CHo singlet at 3.67, a CfL ^ singlet at 3.95 and a multiplet (two N-CHp Groups), about 4.9 to 5.4 (extended multiplet, 4H), about 5.5 to 6.2 (extended multiplet, 2H), about 8.4 (about 1.8H). PMR byproduct (ibidem) : 6H absorbance range from about 3.6 to 4.1, consisting of a 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).

For example, the following were produced in an analogous manner:

3a- (4-fluorophenylcarbamyl) -benzyl-1,2,4-oxadiazol-5-yl-acet-

(4-fluoro) anilide ; _<

whereby one of 3- (a-carboxy) -benzyl-1,2,4-oxadiazol-5-yl-acetic acid and 2 equiv. 4-fluorophenyl isocyanate to obtain the compound in 45% yield (crystallized with approximately 1 mole of water), m.p. 85 to 87 ° C (subl.). IR (.KBr pellet, values in cm " ¹ ): 3400-3500, approximately 3200-3300, 3150, 3075, 1670, 1620-1640, 1585, 1560, 1550 sh, 1510, 1415,

5098B3 / 09 3 7

1235 sh, 1225, 11β5, 845.

PMR (approximately 7: 1 mixture of CDCIU and dg-DMSO, 60 Mc, TMS, S "values in ppm): 4.06 (S, 2H), 5.55 (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 (broadened singlet) and 10.05 (ibidem ),

together about 1.6H, and

acet
1,2,4-0xadiazol-3 _> 5-diyl-bis - / (4-chloro-anilide _t whereby 1.5 g (8 mmol) 1,2,4-0xadiazol-3,5-diyl-bis- acetic acid and about 14 mmol of 4-chlorophenyl isoo / anate 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 obtained. The bisanilide melted with decomposition at 240 to 247 ° C (discoloration at 220 ⁰ C). The second product melted at 182-184 ° C. _CEFC
1,2,4-0xadiazol-3,5-diyl-bis - / (4-chloro) anilide: IR (KBr pellet, values in cm " ¹ ): 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 ¹ split pattern , 8H), 10.5 (slightly broad S) and 10.6 (ibidem) together about 1.8H.

1,2,4-0xadiazol-3-yl-acetic acid-5-yl- (4-chloro) -acetanilidi IR (KBr pellet, values in cm " ¹ ): + 3500, + 2550 to + 2650, 3265, 3120 , 3040, 2950, 1710, 1665, 1595, 1540, 1500, 1435, 14O5, 1380, 1250, 1195, 1100, 850, 755.

PMR (d ₆ -DMS0, 60 Mc, DSS, £ values in ppm): 3.83 (S, 2H), 4.22 (S, 2H), approximately 7.5 (center of an AA ¹ BB ⁵ 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-oxadiazo1-3-yl-acetamido] -cephalosporanic acid

To a suspension of 390 mg (1.45 mmol) 7-amino-cephalosporanic acid in 8 ml of dry dichloromethane was added 0.3

HO 9883/0937

(2.18 mmol) triethylamine. Anhydrous conditions were used and stirred the mixture for about 5 minutes. Then 0.067 ml (0.77 mmol) PCI was added. The emerging Suspension was stirred for about 5 minutes and then 327 mg (1.5 mmol) of 5- (N-propen-3-yl) -carbamoylmethyl-1 ^^ - oxadiazol-J-yl-acetic acid, suspended in 4 ml of dichloromethane, introduced. 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 became.

The layers were separated at pH 6.5. The organic layer was discarded and the water layer was extracted at pH 6.5, 5.0 and 4.0 with 25 ml volumes of ethyl acetate. The extracts were discarded. The remaining water layer was further extracted at pH 3.8, 2.5 and 1.5 with 25 ml volumes of ethyl acetate. These extracts were combined, washed with a small volume of ice 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 CHg singlet at 3 , 84, a CH ₂ singlet at 3.97 and an N-CH ₂ multiplet, a 5H absorption range of approximately 4.6 to 5.4, consisting of an AB quartet at 4.63, 4.85, 4 , 97 and 5.20 (J _Aß approx. 12.8 cP), a doublet at 5.12 (J = 4.8 cP) and a CH ₂ multiplet, a 2H absorption range of 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, O cP) at 9.25.

609.883 / 0937

Example 32

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

In the same way as described in Example 13, 1048 mg (4 mmol) of 5-benzyl-1,2,4-oxadiazol-3-yl-acetic acid are converted into the acid chloride transferred, being 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 were added. The reaction mixture is stirred for a further 30 minutes and then treated as usual. In the isolation process, the desired one became Compound obtained by extraction with ethyl acetate at pH decreasing from 6.0 to 4.5. 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, d ₆ -DMSO, DSS, ί-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 ^f 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 Pho sphortri chloride '

It has been found that the procedure described in Example 23, in which the amine, the 1,2,4-oxadiazole acetic acid and -Phosphorus trichloride used in 2.5: 1: 0.58 molar ratios is, for the production of amides in the case of secondary amines and primary amines has a wide field of application. This process is particularly suitable for amines of a somewhat more difficult nature, for example those in which the production the 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- (Thlazol-2-yl) -3-ethyl-1,2,4-oxadiazol-5-yl-aeetamide

B. N- (4-pyridyl) -3-niethyl-1 ^^ - oxadiazol-S-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 76%, m.p. 170.5-171.5 ° C (subl.) isolated by extraction with ethyl acetate and extracted from ethyl acetate

crystallized.

IR (KBr pellet, values in cm " ¹ ): 3300, 3200, 3090, 2980, 2940, + 2880, + 2760, 1680, 1600 (very intense), + 1570 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).

S09883 / 0937

B. Yield 40%, melting point 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 58%, m.p. 53 ⁰ C. Since the crude product obtained did not solidify easily, it was subjected to column chromatography over silica using n-hexane, n-hexane / toluene mixtures, toluene and finally a 3: 1 Subjected to mixture of toluene and diethyl ether as an eluent. The compound was then crystallized from toluene / heptane.

IR (KBr pellet, values in cm " ¹ ): 3000, 2950, 1660, 1505, 1420, 1400, 1375, 1315, 1270, 1180, 1135, 785, 720. PMR (CDCl ₃ , 60 Mc, TMS, δ 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 80%), 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, 1360, 1305, 1230, 745.

PMR (CDCl ₃ , 60 Mc, ίί 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).

609883/0937

Example 34

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

Using anhydrous conditions, a mixture of 3.1 g (20 mmol) of 5-ethyl-1,2,4-oxadiazol-3-ylacetic acid, 2.2 ml of thionyl chloride, 2 microdrops of dimethylformamide, and 60 ml of carbon tetrachloride was moderately for about 20 Minutes cooked. According to the IR spectrum, a complete conversion of the carboxylic acid into the acid chloride had then taken place. The resulting solution was evaporated in vacuo and the residue was dissolved in 20 ml of ethyl acetate. In the meantime, 5.6 ml of triethylamine at 10 ⁰ C to a suspension of 5.44 g (20 mmol) were added crude 7-aminocephalosporanic acid in 50 ml of ethyl acetate. Then 5.1 ml of trimethylehlorsilane were added. The mixture was stirred for 60 minutes at room temperature. Then 2.36 ml of quinoline and the solution of the acid chloride were added dropwise. The reaction mixture was additionally stirred for 30 minutes at room temperature. The contents of the flask were poured into 75 ml of ice water. The pH was adjusted to 7.0, the layers were separated and the organic layer was discarded. The desired compound was extracted from the water layer by a number of extractions with 100 ml volumes of ethyl acetate at pH values which were gradually lowered from pH 5.0 to 2.0. The combined extracts were washed twice with small volumes of ice water, once at pH 1.0 and once at pH 2.0. The extract was treated with activated charcoal, dried over anhydrous magnesium sulfate and filtered and concentrated in vacuo to approximately 25 ml. The resulting crystalline precipitate was filtered on the pump, washed with dry ethyl acetate and carbon tetrachloride and dried to constant weight. Yield 5.9 g (approx. This product was 90 to 95% pure.

