DEL0019646MA - - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

Registration date: August 17, 1954. Advertised on October 6, 1955

GERMAN PATENT OFFICE

It is known that the esters of penicillin with amino alcohols that are mono- or disubstituted on nitrogen have in the case of intramuscular injection in the form of their salts, the property of being in certain body tissues, z. B. in the lung tissue, to accumulate in higher concentrations than in the blood. Based on these Properties these esters offer advantages in the treatment of infections of the tissues concerned, because with them a higher concentration of ίο penicillin can be achieved than with the corresponding ones Doses of an otherwise common penicillin salt or you can get a high one with an injection Maintain the concentration of penicillin in the inflamed tissue for an extended period of time.

It has now been found that there is an even greater accumulation of penicillin in certain Organs can be achieved by esters of penicillin with basic substituted phenols or Thiophenols used. The esters of unsubstituted phenol and thiophenol and those of Benzyl alcohol are already known [cf. Journal of the American Chemical Society, Vol. 75 (1953), P. 3636]. The esters of penicillin with basic substituted phenols and thiophenols are, however not yet shown. You own that

509 565/41

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lx'deiileiiden advantage that a higher percentage the amount of penicillin enriched in the tissue that is being matured is present in the form of free penicillin is. The toxicity of the new esters is somewhat lower than that of the known lister.

The present invention relates to a process for the preparation of such new esters of penicillin. These esters are mono- or diesters of phenols or thiophenols that have the general ίο formula ^, _T >

γ - N

where X _{1 is} a TIO or HS group and X. is a hydrogen atom or an HO or HS group and R ₁ and K _{1 are} alkyl groups or parts of a group which, together with the nitrogen atom, form a heterocyclic ring , while Y is an alkylene group which is bonded to a carbon atom of the benzene nucleus either directly or via one of the following groups: - O -, --NH--,

NR, (X), --COO ---, -CONH--,

CONR, NHCO, NRCO, NHCS--,

NRCS, CSNH or -CSNR, where

the group R is in each case an alkyl or an alkylene radical. The method according to the invention consists essentially in that a compound of the above composition is based on an anhydride of penicillin can act with a carboxylic acid, this anhydride of the general formula

Pen C O O - Z

corresponds, in which pen means the penicillic acid residue without a carboxyl group, while Z means an acyl residue including the ayl groups of penicillic acid and represents the monoalkyl ester of carbonic acid.

The production of the penicillin anhydride is difficult and leads to great losses, which is why according to the process a mixed anhydride of penicillin with a low molecular weight aliphatic monocarboxylic acid l) between an aromatic carboxylic acid, e.g. B. benzoic acid, or even better a mixed anhydride of penicillin with a monoester of

• 15 carbon dioxide is used. These mixed anhydrides can easily be produced by the reaction of a , Penicillin salt with a chlorocarbonic acid ester in an inert solvent can be obtained. Chlorocarbonic acid ester correspond to the general formula Cl CO O R, where R represents an alkyl radical.

Can be used as the starting material for the new process

you can use any stable penicillin salt, however, it is recommended to use salts of penicillin with tertiary salts

Amines, e.g. B. the triethylamine salt or the N-Athylpiperidinsalz or metal salts such as the sodium or potassium salt to be used.

In your erlindungsgemäßen Wiest erungs decaying reu various solvents can be used, with the exception of organic compounds containing hydroxyl groups, since these compounds otherwise react with the ^r in the method \ erwendeten penicillin derivative. The solvent can be immiscible with water, such as the chlorinated hydrocarbons, or it can be water-miscible, such as acetone. In the latter case, the reaction mixture can contain certain amounts of water. If the preparation of the anhydride of penicillin with a carboxylic acid is carried out in the same reaction medium as is used in the esterification, which is generally preferable, the use of a completely or partially water-miscible organic solvent offers the advantage that to that A small amount of water can be added to the reaction medium, as a result of which the solubility of the alkali metal salts of penicillin in the solvent is increased if such a salt is used as the starting material. On the other hand, water present in the reaction medium tends to decompose the anhydride, which then lowers the yield. Benzene can also be used, but it is less suitable than the oxygen-containing organic compounds. The aliphatic hydrocarbons are unsuitable because of the low solubility of the reactants in these solvents.

The inventive method is preferably carried out at low temperatures, e.g. B. between - 20 to + 40 °, in particular at o °, carried out. In general, the esterification of the penicillin anhydride can be carried out directly after the preparation of this anhydride without its special isolation.

The presentation of this penicillin anhydride and, in certain cases, the subsequent esterification is best carried out in the presence of a basic catalyst. If you use a metal salt of If penicillins are used, a small amount of an organic base, e.g. triethylamine or pyridine, are added to the reaction mixture, for example ο, οτ to 0.02% pyridine.

