DE2155081B2 - 7- (Isoxazol-5-yl-acetamido) cephalosporanic acid derivatives, processes for their preparation and pharmaceutical compositions containing them - Google Patents

Description

a salt, a tri- (lower) -alkylsilyl-. Di (lower) alkyl monohalosilyl. Benzyl or Phcnacylester or a Saceharylderivat der 7-Aminocephalosporanic acid with either a reactive window of an acid or the general forms!

R ¹

(ViI

COC) II

45

or with an akihen functional derivative this acid, which is used as acylic agent for a primary Nmino group is suitable. or one like that A / olide of an acid of the general formula VI

COOH or the free acid of the general formula VI in the presence of a carbodiimide reagent or that one

b) a di- or trialkylsilyl ester of 7-isocyanatocephalosporanic acid either with an acid of the general formula VI in an inert organic solvent system in the presence of an organic base or an organometallic compound of the general formula AMe ¹ . A-Me "- Hai or Λ · - Me" - ■ - A. wherein A is a group of the general formula

R ¹

(VIII

CH,

Me '' in lithium, sodium or magnesium atom, the number 1 or 11 means the valency and Hai a chlorine or bromatoni, in an anhydrous organic solvent medium under conditions that enable the reactions iles CiTignard-Reformatsky type.

Sits, any intermediate products obtained are hydrolyzed and / or the end products obtained if desired, converted into the alkali metal, alkaline earth metal or amine salts.

6. Pharmaceutical compositions consisting of one or more 7- (lsoxazol-5-ylacelamidol-cephalosporiins.üurederivaten according to claim 1 and usual Hills and TriigerslolTei ..

The connection concerns 7- (lsoxazolo-yl-acetamidol-cephalospor.ic acid derivatives of the general form!

RR ¹

CH-, CO NH CH CH CW ₂ CO NC CIl, O COCH.,
Γ

COOK orin R a low lime \ l-. the 2,6-dichlorophenyl. 2.4. (> - 1 nnictln! Phenyl or 4-nitrophenyl group and

^ in hydrogen atom, a methyl group or a oratom, as well as their alkali metal, Erdjlimetail- and amine salts.

In this connection, the term "lower" means as applied to the alkyl groups. that group contains at most 4 carbon atoms.
The preparation of the 7- (isoxazole-, 1-acelamidoj-cephalosporanic acid derivatives according to the invention) is carried out in a manner known per se

) a salt, a tri- (lower) -alkylsilyl-. Di- (low) -alkylmonohalosilyl-. Benzyl or phenacyl ester or a saccharyl derivative of ^7- aminocephalosporanic acid either with a reactive ester of an acid of the general formula

RR ¹

! I.

CH, COC) H

or with an active functional Dem al this acid, which is used as an acylation agent for a primary amino group is suitable. or an azolide of an acid of the general formula V! or the free acid of the general formula VI in the presence of a C:.; hodiimide reagent or that he

hi a di- or trialkylsilyl ester of 7-isocumaioeephalosporanic acid either with an acid of the general formula VI and an internal organic solvent system in the form of an organic base or an organometal compound of the general formula AMe ¹ . A Me "Hai or A -Me" A. wherein A is a group of the general formula

3 f.

40

RR ¹

(Vl

'CH,

Me a lithium, sodium, or magnesium atom. the number 1 or II means the valency and Hai a chlorine or bromine atom in one anhydrous organic solvent medium under conditions, the reactions of the (irignard-Reformalsky type favor.

converts, any intermediate products obtained Imlrolysieri and / or the end products obtained if desired into the alkali metal. Frdalkalimelallodci Amine salts transferred.

As an active ester of the acid of the general formula VI are e.g. the 2,4-dinitrophenyl ester. the p-nitrophenyl ester "or the N-hydroxysuccinimidesler ueeiunet. Active functional derivatives known as Acylating agents suitable for a primary amino group include the corresponding carboxylic acid chlorides. Carboxylic acid bromides, acid anhydrides, including those made from stronger acids such as lower ones aliphatic carbonic acid monoesters, alkyl or aryl sulfonic acids and sterically hindered acids. such as diphenylacetic acid. mixed anhydrides produced.

