DE2215039A1 - New acyloxyalkyl ester derivatives of penicillin and cephalosporin - Google Patents

Description

DIPL.-CHEM. DR. RER. NAT. WALTER NIELSCH

PATENT ADVOCATE

2 HAMBURQ 70, POST BOX 1091 * · SCHLOSS-STRASSE 112 ■ TELEPHONE: 65Ϊ97Ο7 · ^ C I VvWV

Yamanouchi Pharmaceutical Co ,, Ltd. No. 5-1, Nihonbashi-Honcho 2 chome, Chuo-ku, Tokyo / Japan

New acyloxyalkyl ester derivatives of penicillin and cephalosporin

The present invention relates to new aeyloxyalkyl ester derivatives of penicillin and cephalosporin, each of which is able to easily pass through the Intestinal tract to be adsorbed when administered orally and which has antibacterial activity by breaking its ester bond in the body, More specifically, the invention relates to an acyloxyalkyl ester derivative of 6- (ct-aminophenylacetamido) penicillanic acid, 7- (α-Aminophenylacetamido) -cephalosporanic acid or 7- (α-aminophenylacetamido) -desacetoxycephalosporanic acid with the general formula

(I)

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OFHQiNAL INSfBCTBD

in which Λ means

1 2

wherein R and R each represent an unsubstituted alkyl, alkenyl, cycloalkyl or phenyl radical or a substituted one Alkyl-cycloalkyl-alkenyl or phenyl radical with a phenyl group, a phenoxy group or a halogen atom and R ^ is a hydrogen atom or a Represents acetoxy group.

Likewise, 6- (a-aminophenylacetamido) is penieillanic acid (hereinafter this acid is simply called "ampicillin") well known as semi-synthetic penicillin, which can be administered orally but is the extent of absorption by oral administration not yet sufficient and so it has generally been desired to increase the amount of ampicillin, which can be absorbed when administered orally. As an ampicillin derivative, which is a remarkably increased

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Have absorbency for oral administration., Belongs to the acyloxymethyl ester of ampicillin, in particular the pivaloyloxymethyl ester of ampicillin (commonly called "pivampicillin") which is developed and described in the Belgian patent specification Mr. 721 525 and in the journal Jour.Med. Chem. Y ^ ₃ 607-612 (1970).

For the same requirement is the acyloxymethyl ester of 7- (α-aminophenylacetamido) cephalosporanic acid (hereinafter the acid is called "cephaloglycine" for simplicity) and 7- (a-aminophenylacetamido) _ desacetoxycephalosporanic acid (hereinafter the acid is simply referred to as "cephalexin") have been found to be easily adsorbable derivatives of the above

named acid, as in the Offenlegunnsschriften 585 and 1 951 012 is given.

It is believed that each of these acyloxymethyl esters is absorbed in the intestinal tract and enzymatically hydrolyzed to split off formaldehyde and the acid and that the antibacterial activity is present as ampicillin (cephaloglycine or cephalexin). Recently, the problem of increasing the oral absorption of ampicillin (cephaloglycine or cephaloxin) has been solved by the development of the acyloxymethyl ester thereof. However, these acyloxymethyl esters of them have not been put to practical use as medicaments because hepatotoxicity has unfortunately been revealed in studying the toxicological development of them (Antimicrobial Agents and Chemotherapy - 1970, pp. 4 * 12 - 454, particularly, p. 453).

It is also known that formaldehyde is considerable ⁺ German

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possesses toxic properties (about 50 times) in comparison with those of other aldehydes which have molecular weights greater than that of formaldehyde (Chemical Abstracts, JjS, 482 * Jh (195) and Chemical Abstracts, $ 5, 8653d (I96I)) and also one has harmful effects on the liver (Biochem. Pharmacol., 16 , 1533-1537 (1967); Chemical Abstracts, 6 £, 58O92x (1968); and Biochem. Jour., 111, 665-678 (1969)) From these known facts, the inventors have noted that the above-mentioned hepatotoxicity of the acyloxymethyl ester is based on the formaldehyde, which is split off from the ester in the body by hydrolysis and they have set out to produce acyloxyalkyl esters (with the exception of the acyloxymethyl esters and therefore the term "acyloxyalkyl esters or esters "the acyloxymethyl esters or esters) exclude ampicillin, cephaloglycine and cephalexin as the easily adsorbable derivatives of these that do not contain formaldehyde in the K splitting off bodies.

As mentioned above, the pivaloyloxymethyleeter, which is the acyloxymethyleter of ampicillin is known. However, the acyloxyalkyl esters, which the inventors intend to have not yet been described in the technical literature and also processes for producing these esters have not yet become known. Furthermore, the manufacturing this ester first proved very difficult. This is also evident from a description about the starting materials of the compounds of this invention eowiG the acyloxyalkyl esters of benzylpenicillin im "Journal of Chemical Society", 2127-2130 (1965), in particular on pages 2128-2129, is described in the same report on the acyloxyalkyl esters of

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Benzylpenicillin with the exception of the acyloxymethyloster of thesea that these compounds are generally difficult to recrystallize (and thus difficult to recrystallize pure) and that there are as yet no practical descriptions of the manufacture of these There are esters.

Among the technical difficulties described above, the inventors have tried to improve the reaction of the Potassium salts of natural penicillin, e.g. have, in contrast to the above statements, the acyloxyalkyl ester of benzylpenicillin obtained in a relatively high purity state. The inventors were also able to use the acyloxyalkyl esters obtained from natural cephalosporin such as N-protected cephalosporin C in the same manner. So is found that it must be possible by the inventors to use the acyloxyalkyl esters of ampicillin or Obtain cephaloglycine by treating these compounds in accordance with known methods.

These novel compounds of this invention are obtained as solid compounds in unexpectedly high purity Condition and it will be described below that the results of the animal tests have shown that the Absorption of these compounds by oral administration was good and they enzymatically established their ester bonds in the blood break down to yield ampicillin, cephaloglycine or cephalexin therein, xvelche antibacterial activity showed.

It is also one of the advantages of this invention that these new compounds are stable to β-lactamase.

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So it is the goal of the penieillin derivatives and cephalosporin derivatives, which have lower harmful properties and have good oral absorption by d ^ 'e to provide the present invention.

(i). As already mentioned above, the aeyloxyalkyl esters of ampicillin or cephaloglycine under the novel compounds of this invention can be obtained by reacting the alkali metal salt of natural Penicillin such as benzylpenicillin or phenoxypenicillin or the alkali metal salt of natural N-protected Cephalosporin such as cephalosporin C and the acyloxyalkyl halide represented by the general formula (IV)

0
X-CH-CR ² (IV)

1 2
wherein R and R each represent an unsubstituted alkyl, cycloalkyl, alkenyl or phenyl radical or a substituted alkyl, cycloalkyl, alkenyl or P ^b 3nyl group with a phenyl group, a phenoxy group or a halogen atom and X represents a halogen atom

+ and then subsequently the procedure which is in the Laid-Open Specification 2 029 195, using the acyloxyalkyl ester compound, applies so obtained as the starting material.

This means that the acyloxyalkyl esters of natural penicillin or N-protected & m cephalosporin C are caused to react with a phosphorus halide in an inert solvent in the presence of a tertiary amine. Examples of the inert solvent which can be used in this reaction include: toluene, chloroform, dichloromethane, ⁺ German

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2215038

Dichloroethane, trichloroethylene and the like. As the tertiary amines, ordinary tertiary amines can be used such as pyridine, Ν, Ν-dimethylaniline and triethylamine are used but the use of an aromatic amine such as Ν, Ν-dimethylaniline is particularly preferred. Phosphorus halides are phosphorus pentahelloride, phosphorus methabromite and the like, for clarification purposes. but the use of phosphorus pentachloride is particularly preferred.

For example, when phosphorus pentachloride is used, the reaction is carried out with cooling, preferably at a temperature of from 0 to -3O ⁰ C. The amount of the tertiary amine used in this reaction is preferably 3 to 5 moles per mole of the phosphorus halide such as phosphorus pentachloride. On the other hand, it is preferred to use the phoaphorhalide in a slightly excess molar amount to the starting material.

The iminohalide compound obtained is then reacted with a lower alcohol without removing it from the reaction product liquid is isolated to form an imino ether compound. As the lower alcohol can such aliphatic alcohols as methanol, ethanol, propchol and the like can be used. In this case it is preferred to add the lower alcohol in an excess molar amount to the starting material use. The reaction is preferably carried out at a temperature approximately corresponding to that which has been used in the preparation of the iminohalide compound and has already been mentioned above. The above prepared imino ether compound is then reacted with a phenylglycine or with a reactive derivative of phenylglycine. A phenylglycyl chloride.hydrochloride is mostly preferred among the

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reactive derivatives of phenylglycine, but other acid halides, acid anhydrides, mixed acid anhydrides and the like can also be used in this reaction. When the phenyl glycyl chloride, hydrochloride is used, it is preferred to add the hydrochloride to a solution of the imino ether compound in in an equimolar amount to an excess molar amount to the imino ether compound and to carry out the reaction with cooling, mostly at the same temperature as in the previous one Step. Likewise, it is preferred, in order to achieve a better port step of the reaction, a tertiary Amine to be used, such as pyridine and H, N-dimethylaniline in this implementation.

The obtained reaction product from the above reaction is terminated with water or alcohol treated. This treatment can be carried out with the isolation of the desired product. The acyloxyalkyl esters of ampicillin or cephaloglycine with the formula

)) —CHCONH

(II)

P 2 COOCHOC-R ^

H ₂ OCOCH ₃

COOCHO-C-R

Rl

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(III)

-Ο 1 2
in which P and R have the meaning already mentioned, can be carried out by extraction according to a method known per se.

(ii). The acyloxyalkyl esters of Cephalexin among the novel compounds of this invention can be prepared in the following manner.

So the Acyloxya.lfcy; J.esfeer. of natural penicillin can be reacted with perbenzoic acid or performic acid to form an S-oxide compound and this product is heated in the presence of an inorganic or organic acid ₃ such as phosphoric acid, sulfuric acid _s phenyl dihydrogen phosphoric acid, p_toluenesulfonic acid and the like and a weak base ₃ such as pyridine, quinoline , benzimidazole and the like can be used around the ring zv expand.

Then, using the acyloxyalkyl esters of 7-acylaminodesaeetoxycephalosporanic acid as the starting material, the same procedure as in the method (i) _? as explained above, performed. That means, the reactions with a phosphorus halide, a lower alcohol, a phenylglyeylchlorid, H -ydrochlorid and with water or alcohol are connected in order to obtain the desired product with the following general formula:

_(III ,,

i COOCHO-C-R

1 2

in which R and R ctie have the meanings already explained

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(iii). Furthermore, the compounds produced by the aforementioned general formulas (II), (III) and (III ^J ) can also be grounded by adding 6-aninopenicillanic acid, 7-aminocephalosporanic acid and T-aminodeacetoxycephalosporanic acid, respectively, produced according to various known methods, reacted with an acyloxyalkyl halide to form an acyloxyalkyl ester and then acylated the acyloxyalkyl ester using a! -..- active derivative of phenylglycine such as phenylfilycylchloride.

As an example of the preparation of the compounds of this invention, the following reaction flow scheme is used reproduced:

Benzyl penicillin

O H ρ

COOCKO-C-R

PX _r

CH ₂ -C = N --r - r ''

CCjOCHO-O-R

COMH-

COOCHO-C-R

^ Jürhitzen Ringerweitcrunp;

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(R ⁴ : lower alkyl group)

C-R

'S-

I. \

COOCH3-CR ²

ή ¹

I) / Λ-CHCOCl \ ' NH. HCl

2) water or alcohol

CR
/ Ir CH ₂ -C = N

^1H 3

COOCE R ¹

R ^4- OH Zj.
R: lower

Alkyl group)

i = \

L ^ -CH-CONH-

NH ₂

CCOCH) -CR ²

CH,

0 COOCHO-CR ²

Anpicillin. he reads acyloxyalky

1)

Vl

NH ₂

-HCl

2) water or alcohol

^ CHCONH

CH,

ί

"COOCHC-C-R

R ¹

Cephalexin, acyloxyalkyl ester

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~ 12 -

1 2

The examples of the R and R groups of the compounds of this invention are a straight-chain alkyl group such as a methyl group, a ethyl group, a propyl group, a hexyl group, a heptyl group and the like; a branched chain alkyl group such as an isopropyl group, an isobutyl group, a tert-butyl group, _3, a 2-ethylbutyl group and the like; a cyclic alkyl group such as a cyclopentyl group, a cyclohexyl group, and the like · a phenyl group; a phenyl-substituted alkyl group such as a benzyl group, a phenethyl group, a 3-phenylbutyl group, a 2-ethyl ~ l ^{i-phenylbutyl} group, an ii-phenylcyclohexyl group and the like; _s a halogen-substituted like a phenoxy-substituted alkyl group such as a phenoxymethyl group, a 3-phenoxypropyl group, a Phenoxycyclopentylgruppe and the like * alkyl group, such as fine trichloromethyl group, a 2-Chloroäthylgruppe, a-ii Chlorocyclohexylgruppe and; and an alkenyl group such as a vinyl group, an allyl group, and the like.

The compounds of this invention are the esters of δ-ta-aminophenylacetamido-penicillanic acid (generally called ampicillin), 7- (a - / \ minophenylacetamido) -cephalosporanic acid (commonly called cephaloglycine) and T-ia-aminophenylacetamido-de-acetoxy-cephalosporanic acid (commonly called cephalexin).

The typical examples of these esters are as follows:

Example no.