The esters can be isolated as such from the reaction mixture or can be given in the form isolate their salts with a physiologically harmless acid. Suitable acids for this are e.g. B. Hydrochloric acid, hydrogen bromide and hydriodic acid, sulfuric acid, citric acid, lactic acid, benzene sulfonic acid, Toluenesulfonic acid and penicillin. The new esters are usually viscous oils per se or amorphous powders, although in some cases they may be crystalline. The salts are crystalline or amorphous substances.

If the esters are to be isolated, the reaction mixture can, for. B. with an aqueous sodium bicarbonate solution and water and then dried over anhydrous magnesium sulfate, whereupon the solvent is evaporated off in vacuo and the ester is obtained as a residue. If wants to produce a salt of the penicillin ester, the solution of the acid in question is washed and added dried reaction mixture. If the salt then does not precipitate, the precipitation can take place can be achieved by subsequent addition of a suitable solvent.

A large number of pharmacological studies have been carried out with those according to the invention new connections made. In

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the following table I are the determined values of the penicillin level in the blood, in the lungs, liver, Kidney and spleen of guinea pigs compiled ι and 2 hours after the subcutaneous injection. the Numerical values represent international units of penicillin. Several according to the invention were compared Process produced compounds with the sodium and the procaine salt of penicillin.

Table I.

Derivatives of
Benzyl penicillins

Sodium salt

Procaine salt

4- (ß-diethylaminoethyl) phenyl ester citrate

4 - (/? - piperidinoethyl) phenyl ester hydrochloride

4- (ß-Diethylaminoethoxy) phenyl ester citrate

4- (cw-diethylaminoaceto) -phenylester-hydrobromide

4- (N-methyl-N-diethylaminoethyl) aminophenyl ester dihydrochloride

4 - (/ 9-Diethylaminoethyl thiocarbamido) phenyl ester citrate

4- (β-diethyl aminoethyl carboxamido) phenyl ester citrate

4- (tt) -Diethylaminoacetamino) -

phenyl ester hydrochloride

3- (ω-diethylaminoacetamino) -

phenyl ester hydrochloride .......

4- (γ-diethylaminopropyl) phenyl ester citrate

4- (ß-Diethylaminopropyl) phenyl ester citrate

4- (/ 3-dimethylaminoethyl) phenyl ester citrate

2- (/ 3-diethylaminoethyl) phenyl ester hydrobromide

3- ((3-Diethylaminoethyl) phenyl ester citrate

Hours after injection penicillin levels in

blood
IE / ccm

lung

Liver IU / g

kidney

MIz IU / g

000
000

000
000
000
000
000
000
000
000
000
000
000
000
000
000

26.0

i4, o
5.9

i5, o
8.8

12.0

20.0
7, ¹

25.0
13.0

3.2
3.6

13.0

14.0
6.9

6.5
3.9

3.5

7.9
13.0

7.6
5.9

17.0
7.7

4.9

10.0
9.2

35, o 8.1

5.5 1.9

151.0 35, o

56.0

66.0 17.0

15.0 6.6

27.0 23.0

19.0

15.9 12.4

40.0 14.8

20.0 12.0

53, o 30.0

37, o 13.0

53, o 22.0

39, o 28.0

59, o 31.0

9.7 3.4

16.0

4.9 3.2

18.0 17.0

8.6 3.5

10.0

13.5

15.0

6.9 4.8

11.0 3.6

10.0 10.0

18.0 4.9

8.7 11.0

3.6

10.0

87 52

77

37 40

78 48

33

18th

39

37 32

101

14th

49 124

38 20

36 34

11th

! 9

46

30th

4.3 2.2

5.7

-

3.7 3.4

5.2 3.5

5.4

2.0

5.0 ΐ, 8

6.3

2.3

5.4

2.3

4.4 3.9

4.4

2.4

4.7 5.5

4.2

3.4

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For comparison, the distribution of penicillin was also examined after injection of phenylleis. The animals, weighing about 200 g, received injections corresponding to 25,000 IU of penicillin. After 1 hour, the concentration of active penicillin in the blood and lung tissue was determined. ^{1.7 μ / cm 3} were found in the blood and 0.0 IC / g in the lungs. This shows that the strong Akkuniuliening in the lung tissue, which z. B. in the. | - (// - 1) iäthylaminoäthyl) -phenylest it is ten times the concentration in the blood, is not due to the phenyl residue, but is based on the presence of a tertiary amino group in the side chain of the phenol derivative.