As azolide of the acid of the general formula VI, an amide of the same is used, its amide nitrogen Is part of a quasi-aromatic S-membered ring. which carries at least 2 nitrogen atoms. Such 5-membered rings are imidazole. Pyrazole. Triazole. Benzimidazole. Benztriazole and the substituted ones Derivatives of these compounds.

Methods for Carrying Out These Reactions to Form a Cephalosporin, and Methods to isolate the connections made in this way are /. From British Patents 9 32 644. 9 57 570, 9 59054, 9 52 519, 9 32 530, 9 67 1OS and 9 67 890 are known.

That according to the above process in the form of an ester. Salt or amide obtained product can be known per se. Procedures are converted into the corresponding cephalosporanic acid. So z. B .. if a tri- (lower) alkylsilyl ester or a phenyl ester of aminocephalosporanic acid is used, the ester group easily forms the corresponding acid of the general Formula I can be hydrolyzed.

The reaction of a di- or trialkylsilyl ester of 7-isocyanatocephalosporanic acid with the acid of the general formula VI is preferably in toluene. Dichloromethane or Bcn / onitrile carried out, line small amount of an organic base. z. B. one substituted imidazole. serves as a catalyst.

The isocyanate starting materials can be obtained by combining phosgene with a cephalosporanic acid derivative converts its 7-amino group optionally by a group which is a light The conversion of the 7-amino group into an isocyanate group is permitted, substituted. Hin such a substituent can simultaneously with the introduction of the protective group for the carboxyl group of 7-aminocephalosporanic acid to be introduced. Preferably the substituent of the 7-amino group is a tri- (lower-alkylsilyl group. If this substituent is an easily separable group, the reaction proceeds smoother with phosgene than with an unsubstituted 7-amino group. The reaction with phosgene muli inert organic in a mil respect to the reactivity of the resulting isocyanate group Solvent medium to be carried out.

Toluene and methylene chloride or mixtures of these solvents are particularly suitable. Farther To facilitate the reaction, an organic base can be used to bind the hydrogen chloride formed can be added. Preferably this is a tertiary amine. like triethylamine, the one with the isoeyanate group not reacted. Because high temperatures lead to a decomposition of the cephalosporan acid framework the reaction is preferably carried out at very low temperatures. preferably at -40 C, carried out.

The substituted isoxazol-5-yl-acetic acid starting materials of the general formula VI were carried out according to the procedures given below manufactured.

RR ¹

R ^! -CC-

- N

Way 1
R'-CsC-CHXOOH

Wee 2

IV-C = C-CHXH ₁ OH

Wee 3

1. Butvllithium.TMEDA

^{CH j} 2. CO ₂ : H ₃ O

RR ¹

Ox \ llation

^L CHXOOH

¹ CH ₁ CiFOH

The starting nitrile oxides can according to known> o \ on G r u η d m a η η. O u i 1 i c o et al .. Synthesis. 1970. 344, processes described and the processes cited therein.

The reaction with n-butyllithium was in counter; of tetramethylenediamine (TMEDAl can be used in aprotic is see solvents such as toluene or tetrahydrofuran, take place. Path 1 allows the greatest possible variation in the desired connections.

The cephalosporanic acid derivatives of the general formula 1 according to the invention have anubiotic properties which are valuable for humans and animals. They have special effects on gram-positive organisms and also show a good effect on penicillin-resistant staphylococci. This applies in particular to those compounds in which R is the 2,6-dichloropheny group and R ^{1 is} a hydrogen atom or a methyl group.