1-acetoxyethyl ester 2

1-Pivaloyloxyfe'thylester i |

1-pivaloyloxypropyl ester
l-acetoxy-2-propenyl ester 8

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Example Nc

l ~ Bonzylcarbonyloxybutylester

l-Cyclohexylcarbonyloxyäthylester 16

1-phenoxyacetoxyethyl ester 20

1 ~ acetoxy-3 ~ phenylpropyl ester. 22nd

1-acetoxy-2,2 "2-trichloroethyl ester 24

α-Benzoyloxybenzyl ester 10

1-acetoxypropyl ester 6

1- (2-ethylbutyryloxy) propyl ester 33

l-isobutyryloxy-2-methylpropyl ester 45

l-Cyclohexyl-l-isobutyloxymethyl ester 41 a- (3-Phenylpropionyl) benzyl ester

1-Benzoyloxy-3-phenylpropyl ester 52

alpha-pivaloyloxybenzyl ester 49

l'-propionyloxyethyl ester 25

1-heptanoyloxyethyl ester 27 l-Cyclopentanecarbonyloxy-2-phenoxyethyl ester

1-octanoyloxyethyl ester 26 1- (2-ethylbutyryl) oxyethyl ester

1- (2-Phenylacetoxy) ethyl ester 28

1-isobutyryloxypropyl ester 31 1- (2-phenoxyacetoxy) -2-methylpropyl-

ester 42

1-acetoxyheptyl ester 47

l-tert -Butyryloxy-3-phenylpropyl ester 51

1- (2-Phenylaeetoxy) -3 ~ phenylpropyl ester 53

l-propionyloxy-2-phenylethyl ester 91

1-propionyloxypropyl ester 92

1-butyryloxy-1-cyclopentylmethyl ester 94

l-butyryloxy-2-ethylbutyl ester 97

1-heptanoyloxybutyl ester 96

l-butyryloxy-2 _a 2-dimethylpropyl ester 102

1-isobutyryloxy-2j2-dimethylpropyl ester 104 1- (3-phenylpropionyloxy) propyl ester

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Example no.

1-propionyloxy-2,2,2-trichloroethyl ester 108

1- (2-phenoxyacetoxy) butyl ester 109 l-Cyclopentanecarbonyloxybutyl ester 9 ^

alpha-butyryloxybenzyl ester 110

1-Benzoyloxyprpylester 111

1-Benzoyloxy-2-phenylethyl ester 113

These ester compounds can also be obtained as the salts of mineral acids such as hydrochloric acid will.

To illustrate the excellent properties of the compounds of this invention, the oral adsorbable properties of the compounds of this invention studied comparatively with those of Ampicillin and the pivaloyloxymethyl ester of ampicillin. That means it was the concentrations of the samples determined in the blood when administered orally and measured accordingly. The experimental The procedure and the results are described in more detail below.

Experimental implementation

Any of the compounds of α-aminobenzylpenicillin. Trihydrate, α-aminobenzylpenicillin .. ivaloyloxymethyl ester (commonly called pivampicillin) hydrochloride monohydrate and the hydrochlorides of the compounds of this invention shown in the following table were orally administered to rats (Male, each group consisting of 5 rats) in an amount of 20 mp / kg as or-aminobenzylpenicillin and after The blood was withdrawn for 0.5 hour and the concentration of α-aminobenzylpenicillin in the blood plasma was determined determined for each individual case. The results are

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shown in the following table.

Material administered ampicillin trihydrate Ampicillin, pivaloyloxymethyl ester hydrochloride, monohydrate Ampicillin. 1-pivaloyloxyethyl ester, hydrochloride Amipicillin. 1-acetoxypropyl ester. Hydrochloride Ampicillin. 1-benzoyloxyethyl ester, hydrochloride Ampicillin.1-propionyloxypropy1-ester Hydrochloride Ampicillin.l-propionyloxybutyl ~ ester.Hydrochloride Ampicillin. l-pivjtloyloxybutylester.Hydrochloride Ampicillin. 1-cyclohexylcarbonyloxybutyl ester.hydrochloride Ampicillin.l-isobutyryloxy-2-methylpropyl ester.hydrochloride Ampicillin α-acetoxybenzyl ester. Ampicillin hydrochloride. ot-butyryloxybenzy 1-ester hydrochloride Ampicillin. 1- (2-ethyloxy) ethyl ester, hydrochloride Ampicillin. l ~ -isobutyryloxybutyl ester

(A) Example 1.0

3 ^ 80

5.02 4

6.38 6

4.18 18

4.00 29

5.36 35

7.91 39

4.24 41 4.13 45 5 _t l8 48 5.00 14 4.21 27 8.29 37

Note: (A) The ratio of the concentration of ampicillin in the blood plasma if any of the above said compounds was administered with the concentration of ampicillin in the blood plasma when

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Ampicillin.trihydrate was administered after 0 ^ 5 hours since the administration. The first two connections are known connections and the other connections of the accompanying table are the compounds of this invention.

In addition, the concentration of ampicillin in the blood plasma after 0.5 hours after ampicillin. Trihydrate administered was determined and was approximately 10 OOMg / ml in each group.

Hydrolysis of cephalexin acyloxyalkyl ester in rat plasma:

Experimental implementation:

Rat plasma solutions containing cephalexin or the cephalexin, cyloxyalkyl ester containing the comparative compound of this invention in an amount of 10 pg / ml or 2.5 µg / nil as cephalexin _; were treated and after an incubation time of 30 minutes at 37 ° C., the plasma solution was placed on top of a culture medium which contained Streptococcus haemolyticus Cook. Then, after performing a prediffusion for 2 hours at i \ ° C, the incubation was carried out for 16 hours at 37 ° C and then the length of the inhibition zones was determined.

The ratio of antibacterial effectiveness (θ) was measured by the method given in "Jour. Penicillin", 1 » ¹⁰ ° (19 * 17), the value of 100 χ Θ representing the hydrolyzed percentage.

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θ log ^S H - ³ L ^U H - ^U L log 1 no _ ^S L - ⁰ L

x log A

^S H ~ ^U E In the above formula, S "and S _T mean the

ti li

Lengths of the zones of inhibition if the solutions contained 10 μρ7ηι1 and 2.5μβ / π1 each of cephalexin and these were used; U "and U ₁ . mean the lengths

ti Ij

the zones of inhibition when the solution in each case 10μ g / ral and 2.5 yg / ml of Cephalexin.icyloxyalkylesters contained _s which is the compound of this invention and was used; and A is the concentration ratio of cephalexin to cephalexin acyloxyalkyl ester. This is 10/2 _; 5 = 4.

The results obtained are shown in the following table.

Material administered Hydrolyzed example

Percentage Wr. (100 χ Θ)

Cephalexin.pivaloyloxymethy1-

ester.hydrochloride (control) 8l, 6 cephalexin.1-acetoxyethyl-

ester.hydrochloride 7 ^ ₉ 5 86

Cephalexin.1-propionyloxyethyl

ester · hydrochloride 82.6 90

Cephalexin.l-propionyloxy-2 ₃ 2,2-

trichloroethyl ester hydrochloride 8l, 0 cephalexin.1-acetoxypropyl-

ester. Flydrochloride 75.7 87

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Material administered

Cephalexin.1- (2 - pheny lacetoxy) propyl ester. Hydrochloric! Cephalexin. 1-butyryloxybutyl ester. Hydrochloride cephalexin. 1-valeryloxybutyl ester hydrochloride Cephalexin. 1-pivaloyloxybutyl ester. Hydrochloride Cephalexin. 1-cyclohexylcarbonyloxybutyl ester hydrochloride Cephalexin. 1-benzoyloxybutyl ester, hydrochloride Cephalexin, 1-propionyloxy-2-methylpropyl ester, hydrochloride Cephalexin. 1-propicnyloxyheptyl ester hydrochloride Cephalexin. 1-acetoxy-3-phenylpropyl ester hydrochloride Cephalexin. 1-propionyloxy-3-pheny1-propyl ester, hydrochloride Cephalexin. α- (2-phenylacetoxy) benzy ester, hydrochloride

Hydrolyzed
percentage
(Θ) example 92.7 91 80.5 98 90.1 101 88.2 102 89.1 - 81.0 110 79.5 105 79.9 - 84.1 106 86.2 107 84.9 113

example 1

In 100 ml of acetone was 11.2 g of benzylpenicillin potassium salt suspended and after addition to the suspension of 1.5 U of potassium bicarbonate and 10 g of 1-acetoxyethyl bromide the resulting mixture was refluxed for 2 hours. The reaction mixture was cooled, filtered and the piltrate was concentrated under reduced pressure.

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The residue thus obtained was washed with 30 ml of petroleum ether, dissolved in 80 ml of ethyl acetate and then the solution thus prepared was filtered. The thus obtained stylacetate solution was washed with 50 ml of 5% aqueous sodium bicarbonate solution and then with 50 ml of v / water. It was then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography and eluted with benzene-thylacetate (in a volume ratio of 3: 1) solvent, and the eluate was concentrated under reduced pressure. There were 7 ₃ 5 g of colorless powdery crystals of Benzylpenicillin.1-acetoxyäthylester obtained. The yield of this product was $ 60.

Example 2

In 75 ml of diehloromethane there was Ί ₃ 2 g of benzylpenicillin. 1-acetoxyethyl ester was dissolved and, after addition to the solution of H, 12 g of N, N-dimethylaniline, the mixture obtained was cooled to -25.degree. Then 2.3 g of phosphorus pentachloride was added to the solution and the mixture was stirred at a temperature of -25 ° C - 5 ° C for 2.5 hours. Then 45 ml of methanol was added dropwise to the solution at the same temperature, and the mixture was stirred for further 2.5 hours to obtain the imino ether solution. 6.86 ml of N, N-dimethylaniline were added to the solution thus prepared, and then 2.5 g of D (-) - a-phenylglycylchloride.Hydrochloride slowly over the course of one hour while stirring at a temperature of -25 ° C -5 ° C added. After stirring the reaction mixture for 2 hours at the same temperature, 50 ml of a cold saturated aqueous sodium chloride solution was added to the reaction mixture and the mixture

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was stirred for 0.5 hours at a temperature of about -5 C to O'C. Thereafter, the dichloromethane layer was _separated} washed with 30 ml 0.5N hydrochloric acid and then nachtrewaschen with 30 ml aqueous saturated sodium chloride solution. Then, the solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature to obtain a delicate residue. After adding 50 ml of cold water to the residue and 20 ml of ethyl acetate, followed by shaking, the aqueous layer formed was separated. After washing the aqueous layer with 20 ml of ethyl acetate, 30 ml of ethyl acetate was added and then 10 g of sodium chloride were added and shaken again. The resulting ethyl acetate layer was separated and the aqueous layer was further extracted with 20 ml of ethyl acetate. The ethyl acetate layer which had been separated was combined with the ethyl acetate extract layer obtained above, and the mixture was washed with 20 ml of a cold and saturated aqueous sodium chloride solution and finally dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature. The residue was with. 50 ml of ether were mixed and the crystals formed were separated. The crystals were washed with a small ^ tight ether and dried. 3.5 g of white powder of Ampicillin.l-acetoxyethyl ester hydrochloride with a melting point of 103 to 105 ° C. (with decomposition) were obtained in a yield of 1% .

Elemental analysis as C ₂₀ E ^! 26 ^N 3 OgSCl: N (S) S (Ji) Cl (58) C. {%) H CO 8th, 90 6.79 7 ₅ 51 calculated 50, 90 5, 55 8th, 35 6.37 7, 72 found 50, 14th 5, 98

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Example 3

_{H 3} 2 er benzylpenicillin potassium salt was suspended in 120 ml of acetone and, after addition to the suspension of 5.1 g of 1-pivaloyloxyethyl chloride and 3 ml of 25% aqueous sodium iodide solution, the mixture was refluxed for 5 hours. After cooling, the reaction mixture was treated as described in Example 1. 8.5 g of the colorless powdery crystals of benzylpenicillin.1-pivaloyloxyethyl ester were obtained in a yield of 63 % .

Example 4

In 75 ml dichloromethane ^ ₃ 6 & Benzylpenicillin.1-pivaloyloxyäthy.lester was dissolved and after addition of k, 12 ml Ν, Ν-dimethylaniline to the solution, the mixture to ~ 25 ° C was cooled. Then 2.3 g of phosphorus pentachloride was added to the mixture. The resulting mixture was 2 _S 5 hours at a temperature of -25 ° C - stirred 5 ° C. Then, 45 ml of methanol was added dropwise to the solution at the same temperature, and the mixture was further stirred for 2.5 hours to obtain an imino ether solution. After the addition to the solution of 6 _S 86 ml Ν, Ν-dimethylaniline was 2.5 g of D (-) - a-Phenylglycylchlorid.Hydroehlorid slowly to the solution over a period of one hour with stirring hei -25 ° - 5 ° C was added . The mixture was then stirred for 2 hours at the same temperature and then treated further as described in Example 2. There were RTEs Ampicillin.1-pivaloyloxyö'thylester hydrochloride with a melting point of 111 to ll ^ TC received 3 »^ g white powdery (with decomposition) in a yield of 66%.

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as C ₂₃ H 32 ^N. 3 ° 6 SCl: S. (%) Cl ( C (S) H (%) N (S) 6, 24 6, 90 53.74 6, 27 8th , 17th 5, 94 7, 03 53.21 6, 86 " 7th , 98

ElementaranalySG

calculated:
found:

Example 5

In 80 ml acetone 7 ₅ 4 g Benzylpenicillinkaliumsalz was suspended. After adding 4.3 g of 1-acetoxypropyl bromide to the suspension and 1 ml of 25% aqueous sodium iodide solution, the mixture was refluxed for 5 hours. After the reaction mixture had cooled, 80 ml of ice water were added and the oily material formed was extracted twice with 100 ml of ether each time. The ether extracts were combined. The ether solution obtained in this way was washed with 50 ml of 5% aqueous sodium bicarbonate solution and in each case twice with 50 ml of water each time. It was dried over anhydrous sodium sulfate and concentrated under reduced pressure at low temperature. The residue obtained was washed with petroleum ether, and the oily material then obtained was separated by decantation and dried under reduced pressure. 7.0 g of viscous benzylpenicillin. 1-acetoxypropyl ester were obtained in a yield of 81 % .