609883/0337

The combined filtrates were evaporated in vacuo, whereby 1.3 g of a light yellow material was obtained, which by repeated trituration with diethyl ether to give 0.65 g of additional product. According to that Thin layer chromatogram and the IR spectrum had this 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 (dg-DMSO, 60 Mc, δ * values in ppm, DSS):. 1.30 (T, J = 7.5 cP, 3H), 2.05 (S, 3H), 2.95 (Q, J = 7.5 cP, 2H), 3.6 (broadened S, 2H) , 3.77 (S, 2H), 4.60 to about 5.25 (AB-Q, J = 12.8 cP) and about 5.15 (D, J = 4.8 cP) together 3H, about 5.25 (Q, J = 4.8 cP and J ¹ = 8.0 cP, 1H> 9.2 (D, J ¹ = 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 oc-ethyl caproate dissolved in 12.5 ml Treated ethyl acetate j. 5.3 g of the somewhat purer sodium salt of cephalosporin were obtained.

Example 35

Preparation of 7- [3-carboxymethyl-i, 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

609883/0337

was discarded and the water layer was extracted several times with 50 ml volumes of ethyl acetate at pH 5, Q ₅ 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 3si5p 3 »0, 2.5 and 2.0. These extracts were combined and filtered to the pump _P by a small amount of precipitate (about 300 mg) to remove, 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 a-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 _S 2 g. It contained approximately 65% of the desired monosodium salt according to the PMR spectrum. 6.0 g of this product were 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 x 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 weight skoiistanz. Yield 4.0 g «The purity of the product was at least 85%. It did not contain a major amount of by-product, but rather small amounts of approximately three impurities. This product could also be converted into the monosodium salt.

PMR (d ₆ -DMSO, 60 Mc, DSS, ξ 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 3Ή, about 5.7 (Q, J = 4.8 cP and

50988370937

■ - - 82 -. "2365703-

J «approx. 8.1 cP, 1H), 9.35 (D ₉ J ⁵ approx. 8.1 cP, approx 0.9H).

IR of the monosodium salt (KBr pellet, values in cm): about 3500 and about 2.500, about 3300, + 1770, + 1740, + 1720, 169O ₉ + 1610, + 1590, about 155O _s 1420, + 1390, + 1360, about 1270, 1240.

Example 36

Preparation of n-heptyl-3-niethyl-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. When the saturated solution reached room temperature, it was 5.7 g. (0.04 mol) 3-methyl-1,2,4-oxadiazol-5-ylacetic acid introduced. 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 barrels 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, 6.8 g of the desired product with a purity of about 95 %. (the impurities are mainly small amounts of n-heptanol) was obtained, bp. 108 ⁰ C at 0.25 mm Hg, n ^ ° = 1.450.

IR (NaCl window, fourth in cm " ¹ ): 2940, 2860, 1745, 1590, 1465, 1440 sh, 1395, 1350, 1290, + 1250, 1200, 740. PMR (CDCl ₇ , 60 Mc, TMS, ζ Values in ppm): 0.88 distorted

509883/0937

Triplet, 3H), from about 1.0 to 1:, 9 (broad absorption range, 10H), 2.38 (S, 3H), 3.93 (S, 2H), 4.17 (T, J = 6.4 cP, 2H).

The process described above is generally applicable to the preparation of primary alkyl esters of the very sensitive but reactive 1,2,4 ~ oxadiazol-5-yl-acetic acids, yields of over 50% being obtained. For example, 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 results in a mixture of both esters in exactly the same ratio as in the mixture used the alkenols 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) of PCl ^ 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 (Celite) filtered and evaporated completely in vacuo. The residue is dissolved in 75 ml of acetone with

€ 09883/0937

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 is obtained g (37%) essentially pure, almost colorless product.

IR (KBr pellet, fourth in cm " ¹ ): + 3550 and + 2550, 3285, 1780, 1740, 1715, 1660, I63O sh, 1580, 1540, 1410, 1380, 1350, + 1250 (intense with shoulders), 1150, 1120, 1105, 1070, 1040, 725, 700.

PMR (dg-DMSO, 60 Mc, DSS, S values in ppm): 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 ^ 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-α-carbomethoxy-1,2,4-oxadiazol-5-yl-acetamido] -cephalosporanic acid

Using anhydrous conditions, a solution of 1.09 g (7 mmol) of methyl 3-methyl-1, 2,4-oxadiazol-5-yl acetate in 15 ml of tetrahydrofuran at -100 ⁰ C cooled. 3.3 ml of a 2.34 η solution (7.7 mmol) of n-butyl lithium in η-hexane are then added dropwise, the reaction temperature being kept below -90.degree. 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 ⁰ C to -95 ⁰ 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

509.883 / 0937

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 uh-resolved 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 ₁ 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-cc- (morpholinocarbonyl) -1,2,4-oxadiazol-5-yl-acet-

amidol-cephalosporanic acid

3-methyl-1,2,4-oxadiazol-5-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 to 1660, 1585, 1530 to 1555, 1450, 1390, + 1240 (with school

B09883 / Ö337

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

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

<f 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, £ V ¹ - 0.7 cP, approx. 0.2H), 5.78 (center of 2 Doublets, J approx. 4.6 cP

and S 0 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 3 9

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

Using anhydrous conditions, a solution of approximately 1 mole of n-butyllithium in η-hexane is added dropwise to a solution of 50 g (0.51 mole) of 3,5-dimethyl-1,2,4-oxadiazole and 150 ml (1 mole) TMEDA added to 1400 ml toluene. In order to keep the reaction temperature is from -71 to -76 ⁰ 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 separated by filtration through a glass filter under a layer of dry air. The filter cake is washed with diethyl acetate and diethyl ether. The solid is suspended in a mixture of 250 ml of ice water and 10 ml of diethyl ether. Concentrated phosphoric acid is slowly and carefully added to the stirred suspension until a clear, brown solution with a pH of 2.0 is obtained. The solution is saturated with sodium chloride, cooled externally with ice and continuously extracted with dichloromethane. 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

509883/0937

5-yl ~ acetic acid, a relatively small amount of re-stored Product and also contains a considerable part of the desired bisacetic acid derivative, is evaporated in vacuo » The residue (58 g), which is partially solidified., Is 3 times with 50 ml volume of η-hexane, the 2% by volume of diethyl ether contains, stirred to remove the valeric acid present, resulting in a small loss of oxadiazole acetic acids. The acid residue (product 1) is temporarily stored in a refrigerator. The remaining water layer will be on added crushed ice and extracted continuously with diethyl ether until practically all of the 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid removed from the water layer. However, there was still a small amount of rearranged in the ether extract Product and a substantial amount of the bisacetic acid derivative present.