The substances according to the invention have proven themselves on the basis of comparative experiments in vitro with regard to its antibacterial effect against the sodium salt of W. F. Wick. Appl. Mierohiol .. 15.765 (1967). known 7- (2-phenyl-2-aminoaeetamidoidesacetoxyccphalosporanic acid. that from Chem. Britain 1, 14 (1965). known sodium salts of the 7- (thienyl-2-acetamido) -cephalosporansäjre and the Na-SaI / der also from Chem. Britain. I. 14 (1965). known 7 - (Thicnyl - 2 - acetamido) - 3 - pyridinomethyl-3-cephcm-4-carboxylic acid c proven superior.

The invention therefore also relates to pharmaceutical products Compositions consisting of one or more 7- (isoxazolyl-5-yl-ucetamido) -cephalosporanic acid derivatives of general formula 1 and customary auxiliaries and carriers. The inheritance-related Compounds are conveniently presented in the form of a non-oxidizing salt for therapeutic purposes. such as the sodium, potassium or ('aleium salts used. Other salts that can be used include the non-toxic, appropriately crystallizing salts with organic bases such as amines. / .. B. Tnalkylamines, Procaine and Diben / .ylamine. a.

Can be used in the treatment of bacteria infections the antibacterial compounds of the invention are administered orally or parenterally. The dose units can be 111 in the form of liquid (^ preparations, such as solutions, suspensions, dispersions or emulsions or in solid form as powders, tablets and capsules η.

Suitable carrier materials and binders are physiologically tolerated constituents which facilitate the administration of the therapeutically effective compound. The carrier materials can be used as diluents, as face masking agents. serve as binders, as agents to delay the action and as stabilizers.

Examples of carrier material are water, gelatine, gum arabic, alginates, dextran, polyvinyl, May contain pyrrolidone and sodium carboxymethyl cellulose, aqueous ethanol. Syrup, isoionic Saline, isotonic glucose, starch and lactose.

The substances according to the invention can also / ui treatment of bacterial infections by Fours are used.

The compounds according to the invention according to Examples 1 to 5 and the sodium salt according to the invention, der ~ -; | "3 - (2.6 - dichlorophenyi) - 4 - methylisoxazoi-5 - yl] - acetamido, - cephalosporanic acid. der 7 -: [3 - (2.6 - dichlorophenyi) - 4 - ehlorisoxazol - 5 - yl] - acetamido! - cephalosporanic acid and the 7 -! [3-methyl-4-chloroisoxazole-5-vl] acetamido; -cephalosporanic acid were tested for their antibiotic activity in vitro with the help of an agar serial dilution test examined in the following manner. The Na salts were used as substances to be compared with 7 - (2 - phenyl - 2 - amino - acetamido) - dcsaeeloxyeephalosporanic acid (Cephalexin). 7- (Thicnyl-2-acetamidol-eephalosporanic acid (Cepha'.otin) and 7- (thienyl - 2 - acetamido) - 3 - pyridinomethyl - 3 - cephem-4-carboxylic acid (Cephaloridin) is used.

A stock solution of the antibiotic with a concentration of 2.0 ng. ml prepared in a suitable sterile rack, twofold dilutions were made with the aid of a sterile 120 molar phosphate buffer with a pH of 6.5 (KlI ₂ PO _{4 - NaOH).} 1 ml of each dilution was introduced into 19 ml agar (brain-heart infusion) in sterile Petri necks.

The hardened surface was inoculated with the test organisms and incubated at 37 ° C. for 24 hours.

The minimum inhibiting concentration (MIC) was expressed in i »ml and denotes the minimum concentration of antibiotic which completely inhibits the digestive organism. The results obtained and the LD _M) values for some of the compounds are shown in the following sections.

"abelle I

/ discovery

M IC values in up, at ml at Hey at at game 2 game 3 game -4 game 5 game I.