Example 6

4.34 g of benzylpenicillin.1-aeetoxypropyl ester was added to 44 ml of dichloroethane dissolved. After adding to the solution of 4.12 ml of Ν, Ν-dimethylaniline, the mixture was up -25 C cooled. Then, after adding 2.3 g of phosphorus pentachloride, the resulting mixture became 1.5 hours stirred at -25 ° C - 5 ° C. Then, after adding 40 ml of methanol in drops at the same temperature, the Mixture stirred for a further 2.5 hours to remove the imino-

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ether solution to .receive. (-) - After the addition of 6.86 ml of NJN-dimethylaniline to the solution 2.5 ED was a-Phenylglycylchlorid.Hydrochloric * slowly over one hour with stirring at -25 - 5 ° C added. The mixture was then stirred for 2 hours at the same temperature and left to stand for a further 16 hours at a temperature of -20.degree. C. to -25.degree. To the reaction product mixture, 50 ml of a cold and saturated aqueous sodium chloride solution was added, and the mixture was vigorously stirred for 10 minutes at 0 to 5 ° C. Then the formed aqueous layer was separated from the dichloroethane layer. The Dichloroäthanlösunf _s was separated and was then washed with 30 ml 0.5 η hydrochloric acid, saturated with sodium chloride, and washed with 30 ml of saturated aqueous sodium chloride solution. Then, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature to obtain an oily product.

The oily product thus obtained was dissolved in a mixture of 50 ml of cold water and 50 ml of ethyl acetate and the aqueous layer was separated. The aqueous layer was washed twice with 20 ml of ethyl acetate each time washed, saturated with sodium chloride, and the oily material formed was twice with 30 ml each Ethyl acetate extracted. The obtained ethyl acetate extracts were combined and the mixture was used 3 times Washed with 20 ml of saturated aqueous sodium chloride solution and finally over anhydrous magnesium sulfate dried. Thereafter, it was concentrated under reduced pressure at a low temperature. When 50 ml Ether was added to the obtained residue and the mixture was stirred, precipitates became precipitates

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C. (X) H (X) N (X) S. (X) Cl ( 51 , 90 5, 81 8th, 65 6th , 60 7, 30th 51 , 03 6, 22nd 8th, 31 6th , 05 7, 53

- 24 -

formed, which were separated by filtration. It

was washed with a small amount of ether and dried

+)
net. There was added 3.2 g powdered Ampicillin.1-acetoxypropylester.Hydrochlorid having a melting point of 95 to 100 ⁰ C (with decomposition) in a yield of 6656
obtain. +) white

Elemental analysis as

calculated
found

Example 7

7.4 g of benzylpenicillin potassium salt were suspended in 40 ml of dimethylformamide and, after addition of 3.2 g
1-acetoxy-2-propenyl chloride, the mixture was stirred for 16 hours at room temperature. The reaction mixture
was dispersed in 50 ml of ice-free water and then extracted twice with 50 ml of ethyl acetate each time.
The ethyl acetate extracts were combined. The mixture
was washed with 50 ml of 5X aqueous sodium bicarbonate solution and then rewashed with 50 ml of water. It was dried over anhydrous magnesium sulfate
and under reduced pressure at low temperature
constricted. When the obtained residue was dried under reduced pressure, there became 6.5 g of oily benzylpenicillin. l-acetoxy-2-propenyl ester in one yield
received by 76 % .

Example 8

4.32 g of benzylpenicillin. 1-acetoxy-2-propenyl ester was added to 43 ml of dichloroethane dissolved, and after adding to the solution 4.12 ml of N, N-dimethylaniline, the mixture became cooled to -25 ° C. Then after adding 2.3 R

2 0 9 8 4A / 1226

Phosphorus pentachloride stirred the mixture at -25 ° C - 5 ° C for 1.5 hours.

Then, 40 ml of methanol was added dropwise to the solution at the same temperature as above added and the mixture was stirred for 2.5 hours to obtain a ₃ Iminoätherlösung.

The solution was mixed with 6.86 ml of N, N-dimethylaniline and then 2.5 g of D (-) - α-phenylglycylchloride-hydrochloride was added slowly over the course of one hour. Then, after stirring the mixture for 2 hours at the same temperature, the mixture was allowed to stand for 16 hours at a temperature of -20 to -25 ° C. By treating the mixture as described in Example 6, 3.5 g of the white powder of ampicillin.1-a cetoxy-2-propenyl ester.Hydrochloride with a melting point of 115 to 118 ° C (with decomposition) in a yield of 72 % obtain.

Elemental analysis as C ₂₁ HpgN, OgSCl:

C (S) H (S) N ($) S (JO Cl (S)

Calculated 52.12 5, Hl 8.68 6.63 7.33 found 51.49 5.90 8.27 6.23 7.60

Example 9

In 60 ml of dimethylformamide was 11.2 g of benzylpenicillin potassium salt suspended and after adding 3.0 g of potassium bicarbonate and 9 g of α-benzoyloxybenzyl bromide the mixture was stirred to the suspension for 16 hours at room temperature. The reaction mixture was dispersed in 100 ml of ice water and 3 times with

209844/1226

extracted 50 ml of ethyl acetate each time. The methyl acetate extracts were combined and the mixture was washed with 50 ml of 5 # aqueous sodium bicarbonate solution and then rewashed with 50 ml of water. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at low temperature. The residue obtained was washed with a small amount of petroleum ether and dried under reduced pressure. 12.8 g of viscous benzylpenicillin.abenzoyloxybenzyl ester were obtained in a yield of 78.2 % .
Infrared absorption spectrum:

vNH 3300 cm "- ¹ , vC = 0 1790-1760 cm" ¹ (0-lactam, ester), 1740 cm " ¹ (ester), 1660 cm" - ¹ (amide).

Example 10

In 50 ml dichloromethane was added 5,5-g Benzylpenicillin.α benzoyloxybenzylester dissolved and, after addition of 4.12 ml of Ν, Ν-dimethylaniline the mixture was cooled to -25 ⁰ C.

Then, after addition of 2.3 g of phosphorus pentachloride, the Gemieh for 1.5 hours at -25 was - stirred 5 ⁰ C. Then, 40 ml of methanol was added dropwise to the mixture at the same temperature, and the mixture was further stirred for 2 hours to obtain an imino ether solution.

6.86 N, N-dimethylaniline was added to the solution thus prepared added and was added to the mixture 2.5 g of D (") - a-phenylglycylchloride.Hydrochloride slowly in the course of one hour with stirring at -25 - 5 ° C.

209 84 4/1226

The mixture was then stirred for two hours at the same temperature and 50 ml of cold saturated aqueous sodium chloride solution were added to the reaction mixture and the mixture was stirred at a temperature of -5 ° to ⁰ ° C. for a further 0.5 hours. Then the dichlorome-

Thane layer separated with 30 ml of O ₃ 5 η aqueous hydrochloric acid solution which was saturated with sodium chloride, washed and then washed with 30 ml of saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and then concentrated over anhydrous magnesium sulfate to give an oily residue. The residue was dissolved in a mixture of 100 ml of cold water, 30 ml of ethyl acetate and 20 ml of petroleum ether with stirring, and then the formed aqueous layer was separated. The aqueous layer was washed with a mixture of 20 ml of ethyl acetate and 10 ml of petrol, and then a small amount of activated charcoal was added to the aqueous solution and then filtered, a layer of 30 ml of ethyl acetate was added via the piltrate and the mixture was mixed with sodium chloride Stir saturated.

The ethyl acetate layer thus formed was separated, and the aqueous layer was separated and extracted twice with 20 ml of ethyl acetate. The ethyl acetate extracts and the separated ethyl acetate layer obtained above ₃ were combined. The mixture was washed with 30 ml of cold and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature. Petroleum ether was added to the residue and the crystals thereby formed were separated by filtration. It was washed with a small amount of petroleum ether and then dried to give 4.5 white powder of Ampicillin.a-banzoyloxybenzylester.hydrochloride having a melting point

2098Ai / 1 226

from 145 - 146 ° C (with decomposition) in a yield of 74.8 % .

Infrared tab's absorption spectrum:

VNH ₃ + 3350, 3200 cm " ¹ JV ^ _{4. 27OO} -26OO cm" *

VC = O 1780 cm ^-1 (lactam), 1750 1740 cm "^ ¹ (ester),

1680 cm "- ¹ (amide)

Elemental analysis as C, _o H, _o N, OgSCl:

calculated
found

Example 11

11.2 g of benzylpenicillin potassium salt was suspended in 60 ml of dimethylformamide, and after adding 3.0 g of potassium bicarbonate and 8.2 g of 1- (phenylacetoxy ') butyl bromide to the suspension, the mixture was stirred at room temperature for 16 hours. The mixture was then treated as described in Example 9. 10.3 g of viscous benzylpenicillin.l- (phenylacetoxy) t> utyl ester were obtained in a yield of 65.3 % .

Infrared absorption spectrum:

vNH 3300 cm "- ¹

vC = O 1780 cm ^-1 (3-lactam), 1760 cm "*, 1740 cm ^X (ester), 1670 cm ^λ (amide).

C. (ί) H (*) N (S) Cl (50 60 , 45 5, 07 7th , 05 5 , 95 60 , 16 5, 60 6th , 89 6th , 20

2098U / 1226

Example 12

5.3 ε benzylpenicillin.1- (phenylacetoxy) butyl ester was dissolved in 50 ml dichloromethane. Then 4.12 ml of Ν, Ν-dimethylaniline was added to the solution. The mixture was cooled to -25 ° C. Then, after adding 2 ₅ 3 g of phosphorus pentachloride, the mixture was stirred at -25 ° C - 5 ° C for 1.5 hours. Then, 40 ml of methanol was added dropwise to the mixture at the same temperature, and the mixture was further stirred for 2 hours to obtain an imino ether solution.

After adding 6.86 ml of Ν, Ν-dimethylaniline to the solution, 2.5 g of D (-) - a-phenylglycylchlorid.Hydror Chlorid was slowly added to the mixture over the course of one hour while stirring at -25 ° -5 ° C added. Thereafter, the mixture was stirred for a further 2 hours at the same temperature and then the reaction mixture was treated as described in Example 10. 3.95 g of the white powder from Ampicillin.1 ~ (phenylacetoxy) butyl ester with a melting point of 135-138 ° C. (with decomposition) were obtained in a yield of 67 _s 9 % .

Infrared absorption spectrum:
VNH ₅ ⁺ 3400 cm ~ ¹ , 3200 cm ^-1

VNH ₂ ⁺ 2700 to 2600 cm ^"a

vC = 0 1780-1740 cm ~ ¹ wide (ß-lactam, ester), 1680 cm - ¹ (amide).

Elemental analysis as

209844/1226

- 30 H (50 N (?) Cl 2215039 (JO 5, 95 7th , 29 6 ₃ C. , 38 S ₃ U6 7th , 11 6, (56) 58 07 15th 58 33

calculated
found

Example 13

11.2 ρ benzylpenicillin potassium salt was suspended in 60 ml of dimethylformamide. After addition of 3.0 g of potassium bicarbonate and 7 _S 8 g α- (butyryloxy) benzyl bromide to the suspension, the mixture was stirred for 16 hours at room temperature.

The mixture was treated as described in Example 9. 11.7 g of oily benzylpenicillin-o (butyryloxy) benzyl ester were obtained in a yield of 76.2 % .

Infrared absorption spectrum:

ν NH 3300 cm " ^α

vC = O I79O-176O cm ~ ¹ wide (B- lactam, ester) 1740 cm - ¹ (ester), I66O cm ^-1 (amide)

example Ik

5.1 g of benzylpenicillinot (butyr.yloxy) benzyl ester were dissolved in 50 ml of dichloromethane. After the addition of *}, 12 ml Ν, Ν-dimethylaniline to the mixture was cooled to -25 ⁰ C this.

After adding 2 ₃ 3% phosphorus pentachloride, the mixture was stirred at -25 ° -5 ° C. for 1.5 hours. Then 40 ml of methanol was added dropwise at the same temperature. The resulting mixture was stirred for 2 hours to obtain a _s Iminoätherlösung.

After adding 6.86 ml of Ν, Ν-dimethylaniline to the solution

2098U / 1226

was slowly added 2.5 g of D over one hour (-) - "- 5 ° C was added - Bhenylglycylehlorid.Hydrochlorid _un ter stirring at -25 °. Thereafter, the resulting mixture was stirred for 2 hours at the same temperature and then the reaction mixture was worked up as described in Example 10. 3.8 g of white, powdery ampicillin.α- (butyryloxy) -benzylester.hydrochloride with a melting point of 128 to 130 ° C. (with decomposition) were obtained in a yield of 67.7 % .

Infrared absorption spectrum:

> NH ₃ + 3350 cm ~ ¹ , 3150 cm "*

VNH ₂ ⁺ 27ΟΟ-26ΟΟ cm - ¹

vC = O 178Ο cm - ¹ (ß-lactam), 176Ο-175Ο cm " ¹ (ester) 1680 cm" ¹ (amide)

Elemental analysis as C _{? 7} H, pN, Oi-SCl:

calculated
found

Example 15

11.2 g of benzylpenicillin potassium salt were suspended in 60 ml of dimethylformamide. After adding 0 g of potassium bicarbonate and 6.8 g of 1-cyclohexylcarbonyloxyethyl bromide to the suspension for _{3 seconds, the mixture was stirred for 16 hours at room temperature.}

The batch was then treated further as described in Example 9. 11 g of oily benzylpenicillin.1-cyclohexylcarbonyloxyethyl ester were obtained in a yield of 74.9 % .