In a further series of experiments, the decrease in the penicillin level after injection of a of the compounds according to the invention, namely the citrate of benzylpenicillin [4 - (/? - diethylaminoethyl) phenyl] ester (Compound I) with that of the benzylpenicillin diethylaminoethyl ester - hydroiodide (II), the sodium salt of benzylpenicillin (III) and the corresponding procaine salt (IV) with one another compared (see Table II). These compounds were given to guinea pigs in doses of 50,000 IU each The animal is injected subcutaneously and the penicillin spicgel is injected at various intervals after the injection Blood and in the lungs determined. The results are given in Table II, the numbers denoting indicate international units per ecm blood and g lung.

Table II

after the injection

blood

lung

lung

III

blood

lung

IV

blood

lung

3 4th 5

16.0
13.0

8.4
8.5
3.3
1.7

197.0

108.0

40.0

² 3> °

5.3

2.3

2.8

90.0
38.O
11.0

2.8

1.3

73.0
26.0

1.7
0.5 0.1 0.1

35.0
8.1
o, 7
o, 3
0.4
0.07

17.0

14.0

5.9

2.1

5.6

5.5
1.9

1.7
1.0

The table shows that the! Connection to a stronger Akkumu-Ii (MMiHg in the lungs and have a longer lasting effect than any of the other penicillin compounds leads.

In Table II represent the numbers for the compounds I and II the value for the total penicillin, i.e. H. both for the free penicillin and for the Penicillin ester. The higher the proportion of free penicillin compared to the penicillin ester, the more but the antibiotic effectiveness is greater. It

Table III (Total
penicillin penicillin
ester Free
penicillin lung Total
penicillin penicillin
ester Free
penicillin l'enici Hi 11 connection 4.8
7.2
4.3 0.6
3.7 4, o
4.6
4.3 71.0
8.0
1.8 7.3
3, o 51.O
2.8
1.8 J blood 11th Sodium salt

was therefore the distribution of free penicillin and of penicillin as an ester compound after injection of penicillin esters in the animal body. Monkeys were given a dose of 50,000 IU intramuscularly of the above-mentioned compounds I and II and the sodium salt of penicillin per kg of body weight injected and 2 hours later the penicillin level in the blood (IU / ccm) and lungs (IU / g) and the concentration determined by free penicillin and penicillin esters. The results are shown in Table III.

In addition, the sensitivity of a number of bacterial strains to the sodium salt was determined of the penicillin and the compound I mentioned in dilution series tested.

On (inind the slow splitting off of free Penicillin from compound I was to be expected when using this technique, the sodium penicillinate would give about twice the activity of compound I. This was also in the most attempts do. However, it was still found that.! the penicillin-resistant strains of Mierocoecus pyogenes v. aurius, the penicillinase produce a lot compared to compound I.

Table IV

Bacterial strain
Xr.

CJ (not resistant)

CJ 5 (resistant). .

CJ 7

CJ 8

CJ 9

C] 10

CJ II

Penicillin concentration
Sodium salt | Connection!

0.03
185.0
185.0
185.0
l6.0
250.0

8.0
185.0

0.06
36.0
24.0
48.0

8, o
185.0

6.0
62.0

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were more sensitive than to sodium penicillinate.

The microorganisms studied were all great

highly virulent, resistant micrococci isolated from patients. The figures in Table IV give the concentrations of penicillin in IU / cc, which show a 5o ° / ₀ inhibition.

The following examples illustrate the preparation of the new compounds according to the invention.

Example ι

18.6 g (0.05 mol) of the potassium salt of benzylpenicillin were suspended in 100 ecm of methylene chloride containing 4.8 ecm (0.05 mol) of ethyl chlorocarbonate. The mixture was cooled by ice and 2 ecm of an i ° / _o pyridine solution in methylene chloride added, the mixture was allowed to stand 30 minutes under stirring and then a solution of 9.65 g of 4 -.. (/ 3-diethylaminoethyl) phenol was added in 40 cc of methylene chloride at once After further 30 minutes long standing was the precipitated potassium chloride was filtered off and a solution of 5.25 g (0.025 mol) of citric acid monohydrate in 100 ecm butanol was added to the filtrate, whereupon the methylene chloride was evaporated in vacuo. Then a further 5.25 g of citric acid monohydrate in 100 ecm butanol were added, whereupon 28 Separate up to 29 g of citrate of benzylpenicillin [4 - (/ 9-diethylaminoethyl) phenyl] ester with a purity of 95 to 100 ° / ₀ and a melting point of F - 80 ° (decomp.). The rotation was: ( α)! ⁰ = + I ₃ 6 ° (c = 2.5 _^0/0 in water).