P * ") C'cphii- Ccplia- Ccpha-

le \ in loiin loridiii

(Nu- INn- (Nu-

Sal / I Sal / 1 SuI /)

Test organisms 0, (KI7 0.015 O.Od 0.06 0.12 0.03 0.025 0.06 0.5 0.03 0.06 grii m positive
Bacillus subldis 0.015 (1.06 0.2s 0.5 0.12 0.03 0.025 0.25 3 0.25 0.06 ATCC 6633
Staphylococcus 0.5 0.12 0.06 0.03 0.25 1.5 0.25 0.06 aureus A 55 l), (X) 7 0.06 0.1 2 Sluphyloeoccus 0.12 0.25 0.25 I. 0.12 0.2s 0.12 0.5 12.5 I. 0.12 aureus A321
Staphylococcus 0 I ~ * 0.25 0.12 0.5 12.5 I. 0.06 aureus A 355 0.06 0.12 0.25 1 Staphylococcus I. 0 "'s 0.025 0.06 0.25 0.06 0.015 aureus L160 " (). (K) 7 0.03 0.06 0.1 2 i Streptococcus j (, 1.5 25th KH) 25th 12.5 hacmoijticus A266 0.5 I. 6th Streptococcus 0. (H 17 0.03 0.06 0.5 I. 0.1W 0.04 ! 3 0.25 0.015 faecalis LSO
Diplococcus pneumoniae 1.54 ς | j 12.5 KH) 50 12.5 0.06 (l 6th 3 gram negative 1 1 2.5 Brucella 1 StI IOD -, 6th 12.5 12.5 0.75 0.25 I. melitensisA4XK
m
Pasteurella ■ Kh) KK) 50 i.5 O.5 nnillocida Λ 723 12.5 50 > 100 1 Klchsiella pneumoniae AWN approximately U) <"Img kg) hot 1000 - .. SOOO 7 (H) O ■: IOP • 4000 .-- 4 (MtT the mouse
¹ P- 1250 SC.

chlorophenvll-4-metal isoxa / ol-5-> lj-acctamido: -eephalospornnsäiirc. -4! I.-hlor>.> \ :. Ail-5-yll-acciamido; -cc _P halosp _t , ran «H.rc.

Table 2

MIC values in µg.'ml

link

Test organism (gram-negative
Proteus rettgeri A 821
Proteus mirabilis H ₃
Proteus mirabilis L93

Example 4

3 3

1.5

1.5

Cephalexin Cephalotin Cepha
loridin iNa-Sal / l iNa-Sal / l (NASA 12.5 12.5 12.5 25th 12.5 6th 12.5 0.6 3

The above tables show the superior effect of the substances according to the invention the known reference substances.

The in vivo investigations of the sodium salt of 7 -! [3 - methylisoxazol - 5 - yl] - acetamido} - cephalosporanic acid (Example 4) led to the following results:

a) The ED ₅₀ values of the abovementioned salt and of cephalotin (as a comparison substance) were determined under the conditions given below and

with the achievement of the results also given below:

Test animal:

Female mice (Swiss SPF), 10 mice

Group, each with the same dose

treated grazing.
Route of infection:

Intrapcritoneal administration of Stapl

coccus aureus A 2001.

509 52

£ 79

Dose:

5 times a day.
Duration of treatment:

1 day.
Observation period:

7 days.
Parameter:

ED _5n (probability analysis).

Results:

IJnlcrsuchle
link

Example 4

Cephalotin

KNa-SaIz)

Disclaimer:

subcutaneous
subcutaneous

23 (10 52)
43 (12 155)

10

b) In an investigation analogous to that under a), after intra-peritoneal administration of Escherichia coli 656! obtained the following results:

Untersudile
link

Vcrahrcichungswq:

Example 4 intraperitoneally

Cephalotin intraperitoneally
(Na-SaIz)

100 (56 178) 115 (63-207)

"5 possessed both in experiment a) and in experiment b) the compound according to the invention the greater effective wedge.

example 1 Sodium salt of 7 -! [3- (2,6-dichlorophenyl) -isoxazol-5-yl] -aeetamido | -ccphalosporanic acid