2098U / 1226

C ( %) H , 74 N (*) Cl ( 57, 70 5 , 97 7, 48 6, 31 57, 51 5 7, 35 6, 20th

Infrared absorption spectrum:

vNH 3300cm ' ^Λ

vC = 01780 cm "^ (ß-lactam)

1760 cm ^"1 J 1740 cm ^-1 (ester), l66O cm

Example 16

4.9 g of benzylpenicillin.1-cyclohexylcarbonyloxyethyl ester were dissolved in 50 ml of dichloromethane. Then, to the solution 4 _S 12 ml N, N-dimethylaniline was added. The mixture was cooled to -25 ^0C. Then, after the addition of 2.3 g of phosphorus pentachloride, the resulting mixture was stirred at -25 ° -5 ° C. for 1.5 hours. Then, 40 ml of methanol was added dropwise to the mixture at the same temperature. The resulting mixture was further stirred for 2 hours to obtain an imino ether solution.

6.86 ml of Ν, Ν-dimethylaniline were added to the solution. Then 2.5 g of D (-) - o-phenylglycyl chloride was slowly added. The hydrochloride was added over the course of one hour while stirring at -25 ° -5 ° C.

Then, after stirring the mixture for 2 hours at the same temperature, the reaction mixture became with 50 ml of cold and saturated aqueous sodium chloride solution were mixed thoroughly. It was then a further 0.5 hours at at a temperature between -5 ° C to 0 ° C.

The dichloromethane layer formed was separated and mixed with 30 ml of 0.5 η hydrochloric acid, that with sodium chloride Was saturated, washed and then rewashed with 30 ml of saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate

209844/1228

and concentrated under reduced pressure at a low temperature to obtain an oily residue. The residue was dissolved in a mixture of 50 ml of cold water and 20 ml of ethyl acetate with stirring, and then the aqueous layer formed was separated. The aqueous layer was washed with 20 ml of ethyl acetate and then mixed with a small amount of activated charcoal and filtered off. To the obtained piltrate, a layer of 30 ml of ethyl acetate was added, and then sodium chloride was added to the mixture with stirring to saturate the reaction. The ethyl acetate layer was separated and the aqueous layer was further separated and extracted twice with 20 ml of ethyl acetate each time. The ethyl acetate extracts were combined with the ethyl acetate layer ₃ obtained above, and the mixture was washed with 30 ml of cold saturated sodium chloride aqueous solution. Then, it was dried over anhydrous magnesium sulfate and concentrated under a changed pressure at a low temperature. The residue obtained was mixed with ether and the crystals formed were separated by filtration. They were washed with a small amount of petroleum ether and dried. 3.6 g of white powder of ampicillin.1-cyclohexylcarbonyloxyethyl ester with a melting point of 13 ^ - 137 ° C. (with decomposition) were obtained in a yield of 66.5%. obtain.

Infrared absorption spectrum:

+ 3350 cm ~ \ 3150 cm ^ ^ _{+ 2JQ0} ^ -1

vC = O 178O cm- ¹ (β-lactam), 1755 cm ~ ^a , 17 ¹ JO cm. " ¹

(Ester) 1680 cm " ¹ (amide)

209844/1226

Elemental analysis as Cp ₁ -H-, ji, N, OgSCl:

C. (%) H (*) N (*) Cl (Jt) 55 , 60 6, 35 7, 78 6, 56 55 , 17th 6, 82 7, 50 6, 25th

calculated
found

Example 17

In 60 ml of dimethylformamide was 11.2 g of benzylpenicillin potassium salt suspended. After adding 3 g of potassium bicarbonate and 6.9 g of 1-benzoyloxyethyl bromide, the The mixture was stirred for a further 16 hours at room temperature.

The reaction mixture thus obtained was dispersed in 100 ml of ice water and then extracted three times with 50 ml of ethyl acetate. The ethyl acetate extracts were combined and each mixture was washed with 50 ml of 55% aqueous sodium bicarbonate solution and then with 50 ml of water. Activated charcoal was added and then filtered. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature. The residue was washed with a small amount of η-hexane and then dried under reduced pressure. 10 g of viscous benzylpenicillin-1-benzoyloxyethyl ester were obtained in a yield of 68.9 % . *

Infrared absorption spectrum:

vNH 3300 um, vC = O 1780-1750 cm wide (ß-lactam. ester), 1735 cm " ¹ (ester), 1660 cm" ¹ (amide)

Example 18

In 50 ml of dichloromethane was 4.8 g of benzyl penicillin. 1-benzoyloxyethyl ester dissolved and then added to the solution 4.12 ml of Ν, Ν-dimethylaniline were added. The mixture was cooled to -25 ° C. After adding 2.3 g

209844/1226

Phosphorpenta.chlorid the mixture was for 1.5 hours at -25 - stirred 5 ° C. Then, hO ml of methanol was added dropwise to the mixture at the same temperature, and the mixture was further stirred for 2 hours to obtain an imino ether solution.

Then 6.86 ml of N, N-Dn: methylaniline was added to the solution added and further 2.5 gD (-) - a-phenylglycyl chloride. The hydrochloride was slowly added to the solution over the course of one hour while stirring at -25-5 ° C.

Then by stirring the mixture for 2 hours at the same temperature, the reaction mixture was mixed with 50 mL of cold saturated aqueous sodium chloride solution and stirred for half an hour at a temperature between -5 ° C to 0 ⁰ C. The dichloromethane layer formed was then separated off, washed out with 30 ml of a 0.5 μm aqueous hydrochloride solution which was saturated with sodium chloride and then rewashed with 30 ml of saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at low temperature. An oily residue was obtained. After adding 50 ml of η-hexane to the residue, the insoluble matter was dissolved in 50 ml of cold water and 30 ml of ethyl acetate with stirring. Then the formed aqueous layer was separated. The aqueous layer was washed with 20 ml of ether. A small amount of activated charcoal was added and the mixture was filtered. A layer of 30 ml of ethyl acetate was attached to the piltrate, and sodium chloride was added to saturate with stirring. Then the ethyl acetate layer thus formed was separated and the aqueous layer was separated and further two! "IaI each with 20 ml of ethyl acetate

209844/1226

extracted. The ethyl acetate extracts were combined with the ethyl acetate layer separated above, and the mixture was washed with 30 ml of cold and saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at low temperature. The residue thus obtained was mixed with n-hexane and the crystals formed were separated by filtration. It was washed with a small amount of petroleum ether. It was dried and 3.65 g of white powder of Ampicillin.1-benzoyloxyäthy.lester with a melting point of 137-138 ° C. were obtained (with decomposition) in a yield of 68.7 %.

Infrared absorption spectrum:
, ρ ⁺ 3 ¹ JOO cm - ^1, 3200 cm ~ ^Λ

VNH _{2 2700-2600} cm ^"a

VC = O 1780 cm "- ¹ (ß-lactam), 1760-1735 cm ^ ¹ (ester), 1685 cm - ¹ (amide)

Elemental analysis as

calculated
found

Example 19

11.2 g of benzylpenicillin potassium salt were suspended in 60 ml of dimethylformamide. After adding 3.0r potassium bicarbonate and 8.0 g of 1- (phenoxyacetoxy) ethyl bromide to the suspension, the mixture was stirred for 16 hours at room temperature. By treating the so

2 09844/1 226

C. (%) H (Ji) N (%) Cl (J «) 56 , 23 5.28 7, 87 6, 6H 56 , 08 5.70 7, 57 6, 60

obtained mixture as described in Example 9., Ιο, β g of oily benzylpenicillin,! - (phenoxyacet · oxy) ethyl ester was obtained in a yield of 68.8 % .

Infrared absorption spectrum:

vNH 3420 cm ^-1

VC = 1790 cm ^-1 (0-lactam), 1765 cm ^-1 , 17 ¹ JO cm ^-1

(Ester), 1685 cm ^-1 (amide)

Example 20

In 50 ml of dichloromethane was 5.13 g of benzylpenicillin. Dissolved 1- (phenoxyacetoxy) ethyl ester. Then 4.12 ml of Ν, Ν-dimethylaniline was added. The mixture -. ' was cooled to ~ 25 ° C. Then, after addition of 2.3 g of phosphorus pentachloride, the mixture was stirred for 1.5 hours at -25 ⁰ C - 5 ° C by stirring. Then, 40 ml of methanol was added dropwise to the mixture at the same temperature, and the resulting mixture was further stirred for two hours to obtain an imino ether solution.

Then 6.86 ml of N, N-dimethyl aniline was added to the solution added and further 2.5 g of D (~) -a-phenylglycylchloride.hydrochloride slowly added to the mixture over the course of an hour with stirring at -25 ° C - 5 ° C .

Then, after further stirring the mixture for two hours at the same temperature, the reaction mixture became treated as given in example 18.

There were 3.5 U of white powdery Ampicillin.1- (phenoxyacetoxy) äthylGSter.Hydrochlorid with a melting point

209844/1226

from 116-119 ° C (with decomposition) in a yield of 61.7% .

Infrared absorption spectrum:

⁺ 3350 cm " ¹ , 3200 cm" ¹

+ ^ ₁

₂ 27ΟΟ-26ΌΟ cm

vC = O 1790-1745 cm " ¹ wide (e-lactam, ester), 1690 cm"" ¹ (amide)

Elementary analysis as C ₂ gH- _5O N, O ₇ SCl:

C (JS) H (Z) N (?) Cl (%) calcd 55.36 5.36 7.45 6.29 found 55.04 5.74 7.29 6.40

Example 21

In 100 ml of dimethylformamide there was 13.2 g of benzylpenicillin potassium salt suspended, and then 3 g of potassium bicarbonate and 11 g of 1-acetoxy-3-phenylpropyl bromide were added to the suspension added. The mixture was stirred at room temperature for 16 hours.

The reaction mixture was dispersed in 150 ml of ice water and the mixture was treated as in Example 9. 16 g of oily benzylpenicillin. 1-acetoxy-3-phenylpropyl ester were obtained in a yield of 88 % .

Infrared absorption spectrum:
vNH 3320 cm " ¹

vC = 0 1790-1730 cm " ¹ wide (8-lactam, ester)

1660 cm " ¹ (amide)

209844/1226

Example 22

In 5Q ml of dichloromethane there was 5.62% of benzylpenicillin. 1-acetoxy-3-phenylpropyl ester dissolved. Then t-furde to the solution add 4.12 tablespoons of N, N-dimethylaniline and the mixture was cooled to -25 ° C.

After further addition of 2.3 β phosphorus pentachloride was the mixture was stirred at -25 ° -5 ° C. for 1.5 hours. Then, 40 ml of methanol was added dropwise to the mixture at the same temperature. The mixture was Stirred for another two hours to add an imino ether solution to obtain.

Then 6.86 ml of N, N-dimethylaniline was puffed into the solution. This was followed by the addition of 2.5 β D (-) - a-Phenylrrlycylchlorid.Hrochlorid to the mixture over the course of one hour with stirring at -25-5 ° C

After stirring the mixture for 2 hours at the same temperature, the reaction mixture was mixed with 50 ml of cold and unsaturated aqueous sodium chloride solution and then stirred for half an hour at a temperature of -5 ° C to ^{0 ° C.} The dichloromethane layer was separated off, washed with 30 ml of 0.5 η was aqueous hydrochloric acid which was saturated with sodium chloride and then washed with 30 ml of saturated aqueous sodium chloride. Then, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature to give an oily residue. When 50 ml of ether was added to the residue and the batch was stirred, the batch solidified. The solidified material was dissolved in 50 ml of ice water and washed twice with 30 ml of ither each time. On the aqueous layer formed in this way, 30 ml of ethyl acetate was added as

2098U / 1226

- HO -

layering applied and then was sodium chloride added while stirring until saturation has occurred was. Then the ethyl acetate layer was separated and the aqueous layer thus obtained was extracted twice with 20 ml of ethyl acetate. The ethyl acetate extracts were combined with the ethyl acetate layer obtained as above and the mixture was mixed with 30 ml of cold and saturated aqueous sodium chloride solution washed. Then it was dried over anhydrous magnesium sulfate and under reduced pressure concentrated at low temperature. The residue was dissolved in a small amount of ethyl acetate and it ether was added to the solution to cause the product to fall over. The obtained crystals were filtered off and washed with a small amount of petroleum ether and dried to 3.3 Γ of the white powdered ampicillin. 1-acetoxy-3-phenylpropyl ester. Hydrochloric ^ .with a Melting point of 118 - 122 ° C (with decomposition) to be obtained in a yield of 53.3 ^.

Infrared absorption spectrum:
⁺ - 3 ¹ JOO cm ^"1, 3200 cm" ¹
+ 2700-2600 cm " ¹

vC = 0 1780 cm " ¹ (ß-lactam), 1760-17 ^ 0 cm" ¹ (ester), 1680 cm " ¹ (amide)

Elemental analysis as

calculated 57.67 5.7 ¹ J 7.48 6.31

found 57.28 6.12 7.18 6.55

2 09 8 4A / 1 226

Example 23

In 50 ml of dimethylformamide, 11.2 g Benzylpenicillinkaliumsalz was suspended and after the addition of 0.7 g Kaliumbicarbona.twaxde 6.9: l-Äcetoxy _2,2-J 2-trichloroäthylbromid dropwise to the mixture in the course of 25 minutes with stirring to add. After the mixture had been stirred for a further 2 hours at room temperature, the reaction mixture was - - - disconnected in 50 ml of ice water and then extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extracts were combined and the mixture was washed with 50 ml of 5% strength aqueous sodium bicarbonate solution and then rewashed with 50 ml of water. It was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure at low temperature. The residue obtained was mixed with 75 ml of ether with stirring and then the insoluble matter was removed by decantation. 100 ml of petroleum ether were added to the ethereal solution with stirring and the oily material thus formed was separated off by decantation and dried under reduced pressure. It was 9 _S Benzylpenicillin.l-acetoxy-2,2,2-trichloroäthylester get 8 g of powder in a yield of 62.2%.