In the above example, the ethyl chlorocarbonate can be replaced by an equivalent amount of another chlorocarbonate or an acid chloride, as indicated below, the relevant yields of the citrate of benzylpenicillin - ^ - (/ 3-diethylaminoethyl) phenyl] ester being : Chlorkohlensäuremethylester 57 ° / _0, chlorine carbonic-propyl ester 73%, chlorine carbonic-butyl ester 72%, chloroformic acid isobutyl ester 72%, chlorine carbonic-hexyl ester 77%, trimethylacetyl chloride 62%, diphenylacetyl chloride, 59 ° / ₀ , ct-ethylcaproic acid chloride 57%, benzoyl chloride 70 ° / _n .

Example 2

18.6 g of the potassium salt of benzylpenicillin were suspended in 100 ecm of methylene chloride containing 4.8 ecm of ethyl chlorocarbonate. The mixture was cooled with ice, followed by 2 a i ° / _o added in methylene chloride ecm solution of pyridine and long after 30 minutes of stirring 9.65 g (4 - (/ -? Diäthylaminoäthylphenol) were added After an additional 30 minutes, the was. reaction mixture with 200 cc of 2 ° / _o sodium bicarbonate solution, whereupon the methylene chloride layer over magnesium sulfate, was dried. the methylene chloride was chased under reduced pressure, the residue is dissolved in 150 cc of methyl isobutyl ketone and then added a solution of 7.5 g of lactic acid in 30 cc of methyl isobutyl ketone. The weight of the precipitated crystals was 20.1 g. A further 2.6 g could be obtained from the mother liquor, resulting in a total yield of 22.7 g of lactate of benzylpenicillin [4- (ß-diethylaminoethyl) phenyl] ester, that is 75% of theory, the degree of purity was 100% and the rotation (a) f = + 168 ° (c = 2% in water).

If you methylene chloride by trichlorethylene and the chlorocarbonic acid ethyl ester by a corresponding Replaced amount of benzoyl chloride in the above example, the lactate of benzylpenicillin [4- (ß-diethylaminoethyl) -phenyl] ester obtained in a yield of 60% of theory.

If the potassium salt of the above example was replaced by 17.8 g of the sodium salt and methyl ethyl ketone was used as the solvent instead of methylene chloride, 15.6 g of lactate of benzylpenicillin [4- (β- diethylaminoethyl) phenyl] ester were obtained accordingly a yield of 50% of theory.

Example 3

18.6 g of the potassium salt of benzyl penicillin were suspended in 100 ecm of methyl isobutyl ketone. The suspension was cooled to O °, and then 4.8 cc Chlorkohlensäureäthylester and 2 a i ° / _o ecm pyridine solution in methyl isobutyl ketone were added sequentially. The mixture was left to stand for 1 hour with stirring, whereupon 9.65 g of 4 ~ ( β-diethylaminoethyl) phenol were added. After a reaction time of 30 minutes, the mixture with 200 cc of 2 ° / _o sodium bicarbonate solution was washed. The methyl isobutyl ketone layer was then dried over magnesium sulfate and 7.5 g of lactic acid dissolved in 30 ml of methyl isobutyl ketone was added to the dried solution. After standing at 0 ° for 2 hours, 19.6 g of lactate of benzylpenicillin [4 - ( β - diethylaminoethyl) phenyl] ester corresponding to an amount of 65% of theory were filtered off.

If the ethyl chlorocarbonate is replaced by a corresponding amount of benzoyl chloride in the above Replaced example, 16.5 g of lactate of benzylpenicillin [4- (^ -diethylaminoethyl) phenyl] ester were accordingly obtained a yield of 55% of theory.

Example 4

3.72 g of the potassium salt of penicillin were suspended in 75 ecm of methylene chloride and 0.96 ecm of ethyl chlorocarbonate in 20 ecm of methylene chloride added. The mixture is cooled to 0 ° and 0.02 g of pyridine in 2 ecm of methylene chloride was added. After stirring for 30 minutes, it became a solution of 2.9 g of 4- (γ-diethylaminopropyl) phenol hydrobromide and 1.40 ecm of triethylamine in 50 ecm of methylene chloride added. After standing at 0 ° for 2 hours, the solution was washed with a saturated sodium bicarbonate solution and washed with water, after which the methylene chloride layer over magnesium sulfate dried. After removing the magnesium sulfate by filtration, 50 ecm of isopropanol and 2.1 g citric acid monohydrate in 20 ecm acetone added. On addition of 100 ecm of ether crystallized the citrate of benzylpenicillin [4- (γ-diethylaminopropyl) phenyl] ester out. The yield was

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70%, the degree of purity corresponded to 755 IC / mg and the melting point was 95 ^° (with decomposition).