Cl

Cl

C O S

ü il H H H / \

C - CH, - C - N - C - C CH,

= C - NC - CH ₂ - O - C - CH,

COONa

il ο

In a three-bulb flask. the one with a gas inlet pipe, a thermometer and a dropper is provided. 500 mg (1.8 mmol) of 7-aminocephalosporanic acid are suspended in 10 ml of ethyl acetate under a nitrogen atmosphere. The suspension is cooled in an ice bath, and then 0.3 ml (2.2 mmol) of triethylamine added. After 5 minutes 0.3 ml (2.2 mmol) of trimethylchlorosilane are added to the Mixture given, and then stirred for 1 hour at room temperature.

The mixture is cooled again, and after adding another triethylamine equivalent, 3 - (2.6-dichlorophenyl-isoxazol-5-yl-acetyl chloride (obtained by the reaction of 3- (2,6-dichlorophenyl) -isoxazole-5- yl-acetic acid with thionyl chloride in diethyl ether with a trace of dimethylformamide) in 5 ml of ethyl acetate was added dropwise to the reaction mixture, the temperature being kept below 5 ^° C.

After the addition, the ice bath is removed and the reaction mixture over a period of 2 hours stirred at room temperature. The reaction mixture is then poured into a mixture of 30 ml of water and Pour 30 ml of diethyl ether while cooling with ice, while maintaining the pH at 7.0. The watery one Layer is washed with a further 30 ml of diethyl ether and 30 ml of ethyl acetate. After adding 50 ml of ethyl acetate, the aqueous layer is acidified to a pH of 1.7. The layers are separated, and the aqueous layer is extracted again with 50 ml of ethyl acetate.

The combined Äthylacctalschichten are once with ice water acidified to a pI value of 1.5 and washed twice with E. ice water. After separation, drying over magnesium sulfate and a "treatment with activated charcoal, the Äthylacctalschicht is reduced to about" its volume, and then sodium caproate is added. The precipitated sodium salt is washed once with ethyl acetate and twice with η-hexane and dried in vacuo after filtration. The yield is 438 mg (0.8 mmol = 44%). According to the compound is pure according to thin-layer chromatography.

A partial analysis of the IR analysis of the final product

55

6o

(KBr disk. Values in cni Ester O ¹ ) resulted in the conclusions Values: 1670 C- O i 3430 Ϊ C = C. i 3280J NH c ---- O 1760 c - ■ = O C- Cl // - lactam and C = O C- 1690 Amide 1600 Carboxylation 1558 or C = N 1230)
10251 - C ester 782

Analysis of the NMR spectrum of the end product dissolved in hexadeuterodimethyl sulfoxide (60 M < Λ values in ppm, tetramethylsilane as an internal star dard) resulted in the following:

Ä7Q

IX) -CH ₃
Ϊ - CH ₂
O

I!

CH ₂ -C

C) -CH ₂

C "- H

C ₇ -H

Isoxazole - (

2.3

3.07 ■ -> 3.71 (AB-Ouartetl) (J ^ 17.5 eps, 2 protons)

3.98 (2 protons)

4.73 5.20 quartet (J * 12 cps, 2 protons)

4.98 and 5.05 doublet (J * 4.5 cps. 1 proton)

5.47 --- ♦ 5.66 quartet (J * 4.5 cps. J '* H cps. I proton)

6.51 (1 Proion)

7.55 sharp narrow impact pattern (3 protons)

9.22 and 9.35 doublet (J '% S cps, 1 proton)

Elemental analysis C ₁ , H ₁₁₁ N ₃ O ₇ SCl ₂ Na ■ ¹ Z ₂ H ₂ O:

Found

Calculated with (with
¹ , mole of crystal water)