Infrared absorption spectrum:
VNH ¹ 3300 cm " ¹
vC = 0.178O-1860 cm " ¹ wide (β-lactam, ester), 1660 cm" ¹

Example 24

In 50 ml of dichloromethane was 5.24 g of benzylpenicillin.

l-aoetoxy-2,2,2-trichloroethyl ester and dissolved after

209844/1226

By adding 4.12 ml of N, N-dimethylaniline, the mixture was cooled to -25 ° C. After adding 2.3 P phosphorus pentachloride, the mixture was stirred at -25 ° -5 ° C. for 1.5 hours. Then, 40 ml of methanol was added dropwise to the mixture at the same temperature, and the resulting mixture was further stirred for two hours to obtain an imino ether solution .

Then 6.86 ml of N, N-dimethylaniline was added to the solution prepared above, and then another 2.5 CD (-) - α-phenylglycylchloride.Hydrochloride was slowly added to the mixture over the course of one hour while stirring at -25-5 ° C added.

Then, after stirring the mixture for two hours at the same temperature, the reaction mixture was mixed with 50 ml of cold and saturated aqueous sodium chloride solution and the mixture was further stirred at a temperature of -5 ° to ⁰ ° C. for half an hour.

The dichloroethane layer formed was then separated off and washed with 30 ml of 0.5 μm aqueous hydrogen chloride solution and then rewashed with 30 ml of saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature to give an oily residue. The residue was dissolved in 50 ml of ethyl acetate, and then η-hexane was added to the solution, whereby an oily product was formed. became. The oily product was separated by decantation and dried under reduced pressure and mixed with 50 ml of water. Then a small amount of activated charcoal was added and mixed further. The mixture was stirred for 30 minutes at room temperature and filtered. The piltrate was covered with a layer of

209844/1226

2215033

30 ml of ethyl acetate was covered over and then sodium chloride was added with stirring until saturation. The ethyl acetate layer thus obtained was then separated off and the aqueous layer was extracted twice with 20 ml of ethyl acetate each time. The ethyl acetate layer and the extracts were combined, and the mixture was washed with 30 ml of cold and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Then, it was concentrated under reduced pressure at a low temperature. The residue obtained was dissolved in a mixture of 10 ml of benzene and 3 ml of ethyl acetate and, after the insolubles were filtered off, petroleum ether was added to the filtrate _3, whereby white precipitates were formed. The precipitates were separated by filtration, washed with a small amount of petroleum ether and dried. 3.06 g of the white powder of ampicillin.1-acetoxy-2,2,2-trichloroethyl ester with a melting point of 148-149 ° C. (with decomposition) were obtained in a yield of 53.1 % .

Infrared absorption spectrum:
VNH ₃ ⁺ 3 ¹ JOO cm " ¹ , 3200 cm" ¹

VNH ₂ + 2700-2600 cm " ¹

vC = 0 179O-1770 cm " ¹ wide (ß-lactam, ester) 1680 cm" ¹ (amide)

Elemental analysis as C ₂

C. (%) H (50 N (JS) Cl (58) calculated 41 , 76 4th , 03 7.30 24 , 65 found 41 , 30 4th , 51 7.05 25th , 24

209844/1226

Similarly, by the same methods as above explains the compounds represented by the following formula, in addition are given in the following table and the results are also in the same table shown, are produced.

COOCHO-CR ² 'HCl

209844/1 226

In-melt elemental analysis

game " _Λ point found" Calculated

No. ΈΤ R ¹ Q (C) C (St) H (E) N (Si) Cl (I) C (E) H (St) N (E) Cl (E)

25 -CH ₂ CH ₃ -CH ₃ 107-110 51.48 6.24 8.37 7.05 51.90 5.81 8.65 7.30

26 - (Oy ₆ CH ₃ -CH ₃ 55.89 7.14 7.28 6.41 56.15 6.89 7 _S 56 6.37

27 -CH (C ₂ H ₅ ) ₂ -CH ₃ 88-107 54.24 6.80 7.56 6.83 54.59 6.49 7.96 6.71

28 -CH ₂ -Zj ^ -CH ₃ 150-152 56.90 5.86 7.26 6.64 56.98 5.52 7.67 6.47

29 -CH ₂ CH ₃ -CH ₂ CH ₃ 100-104 52.63 6.49 8.22 7.18 52.85 6.05 8.40 7.09 ■ 30 - (CHg) ₂ CH ₃ -CH ₂ CH ₃ 113-120 53.40 6.45 7.97 6.80 53.74 6.27 8.17 6.90

31 -CH (CH ₃ ) ₂ -CH ₂ CH ₃ 130-136 53.31 6.56 8.05 6.96 53.74 6.27 8 _S 17 6.90

32 -C (CH ₃ ) ₃ -CH ₂ CH ₃ 125-128 54.14 6.77 7.52 6.88 54.59 6.49 7.96 6.71

33 -CH (CH ₂ CH ₃ ) ₂ -CH ₂ CH ₃ IO5-IO8 55.05 6.87 7.57 6.60 55.39 6.69 7.75 6.54

34 -CH ₃ - (CH ₂ ) ₂ CH ₃ 95-99 52.34 6.48 8.21 7.18 52 ₃ 85 6.05 8.40 7.09

35 -CH ₂ CH ₃ - (CH ₂ ) ₂ CH ₃ 122-126 53.30 6.56 8.02 7.14 53.74 6.27 8.17 6.90

36 - (CH _{2) 2} CH ₃ - (CH 2) ₂ CH _{3 122-123 54.13 6.83 7.64 6.60 54.59 6.49} 7.96 6.71

37 -CH (CH ₃ ) ₂ - (CHg) ₂ CH ₃ 106-110 54.19 6.66 7.53 6.54 54.59 6.49 7.96 6.71

38 - (CH ₂ ) ₆ CH ₃ - (CH ₂ ) ₂ CH ₃ 105-110 57.12 7.58 6.98 6.24 57.57 7.25 7.19 6.07

39 -C (CH ₃ ) ₃ - (CH ₂ ) ₂ CH ₃ 111-115 55.02 6.91 7.50 6.67 55.39 6.69 7.75 6.54

40 -CHiCH ^ H ^ -iCH ^ CHj 85-104 55.88 7.15 7.30 6.59 56.15 6.89 7.56 6.37

41 ζ _Ε "\ _ - (CPg) ₂ CH ₃ 127-130 56.70 6.87 7.03 6.44 57.08 6.74 7.40 6.24

42 -CH ₂ O- ^ J- (CH ₂ ) ₂ CH ₃ 117-120 56.35 6.12 7.00 6.12 56.80 5.79 7.10 5.99

43 -CH ₃ -CH (CH ₃ ) ₂ 115-119 52.48 6.55 8.17 6.90 52.85 6.05 8.40 7.09

44 -CH ₂ CH ₃ -CH (CH ₃ ) ₂ 126-128 53.29 6.60 8.02 6.87 53.74 6.27 8.17 6.90

45 -CH (CH ₃ ) ₂ -CH (CH ₃ ) ₂ 124-126 54.17 6.85 7.59 6.95 54.59 6.49 9.96 6.71

46 -C (CH ₃ ) -CH (CHj) ₂ 127-130 55.10 6.94 7.51 6.68 55.39 6.69 7.75 6.54

47 -CH ₃ - (CHg) ₅ CH ₃ 108-112 54.87 6.99 7.44 6.32 55.39 6.69 7.75 6.54

48 -CH ₃ h £ 3 55.86 5.69 7.48 6.81 56.23 5.28 7.87 6.64

49 -C (CH ₃ ) ₃ - // ~ ^ 143-144 58.31 6.32 7.00 6.10 58.38 5.95 7.29 6.15

50 -CH ₂ - <f_ ^ // Jy 128-130 60.73 5.68 6.79 5.72 61.03 5.29 6.89 5.8l

51 -C (CH ₃ ) ₃ -CH ₂ CH ₂ - ^ J 59.25 6.87 6.38 5.95 59.64 6.34 6.95 5.81

209844/1 226

⁵² ~ £ 3 "^ tt ^ Cj) 136-140 61.22 5.90 6.46 5.83 61.58 5.49 6.73 5.68" ^GH 2V == / - QH _s ca _2. ^ ^ 105-110 61.87 5.89 6.24 5.39 62.11 5.69 6.58 5.56

Reference 1

In 120 ml of acetone was 11.2 g of benzylpenicillin potassium salt suspended. After adding 5.1 g of 1-pivaloyloxyethyl chloride and 3 ml of 2536 aqueous sodium iodide solution, the mixture was refluxed for 5 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue obtained was washed with 30 ml of petroleum ether and dissolved in 80 ml of ethyl acetate and the resulting solution was filtered. The ethyl acetate solution was washed with 50 ml of 53> strength aqueous sodium carbonate solution and then washed with 50 ml of water. It was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography and then eluted by a benzene-ethyl acetate mixture (3: 1 by volume). The eluate obtained was concentrated under reduced pressure. It was 8.5 g of benzyl penicillin. 1-pivaloyldxyäthylester obtained.

Example 54

In 25 ml of chloroform, 5.0 g of benzylpenicillin. 1-pivaloyloxyethyl ester was added dissolved and then a chloroform solution containing 1.5 g of perbenzoic acid was slowly added added to the solution with stirring and ice-cooling. Then, after stirring the mixture for 10 minutes at room temperature the mixture twice, each time with an aqueous one

209844/1226

Sodium bicarbonate solution and water and washed over dried anhydrous magnesium sulfate. Then the solvent was distilled off. There were 4.9 g of amorphous Benzylpenicillinsulfoxyd.l-pivaloyloxyäthylester obtain.

The infrared absorption spectrum and the NMR spectrum of the product showed the same structure. Furthermore, the NMR spectrum showed the presence of the stereoisomer, which is due to the difference in the steric structure of the Esterres
became.

Elemental analysis as Cp, H, _o N ₂ O ,, S:

calculated
found

Example 5 5

4.8 g of benzylpenicillinsulfoxyd.l-pivaloyloxyethyl ester were added to 24 ml of aqueous dioxane dissolved. After adding to the solution of 123 mg of phenyl dihydrogen phosphate. Monohydrate and 57 vl of absolute pyridine, the mixture was heated to 105 ° C. for 4 hours. It became a * orange-yellow reaction mixture obtained. The solvent was distilled off under reduced pressure and the residue thus obtained was dissolved in benzene. The solution was subjected to silica gel column chromatography subjected and the product was developed and eluted with a mixture of benzene and ethyl acetate (10: 1 im Volume ratio). By distilling off the solvent from the pale yellow eluate under reduced Pressure was 3.7 g of the pale yellow powder of 7-phenylacetamidodesacetoxycephalosporanic acid.l-pivaloyl-

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C. (%) H (*) N (Z) S. (Z) 57 , 73 6.32 5 , 85 6th , 70 57 , 81 6.53 5 , 67 6th , 53

oxyäthylesters obtained. The nuclear magnetic resonance spectrum of the product agreed well with the structure match.

Nuclear magnetic resonance spectrum (CDCl, solution):

δ: 1.22 (9H, singlet, -C (CH ₃ ) J, 1.51 OH, doublet, J = 5.5 Hz ₅ CH ₃ ), 2.09 (3H, singlet, CH ₃ ), 2, 90, 3.20, 3.31, 3.61 AB moiety (2H, -S-CH ₂ -), 3.6 (2H, singlet, 0-CH ₂ -), 4.88 (IH, doublet, J. = 4Hz, lactam), 5.69 (IH, quartet, J = 4 Hz, 8.5 Hz, lactam), 6.48 (IH, doublet, J = 8.5 Hz, NH), 6.95 (IH , Quartet, J = 5.5 Hz, -CO -CH-Oc-), 7.30 (5H, singlet, aromatic H).

Elemental analysis as C ₂ , H _{2 gN 2} OgS:

C (%) H CS) N (Ji)

calculated 59, 98 6, 13th 6th , 08 6th , 96 found 59, 85 6, 27 6th , 01 6th , 73 Example 56

8.4 g of benzylpenicillin.1-acetoxyethyl ester were added to 42 ml of chloroform and then slowly dissolved a chloroform solution containing 2.76 g of perbenzoic acid added to the solution with stirring and ice cooling .

Then the mixture was, as indicated in Example 54, further treated. 8.2 g of amorphous benzylpenicillin · sulfoxyd.l-acetoxyethyl ester were obtained. The infrared absorption spectrum and the NMR spectrum of the product agreed well with the structure. Furthermore showed the HMR spectrum that the presence of the steroid isomer, which by the difference in steric structure

2098 A4 / 1226

the ester residue group: p.ß is conditional, has been detected. Elemental analysis as C ₂₀ H _{2 JIjN 2} O ^ S:

C (S) H (S) N (S)

calculated 55.04 5j 54 6.42

found 55.19 5.66 6.31

Example 57

In 40 ml of dioxane, 7.0 g of benzylpenicillinsulfoxyd.lacetoxyäthylester was dissolved and after addition to the solution of 195 mg of phenyl dihydrogen phosphate monohydrate and 91 yl of pyridine, the mixture was refluxed. The reflux treatment was carried out so that the dioxane distilled, dehydrated through a molecular sieve and was returned to the reaction mixture. After performing the reflux treatment for 7 hours, the solvent was distilled off from the reaction mixture under reduced pressure. The received The residue was dissolved in benzene. Then the solution was subjected to silica gel column chromatography and the product was replaced by a mixture of benzene and ethyl acetate (10: 1 by volume) developed. Distilling off the main fraction of the eluate under reduced pressure gave 5.2 g of a pale yellow powder of 7-phenylacetamidodesa-acetoxycephalosporanic acid 1-acetoxyethyl ester obtain.