The remaining amount of the bisacetic acid derivative became complete removed from the cooled water layer by continuous extraction with ethyl acetate at 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 with the product 1 combined and dissolved in approximately 250 ml of water. A few drops of concentrated phosphoric acid were added to this solution (up to pH 2.0) and a small amount of sodium chloride. The solution was made with an ice bath cooled for 18 hours, with dichloromethane (heavier when the water layer) was extracted. The practically pure extract from 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% des used 3,5-dimethyl-1,2,4-oxadiazoles). Recrystallization 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

Extract is treated with activated charcoal and completely evaporated. The almost colorless, crystalline residue weighs 23 g (product 5). To remove the rearranged by-product, this residue is stirred for several hours in a mixture of 60 ml of dichloromethane and 40 ml of ether. The undissolved, colorless, crystalline mass is separated off by filtration, washed with dichloromethane and η-hexane and dried to constant weight, yield 18.9 g (20%) of pure 1 ^^ - oxadiazol-jJ ^ -diyl-bisacetic acid, m.p. . 109 to 111 ° C (a partial decarboxylation starts at about 100 ⁰ C). IR (KBR pellet, fourth in cm): very intense absorptions at + 2900 to 3200, 1700 to 1720, 1430 to 1240; a number of other, less intense absorptions at + 3400, 2500 to 2700, 1595, 1-410 sh, 1375, 1320, 1290, 1200, 1170, 945, 920, + 890, 850, 730 occurred.

PMR (approx. 1: 1 mixture of CDCl ₃ and dg-DMSO, 60 Mc, S values in ppm): 3.75 (S, 2H), 4.02 (S, 2H), approx. 9 (broad S, about 2H).

Stability of 1,2,4-0xadiazole-3,5-diyl-bisacetic acid: One small sample was dissolved in slightly moist diethyl ether. The solution was refluxed for 24 hours. By Thin layer chromatography found that less than 5% of the 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid had degraded.

Comments on the reaction conditions and isolation processes in the production of 1 ^^ - oxadiazole ^^ - diyl bisacetic acids:

The method described above is only an illustration of the reaction conditions and isolation methods. It was found that the second reaction with lithium, which takes place in a lateral position to C ^ of the oxadiazole ring in many cases (if no additional activating substituents such as phenyl are present), proceeds more slowly than the often very fast and complete first reaction with Lithium lateral to Cc. In the example given above, the second reaction with lithium did not proceed further than at most 30 to 35% _t da no more

5G9883 / Ö937

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-yl-acetic acid) was not isolated and his presence through. Neither does 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 3-methyl-1,2,4-oxadiazol-5-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 proceed relatively slowly, thus generally when the introduction of the lithium is lateral to Cj-

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

The double reaction with lithium often requires the use of a more powerful reagent. Hence often, but not generally, the very strong complex of n-BuLi: TMEDA is the reagent of choice. Other reagents that are different 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 lighter. Such The situation arises when the C ^ 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 classified as sensitive connections. That • suitable isolation procedures therefore vary according to the type of 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 you first get the double lithium salt of bisacetic acid can be isolated by filtration, because then only that part of the water is required which is necessary to dissolve the double Lithium salt is needed. Depending on the individual case (the nature of the bisacetic acid and the relative extent of its

S09883 / Ö937

- ⁹¹ "2 g 6 § 7 ο 5

formation, the type of by-product (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 can achieve concentrations in vacuo at pH values of be about 8 or 5.5 or continuous extractions with n-pentane at pH 5.0 to remove the by-products or constituents such as valeric acid, TMEDA and diisopropylamine.

With these factors in mind, a number of bisacetic acids made us to be isolated. Below are some values for two examples. It will also explains the possibility of having an extra substituent in one of the two possible positions.

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

3-Benzyl-5-methyl-1,2,4-oxadiazole is used as the starting material and n-BuLi / TMEDA as the reagent, the compound is obtained in about 30% yield, mind is that the compound with about 0.5 moles of diethyl ether crystallized. In this state the product is a solid at room temperature.

PMR (CDCl, with a trace of dg-DMSO, 60 Mc, OMS, Q values in ppm): 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) anilide obtain.

cc- (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

5O9883 '/ Ö§37

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 ₇ 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 is added dropwise over 3 hours to an effectively cooled solution of 66 g (0.58 moles) of 3-hydroxymethyl-5-methyl-1, 2,4-oxadiazole and 87 ml of Ν, Ν, Ν ', N'-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 at -70 ° C. for 1 hour. Dry, gaseous carbon dioxide is passed over the surface of the stirred reaction mixture for 10 hours at -70 ° C. with thorough cooling. The temperature can then gradually rise to -5 ° C. The educated lower

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 500 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 vacuo to a volume of approximately 500 ml
concentrated. 600 ml of ethyl acetate are added and the
The resulting solution is again concentrated in vacuo to a final volume of 250 ml. The resulting crystalline precipitate is filtered in 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 at 92 to 96 ° C with severe decomposition. According to the Dünnschichtehromatogrammen, IR and PMR spectra, both batches essentially identical ¹ are illustrated. Overall yield 45.1 g (approx. 55%) with a purity of approx. 96? &.

IR (KBr pellet, values in cm " ¹ ): 3440, 1745, 1720, 1600, 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, 6 values in ppm): 3.95 (S, 2H), 4.66 (S, 2H), approximately 7.5 (broadened S, about 2H).

Example 41

Preparation of sodium 7- (5-ethyl-1,2,4-oxadiazo1-3-yl-acetamido ) -3- (5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl) -3-cephem-4-carboxylate

The same conditions were used as in Example are described. Starting from 1.55 g (10 mmol) of 5-ethyl-1,2,4-oxadiazol-3-yl-acetic acid and 3.44 g (10 mmol) of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl-mercaptomethyl) -3-cephem-4-carboxylic acid with a purity of about 92% is obtained 2.58 g of the almost pure desired product.

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

IR (KBr pellet, values in cm " ¹ ): + 3450 (H ₂ O), 3280, 3050, 2985, 2940, 1765, 1680, 1610, 1580, 1550, 1415 sh, 1390, 1370. HMR (dg- DMSO, 60 Mc, DSS, £ values in ppm):, 1.28 (T, J = 7.5 cP, 3H), 2.69 (S) and 2.93 (Q, J = 7.5 cP ) together 5H, about 3.6 (2H), 3.77 (S, 2H), from about 4.25 to 4.7 (AB-Q, J about 13 cP, 2H), 5.0 (D, J approx. 4.9 cP, 1H), 5.55 (Q, J approx. 4.9 cP, J ¹ approx. 8.2 cP, 1H), 9.2 (D, J «approx. 8.2 cP, approximately 1H).

509883/0937

Example 42

Some of the penicillins and cephalosporins that work accordingly the corresponding examples were prepared for their antibiotic activity in vitro mit.einem agar serial dilution test and / or in some cases with a serial micro-dilution test and these tests were carried out as follows.

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.}

Bl micro serial dilution test.

2 drops of a stock solution of the compound to be examined (Antibiotic) in a known concentration are 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 organism 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 to control the growth of the test organisms in the pure medium.

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

509803/0937

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

The MIC values of the compounds examined and of benzylpenicillin, Phenoxymethylpenicillin, Ampicillin, Cephalexin, Cephalotin, Benzylcephalosporin, Benzyldesacetoxy-cephalosporin as comparison compounds are listed in the following tables. The MIC values obtained by serial micro-dilution experiment are set in brackets.

SQ9S83 / ÖS37

cn ο co. approx approx

ο-co Ca *

Examined
link

Bac.Subt.ATCC 6633 Staph.aureus A 321

. ■ A355 ·)

A2000

A2001

Strep, haem. A 266 • Strep, faec. L 80 Dipl.pneum. L 54 Haenuin / i. A 1030 Brucmelite. A 488 Past.MuIto. A 723 adhesive pneum. A 809 Salra.dubl. P 43 Salm.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

tomorrow

L 93 A1200 2241

benzyl desacetoxy ceph. (K-SaIz)

Ό.5

25 12.5 * 1

> 100 3

> 100 "25 100> 100

> 100

100

> 100

> 100

> 100

> 100

> 100

50

> -100

Cefalexin (acid)

"" θ. 3 '1.5 12.5 12.5

0.25 100

(125)

12.5

1.5

> 100

> 100

> 100

12.5

25th

12.5

> 100

Penicillin G.