C 44.97 45.10% C 45.03% C 45.26%

H 3.31 3.38% H 3.34% H 3.08%

N 7.70 7.72% N 7.71% N 7.54%

S 5.70 5.67 "/ ,, S 5.68% S 5.75%

Example 2 The sodium salt of 7-j [3- (2,4,6-trimethylphenyl) -isoxazol-5-yl] -acetamido} -cephalosporanic acid

O S

- CN-CH-CH CH ₂ O

O == CN C-CH ₂ -OC-CH ₃

2.8 ml (20 mmol) of triethylamine were added dropwise to a stirred suspension of 2.7 g (10 mmol) 7-Aminocephalosporanic acid in 40 ml of dry dichloromethane at OC. Subsequently were 2.55 ml (2OmMoI) trimethylchlorosilane added dropwise. After the addition was complete the reaction mixture was kept at 0 C for a few minutes, whereupon the ice bath was removed. The mixture was then stirred at room temperature for 1 hour. Afterward 1.2 ml (10 mmol) of quinoline were added, whereupon a solution of about 10 ml M oil 3 - (2,4,6 - trimethylphenyl) - isoxazol - 5 - ylacetyl chloride in 20 ml of dry dichloromethane was added at 5 ° C. After a few minutes of stirring at room temperature the reaction mixture was poured into ice-cold water, followed by dilution Sodium hydroxide solution was added. At a pH of 7 the layers were separated and the water layer extracted twice with diethyl ether. The organic layers were discarded and the Water layer at a pH of 5 to 1 again-COONa

fetches extracted with diethyl ether. The organic layers were separated by thin-layer chromatography

4 «, examined graphically. The purest extracts were made combined, washed with water, dried over anhydrous magnesium sulfate, filtered, in vacuo concentrated and finally treated with a solution of sodium d-ethylcaproate in ether. Of the solid precipitate was collected by filtration. washed with diethyl ether and in vacuo Dried constant weight. Yield 2.5g. To produce the crystalline monohydrate, the crude product that, according to thin layer chromatography, does not contain any other sulfur-containing substances contained, recrystallized from acetone. The final product (1 g) was small with the exception of the presence Trace of acetone pure. It contained 1 mole of water per mole of cephalosporin.

Analysis of the NMR spectrum of the end product dissolved in hexadeuterodimethyl sulfoxide (60 Mc / »- values in ppm. internal standard 2,2-dimethylsila pentane-5-sulfonate) gave the following values:

Ν —Η
Q ₁ H ₂
Isoxazolyl - C ₄

9.26 and 9.12 (doublet. J * 8.5 cps. About 0.8 protons) 6.93 (slightly broadened singlet. 2 protons) 6.33 (singletl. 1 proton)

Ä7Q

13 14

continuation

C ₇ -H 5.66. 5.58, 5.52 and 5.44 (weakly broadened signals, J = 8.5 cps and

• Άπ * 4.7 cps. I proton)

C _h - H 5.04 and 4.96 (J _ΛΒ = 4.7 cps) 1

^h I 3 protons

O-CH ₂ 5.20. 4.99. 4.92 and 4.71 (J _AB * 12.5 cps) j

CH ₇ - CO 3.92 (broadened singletl. 2 protons)

S-CH ₂ -, 3.72. -3.43.-3.33UiHl- 3.04 (broadened signals, / \ B-Quartctl, J _AH * 17.5cps,

2 protons)

p-CH, 2.27 (3 protons)

(o-CH ₃ ) ₂ 2.07 (singlet)

O —CO — CH ₃ 2.01 (singlet)

9 protons

Example 3
Sodium salt of 7 - {[3- (2,4,6-trimethylphynyl) -4-methylisoxazol-5-yl] -acetamido} -cephalosporanic acid

H, C- <> - C C O S

it H / \

C - CH ₁ - CN - CH - CH CH, O

, / "ί i I 'Il

O O = C N C - CH, - O - C - CH,

C.
COONa

1.38 ml (lOmMol) of triethylamine were drop- main reaction product, a small amount of 7-amino

white to a stirred suspension of 1.3 g (5 mmol) of cephalosporanic acid and a small amount of one