NMR spectrum of the product (CDCl 3, solution): δ: 1.51 (3H ₁ doublet, J = 5.5 Hz, CH ₃ ), 2.09 (3H ₁ symphonic, CH ₃ ), 2.13 (3H ₃ singlet , CH ₃ ), 2.97, 3.28, 3.38, 3.70, AB grouping (2H, -S-CH ₂ ), 3 ₅ 6l (2H, singlet, d-CHg-), 4, 92 (IH, doublet, J = 4.5 Hz, lactam), 5.76 (IH, quartet, J = 4.5 Hz, 9 Hz, lactam), 6.75 (IH, doublet ^ J = 9 Hz, NH), 6.97 (IH, quartet, J = 5.5 Hz), -0 -? - 0 -), 7.30 (5H ₁ singlet,

209844/1226

aromatic H).
Elemental analysis as Cp ₀ HppNp0, -S:

C. (S) F. f of \
V fi J N (P calculated 57 , 40 5 , 30 6, 69 found 57 , 59 5 , 39 6, 44

Beis pie l 5 .. 8 _

In 44 ml of chloroform, 8.7 g of benzylpenicillin-1-aoetoxypropyl ester was dissolved, and then a chloroform solution containing 2.76 g of perbenzoic acid was slowly added to the solution with stirring and ice-cooling. Then, by treating the mixture as indicated in Example 54, ₃ 8.5 g of amorphous benzylpenicillinsulfoxyd.l-acetoxypropyl ester were obtained. The infrared absorption spectrum and NMR spectrum of this product were in good agreement with the structure. Furthermore, the NMR spectrum showed that the presence of the steric isomer formed by the difference in the steric structure of the residual ester group was present.

Elemental analysis as Cp ^ HpZ-NpO ₇ S:

C (56) H (%) N

calculated 55.99 5.82 6.22 found 56.11 5.88 6.15

Example 5Q

4.4 g of benzylpenicillinsulfoxyd.l-acetoxypropyl ester were added to 25 ml of aqueous dioxane dissolved and after adding 122 mg of phenyldihydrogenphosphate monohydrate to the Solution and 57 vil pyridine, the mixture was heated, as in Example 57) subjected to the reflux treatment. The product obtained was then worked up as indicated in Example 57. 3.4 g of the pale yellow powder

209844/1226

■ aas 7-phenylacetamidodesacetoxycephalosporanic acid acetoxypropyl ester has been received.

The NMR spectrum of the product (CDCl3 solution): δ: 0.98 (3H, triplet, J = 7 Hz ₉ CEL) ₉ 1.78 (2H multiplet, CH ₂ ) _a 2.09 (3H ₉ singlet, CH ₃ ), 2.14 (3H, singlet, CH ₃ ), 2.93, 3.25, 3.35, 3.65, ΛΒ grouping (2H, -SCH ₂ -), 3.62 (2H, Singlet, 0-CH ₂ -), 4.90 (1 H doublet, 4.5 Hz, lactam), 5.72 (IH, quartet, J = 4.5 Hz ₅ 9 Hz ₉ lactam), 6.5 (IH , Doublet, J = 9 Hz, NH), 6.8l (IH, triplet, J = 5.5Hz, -0-CH-O-), 7.28 (5H, singlet, aromatic H).

Elemental analysis as C ₂₁ H ₂ ^ N ₂ OgS:

C (*) H (Sf) N (% calculated 58.32 VJl , 59 6th , 48 found 58.42 5. »51 6th , 38

The product could be further separated into two stereoisomeric crystals by a silica gel column chromatography treatment, which was formed by the steric structure of the ester residue group. The isomer, which is slightly soluble in ether, has a melting point of 144-146 ° C and £ 7 ² ° = + 33.9 (C = 1, CHCl ₃ ), while isomer _9, which is soluble in ether, has one Has a melting point of 151-154 ° C

and Γα7 ² ρ = + 47.9 (C = 1, CHCl ₃ ),

Example 60

a). 10 g of benzylpenicillin.1-pr '-' pionyloxyethyl ester was added to 50 ml of chloroform dissolved. Then, a chloroform solution of 3.2 g of perbenzoic acid was slowly added to the solution added with stirring and ice cooling.

The mixture became thin for another 10 minutes at room temperature

2098U / 1226

stirred. The raw mixture was mixed twice each aqueous sodium bicarbonate solution and then with Washed with water and dried over anhydrous magnesium sulfate. Then the solvent was reduced under reduced pressure Distilled pressure. 10.1 g of amorphous eenzylpenicillinsulfoxyd.1-propionyloxyethyl ester were obtained obtain.

b). 9.0 g of benzylpenicillinsulfoxyd.1-propionyloxyethyl ester were dissolved in 50 ml of absolute dioxane. Then the solution became 244 hip; Phenyl dihydrogen phosphate monohydrate and 114 yl pyridine added. The mixture was heated to 105 ° C for 7 hours. The solvent was then distilled off from the pale brown reaction mixture under reduced pressure unc ^1, the thus obtained residue was dissolved in benzene. The solution was washed with water twice, dried over anhydrous magnesium sulfate, and subjected to silica gel column chromatography. It was then eluted with a mixture of benzene and ethyl acetate (10: 1 by volume). Then the solvent was distilled off from the pale yellow eluate under reduced pressure. 6.8 g of the pale yellow powder of 7-phenylacetamidodesacetoxycephalosporanic acid. 1-propionyloxyethyl ester were obtained.

UtJ ¹ Q = + 42.8 (C = 1, chloroform) Elemental analysis as Cp ^ HpnNpOgS:

calculated: N 6.48 %
found: N 6.42 %

Nuclear magnetic resonance spectrum (CDCl, solution): δ: 1.12 (3H, triplet, J = 7.5 Hz, -CH ₃ ), 1.51 (3H, doublet, J = 5.3 Hz, -CH,) , 2.10 (3H, singlet, CH ₃ ),

209844/1226

2.37 (2H ₃ quartet, J = 7.5 Hz, -CH ₂ -), 2.95, 3.27 _s
3.38, 3.69 (2Hj AB grouping, -S-CH ₂ -), 3 ₃ 6l (2H ,.
Singlet, tf-CH ^), 4 ₅ 91 (IH, doublet, J = 5 Hz, lactam), 6.62 (IH, doublet, J = 9 Hz, NH) -, 7.02 (IH, triplet, J. = 5.5 Hz, -CH), 7 ₃ 30 (5H, singlet, aromatic H).

Furthermore, the compounds represented by the following formula could be prepared by the same procedures as indicated in Examples 5 ^ -60. The yields and the properties
are given in the following table along with the practical structures of the compounds.

COOCHO-CR ²
i ¹

209844/1226

Tabel

l'qj ° from elemental analysis

game ρ ₁ , _ ₁ loot calculated found

^Nr · ^RR chloroform) (55) N (*) Ν

61 -CH ₂ - ^ J) -CH ₂ CE ₅ + 33.2 69 5.50 5.30

62 -CH ₂ CPL -CH ₃ CH ₃ - 60 6.27 6.03

63 -CH ₂ CH ₃ -CTi ₂ CH ₂ CH ₃ + 40.8 62 6.08 5.94

64 (h) -CH ₂ CH ₂ CH ₃ + 29.1 85 5.44 5.12

65 "CH ₃ -CH ₂ CH ₂ CH +41.0 72 6.27 6.22

66 - (CH ₂ J ₆ CH ₃ -CH ₂ CH ₂ CH ₃ + 36.0 77 5.28 5.07

67 -σΗ ^ ^Η 2 ° ^Η 3 -CH ₉ CH ₉ CH, +35.4 8l 5.57 5.52

^ H ₂ CH ₃ ^D

68 -CH ₂ CH ₂ CH ₃ -CH ₂ CH ₂ CH ₃ + 39.9 72 5.90 5.72

69 -CH ₂ - ^ _ \) -CH ₂ CH ₂ CH ₃ +38.2 79 5.36 5.39

70 -CH ₂ CH 1 ^H 3 -CH ₂ CH ₂ CH ₃ +43.2 90 5.73 5.40

71 - (CH ₂ ) ₃ CH ₃ -CH ₂ CH ₂ CH ₃ +45.6 77 5.73 5.56

72 -G-CH ₃ -CH ₂ CH ₂ CH ₃ + 34.8 81 5.73 5.52 ^ CH ₃

73 -CH ^ "3 -CH ₉ CH ₉ QL - 75 5.90 5.67

^ CH ₃ 2 2 3

74 -Qc ^ H ₃ -CH ^ h ³ + 31.8 77 5.73 5.51

CH

75 -CH ₉ CIL -CHw ⁵ +51.1 64 6.08 6.14

d 3 XH,

76 -CH ₂ - ^) - (CIy ₅ CH ₃ + 36.0 82 4.96 4.73

77 -CH ₂ CH ₃ - (CH ₂ J ₅ CH ₃ + 43.2 70 5.57 5.53

844/1226

+ 33 , 4 78 5 , 50 5, 62 + 35 , 6 71 5 , 36 5, 44 + 35 , 0 28 5 , 23 5, 21st

- 55 -

78 -CH ₃ (O

79 -CH ₂ CH ₃

80 -CH ₂ CH ₃ -CCl

81 -CH ₂ CH ₂ CH ₃ -CH ₂ -0 - ^ _ ^ + 20.9 63 5.20 5.34

82 - (/ _ \) -CH ₂ GH ₂ CH ₃ + 18.1 49. 5.50 5.66

83 -CH ₂ CH ₃ - ^ _ ^ / + 30.2 44 5.66 5.36

84 -CH ₂ CH ₂ CH ₃ - ^ JJ + 24.9 61 5.50 5.48

85 -Ο ^ - ^ Λ Η ^ ") ^! + 27.4 88 5.03 5.05

Reference 2

a). In 100 ml of acetone, 11.2 g of benzylpenicillin potassium salt was suspended, and after adding to the suspension 1.5 g of potassium bicarbonate and 10 g of 1-acetoxyethyl bromide, the mixture was refluxed with heating for 2 hours. After cooling, the reaction mixture was filtered and the piltrate was concentrated under reduced pressure. The residue thus formed
was washed with 30 ml of petroleum ether and in 80 ml
Dissolved ethyl acetate and then filtered. The filtered ethyl acetate solution was washed with 50 ml of 5 # aqueous sodium bicarbonate solution and then rewashed with 50 ml of water and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The concentrate was subjected to adsorption chromatography on silica gel packed in a column, and the adsorbed product was treated with a mixture of benzene and ethyl acetate (3: 1 im

2098U / 1226

Volume ratio) and the resulting eluate was concentrated under reduced pressure. It became 7.5 g of the colorless powdery crystal of benzylpenicillin. 1-acetoxyethyl ester obtained in a yield of 60 % .

b). 8.4 g of benzylpenicillin.1-acetoxyethyl ester were added to 42 ml of chloroform dissolved. Then, a chloroform solution containing 2.76 g of perbenzoic acid became slow added to the solution with stirring and ice cooling. After that, the mixture was left for 10 minutes at room temperature stirred and washed twice with aqueous sodium bicarbonate solution and then with water rewashed. It was dried over anhydrous magnesium sulfate and the mixture solvent was distilled off. This gave 8.2 g of amorphous benzylpenicillinsulfoxyd.1-acetoxyethyl ester obtain.

The infrared absorption spectrum and the NMR spectrum of the product were completely agreed with the structure.

Elemental analysis as C ₂₀ Hp ^ NpO ₇ S:

C (35) H (%) NU)

calculated 55.04 5.54 6.42 found 55.19 5.66 6.31

c). In 40 ml of anhydrous Diaxan, 7.0 g of benzylpenicillinsulfoxyd.1-acetoxyethyl ester was added dissolved. Then 195 mg of phenyl primary phosphate was added to the solution. Monohydrate and 91yl pyridine added. The mixture was then refluxed. The reflux process

209844/1226

was carried out so that the dioxane through a molecular sieve was dehydrated and returned to the reaction mixture became. After the reflux treatment was carried out for 7 hours, the solvent was distilled off from the reaction mixture under reduced pressure and the The residue was dissolved in benzene. The solution was subjected to silica gel column chromatography. That Product was developed from a mixture of benzene and ethyl acetate (10: 1 by volume). By · distillation of the solvent from the column eluate under reduced pressure, 5.2 g of pale yellow powder was obtained 7-Phenylacetamidodeacetoxycephalosporanic acid. 1-acetoxyethyl ester obtain.

Elemental analysis as ^C 2i ^? 2 ^H 2 ⁰ 6 ^S:

C (%) H (%) N (Si)

calculated 57.40 5.30 6.69 found 57.59 5.39 6.44

Example 86

1.57 g of 7-phenylacetamidodesacetoxycephalosporanic acid 1-acetoxyethyl ester was dissolved in anhydrous dichloromethane. After the addition of 1.5 g Dimethy! Aniline to the solution 865 mg of anhydrous phosphorus pentachloride under cooling at a temperature below -20 ⁰ C was then added. The mixture was stirred for 3 hours at a temperature of -15 ° C to -10 ⁰ C. To the orange-yellow reaction mixture was added dropwise 12 ml of methanol was added at a temperature below -20 ⁰ C and then the mixture was further stirred for 1.5 hours at -20 C e ^ .ner temperature. Then 2.5 g of Ν, Ν-dimethylaniline and 930 mg of D (-) - a-phenylglycylchloride were added. Hydrochloride was added and the mixture was allowed to stand overnight at -20 ⁰ C. The reaction mixture

209844/1226

was mixed with a saturated aqueous sodium chloride solution and, after shaking the As a mixture, the organic layer was separated and dried over anhydrous magnesium sulfate. Then became the solvent is distilled off under reduced pressure. The residue was dissolved in water and the solution was washed with ether and saturated with sodium chloride. This formed an oily material, which was extracted with dichloromethane. The dichloromethane extract was saturated with aqueous sodium chloride solution washed and dried over anhydrous magnesium sulfate. The solvent became under reduced pressure distilled off. Adding ether to the residue and allowing the mixture to stand gave 1.63 g of the white Powder of y-ia-aminophenylacetamido / desacetoxyeephalosporanic acid, 1-acetoxyethyl ester, hydrochloride with a melting point of 112-143 C.