♦) Penicillanase-producing strain penicillin
V.

(0.002)
(0.045)
(25)

Ampicillin Cephalosporin Cephalotin G (K-SaIz) (Acid) 0.03 0.09 0.12 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. ; ' : 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 6th r.5
/ oV 3 50 \ ³ )
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,
• ι > 100!

CO

CD

cn

CD

cn

Examined connection -

Connection A

Connection connection connection B connection C connection D connection E

Ex. Ex. Ex, 7 9

Bac.Subt.ATCC 6633 Staph.aureus A 321

A355 «) A2000 ■ A2001

Strep.haem. A 266 Strep. £ aec. L 80 • Dipl.pneum. L 54 Haenwinfl. A 1030 Brotc.melit .. A 488 Päst.Multo. A 723 adhesive pneum. A 809 Salm.dubl. P 43 .Salm.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 L 93 A1200 morg. 2241

¹ ) penicillinase producing strain

25th
25th

75 (0
25 (0
(

O.

Q.
0.
0.
■ 0.
0.5

12.5

0.5

(125)

12.5

> 100
> 100

>, 100

25th

> 100
'> 100

> 100
'50

> 100

25th

> 100

> 100

3)

0.
0.
0.
0.
0,

12th

5 (0.6)

75 (1.0

75 (0.6

5
5

50

0.75

(30)

'1.5
3 ".-: '
3

12th
12th
6th

> 100
> 100
> 100
1.5
25th

12.5
.
> 100

12.5

12.5

12.5

> 100
12.5

(8th)
(8th)
(4)

■ ' 6 ■
25th

> 100
> 100

> 100

> 100

> 100

> 100

> 100

3 '

> 100

100

> 100

> 100

0.03 ■

0.25
25 (125)

.5 (23)

(2.5)

1.0

0.06

(1.2).

100

100

> 100

■

2.5 '

> 100

> 100

> 100

100

12.5

100

> 100

0.06 I 0.12

1 (0.15) 1

(0.11) 0.03 6

0.25 (125) 100 50 '50> 100

> 100> 100> 100 > '1OO> 100> 100> 100 > 100> 100> 100

Connection A: 6-

Connection B: 7-

Compound C: 7-

Connection D: 7-

Connection E: 7-

. (3-Methoxymethyl-1,2,4-oxadiazol-5-yl) -acetamido] -penicillanic acid. A-Phenyl- (3-methyl-1, g ^ -oxadiazol-S-ylJ-acetamidoj-cephalosporanic acid -Benzyl-1,2,4-oxadiazol-3-yl) -acetamido1-cephalosporanic acid. (3-Methyl-i ^, ^ oxadiazol-S-yl ^ -acetamidoj-cephalosporanic acid .a-Morpholino- (3-methyl-1 , 2 _f 4-oxadiazol-5-yl) -acetamido] -cephalosporanic acids

CM ι— 4th CM CM CM CM in Cl in I. VO in VO tn ιη
CM ν O ιη ν- Ο Ο τ- Q νο CJ ιη ιη ιη
CM O pi * CM O O ο ο ο « O ω η *
O ιη τ ™ O * * in in CM τ- OJ
τ ~ Γ—
Λ τ-
Λ τ-
Λ ιη CM
τ- CM
τ— O τ-
Λ. • Η ν ~ CM O CO O CM CM O ο
* - * O Λ \ ^^ VO O in in VO ό d in \ J
τ-
Λ ο O O O ίλΐ
τ- Ο τ-
Λ O PQ O ιη * - ' in O r- Ο ιΑ O O O O ρ Pl O d τ— in O O U ί
CM Γ ™
Λ Λ Λ τ-
Α VO τ-
Λ VO kW
r— CM in O O • Η ν- co in co • m ιη O O O O ιη O O Q) v
PQ O O VO co • O co O t— A. m CM O O O O CO O τ- O Pl * co co
CM O d CM O O τ— τ- τ- τ— · CM ta O O ιη co O τ- ο Λ Λ Λ Λ O Λ C- Ο Λ • Η V- ο co in O O
Q ο O O Φ τ— in ¹ IVC A. in VO Q τ- Λ ιη O O O. Λ O O Λ O PQ τ τ— T ™ ^ T- Ο O O O O O O O pi VO ι *. »»
Q in CO VO τ— O Λ Λ Λ Λ Λ Λ I in c— in in O Λ Ö O • Η ν ~
Φ τ- ? -s
in CM •
CM Ο O O O PQ CM in in 1 ffS in τ— O Λ ιη ο O O O Λ O O Λ O, ο CM CM O ο O O O O O O • «- OT in in O Λ ιη CM λ Λ Λ Λ Λ Λ ιη Λ Pl
camouflage Γ "" * co CM O in . ^r ~ • Wj f-Ή
rlr O O in O . O in CM O O O CM i
O Φ ν-
PQ ιη r ~ \ «- in r- r— τ- VO ft * ~ ιη O O O ^Γ " O * VO O VO CJ O . τ— (O Q O ^^ CM
* VO
■ O Τ O τ— Λ Λ Λ VO VO Ai "| —F \ VO O VO in O Λ ο Φ V-
PQ cn • in O CJ O ο CJ ο VO co co co τ— O VO Ο τ ™
Λ O O O CO O Λ O • νο O co in O VO O m O O O O O O Pl
WU O O in τ CM O Λ CM Λ Ά Λ Λ τ- T "*
Λ • rlv-
Φ τ- O O ο ό in ο m O PQ * ■ - *
in in in fc CJ O 'λ . O in XM O O O τ- ιη CM O O O O O τ- O • \ ^ CM _T- tn VO ό 'I. m Λ ν τ- O O O O ιη Λ O PiPQ O ^ A CM T- O CM ^Λ τ ™ * r— O O τ— CQ V- O C. 1- in in O τ- CO Λ Λ Λ O ιη CO ^Λ • Η ν- VO in A * 'CM CM co co A. Ο O O O Λ O O I. O Φ
PQ ο -C CO O ιη O
τ ™ * O O O
τ ™ O Ο "'
τ— Ρ * ο in co Λ VO CM Λ Λ Λ Λ Λ (Q <ϋ
• Η V- co Φ τ-
PQ ιη ^ ->
VO in I. • vo m I. co O* O O co ιη VO • CM O co ¹ τ— O O O CVl ιη
* (Q O * --- ON CO CO co Λ Λ Λ γ- ι— • HO O O -CC ν CV KW CTiO ΚΛ Φ V
PQ ) CT »O v ■ v • ν V- (M •, Ω τ t— ιηνο Ι> -0Ο V CNJ CM -P U ■> - ^ \ v- v ν- ν- CsJ (M Ö Φ in "> < Mf CM τ ι
<■ ->. V * / in CM r- m CM in CM O co in CM τ— ^ _ O * ~ in CM T "·