7-aminocephalosporanic acid in 20 ml of dry di- 35 by-product (possibly the I ₂ -isomer of

chloromethane was added at 0 C. The desired product) was then used twice with

1.26 ml (lOinMol) trimethylchlorosilane washed dropwise with diethyl ether. The organic layers

added at 0'C. After the end of the trimethyls were discarded. The water layer was then

Chlorosilane was added to the reaction mixture at pH 5.0. 4.5 and 4.0 with diethyl

Stirred for a few minutes at 0 C, whereupon the 40 ether extracted. The extract contained at pH 4.0

Ice bath was removed. Then only the desired main product became during 1 hour. The addition

stirred at room temperature. A solution of sodium u-ethyl caproate was then added to this

0.6 ml (5 mmol) of quinoline were added, whereupon the drop-extract gave a colorless solid precipitate

wise a solution of about 4.5 mmol 3- (2.4.6-tri-yield 1.2 g. According to the thin-layer chromatography

methylphenyl) -4-methyl-isoxazol-5-yl-acetyl chloride 45 graphic, the IR and NMR spectra was the final

(in about 90% purity from 1.3 g (5 mmol) of the product only with small amounts of diethyl ether

speaking carboxylic acid) in 10 ml of tiocke- (about 1 percent by weight) contaminated,

nem dichloromethane was added at 5 "C. After analysis of the NMR spectrum of the end product

a few minutes with stirring at room temperature tes. dissolved in an approximately 2: 1 mixture of hexa-

the reaction mixture was poured into ice water. 50 Deuterodimethylsulfnxyd and D ₂ O (60 Mc, Λ-Wertc

The pH was increased to 7 and the layers in ppm. internal standard 2,2-dimethylsilapentane

got seperated. The water layer according to the 5-sulfonate) gave the following:
thin-layer chromatographic analysis

C ₆ H ₂ 6.95 (singleti. 2 protons)

C ₇ -H 5.72 and 5.64 (doublet. J% 4.6 cps, 1 proton)

C ₆ -H 5.10 and 5.02 (doublet. J * 4.6cps) j

O - CH ₂ at 5.15, 4.92, 4.81 and 4.59 (AB-quartet, J * 13.2 cps) j

S-CH ₂ at 3.55 (center of an A B quartet) 1 _{4 protons}

CH ₂ - CO 3.87 (somewhat broadened singlet) j

P-CH ₃ 2.28 (3 protons)

O - CO - CH ₃ 2.05 (singlet) 1

(o-CH ₃ ) ₂ 1.98 (singlet) j

isoxazolyl - C ₄ - CH ₃ 1.71 (3 protons).

879

Example 4

7 -! [3-methylisoxazol-5-yl] acetamido} cephalosporanic acid
H

Il HH H / \

N C-CH ₂ -CNCC CH ₂

O O O- = C-N

CH ₁ -OC-CH,

' Il

COOH

According to the procedure described in Example 1, 3-methylisoxazol-5-yl-acetyl chloride (was prepared from 4.5 mmol of 3-methylisoxazol-5-yl-acetic acid and thionyl chloride) with Ν, Ο-bis-trimethylsilyl-7-amino-cephalosporanate (prepared from 1.224 mg (4.5 mmol) 7-aminocephalosporanic acid) implemented. "

After the reaction and working up the reaction mixture, 790 mg (44%) of one were obtained Pale yellow colored product with a purity according to thin layer chromatography, the IR and NMR spectra of about 70%.