Elemental analysis as C ₂₀ H ₂ jN, OgSCl:

C. (*) H \%) N {%) S. (%) Cl ( calculated 51 , 11 5, 15th 8th, 94 6, 82 7, 54 found 50 , 96 5, 52 8th, 98 6, 54 7, 82

The infrared absorption spectrum and the NMR spectrum The product was completely in line with the structure match.

Example 87

714 mg of 7-PhenylacetG.midodesacetoxycephalosporanic acid 1-acetoxypropyl ester was dissolved in 12 ml of anhydrous dichloromethane. Then 660 mg of Ν, Ν-dimethylaniline were added to the solution and then 390 mg of anhydrous phosphorus pentachloride were added with cooling at a temperature lower than -SIO ⁰ C. The mixture

209844/1226

was' 3 hours at a temperature of -5 ° C to -1O ° C stirred. To the orange-yellow reaction mixture, which was obtained in this way, 8.0 ml of methanol were added dropwise at a temperature below -20 ° C. The mixture was then stirred for a further 1.5 hours in a temperature range from -2O ° C. to - 15 C. the mixture was then stirred for 1.1 g Ν, Ν-dimethylaniline and 408 mg D. (-) - otPhenylglycylchlorid.Hydrochlorid added under stirring at a temperature below -20 ⁰ C. the mixture was allowed overnight at -20 ° C. The reaction mixture thus obtained was mixed with saturated aqueous sodium chloride solution and, after thorough shaking, the mixture was treated as indicated in Example 86. 375 mg of the white crystalline powder of 7- (α-aminophenyl-acetamido) deacetoxycephalosporanic acid 1-acetoxypropyl ester were obtained. Hydrochloride obtained with a melting point of 138-140 C.

Elemental analysis as C ₂₁ HpgN, 0gSCl:

C. (%) H {%) N (50 6th S (JS) 7th Cl (S) 52 , 12 5, 41 8th, 68 6th , 63 7th , 33 52 , 05 5, 50 8th, 49 , 35 , 62

calculated
found

The infrared absorption spectrum and the NMR spectrum of the product completely agreed with the structure.

Reference 3

a). In 120 ml of acetone was 11.2 g of benzylpenicillin potassium salt suspended. 5.1 g of 1-pivaloyloxyethyl chloride and 3 ml of 25% strength aqueous solution were then added to the suspension Sodium iodide solution added. The mixture was refluxed for 5 hours. After cooling down the reaction mixture was treated further as in FIG

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Reference 2, section a given. 8.5 g of the colorless powdery crystals of benzylpenicillin.1-pivaloyloxyethyl ester were obtained obtain.

b). In 25 ml of chloroform, 5.0 g of benzylpenicillin. 1-pivaloyloxyethyl ester was added dissolved. Then, a chloroform solution containing 1.5 g of perbenzoic acid was added to the The solution was added while stirring and cooling with ice. After their addition, the mixture was stirred for 10 minutes and twice each with sodium bicarbonate solution and then washed with water. It was dried over anhydrous magnesium sulfate and the solvent became distilled off. 4.9 g of amorphous benzylpenicillin.1 · pivaloyloxyethyl ester were obtained. The infrared absorption spectrum for the product fully agreed with the structure.

Elemental analysis as C _{2 -JU 0} N ₂ O ₇ S:

C (35) H {%) N (JS) S (58)

calculated 57.73 6.32 5.85 6.70 found 57.81 6.53 5.67 6.53

c). 4.8 g of benzylpenicillinsulfoxyd.l-plvaloyloxyethyl ester were dissolved in 24 ml of anhydrous dioxane. Then 123 mg Phenjädihydrogenphosphat.Monohydrat and 57 yl of absolute pyridine were added to the solution. The mixture was ^{heated to 105 °} C. for 4 hours. Then, the solvent was distilled off from the orange-yellow reaction mixture under reduced pressure, and the residue obtained was dissolved in benzene. The solution was subjected to silica gel column chromatography, and then the product thus adsorbed was developed with a mixture of benzene and ethyl acetate (10: 1 by volume). By distilling off the

20984-4 / 1226

Solvent from the pale yellow eluate under reduced pressure was obtained 3 _S 7 g of the pale yellow powder from 7-phenylacetamidodesacetoxycephalosporanic acid.1-pivaloyloxyäthylesteis. The nuclear magnetic resonance spectrum of the product completely agreed with the structure.

Element ar analysis as C ^ Hpg ^ OgS:

C. (JO H (55) N (*) S. (Si) 59 , 98 6, 13th 6th , 08 6, 96 59 , 85 6, 27 6th , 01 6, 73

expected
found

Reference 4

3.0 g of sodium 7- (2-thfenylacetamido) cephalosporanate and 0.45 g of potassium bicarbonate were suspended in 15 ml of dimethylformamide. Then 2.0 g of 1-acetoxypropyl bromide were added to the suspension and the mixture was stirred at room temperature for 16 hours. The reaction mixture thus obtained was concentrated under reduced pressure at a low temperature, and the residue thus obtained was mixed with water. This produced an oily material and extracted it with dichloromethane. The extract was washed with aqueous sodium bicarbonate solution and then with water. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the product thus atisorbed was developed with a mixture of benzene and ethyl acetate ( J>: 1 by volume). The solvent was distilled off from the eluate under reduced pressure. 1.8 g of yellowish crystalline powder were obtained from the 7- (2-Thiepylaeet ~ amido) cephalosporanic acid.l-acetoxypropyl ester.

209844/1 226

The infrared absorption spectrum of the product was correct completely coincide with the structure.

Elemental analysis as Cp ^ Hp ^ NpOoSp:

calculated: N 5.6 ¹ I %
found: N 5.59 %

Example88

2.65 g of 7-phenylacetamidodesacetoxycephalosporanic acid. 1-pivaloyloxyethyl ester was dissolved in 27 ml of dichloromethane. Then 2.4 ml of N, N-dimethylaniline was added to the solution. Then 1.33 g of phosphorus pentachloride were added with stirring and cooling to -30 ° C. The mixture was stirred for 2 hours and 50 minutes at temperatures between -15 ° C to -10 ⁰ C. To the greenish reaction mixture thus obtained, 18.5 ml of absolute methanol were added dropwise at a temperature below -20.degree. Thereafter, the mixture for an additional hour and 45 minutes was stirred at -20 ⁰ C. Then, 4 ml was N, N-dimethylaniline and 1.43 g D (-) - a-Phenylglycylchlorid.Hydrochloric added to the mixture with stirring at a temperature below -20 ⁰ C. The mixture obtained was then left to stand at a temperature below -20 ° C. overnight. The reaction mixture thus formed was mixed with saturated sodium chloride solution, and after shaking the mixture, the formed aqueous layer was separated from the dichloromethane layer. The aqueous layer thus separated was extracted with dichloromethane, and the dichloromethane extracts were combined with the dichloromethane layer obtained above, and the mixture was dried over anhydrous magnesium sulfate. The solvent was distilled off from the mixture under reduced pressure

2098U / 1226

The residue was mixed with ether and the thereby formed white precipitates were separated by filtration. The precipitates were dissolved in water and the aqueous solution was washed well with ethyl acetate and saturated with sodium chloride. Then became extracted a few times each time with dichloromethane. The extracts were combined and the mixture was blended with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Then it became Solvent distilled off under reduced pressure. By adding ether to the residue obtained, was 1.95 g of white powder from the 7- (° - aminophenylacetamido) -desacetoxyeephalosporanic acid.1-pivaloyloxyethyl ester. Hydrochloride obtained with a melting point of 147 ° C. The infrared absorption spectrum of the product and the The NMR spectrum of the product was completely consistent with the structure.

Elemental analysis as C ₂ , H, _o N, OgSCl:

calculated: N 8.21 %
found: N 8.02 %

Example 89

1.6 g of 7- (2-thienylacetamido) -cephalosporanic acid.l-acetoxypropyl ester were dissolved in 20 ml of dichloroethane. Then 1.36 ml of Ν, Ν-dimethylaniline were added to the solution and then 0.75 g of phosphorus pentachloride was added while cooling to -20 ° C. The mixture was 2 hours and 30 minutes at a temperature of -15 ° C to - 10 ⁰ C by stirring. Then, after cooling was the pale brown solution thus obtained was added to -30 ⁰ C 13.5 ml of absolute methanol, and the mixture was further stirred for 1 hour and 30 minutes at -20 ⁰ C.

209844/1226

Then 2.26 ml of Ν, Ν-dimethylaniline and 0.85 g D (-) - ct-Phenylglycylchloride. Hydrochloride to the mixture added at -2O ° C. The resulting mixture was stirred at -20 ° C. for a further hour.

To the reaction mixture thus obtained was added 15 ml Saturated aqueous sodium chloride solution was added and then shaken. The dichloroethane layer obtained was separated. The dichloroethane layer thus obtained was washed with saturated sodium chloride aqueous solution washed and dried over anhydrous magnesium sulfate. It was under diminished Pressure restricted. The residue thus obtained became mixed with ether and the white crystals so formed were separated by filtration. The rainfall were dissolved in about 40 ml of water and the solution was washed three times each time with stylacetate and saturated with sodium chloride. Then the oily material formed was extracted with dichloromethane. Of the The extract was dried over anhydrous magnesium sulfate and concentrated. By adding ether to 0.95 g of the white crystalline powder from the 7- (α-aminophenylacetamido) cephalosporanic acid l-acetoxypropyl ester was added to the residue. Obtained hydrochloride with a melting point of 85'- 90 ° C. The infrared absorption spectrum and the NMR spectrum of the product was completely consistent with the structure.

Elemental analysis as C ₂ , H _? ON, OgSCl:

calculated: N 7.75 %
found: N 7.62 %

209844/1226

Example 9 0

4.4 g of 7-phenylacetamidodesacetoxycephalosporanic acid. 1-propionyloxyethyl ester was dissolved in 40 ml of dichloroethane. After adding ¹ J ₈ 2 ml of Ν, Ν-dimethylaniline, 2.3 r phosphorus pentachloride was added. added to the solution with cooling to a temperature below -15 ° C. The mixture was stirred for two hours and 30 minutes at -1O ° C. After cooling the resulting dark brown reaction mixture to -30 ° C., 30 ml of absolute methanol was added dropwise to the reaction mixture. The reaction mixture was then stirred for a further hour. Then 7.0 ml of Ν, Ν-dimethylaniline and 2.5 g of D (-) - ct-phenylglycyl chloride. Hydrochloride was added to the mixture in 4 steps at -20 ⁰ C. After stirring the mixture further for one hour, aqueous sodium chloride solution was added thereto and the resulting mixture was stirred well. Then, the organic layer thus formed was separated and washed twice with a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained in this way was mixed with 150 ml of water and 50 ml of ether and shaken well. The aqueous layer formed was then separated off and washed with ether and then rewashed with ethyl acetate. Then, by adding sodium chloride to the aqueous layer, a pale green oily material was formed by salting out. This was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated. When absolute ether was added to the residue thus obtained, 3 ₅ 7 g of white powder of the 7- (ex-aminophenylacetamido) desacetoxycephalosporanic acid were obtained. 1-propionyloxyäthylester.Hydrochlorid obtained.

209844/1226

= + 74.4 (C = 1, methanol)

Elemental analysis as

₂ > N, OgSCl

calculated:
found :

N 8.68 % N 8.65 %

By the same procedures as in Examples 86 - 90 stated, compounds could be prepared which are represented by the following formula.

CHCONH

HCl

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- • 67 Ta_be_lle_.

1R
At-. ^ n ^ ⁰ - ¹ " ^Off " elemental analysis

game ο λ ^beu "calculated

No.RR (chloroform) te (%) net N (#) N (£)

-CH2C3 91 -CH ₂ CH ₃ + 53.1 77 7.50 7.44

92 -CH ₂ CH ₃ -CH ₂ CH ₃ + 57.4 69 8.44 8.26

93 -CH ₂ CH ₃ '-CH ₂ CH ₂ CH ₃ + 49.2 13 8.21 8.23

94 _ /: h \ -CH ₂ CH ₂ CH ₃ + 52.2 81 7.42 7.33

95 -CH ₃ -CH ₂ CH ₂ CH ₃ + 55.7 75 8.44 8.23

96 - (CH 2) ₆ CH ₃ -CH ₂ CH ₂ CH ₃ + 76.6 44 7.22 7.12

97 -CHf ⁰¹ V ^ -CH ₉ CH ₉ CH, + 62.3 66 7.58 7.39

XJICH ^ä * *

98 -CH ₂ CH ₂ CH ₃ -CH ₂ CH ₂ CH ₃ +54.1 78 7.99 8.08

99 -CH ₂ - ^) -CH ₂ CH ₂ CH ₃ + 50.8 75 7.32 7.21

100 -CH ₂ CH ^ ⁰¹ S -CH ₂ CH ₂ CH _3-64 7.78 7.76

CH-T

101 - (CH ₂ ) ₃ CH ₃ -CH ₂ CH ₂ CH ₃ - 72 7.78 7.72

/ 3

102 -C-CH ₃ -CH ₂ CH ₂ CH ₃ + 51.2 75 7.78 7.71 UH-j.