$ 09883/0937

O9> CO

Examined connection -

Example 11K

Ex.
11L

Example,
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 12.5 A2000 1.5 (1.2, 1 6th A2001 1 (0.9) 1 6 V Strep.haem. A 266 0.06 0.25 0.5 ' Strep.faec. ¹ L 80 ioo. 50 6th Dipl.pnevun. L 54. ; 1 1 • 0.5. Haem.infl. A 1Ό30 ■. (125) (5125) (3.7) Bruc.melit. A 488. ' 12.5 6th 0.5. Past.multo. A 723,. 1.5 2 1 Adhesive pnei ^ m. A 809 6th 1.5 > 100 Salm.dublv P 43 100 3 50 SaIm.typh. R 127 > 100 6th > 100 Esch.coli U 20 " > 100 6th > 100 Shig. equir. T 3 25th 3 50. Pseud.aerug. H 10, > 100 > 100 > 100 • 2396, > 100 > 100 > 100 Wyeth A1.O58 > 1Q0 > 100 > 100 Prot.rettg. A 821 12.5 1 . i ■ 3. . from me. H 3 > 100 50 I> ioo L 93; . , 12.5 3 I 25. · A 1200 > 100 25th j> 100 '■ tomorrow 2241 > 100 > 100 J> 100

ro 00 cn cn

O cn

Examined example example 1 example example example example link 13th 18th 1 19th 31 37 38 1.5 (1.2)
1.5 (1.2) Bac.subt. ATCC 6633 0.03 1 (0.9) 0.5 1 • 0.12 6th Staph.aureus A 321 0.12 0.25 6th 1.5 0.5 25th ■ A 355 «)
A200Ö 10
1.5 > 100 12.5 (15)
6 5 6 (1.9 )
3 (1.2) 1.5 (0.9)
1.5 (0.6) co co
CM CM
in in
CM CM A2001 1.5 3 6 (6) 3 (1.2). 0.75 (0.45) .25 (15) Strep.haem. A 266 0.03 (6), 0.5 (2.5) 0.12 Strep, faec. L 80. 6th 6th ■> 100 25th 50 > 100 Dipl.pneum. L 54 1.0 10 3 1.5 " 0.75 12.5 Haem.infl. A 1030 (125) 6th (23). . (V 125) (125.23) (125) cn Bruc.melit. A 488 3 6th 6 ·. · · '- M. O · Past, multo. A 723 ■ 1 12.5 - 25th ns; ■■ 1 12.5 '. ^<o> ICleb.pneum. A 809 > 100. 12.5 '■■■ 50 '6. ■■. '■■■ 3 50 2J Salm.dubl. P 43 3 3 ■ · ■ · ■. 25th 6th 3 100 5 ^ Salm.typh. E 127 25th > 100 100.. 12.5 12.5 100 ^ Esch.coli U 20 50 > 100 . 100 · ' • 12.5 .: 12.5 > 100 Qf Shig. equir. T 3 3 > 100 '. 6th 12.5 '. ; 3, 6 ■ 50 ^r . ^to> pseud.aerug. H 10 > 100 12.5 > 100 > 100 ' > 100. > 100 '- 25th ■> ioo > 100 > 100 '> 100 Wyeth A 1058 > 100 6th > 100 > 100 > 100 > 100 Prot. Rescue A 821 6th 25th 6th 12.5 3, 12.5 25th from me. H 3 100 > 100 50 25th 25th 100 L 93 . 3 25th . 6th • 6, 12.5 50 A 1200 25th > 100 25th 50, 100 > 100 tomorrow 2241 100 > 100 > 100
■ > 100
• > 100

Example 45

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

(a) Compound sodium 7 - [(3-methyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanate (prepared as in Example 10), the acute toxicity was determined in Swiss mice by an intraperitoneal administration certainly. The IDt = Q values are> 6000 mg / kg (Cephalotin LD ₅₀ > 600 mg / kg).

In a protection experiment, _{the following ED 5Q values were} found for this connection:

Connect
manure Appoint
reaching ED ₅₀ (mg / kg, 1.25
4.34 Klebsiella
pneumoniae Escherichia
coli Verb. To
Ex. 10
Cephalotin SC
ip
SC
ip Staph. Proteus
aureus rettgeri
pen.resi-
stent 2.3
0.8 120.0
> 300 31.0
37.6

The blood values or levels of the above-mentioned compound to be examined and of cephalotin were determined according to the intramuscular Administration of 50 mg / kg of these compounds in aqueous solution in rabbits was determined. After half an hour the compound of Example 10 showed a value of 38.3 / Ug / ml, the value for cephalotin was 33.9 / Ug / ml.

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

(b) The EDj-Q of sodium ~ 7 - [(3-methoxymethyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanate (prepared as described in Example 37) is 1.2 mg / kg for one Protective test against a penicillin-resistant Staphylococcus

509883/0937

aureus strain after subcutaneous administration, while for Cepha-iotin a value of 1.3 mg / kg was found. The connection in accordance with Example 37, tests with mice give good blood levels and very strong urine activity against pathogens Germs. The compound can preferably be used parenterally.

(c) The ED ₅₀ - ¥ ert 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 in an attempt to protect against a penicillin-resistant Staphylococcus aureus strain after subcutaneous administration, while a value of 1.3 mg / kg was found for cephalotin.

(d) Mice have 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-roethyl-1,2,4-oxadiazol-3-yl) -acetamido] -penicil-

lanat

Sodium 6- [α-methyl- (3-methyl-1,2,4-oxadiazol-i5-yl) acetamido] -

penicillanate

7- [C 3- (2,6-dichlorophenyl) -1,2,4-oxadiazol-5-yll-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 sodium carboxymethyl cellulose 0.06 to 0.600 g sodium saccharinate 0.1 to 1 g methyl p-hydroxybenzoate 0.06 G
Strawberry flavor 0.1 to 5g

Amaranth 0.010 g

Sucrose 30 g

Water, added to a volume of 60 ml.

509883/093?

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 that have a penicillin or Cephalosporin derivative, prepared according to the previous examples, were prepared in the usual manner. The ingredients of the tablets are listed below:

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 according to the previous examples manufactured ten penicillin and cephalosporin derivatives, a dry powder for injection, prepared in the usual way. One Amount of 100 to 2000 mg sterile sodium salt of the corresponding compound is aseptically in an ampoule, which is suitable for in-

509.883 / U937

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 held so that the exchange of gas or the ingress of microorganisms is avoided. Before use the powder is dissolved in a suitable amount of sterile and pyrogen-free water.

Example 48 (addition to example 37)

The elegant process used in Example 37 (as well as in Example 31) uses intermediate phosphoazo compounds which are produced in situ by reacting the amino group of 7-aminocephalosporanic acid (7-ACA) or related bicyclic amino acids with precisely stoichiometric amounts of phosphorus trichloride (PCI -,) and a tertiary amine (eg triethylamine) in a suitable solvent or a suitable solvent mixture.The desired ß-lactam antibiotics are prepared by subsequent reaction of the phosphoazo compounds produced in situ by adding a generally exactly equivalent amount of 1,2,4 -Oxadiazol-acetic acid, generally 1,2,4-oxadiazol-fj ^ yl-acetic acids, but also certain 1,2,4-0xadiazol-3-yl-acetic acids, for example those which have an activating effect on the C [- Carbon atom of the oxadiazole nucleus bonded substituent group (as for example in Example 3 ¹ ) prepared As indicated in the following examples, the Reaktio The conditions vary and are, to a certain extent, adapted to the individual combination of the bicyclic amino acid and the 1,2,4-oxadiazole acetic acid, always using stoichiometric ratios.

The following are a number of examples which demonstrate the applicability of the method but not the method in terms of it the substituents still limit in terms of yields. With each example there is a brief description of the Reaction conditions, e.g. the quantities, the solvent,

5Q9883 / Ö93?

the reaction times and reaction temperature, the catalyst, if it was used, as well as the yield and spectroscopic data of the isolated β-lactam antiblotics are given. In cases in which the isolation yields are less than 50 % , a recovery of the unconverted bicyclic amino acid can be indicated.