The citrate of BiüizyliM'nicilliii-1 was 4- (// - diethylaniinopropyl) phenyl] ester in a corresponding manner from the. | - (/ M) ethylaminopropyl) phenol hydrobromide obtained as an amorphous powder with a purity of 654 ΙΕ / mg.

With 2.72 g of 3 - (/ M) ethylaminoethyl) -]) henol hydrobromide the citrate of benzylpenicillin [3 - (/ i-diäthylaiiiiii ( > ethyl) phenyl] ester as a white crystalline substance with a purity of 664 IU / mg and a melting point of F. = -89 to 91 ° in a yield of 65 ° / ,, of theory.

With 2.72 g of 2 - (/} - diethy! Aminoethyl) phenol hydrobromide, the citrate of benzylpenicillin [2 - (// - diethylaniinoethyl) phenyl] ester was obtained as an amorphous powder. This was dissolved in water and the hydrobroniide was precipitated by adding an aqueous solution of potassium bromide. The aqueous layer was decanted off, the viscous oil which had separated out was dissolved in 75 ml of methylene chloride and this solution was dried over magnesium sulfate. After filtering, 200 ecm of ether were added, whereby the benzylpenicillin -1 2 - (// - diethylaminoäthyl) -phenyl] -esteras hydrobromide as an amorphous light yellow powder with a purity of (χμ IU / mg and a yield of 35 ⁰ / ii iius fell .

In a corresponding manner gave 4-oxy-ro-diethylamino-acetophenone hydrochloride the liydroliromid of benzylpenicillin -1 4 - («» -diätliylaminoaceto) -phenyl] -ester with a purity of 950 IU / mg.

Example 5

4.4 (1 g of the N-ethylpiperidine salt of benzylpenicillin were dissolved in 100 ecm of methylene chloride, the solution was cooled to o ", whereupon 0.96 ecm ("Ethyl chloroate were added. According to Standing at 0 'for 30 minutes, a solution of 2.0 g of i-oxy-o-dietliylaminoacetanilide hydrochloride and 1.5 ecm triethylamine in 50 ecm methylene chloride added. After standing at 0 ° for one hour, the mixture was left at room temperature overnight. The solution was then made with a saturated sodium bicarbonate solution and with water washed and dried over magnesium sulfate.

Letzleres was filtered off and 2.1 g of citric acid monohydrate in 20 ecm of acetone added, on

With the addition of ether, the citrate of benzylpenicillin-4 - ( >> - dietliylaininoacetamino) phenyl] ester precipitated as an amorphous substance. This amorphous citrate had a purity of o () 2 IU / mg. The yield was 45 "/ (i of theory.

In a corresponding manner gave 2.72 g of N-diethylaniiiio-ethyl -.) - () xybenzamide hydrochloride the citrate of the benzylpenicillin [.] - (i »-d iä ti lylaminoät hylcarboxyamido) -phynyl-ester in a yield of 30 "/" and a degree of purity of 631) IU / mg.

Example ö

^Gu 3.72 K (°. ^{() 1} M "') potassium salt of benzylpenicillin were suspended in 75 ecm methylene chloride and <), <) (> ecm chlorocolylic acid ethyl ester, dissolved in 20 ecm methylene chloride, added. The mixture was cooled to 0 ° and 0 02 g of pyridine in 2 ecm of methylene chloride were added The reaction mixture was left to stand with stirring at 0 ° for 30 minutes, whereupon a solution of 3.4 g of 4- (N-methyl-N-diethylaminoethyl) aminophenol hydrochloride hydrobromide and 2 8 ecm of triethylamine in 100 ecm of methylene chloride was added. The mixture was left to stand for 2 hours at 0 °, after which it was washed with sodium bicarbonate solution and water. After drying over magnesium sulfate, an ethanolic solution of an equivalent amount of hydrochloric acid was added 200 ecm of ether are added and the precipitated hydrochloride is reprecipitated from ethanol-ether, whereby the hydrochloride of benzylpenicillin [4- (N-methyl-N-diethylaminoethyl) aminophenyl] ester is in the form of an amorphous n substance was obtained. The degree of purity was 915 IU / mg and the yield JO ⁰ I ₀ of theory.