103 -CH <^ 3 -CH ₂ CH ₂ CH ₃ + 50.0 71 7.99 7.82

104 -C-CH ₃
CH, _ _cir CH ₃
CF, 209 + 52 , 6 80 7th , 78 7, 65 105 -CH ₂ CH ₃ -CH.
OH ₃ + 60 , 5 74 8th , 21 8th, 14th 106 -CH, ~ ^C1I 2 ^CH 2v_3 ♦ w .3 68 7th , 50 36 107 -CH ₂ CH ₃ -CH ₂ CH ₂ Q) + 48 , 2 72 7th , 32 7, , 25 108 -CH ₂ CE ₃ -CCl ₃ + 56 , 4 64 7th , 15 7, , 02 8U /1 226

109 -CO ₂ CH ₂ CY ₃ -CH ₂ -0-f ^) + 45.5 35 7.12 6.83

110 -If% -CH ₂ CH ₂ CK ₅ +38.7 59 7.50 7.36

111 -CH ₂ CH ₃ -j / ^X ) + 46.6 44 7.70 7.53

112 -CH ₂ CH ₂ CH ₃ \ ^ J +47.4 54 7.50 7.54

- \ __ J + 47.1 59 6.91 6.83

114 -CH ₂ - ^ J) - (CH ₂ J ₅ GH ₃ + 46.9 59 6.82 6.85

115 -CH ₂ CH ₃ - (CIy ₅ CH ₃ + 54.9 51 7.58 7.45

Reference 5

8.63 g of 6-aminopenicillanic acid were suspended in 50 ml of dimethylformamide and 8.3 ml of triethylamine were then added to the suspension. Then, by stirring at a temperature below 10 ⁰ C for ₃ to 6-aminopenicillanic acid to dissolve. To the resulting solution was added dropwise 15 jO g of 1-Acetoxypropylbromid with stirring at 10 ^J C added. Then the mixture was stirred for 2 hours at room temperature.

100 ml of ethyl acetate were added to the reaction mixture and the triethylamine hydrochloride formed was filtered off. The piltrate was then washed twice with 30 ml of saturated aqueous sodium chloride, solution washed and then further with 50 ml of 5% Washed aqueous sodium bicarbonate solution and finally with 50 ml of saturated aqueous sodium chloride solution rewashed. It was then dried over anhydrous sodium sulfate. The solvent was taking

209844/1226

then distilled off under reduced pressure at low temperature. The oily residue obtained was washed with petroleum ether and dried under reduced pressure. It was 9 ₃ 3 g of yellow, oily "6-aminopenicillanic. 1-acetacxypropyl ester was obtained in a yield of 73.7 % .

Infrared absorption spectrum:

VNH ₂ 3350 cm (amino group)

VC = 0.180 cm " ¹ (β-lactam), 1750-1760 cm" ¹ (ester)

Reference 6

8.63 g of 6-aminopenicillanic acid were suspended in 50 ml of dimethylformamide and then 8.3 ml of triethylamine were added to the suspension. It was then stirred to dissolve the 6-aminopenicillanic acid. To the solution obtained, 24.0 g of α-benzoyloxybenzyl bromide was added dropwise with stirring at 10 ^° C. The mixture was then stirred for 2 hours at room temperature. The mixture was then treated further as indicated in reference 5. 13 * 0 g of yellow powder from the 6-aminopenicillanic acid α-benzoyloxybenzyl ester were obtained in a yield of 76.4 % .

Infrared absorption spectrum:

3350 cm (amino group)

vC = 0 178O cm " ¹ , (ß-lactam), 1740-1750 cm" ¹ (ester)

Example II6

In 30 ml of dichloromethane there was 3.2 g of 6-aminopenicillanic acid. 1-acetoxypropyl ester dissolved. 2.5 g of D (-) - ct-Phenylglycylchlorid.Hydrochlorid und 20 ml of dichloromethane, which 1.4 ml of triethylamine

209844/1226

contained, alternatively added to the solution, whereby the solution was maintained at a pH of about 3.

Then, after the mixture was stirred at the same temperature for 2 hours, the reaction product liquid was washed twice with 30 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure at a low temperature to obtain an oily residue. 50 ml of cold water and 20 ml of ethyl acetate were added to the residue. It was then stirred well to dissolve the residue, and after removing the gummy insoluble matter contained therein from the solution, the formed aqueous layer was separated. Then, after washing the aqueous layer with 20 ml of ethyl acetate, 30 ml of ethyl acetate was added to the overlay and it was saturated with sodium chloride.

Then, the thus formed ethyl acetate layer was separated, and the thus separated aqueous layer was further extracted with 20 ml of ethyl acetate. The ethyl acetate extracts were combined with the ethyl acetate layer and the mixture was washed with 20 ml of cold and saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at low temperature. To the residue was added 50 ml of ether and the crystals formed were separated by filtration. By washing the crystals with a small amount of ether and drying the same 2.6 g of white powder of the Ampicillin.l-acetoxypropylester.Hydrochlorid having a melting point of 107 was - 110 ⁰ C (with decomposition) in a yield of 52.9% .

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Elemental analysis as C ^ HggN-rOg

C (%) H (50 N {%) Cl (5?) Calculated: 51.90 5 ₃ 8l 8.65 7.30 found:. 51.48 6.24 8.37 7.05

Example 117

_{4 3} 26 g of 6-aminopenicillanic acid, α-benzoyloxybenzyl ester were dissolved in 40 ml of bichloromethane. Then 2.5 g of D (-) - a-Phenylglycylchlorid.Hydrochlorid and 20 ml dichloromethane with a content of 1.4 ml triethylamine were alternatively and slowly to see the solution with stirring and cooling to a temperature> between -5 ° C to -10 ° C added. This kept the reaction liquid at a pH of about 3. Thereafter, the mixture was stirred for 2 hours at the same temperature ₃ and the reaction mixture thus obtained was washed ζ '·' 9ΐ times each with 30 ml of saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure at a low temperature to obtain an oily residue. 100 ml of cold water and a mixture of 30 ml of ethyl acetate and 20 ml of petrol were added to the residue, and the mixture was then stirred to dissolve the residue. Then, after filtering off the rubbery insoluble matter from the solution, the formed aqueous layer was separated. The aqueous layer was washed with a mixture of 20 ml of ethyl acetate and 10 ml of petroleum ether, and it was mixed with a small amount of activated charcoal and then filtered. To the piltrate was added 30 ml of ethyl acetate as an overlay and then sodium chloride was added with stirring until saturation. The ethyl acetate layer thus formed was separated and the aqueous layer formed was further extracted twice with 20 ml of ethyl acetate each time.

209844/122

The ethyl acetate extracts were combined with the ethyl acetate layer separated above, and the mixture was washed with 30 ml of cold and saturated aqueous sodium chloride solution. It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at low temperature. To the residue was added petroleum ether and the crystals thus formed were separated by filtration, washed with a small amount of petroleum ether and dried to give a 3.4 β white powder of the ampicillin α-benzoyloxybenzyl ester, hydrochloride having a melting point of 145-146 ° C. (with decomposition) in obtained a yield of 57jl % .

Elemental analysis as

calculated
found

C ( %) H (Z 60, 45 5, 07 60, 16 5, 60

7.05

6.89

Cl (y

5.95 6.20

Furthermore, we knew the following by similar procedures according to Examples II6 and 117 the compounds having the following formula are prepared.

H.

_J ^CH 3

HCl

COOCEO-C-R '

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Tabel Example no.

Melting points C)

118 119 120

121

-CH

-CH-

-CH,

-GH -CH

CH-CH,

103-105

111-114 115-118

135-138

122 -CHp CHpCHpCH-T "W I28-I3O 123 -CH, 134-137 124 -CH ₃ 137-138 125 -CH ₂ -O ^ J) -CH ₃ 116-119 126 -CH ₃ / ™ ιττ / ™ * XJ ff \\ 118-122 127 -CH ₃ -CCl 148-149 128 -CH ₂ CH ₃ -CH ₃ 107-110 129 / Γ * TJ \ / ^ ¹ XT
\ VxXx r \ J £ "\ - τΠ · γ -CH ₃ 104-108 130 -CH (C ₂ H ₅ J ₂ -CH ₃ 88-107 131 ~ ^C vO -CH ₃ I5O-I52 132 -CH ₂ CH ~ -CH ₂ CH ₃ 100-104 133 - (CH ₂ ) ₂ CH ₃ -CH ₂ CH ₃ 113-120 134 -CH (CH ₃ ) ₂ -CH ₂ CH 130 136 135 -C (CH ₃ ) ₃ -CH ₂ CH ₃ 125-128 136 -CH (CH ₂ CH) 2 -CH ₂ CH ₃ 105-108 137 -CH ₃ - (CH ₂ ) ₂ CH ₃ 95-99 138 -CH ₂ CH _ ^ r ¹ TJ N Pu
2 2 3 122-126 139 - (CH ₂ J ₂ CH ₃ 122-123 140
1
ί -CH (CH ₃ J ₂ • ^ ^ f * TT ^ πττ 106-110

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j) ₆ CH ₃ - (CF ₂ J ₂ CK ₃ 105-110

142 -C (CH ₃ J ₃ - (CH ₂ J ₂ CH 111-115

143 -CH (CH ₀ CH,) _O - (CH ₀ J ₀ CH, 85-104

144 ( ^H / ~ - (CH ₂ J ₂ CH ₃ 127-130

145 -CH ₀ -O- ^ ^X ) - (CH ₀ J ₀ CH, 117-120

146 -CH ₃ -CH (CH ₃ J ₂ 115-119

147 -CH ₂ CH ₃ -CH (CH ₃ J ₂ 126-128

148 -CH (CH ₃ J ₂ -CH (CH ₃ J ₂ 124-126

149. -C (CH ₃ J ₃ -CH (CH ₃ J ₂ 127-130

150 -CH, - (CH ₀ Jt-CH, 108-112

151 -CH ₃ Λ = / 139-140

152 -C (CH ₃ J ₃ ^ V- / 143-144

153 - ^CE 2 ~ 4f_y "C = / 128-130

154 -C (CH ₃ J ₃ -CH ₂ CH ₀ ^ 7 128-129.5

155 -Y _) / -CH ₂ CH ₂ - ^ / ^X ) 136-140

156 -CH ₉ V 7 -CH ₀ CH ₀ </ ^x ) 105-110

209844/1226

Claims (14)

Claims li acyloxyalkyl esters of 6- (a-aminophenylacetamido) - ■ "'penicillanic acid, J- (a-aminophenylacetamido) cephalosporanic acid or 7- (ot-aminophenylacetamido) desacetoxycephalosporic acid with the general formula CH - CONH - A NH, where A has the following meaning or COOCHO-CR 'R ¹ wherein R and R are each an unsubstituted alkyl, Cycloalkyl, alkenyl or phenyl group or a substituted alkyl, cycloalkyl, alkenyl or Phenyl group with a phenyl group represents a phenoxy group or a halogen atom, and R ^ represents Is hydrogen atom or an acetoxy group as well as the mineral acid salt of the ester. 2098U / 1226 2. The Hydrochloric! dos 6- (a-aminophenylacetamido) -penicillanic acid acyloxyalkyl ester according to claim 1 with the general formula ; IiCONH COOCHOC-R R ¹ wherein R and R each represent an unsubstituted alkyl, Cyclone alkyl, alkenyl or phenyl group or a substituted alkyl, cycloalkyl, alkenyl or phenyl group with a phenyl group is a phenoxy group or represents a halogen atom. 3. The Hydrochloric! of 7- (a-aminophenylacetamido) -cephalosporanic acid acyloxyalkyl ester according to claim 1 with the general formula —CHCONH ! K _S ^ X! H ₂ OCOCH ^> 3 coocno-cn ² 1 2
wherein R and R each represent an unsubstituted alkyl, cycloalkyl, alkenyl or phenyl group or a substituted alkyl, cycloalkyl, alkenyl or phenyl group with a phenyl group, a phtnoxy group or a halogen atom. 2098AA / 1 226 4. The hydrochloride of 7- (a-aminophenylacetamido) -desacetoxycephalosporanic acid acyloxyalkyl ester according to claim 1 with the general formula HCONH—
• NH ₉ χ * COOCHO - ^ - R ² . R ¹ 1 2
where R and R each represent an unsubstituted alkyl, cycloalkyl, alkenyl or phenyl group or a substituted alkyl, cycloalkyl, alkenyl or phenyl group with a phenyl group, a phenoxy group or a halogen atom. 5. ^ - (a-Aminophenylacetamidoipenicillanic acid. 1-acetoxypropyl ester. Hydrochloride. ' 6. O-Ca-aminophenylacetamidoipenicillanic acid. 1-isobutyriloxybutyl ester. Hydrochloride. 1-pivalayl.axyimty! Ester, hydrochloride. 8. ö-fa-aminophenylacetamido-penicillanic acid. α-butyryloxybenzyl ester. Hydrochloride. 9. 6- (a-aminophenylacetamido) penicillanic acid, α-benzoyloxybenzyl ester. Hydrochloride. 10. 6- (α-Aminophenylacetamido) penicillanic acid. l-acetoxy-3-phenylpropyl ester. Hydrochloride. 11. 6 ~ (α-Aminophenylacetamido) penicillanic acid. 1-isobutyryloxybutyl ester. Hydrochloride. 12. Cephalexin. 1-acetoxyethyl ester. Hydrochloride. 13 · Cephalexin. 1-propionyloxybutyl ester. Hydrochloride. 14. Cephaloglycine. 1-acetoxypropyl ester. Hydrochloride. 2098U / 1226 15 · use of the said compounds to 14 as an orally administrable and antibiotic activity comprising following administration in claims 1 UEN active ingredients for producing pharmaceuticals for humans and animals. 209844/1226