B. 7- [3-Methyl-1,2,4-oxadiazol-5-yl-acetamido] -cephalosporanic acid G. 7- [3-Carboxymethyl-i, 2,4-oxadiazol-5-yl-acetamido] -cephalosporanic acid

D. 7- [3-Hydroxyme.thyl-1,2,4-oxadiazol-5-yl-3-cetamido-3-cephalosporanic acid

E. 7- [3-Methyl-1,2,4-oxadiazol-5-yl-acetamido] -3-azidomethyl-3-ceph.em-4-carboxylic acid

P. 7- [3-Methyl-1,2,4-oxadiazol-5-yl-acetamido] -3- [1-methyl-tetrazol-5-yl-niercaptomethyl] -3-cephem- ^ - carboxylic acid

G. 7- [3-Carboxymethyl-1,2,4-oxadiazol-5-yl-acetamido] -3- [1 -methyl-tetrazol-5-yl-mergaptomethyl] -3-cephem- ⁱ } -carboxylic acid

H. 7- [3-Methyl-1, 2,4-oxadiazol-5-yl-acetamido] -3- [5-metb.yl-1, 3,4-thiadiazol-2-yl-mercaptomethyl] -3- cephem- ⁱ l -carboxylic acid

B. 3β, 72 ramol. . 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 7-amino-eephalosporanic acid, 38Ο ml dry acetonitrile, 1 hour at room temperature and 2 hours at 50 to 55 ° C _y yield 84.5 % of practically pure product. The compound has already been described under Example 10.

C. 5.51 mmol 1,2,4-0xadiazol-3,5-yl-fc> is-acetic acid with a purity of about 94 % and 5.51 mmol 7-amino-cephalosporanic acid, 55 ml dry acetonitrile, 30 min at room temperature and 45 minutes at 50 ° C., 80 % yield of almost pure product. The compound has already been described under Example 35.

D. 5.51 mmol of 3-hydroxymethyl-1,2,4-oxadiazol-5-yl-acetic acid (slightly moist) and 7-amino-eephalosporanic acid, 55 ^{ml of} dry acetonitrile, 10 min. At room temperature and 90 min. At 50 ° C,

Yield 27 % (49 % 7-aminocephalosporanic acid recovered) of almost pure product.

IR (KBr compact, values in cm " ¹ ): 54OO-J5OO, 2600, 328θ, 3060, 2950, 1780, 1720-1745 / 1710 (sh), approx. 168Ο, 159Ο, 1550, I4i5 (sh), - 1390, 1560, 1240, ii60 (sh), - 1115, 1080, 1O4O PMR ^ (60Mc, approx. 3: 1 mixture of dg-DMSO and DCO ₂ D, DSS, £ values in ppm): 2.05 ( s, 3H), 3.6 (2H), 4.10 (s, partially deuterated 2H absorption), 4.61 (s, 2H ~ absorption) and approx. 4.65 to 5.2 (AB-q, J ^ 13 cps) and 5.15 (d, J ^ 4.8 cps) all together 5H, 5.75 (d, J ^ 4.8 cps, 1H)

§ The spectrum of the compound in DMSO alone showed an NH absorption at 9.6 (d, JaJ ¹ S, 0 cps) and a full CHp-CON singlet at 4.1. '

E. 5.51 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 7-amino-3-azidomethyl-3-cephem-4-carboxyric acid (of about 90 % purity), 55 ml dry acetonitrile, 1 hr. at room temperature and 1.5 hrs. at 50 ⁰ C, yield 35% (45% of 7-amino-3-azidomethyl-3-cephem-4-carboxylic acid recovered) of pure product. IR (ibidem): + 3500, 3290, 3065, 2800-2900, approx. 26ΟΟ, 2135, 178O, 17Ί5, 1670, I64o ( ^! Sh), 1595/1550, 1440, 1405, 1370, 1340, 1295, · 1265 , 1240, 1195, 1160, 1115, 1075

PMR (60Mc, dg-DMSO, DSS, S values in ppm): 2.37 (s, 3H), 3.6 (center from AB-q, 2H), 4.07 (s) and about 3.75 to 4.6 (AB-q, J ^ 13.5 cps); together 4H, 5.2 (d, J? = f4.9 cps, 1H), 5.75 (q, Jj ^ 4.9 cps, J ^ 8.5 cps, 1H), approx. 9.3 (d, J ^ 8.5 cps, 0.9H)

P. 4 mmol of 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 7-amino-3- (1-methyltetrazol-5-yl-mercaptomethyl) -3-cephem-4-carboxylic acid (with a purity of about 90%) j 35 mL of dry acetonitrile, 1 hr. at room temperature and for 2 hrs. at 50 ⁰ C, 37% yield of nearly pure product (41% of 7-amino-3- (1-methyl-tetrazol-5- yl-inercaptomethyl) -3-cephem-4-carboxylic acid recovered). IR (ibidem) of the sodium salt: 3400-3500 (H ₂ O), + 3300, 3060, + 3030, +2940, 1770, 17OO, 1615, 156O, i420 (sh), 1400, 1365, 1290, 1240,

1180, 1110, 1070, 1015 ■ ■

PMR (6OMc, dg-DMSO, DSS, 8 values in ppm) of the sodium salt: 2.34 (s, 3H), approx. 3.5 (2H), 3.94 (s, 3H), 4.05 ( s, 2H), 4.15 to 4.65 (AB-q, J "v 13 cps, 2H), 5.0 (d, J ^ 4.8 cps, 1H), 5.55 (q, J ^ 4.8 and J ^ 8.2 cps, 1H), 9.35 (> d, J ^ 8.2 cps, 0.8h)

G. 16.6 mmol 1,2,4 ~ oxadiazol-3,5-yl-bis-es.sigsäure and 7-amino-3 ~ f1-methyltetrazol-5-yl-mercaptomethyl) -3-cephem ~ 4-carboxylic acid , 165 ml of dry acetonitrile, 16 hrs. at room temperature and 2 hrs. at 50 C, to yield substantially pure product (20 FO 7-amino-3- (1-methyl-tetrazol-5-yl-mercaptomethyl 39%) -4 -cephem

4-carboxylic acid recovered).

IR (ibidem) of the monosodium salt: 3400-3500 (HpO), + 3300, + 3030, + 2940, + 2800, 1760-1780, 1685, 1585-1610, + 1550, 1410 (sh), 1390, 1360, 1285, 1240, 1175, 1105, 1065, 1010

PMR ^ (60Mc, approx. 3: 1 mixture of dg-DMSO and DCO ₂ D, DSS,

<S values in ppm) of the monosodium salt: 3.75 (broadened s) and 3.85 (s), together 4h, 3.97 (s, 3H), 4.1 (s, partially deuterated 2H ~ signal), 4.35 (slightly broadened s, 2H), 5.1

(d, Jsss4.8 cps, 1H), 5.75 (d, J ^ 4.8 cps, 1H)

§ The spectrum of the compound in DMSO alone shows an NH absorption at 9 ^ 35 (d, J ^ 8.0 cps) and a full CH ₂ -C0N-Sin-

gulett at 4.1.

H. 21.65 mmol 3-methyl-1,2,4-oxadiazol-5-yl-acetic acid and 7-amino-3- (5-methyl-1,3,4-thiadiazol-2 »yl-mercaptomethyl) - 3-cephem-4-carboxylic acid, 220 ml of dry acetonitrile, 3 hours at room temperature and 3 hours at 50 + 5 ° C., yield 58 % of pure product.