Example 7

3.72 g of the potassium salt of benzylpenicillin were suspended in 75 ecm of methylene chloride. Then 0.96 ecm of ethyl chlorocarbonate dissolved in 20 ecm of methylene chloride was added. The mixture was cooled to 0 ° and 0.02 g of pyridine in 2 ecm of methylene chloride was added, whereupon the mixture was left to stand with stirring at 0 ° for 30 minutes. 2.22 g (0.01 mol) of 2-oxy-w-diethylaminoacetanilide were then added and the mixture was left with stirring for 4 hours. After washing with sodium bicarbonate solution and with water, the solution was dried over magnesium sulfate. 2.1 g of citric acid monohydrate, dissolved in 20 ecm of acetone, were then added, whereupon the amorphous citrate was precipitated by adding ether. The citrate was filtered off, dissolved in water and the amorphous hydrobronide was precipitated by adding an excess of aqueous potassium bromide solution. The water was decanted off and the hydrobronide was dissolved in 50 ecm of methylene chloride. The solution was dried over magnesium sulfate and then ether was added. This gave the hydrobromide of benzylpenicillin - [2 - ((D- diethylaminoacetamino) -phynyl] ester as an amorphous substance with a purity of 930 IU / mg.

110 Example 8

3.72 g of the potassium salt of benzylpenicillin were suspended in 75 ecm of methylene chloride and 0.96 ecm of ethyl chlorocarbonate in 20 ecm of methylene chloride were added. The mixture was cooled to 0 °. Then 0.02 g of pyridine in 2 ecm of methylene chloride and, after stirring for 30 minutes, a further 2.22 g of 3-oxy-co-diethylaminoacetanilide were added. The mixture was stirred for 3 hours and then washed with sodium bicarbonate solution and with water. After drying with magnesium sulfate, the equivalent amount of ethanolic hydrochloric acid was added. An amorphous hydrochloride was precipitated by the addition of ether, which was then reprecipitated from ethanol-ether. In this way, the benzylpenicillin - [3 - ( ω - diethylaminoacctamino) -

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L 19646 IVc / 12p

phenyl] ester hydrochloride as an amorphous substance a purity of 1060 IU / mg.

In a corresponding manner, 2.52 g of N-diethyl

aminoethyl-4-oxythiobenzamide to benzylpenicillin ^ - (N-diethylaminoethylthiocarbamidoJ-phenylJ-ester hydrochloride as an amorphous yellowish substance with a purity of 937 IU / mg.

Example 9

1.86 g (0.005 moles) of the potassium salt of benzylpenicillin were dissolved in 45 ecm of methylene chloride and 0.48 ecm of ethyl chlorocarbonate in 5 ecm Methylene chloride added. After cooling to 0 °, 1 ecm i% strength pyridine solution was added in methylene chloride added. After stirring for 30 minutes, 1.025 g of 4 - (/ 3-piperidinethyl) phenol were dissolved in 100 ecm of acetone solved, added. After a reaction time of 30 minutes, the reaction mixture was with Sodium bicarbonate solution and washed with water

ao and dried over magnesium sulfate. After filtering, the solution was evaporated in vacuo, the residue was dissolved in isopropanol and the solution was titrated with ethanolic hydrochloric acid. On addition of ether, benzylpenicillin [4 - (/ 5-piperidinethyl) phenyl] ester hydrochloride crystallized out in a yield of 0.62 g. The melting point was 163 to 167 ⁰ and the degree of purity was 1087 IU / mg.

The benzylpenicillin [4- (/ 3-morpholinoethyl) phenyl] ester hydrochloride with a melting point of 166 to 173 ⁰ and a degree of purity of 1055 IU / mg was obtained in a corresponding manner.

Example 10

To a solution of 0.005 mol of the mixed anhydride of benzylpenicillin and ethyl carbonate, which had been prepared as in Example 9, 0.82 g of 4 - (/? - Dimethylaminoethyl) phenol were dissolved in 25 ecm acetone. After 2 hours the methylene chloride solution was washed with sodium bicarbonate solution and washed with water and dried over magnesium sulfate. After filtering, the Solution evaporated in vacuo and the residue dissolved in dry acetone, whereupon the calculated Amount of citric acid dissolved in acetone added. Thereupon 1.5 g of citrate of benzylpenicillin crystallize - [4 - (/ S-dimethylaminoethyl) phenyl] ester out. By recrystallization from ethanol-ether 0.82 g of crystals with a purity of 718 IU / mg were obtained.

'Example 11

0.01 mole of the mixed anhydride of benzyl penicillin and ethyl carbonate were, as described in Example 9, prepared and to the Reaction solution 2.49 g 4 - (/? - Dibutylaminobutyl) -phenol, dissolved in 32 ecm of methylene chloride, added. After ι hour the methylene chloride solution was like described in the previous examples, washed and dried.

After evaporation in vacuo, the residue was dissolved in 50 ecm isopropanol and this solution titrated with a solution of sulfuric acid in isopropanol. Upon addition of ether, 1.97 g of benzylpenicillin [4- (j8-dibutylaminobutyl) phenyl] ester sulfate were obtained obtained in the form of an amorphous yellow powder with a purity of 710 IU / mg.