Analysis of the NMR spectrum of the end product, dissolved in a mixture of deuterchloroform and hexadeuterodimethyl sulfoxide, to which about D ₂ O was added (60 Mc, Λ values in ppm, tetramethylsilane as internal standard), gave the following values:

Isoxazolyl-C ₄ -H

C ₇ - H

C "- H

CH ₂ - CO -

O - CH ₂ -

S-CH ₂

CO - CHj

lsoxazolyl - CH,

6.12

5.75 and 5.66 (J * 4.5 cps,! Proton)

5.05 and 4.97 (J. ^ 4.5 cps, I proton)

3.78 (2 protons)

5.22 -> 4.68 (J% 13 cps. 2 protons)

3.80-3.15 (J% 18 cps. 2 protons)

2.07

2.25

The partial analysis of the IR spectrum of the end product (KBr, values in cm ') resulted in the following:

± 3280
1780
1750
1670
1230
1380 and 1420

O ₁ N

OH

C = O / ^ - lactam

C = O ester

C = O amide

C - O - C esters

Isoxazole ring absorptions.

Example 5
7-j [3- (4-nitrophenyl) -isoxazol-5-yl] -acetamido} -cephalosporanic acid

CH O S

Il I! / \

C-CH ₂ -C -NH-CH-CH CH ₂ O

, / III Il

OO = CNC - CH ₂ - O - C - CH ₁

Following the procedure described in Example 1, 3 - (4 - nitrophenyl) - isoxazol - 5 - yl - acetyl chloride were obtained (prepared from 1.64 g (6.6 mmol) of the corresponding Acetic acid and thionyl chloride) with N, O-bistrimethylsilyl-7-aminocephalosporanate (prepared in situ from 1.8 g (6.6 mmol) 7-aminocephalosporanic acid) implemented. The reaction product was worked up in the usual way. 1350 mg were isolated

65 (40%) of a pale yellow colored solid. According to thin layer chromatography, IR and NMR spectra, the purity of the end product was about 85%.

Analysis of the NMR spectrum of the end product, dissolved in hexadeuterodimethyl sulfoxide (60 Mc, Λ-Wcrtc in ppm, internal standard 2,2-dimethylsilaptane-5-sulfonate) resulted in the following values:

17th

N - H 9.36 and 9.22 | J = 8.0 ± 0.5 cps, about 0.8 protons)

C "H ₄ 7.9 -» 8.5 (AA'BB 'splitting pattern, 4 protons)

Isoxazolyl -C _-1 -H 7.05 (1 proton)

C - H 5.87, 5.79, 5.73 and 5.65 (weakly broadened signals, J * 8.0 cps and

Jab * 4.6 cps, 1 proton)

C, - - H 5.19 and 5.11 (J _AB = 4.6 ± 0.2 cps) j _{3 protons}

O - CH ₂ (5.19). 4.97, 4.82 and 4.60 (J _AB = 13.0 ± 0.2 cps) j

CH ₂ - CO at 4.0 (slightly broadened singlet. 2 protons)

S-CH ₂ at 3.6 (center of an AB quartet with very faint outer lines.

2 protons)

CO-CH ₃ 2.06 (3 protons).

Claims (5)

Claims: 7-Usoxazol-5-yl-acetamido) -cephaIosporanüurederivaie the general formula RR ¹ / - CH, - CO - NH - CH - CH CH, CO - NC - CH ₂ - O - COCH, wherein R is lower alkyl. the 2,6-dichloropheny! -. 2.4.6-trimethylphenyl or 4-nitrophenyl group and R ^{1 represents} a hydrogen atom, a methyl group or a chlorine atom, as well as their alkali metal. Alkaline earth metal and amine salts. 2. 7 -; [3 - (2,6 - Dichlorophenyl) - isoxazol - 5 - yl] - acetamido; - cephalosporanic acid and their salts. 3. 7 -; [3 - (2.4.6-Trimethyl-phenyl) -isoxazoli-yl] -acetamido; -cephalosporanic acid and their salts. 4. 7 -; [3 - methyl - isoxazol - 5 - yl] - acetamido! - cephalosporanic acid and its salts. 5. Process for the preparation of 7-flsoxazol-5-yl-acetamido) -cephalosporanic acid derivatives according to claim I, characterized in that in a known manner