IR (KBr compact, values in cm " ¹ ): + 3500 and + 2600, 3290, 3050, + 2950, 1780, 1720 (sh), 1685, 1655 (sh), 1630 (sh), 1590, 1540, 1430 (sh), 1390, 1350, 1320 (sh), 13OO (sh), 1240, II80, 1100, IO65, 1050 (sh), 1010

PMR (60Mc, dg-DMSO, DSS, 5 values in ppm): 2.34 (s, 3H), 2.71 (s, 3.7 (2H), 4.05 (s _s 2H), approx. 4.1 to 4.7 (AB-q, J ^ 13.5 cps, 2H), 5.15 (d, J ^ 4.7 cps, 1E) _S 5.7 (q, J ^ 4.7 cps , J ^ 8 cps, 1H), 9.35 (d, J ^ 8 cps, 0.9H)

Example 49 (addition to example 41)

In a manner analogous to Example 41, sodium 7- [5- methyl- 1, 2,4-oxadiazol-3-yl-a-cetamido] -3- [1- methyl-tetra zo 1-5- yl-kidney

captomethylj ^ -eephem- ^ -carboxylate produced:

Starting from 0.994 g (7 mmol) of 5-methyl-1,2,4-oxadiazol-3-ylacetic acid and 1.904 g (7 mmol) of 7-amino-3- (i-methyl-tetrazol-5-ylmercaptomethyl) -37cephem- 4-carboxylic acid with a purity of about 90 % was obtained 1.85 g (55 %) of almost pure cephalosporin. In this case, the ACA derivative was not dissolved by treatment with triethylamine and trimethylchlorosilane, but by adding 14 mmol of Ν, Ο-bis-trimethylsilylacetamide.

IR (ibidem): + j400 (H ₂ O), 5200-3300, 17βθ, 163O, 1βθΟ, 1580,

+ 1540, + 1400 (sh) m 1380, 1355

PMR (ibidem): 2.58 (s, 3H), ca 3.45 (2H), 3.75 (s, 2H), 3.95 (s, 3H), from ca 4-, i5 to 4.65 (AB-q, J «15 * 5 cps, 2H), 5.0 (d, J ^ 4.8 cps, 1H), 5.55 (q, J ^ 4.8 cps, J ^ 8.2 cps, 1H),

9.2 (d, J ^ 8.2 cps, ca 1H).

509883/0937

Claims (1)