Example 12

0.895 g of 4- (/ S-diethylaminoethyl) phenol, dissolved in 30 ecm of methylene chloride, were added to 0.005 mol of the mixed anhydride of benzylpenicillin and ethyl carbonate in methylene chloride. After ι hour the calculated amount of citric acid dissolved in acetone was added. By adding ether, 1.7 g of benzylpenicillin [4 - (^ - diethylaminoethyl) phenyl] ester citrate with a purity of 473 IU / mg were precipitated. The citrate was dissolved in water and the sparingly soluble hydroiodide was precipitated by adding an aqueous solution of potassium iodide. The excreted substance was stirred with ethanol-ether, whereby 0.8 g of amorphous benzylpenicillin - [4 - ( β - diethylaminoethyl) - phenyl] ester hydroiodide with a purity of 724 IU / mg were obtained.

Example 13

0.02 moles of the mixed anhydride of penicillin and carbonic acid ethyl ester were, as in the previous one Examples described, shown. A solution of 0.01 mol of 3, 5-dioxy-diethylaminoacetanilide in 20 ecm of acetone and 0.1 mol of triethylamine were added, whereupon the mixture was left overnight left at o °. After washing with water, sodium bicarbonate solution and water again became the solution dried over magnesium sulfate and then evaporated in vacuo. The residue was dissolved in anhydrous ethanol and added the appropriate amount of hydrochloric acid in ethanol. The hydrochloride precipitated in amorphous form on addition of ether. By falling out of methanol Ether, the hydrochloride was then obtained in crystallized form. Its melting point was 120 ° below

Decomposition. , _,.

Example 14

0.02 mol of the mixed anhydride of penicillin and ethyl carbonate were prepared in the usual manner and then 1.95 g (0.01 mol) of 5-D1-ethylaminomethylresorcinol, suspended in 25 ecm of methylene chloride, added, whereupon the mixture for 2 hours at o ° with stirring and then left to stand overnight at the same temperature. After washing with water, sodium bicarbonate solution and water and subsequent drying over magnesium sulfate, the methylene chloride was evaporated in vacuo. The residue was dissolved in anhydrous ethanol, to which was added ethanolic hydrochloric acid until the _pH value was about 4 hours. The solution was poured into ether, whereby the amorphous hydrochloride compound was obtained. When it was precipitated from methanol-ether, the hydrochloride was obtained as an amorphous powder with a purity of 867 IU / mg.

Example 15

8.72 g (0.02 mol) of the triethylamine salt of benzylpenicillin were dissolved in 100 ecm of methylene chloride,

509 565/41

Claims (1)

L 19646 IYcI12 p whereupon the solution was cooled to 0 ". 2.4 coins (0.025 mol) of fluorocarbon ethyl ester were then added, whereupon the mixture was left _{at 0" for 1} hour. _ ', () () g (0.01 mol) of 4-diethylaminomethylresorcinliydi'oehloi id and 3.5 ecm (0.025 mol) of triethylamine were dissolved in 30 ecm of methyl chloride, whereupon the solution was cooled to o' and the L ( ¹ ISUiIg was added. the reaction mixture was then allowed to stand at room temperature for 3 hours, with water, Xatriuinbicarbonatlösung and water and dried over magnesium sulfate. After evaporation in vacuo the residue mil ether extracted, the ethereal extract was nitrated, and the filtrate was evaporated to a syrup This was then dissolved in acetone and the calculated amount of a 0.5 molar solution of citric acid in acetone was added. The amorphous ("itate was precipitated by pouring the acetone solution into ether. After falling from ethanol-ether, the reaction product became with a degree of purity of 10. | .j receive 1 U / mg. Hey play iö Zn () g of triethylamine salt of benzylpenicillin, which had been dissolved in :>. (> Ecm of chloroform, a solution of 2 ecm of chloroformic acid ethyl ester in 20 ecm of chloroform was added at o. After standing for 10 minutes, a solution of 3.6 g. | - (/) - l> iä (hy] aminoethyl) -phenol in 20 ecm chloroform was added, whereupon the oleisoli was left overnight at 0 ° After washing with water, sodium carbonate solution and more water, the chloroform layer was dried over magnesium sulfate :) Γ> and then evaporated in vacuo. The residue was dissolved in 50 ecm of acetone, whereupon 4 g of citric acid, which had been dissolved in. | o ecm of acetone, was added became. The crystalline citrate of methylpenicillin - [. J - (/> '- dietli \ iaminoethyl) phenyl ester receive. After recrystallization from 50 ecm of ethanol, the yield was Sg. The purity of Substance was 710 IU / mg. When heated, it decomposed at about So °. Example 17 To a solution of 21.75 g of trietliylamine salt Benzylpenieillins in 50 ecm chloroform was a solution of 5 .i3 g of ethyl chlorocarbonate in 50 cm Chloroform added at o ". After 10 minutes Left to stand in this way, a solution of 0.5 g of 4 - (/? - Diälliylaniinoätlioxy) "pheiiol in 50 ecm chloroform was added. The Cieinisch was left to stand at ο overnight and then worked up as in Example ιό. The yield was 15 g of crystallized citrate des l cnzvlpcnieillin - [|! -. (/> ~ diäthylaminoäthoxy) -pheiiyTj-Oster with purity of 715 ΙΕ / mg The substance decomposes on heating at 95 ^0th. Example iS To a suspension of 42 g of the sodium salt of benzylpenicillin in 300 ecm of anhydrous acetone were added 10 drops of anhydrous pyridine and then 11.4 ecm of ethyl chloroate. The mixture was stirred at 0 ° for 1 hour, then 26 g of p-oxybenzoic acid diethylaminoethyl ester were added, whereupon the reaction mixture was left to stand at 0 ° for 12 hours. The precipitated sodium chloride was filtered off and a solution of 25 g of citric acid monohydrate in 250 ml of acetone was added to the clear filtrate. The citrate of the benzylpenicillin ester of p-oxybenzoic acid diethyaminoethyl ester then crystallized out. The yield was 75 S (corresponding to 85% of theory). The degree of purity corresponded to 60.5 IU / mg, and the melting point was 100 ° with decomposition. Example ig 4.9 g of 3-diethylaminomethylthiophenol were added to a solution of 0.02 mol of the mixed anhydride of benzylpenicillin and of the ethyl carbonate in methylene chloride. After standing for one hour, the mixture was washed with a saturated bicarbonate solution. The methylene chloride phase was dried over magnesium sulfate and evaporated to a small volume. When petroleum ether was added, a syrupy substance separated out, which crystallized when left to stand. The pure benzylpenicillin - [2- (diethylaminomethyl) -1 h iophenyl] ester with a melting point of 14T to 142 ⁰ and a rotation («) £" = -f-177 ⁰ (in acetone) was obtained by reprecipitation from ether-petroleum ether receive. Example 20 To 4.35 g of triethylamine salt of benzylpnicillin, which is dissolved in 30 ecm of anhydrous methylene chloride 1.085 g of ethyl carbonate were added at 0 °. After 15 minutes a Mixture of 2.7 g 4- (diethylaminoacetamino) thiophenol hydrochloride and 0.79 g of pyridine in 20 ecm of methylene chloride added. After 2 hours Allowing to stand at 0 °, the mixture was washed with sodium bicarbonate solution. The methyl chloride solution was then dried and evaporated in vacuo to a syrup. This was in 50 ecm isopropanol dissolved and the solution titrated with ethanolic hydrochloric acid. After adding ether it became Benzylpenicillin - ^ - (diethylaminoacetamino) thiophenyl] ester hydrochloride obtained as an amorphous-hygroscopic powder. In an analogous manner, the thiosalicylic acid diethylaminoethyl ester gave the hydrochloride of the benzylpenicillin [2- (carbo - /? - diethylaminoethoxy) thiophenyl]) ester in a yield of ¹ Jo ⁰ J ₀ of theory. The melting point was 135 to 136 °. Pat ε ν ta nsi
Process for the preparation of esters of penicillin with phenols and thiophenols by reacting an anhydride axis penicillin and a carboxylic acid with phenols or thiophenols, characterized in that the phenols or thiophenols are compounds of the general formula > —Y- • N- R "' 565/41 L 19646 IVc / 12p in which X _{1 is} an HO or HS group and X _{2 is} a hydrogen atom or an HO or HS group and R ₁ and R _{2 are} alkyl groups which, together with the nitrogen atom, can be closed to form a heterocyclic ring, while Y is a Is an alkylene group which is attached to a carbon atom of the benzene nucleus either directly or via a -0-, -NH-, -NR-, -CO-, -COO-, - CONH-, - CONR-, - NHCO-, - NRCO-, - NHCS-; - NRCS, - CSNH or CSNR bridge is bound, where R is an alkyl or alkylene radical, used and here the phenol or thiophenol derivatives with the anhydrides of penicillin in the molar ratio ι: ι or ι: 2, whereupon the penicillin esters obtained are expediently isolated in the form of their salts with pharmacologically acceptable acids. Referred publications: Yournal of the American Chemical Society, Vol. 75 [1953]. Pp. 3636 and 3637.