- no - Claims 1. Penicillanic acid and cephalosporanic acid derivatives according to the general formulas C-CH-C-KIi-Q »0 where Q is the groups Cl CH —COU . N CH- COU XXI CH - ^, T ₁ CH - COU _miI CH CIl ' I I H_ means vrorin U is an amido group, for example a saccharyl, succinimido or phthalimido group or a group OE ¹ in which E ^{1 is} a hydrogen atom, a salt-forming kaxion, an ester radical such as a (lower) alkyl group which is optionally substituted by a (lower) alkanoyloxy group, which can also be substituted, a SiIy1-, phenacyl-, benzyl-, benzhydryl- , Means trichloroethyl or tert-butyl group, 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 , (such as pyridinyl), a group -SQ ¹ , in which Q 'is an optionally substituted diazoly.l-, Triazolyl, tetrazolyl, thiazolyl, thiadiazoIyI, thiatriazolyl, Oxazolyl ,. Oxadiazolyl-, Benzimidazolyl-, BenzoxazoIyI-, Triazolo-pyridinyl- or purinyl group, or where X denotes an amino group in which Q is a group of the formula XX means R ^ a (lower) alkyl group such as a methyl, ethyl, propyl, isopropyl _r butyl, sec-butyl, isobutyl, t-butyl group, optionally substituted 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 with one or more (lower) alkyl groups, hydroxyl groups or (lower) - Alkoxy groups means or wherein R ^ an adamantyl group or a phenyl group, optionally substituted with at most three substituents such as a fluorine atom, a chlorine atom, a hydroxy, a lower (alkyl) or a (lower) alkoxy group, or wherein Rv. a mononuclear heterocyclic 5-membered Group such as a furyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl group, optionally substituted with (lower) alkyl groups, means or wherein 609883/0937 2365703 R ₁ denotes an aralkyl group such as a benzyl group, optionally substituted in the phenyl nucleus as described above, or a carboxymethyl group, and in which Z ₁ "in addition to the definitions given above for R _1, a hydrogen atom, a (lower) -alkyl group, optionally substituted by a chlorine or fluorine atom, a (lower) -alkoxy group, a cycloalkyl group, a phenyl group, which itself optionally contains at most three of the previously mentioned 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 group, a mononuclear 5-membered heterocyclic group, a cycloalkyl group, one or two aryl- (lower) -alkyl- or cycloalkyl- (lower ) -alkyl groups, where the phenyl or 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 "means a hydrogen atom in combination when R _{1 means} an acetic acid residue, Q_NH- C CH C ^ CR ₀ - XXIV I ι ^ / ² ■ - ■■■ - ■■■ N · CT wherein Q has the definition given above and Rp is a group of the formula 509863/0937 _2n ^ ^R 4 means in which η means 0, 1, 2 or 3, and R ^ is 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, 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 possibly with at most one of the previously mentioned ^ th substituents may be substituted, or wherein R, and R ^ together with the carbon atom to which they are attached represent an optionally substituted cycloalkyl group,
and in what Z / is a hydrogen atom or an optionally substituted aryl group means and the salts and esters thereof. -2. Penicillanic acid and cephalosporanic acid derivatives according to claim 1, characterized in that R ₁ (in formula XVIII) is a lower alkyl group, an adamantyl, halomethyl, hydroxymethyl, carboxymethyl, (lower) alkoxymethyl, benzyl or phenyl group means, 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 a methyl, ethyl, methoxymethyl, ' 609083/093? 2,6-dichlorophenyl, 2,4,6-trimethylphenyl or a carboxymethyl group means, and the pharmaceutically acceptable salts and esters thereof. 3. penicillanic acid and cephalosporanic acid derivatives according to claim 1, characterized in that Z ^ "(in formula XVIII) 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. 4. penicillanic acid and cephalosporanic acid derivatives according to claim 1, characterized in that Rp (in formula XXIV) is a methyl or ethyl group or a group -CH ₂ -R ^, wherein R ₁ ^ is a branched alkyl, cycloalkyl, Means phenyl, a (lower) alkoxycarbonyl, an N-monosubstituted carbamoyl group or an unsaturated heterocyclic group and the pharmaceutically acceptable salts and esters thereof. 5 · penicillanic acid and cephalosporanic acid derivatives according to claim 1, characterized in that Z <is hydrogen means atom or a phenyl group. 6. penicillanic acid and cephalosporanic acid derivatives according to any one of claims 1 to 5, namely 6 - [(a-Phenyl-3-methyl-1,2,4-oxadiazol ~ 5-yl) -acetamido] -penicillanic acid, 7 - [(3-Benzyl-1,2,4-oxadiazol-5-yl) -acetamido] -desacetoxycephalosporanic acid, 7- L [3- (2,4,6-trimethylphenyl) -1,2,4-oxadiazol-5-yl] -acetamidoj -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! -Acetamido} - 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] -acetamidoJ · - cephalosporanic acid, 7 - [(5-Methyl-1,2,4-oxadiazol-3-yl) -acetamido] -cephalosporanoic acid, 509d83 / 0937 7-? [3- (2,6-dichlorophenyl) -1,2,4 ~ oxadiazol-5-yl! -Acetamido} - * "desacetoxy-cephalosporanic acid, 7 - [(3-methyl-1,2,4-oxadiazol-5-yl) -acetaraido] -desacetoxycephalosporanic acid, 6- [(3- ethyl-1 ^^ - oxadiazol - ^ - yli-acetamldoj-penicillanic acid, 6 - [(a-Methyl-3-methyl-1,2,4-oxadiazol-5-yl) -acetamido] -penicillanic acid, 7 - [(a-Methyl-3-methyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid, 7 - [(cc-methyl-3-ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid, 7 - [(3-Ethyl-1,2,4-oxadiazol-5-yl) -acetamido] -cephalosporanic acid , 6 - [(a-methyl-3-ethyl-1,2,4-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 ^ -oxadiazol-S-ylacetamidoj-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-1,2,4-oxadiazol-5-yl-acetamido) -cephalosporanic acid, 7- (3-methoxymethyl-1,2,4-oxadiazol-5-yl-acetamido) -cephalosporanic acid, 7- (3-methyl-a-carbomethoxy-1,2,4-oxadiazol-5-yl-acetamido) -cephalosporanic acid, 7-L3-methyl-a- (morpholinocarbonyl) -1,2,4 ~ 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-mereaptomethyl) -3-cephem-4- carboxylic acid and the alkali metal, alkaline earth metal and amine salts and the pharmaceutically acceptable esters thereof. 609883/0937 7. Process for the preparation of 6-substituted aminopenicillanic acid and 7-sut) st-aminocephalosporanic acid derivatives according to claim 1, 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 - CH- C! -CH-COOII H ₀ N - CH-CH CH ₉ XXV . COOH XXVI Ρ ' HJ - CH - CH C. I. _f H ₂ N - CH-GH ' -N- XXVII -CH-COOH -N- XXVIII -CH-COOH or H ₀ N - CH ^ CH CH ₉ ² M i : 00H XXIX 509883/093? X represents 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 mononuclear heterocyclic group which contains a sulfur or nitrogen atom such as pyridinyl, means a group -SQ ', in which Q ^{1 means} a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl or purinyl 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 C-CH COOH XXX derive, in which R ^ and Z. have the meanings given above for R ^ and Z. "or are groups which can easily be converted into those _{falling under the definitions of R ^ and Z 1} " and which can be carried out in the used reaction conditions can be influenced or can react (such as protected amino, hydroxy and carboxy groups) or HOOC CH - C "^ C - R *. XXXI wherein R ₂ and Z ^ have the definitions given above for Rp and Z, or are groups that can easily be converted into those that 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) one -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, in which Zp and Z ₇ , have the meanings given above, with the proviso that those substituents of the definitions of R., Z ^ ", Rp, Z ,, Z ₂ and Z ,, which are influenced or can react under the reaction conditions used, are protected, in an inert organic solvent medium and preferably in. Presence of an organic base or with (2) an organometallic compound of the formulas e ^{I] [} -Hal or A-Ke ¹¹ ^ -A, woi A is a group of formulas A-Me ¹ , A-Me ^{I] [} -Hal or A-Ke ¹¹ ^ -A, wherein - CH es-q ^ - '. XXXIII wherein R ^ and Zl have the definitions given above, or xxxiv where Z ₂ and Z ^ have the definitions given above, 509803/0937 means, Me means a metal atom such as a lithium, sodium or magnesium atom, the digits I or II indicate its value and Hal is a halogen atom, preferably a chlorine or bromine atom ,means, in an anhydrous organic solvent under conditions implements that favor a Grignard, Reformatzky or an analogous type of implementation, and then removes the metal residues from the products thus obtained, (3) an acid of the general formulas XXX, XXXI and XXXII with a phosphazo intermediate prepared in situ implemented by reacting phosphorus trichloride and an amine salt of a compound accordingly of the formulas XXV, XXVI, XXVII, XXVIII and XXIX in the presence of a precisely predetermined excess of the used Amine obtained under anhydrous conditions, (4) a penicillanic acid sulfoxide corresponding to the general formulas XXVIII and XXIV, in which Q denotes the group of the formulas XXI and XXII, is ^{heated up to 14O 0} C in the presence of a suitable catalyst, the compounds thus obtained are optionally further substituted or substituents present in others are converted and then the compound obtained is separated and / or isolated and any protective groups present are removed in order to prepare the corresponding penicillanic or cephalosporanic acids, and these acids obtained are optionally converted into their salts or esters to form compounds the general formulas R ₁ C ^ ^ C- CH -C- NH -Q XVIII 609803/0937 Q M- C CII - manufacture in which Q the group - CH-CH • c: CH, ^& 2 N CH - COU XDC , ΛΛ CH
1 CH
I. J ^C I. I.
N C-CH ₂ X COU XX XXIV ; h-cou XXI / + a -CH CH or 0-- , 6 —— κ λλ. - CH CH - N COU ■ XXII XXIII ■ C ' ■ CH, --CH - COU means in which U is an amido group, for example a saccharyl, succiniraido or phthalimido group, or a group OE ¹ , where E ^{1 is} a hydrogen atom or a salt-forming cation, an ester group such as a (lower) alkyl group, optionally substituted by a (lower) alkanoyloxy group , Which can also be substituted, a silyl, 5Ü98Ö3 / 0937 Phenacyl, benzyl, benzhydryl, trichloroethyl or tert-butyl group means, 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 group, a cyano group, a carbamoyloxy group, an optionally substituted mononuclear heterocyclic group, which is a sulfur or nitrogen atom contains, as is a pyridinyl group, a group -SQ ¹ , where Q ^{1 is} a diazolyl, triazolyl, TetrazoIyI, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridinyl or purinyl group,
or where X is an amino group when Q is 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 in a primary or secondary group Position with a fluorine atom, a chlorine atom, a hydroxyl group or a (lower) alkoxy group such as a fluoromethyl, 2-chloroethyl, methoxymethyl, 1-hydroxyethy! Group substituted, or a cycloalkyl group, optionally substituted by one or more (lower) alkyl groups, Hydroxyl groups or (lower) alkoxy groups, or in which R ,. a tert (lower) alkyl or adamantyl group or a phenyl group, optionally substituted by at most three of the aforementioned substituents, or wherein R ^ a mononuclear heterocyclic 5-güedrige Group, for example a furyl, thienyl, isoxazolyl, Isothiazolyl, oxadiazolyl group, optionally substituted by (lower) -alkyl groups, or in which R. an aralkyl group, for example a benzyl group, optionally substituted in the phenyl nuclei as described above, or denotes a carboxymethyl group, 609883/0937 -122. 236570 $ * ' and in what 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, where the phenyl groups can optionally be substituted with 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. denotes an acetic acid radical in which Rp is a group of the formula means in which η means O, 1, 2 or 3, R, 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 atoms, (if η ^. 1), or a (lower) -alkyl-, 509883/09 37 Benzyl or phenyl ester group, 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, a or zv / ei aryl (lower) alkyl or cycloalkyl (lower) alkyl groups, the phenyl and cycloalkyl groups optionally with at most one of the aforementioned substituents may be substituted, or wherein R-7 and Κ together with the carbon atom to which they are attached denote an optionally substituted cycloalkyl group,
and in what Z ^ is a hydrogen atom or an optionally substituted one Means aryl group. 8. Pharmaceutical composition, characterized in that it contains an effective amount of one or more Compounds according to claims 1 to 6 together with pharmaceutically acceptable carriers or diluents contains. - ". 9. ' Antibacterial composition, characterized in that they contain an effective amount of one or more penicillanic acid or cephalosporanic acid derivatives accordingly claims 1 to 6 together with a physiologically acceptable carrier or diluent. B09883 / 093 7