DE2207723A1 - New derivative of 6-aminopenicillanic acid and process for its preparation - Google Patents

Description

for its production

The present invention relates to a new semi-synthetic penicillin and its production.

Since the isolation of 6-aminopenicillanic acid by Batchelor and colleagues in 1960, a very large number of penicillanic acid derivatives have been made obtained with antimicrobial activity. One of the most significant successes to which this research led is the creation of the semi-synthetic penicillins that are resistant to destruction by penicillinases and such expand the range of use of penicillins, i.e. they are used to treat infections caused by staphylococci and other pathogens, which produce this enzyme, make it suitable, which was not the case with the previously known penicillins.

The aim of the invention is to create a new 6-aminopenicillanic acid derivative which, in addition to its resistance to penicillinase

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i has a broad antimicrobial spectrum, which makes it climate |

niche usable. j

The ot-Cp-chlorophenoxy / isobutyryl-ampicillin has now been found the one that has a spectrum similar to that of ampicillin, but also has the advantage of being remarkably resistant against penicillinase and better absorption, possibly due to acylation of the free amino group of ampicillin, which reduces its polar character.

Its resistance to inactivation by lactamases becomes the! steric hindrance resulting from the acylation of the amino group by such a bulky group as the "^ (p-chlorophenoxy) -isobutyryl group, which protects the β-lactam ring and prevents the enzyme from penetrating to the point of attack.

The ot- (p-chlorophenoxy) -isobutyry1-ampicillin, potassium salt monohydrate, is a white crystalline solid substance that softens at 80 ° C, loses the water of crystallization up to 130 ° C and begins to soften, only to decompose completely at 186 ° C.

The spectroscopic data agree with the assumed structure

match.

The IR spectrum of the e £ - (p-chlorophenoxy) -isobutyryl-ampi- j shows

1 '

cillins a broad band at 3350 cm, that of the stretching vibration corresponds to the NH group of the amide compounds. Another gang at 1775 cm corresponds to the stretching vibration of group C = O des; ß-lactam rings and another one at 1675 cm of the stretching vibration!

—1 'of the group C = O of the amide compounds. The gang at 1230 cm speaks of the stretching vibration of the grouping C-O of the ether group. In addition, the bands are observed at 2900 to 3000 cm ", the the stretching vibrations of the groups C-H of the alkyl groups. and another band at 840 cm ", which corresponds to the buckling vibrations of the p-substituted benzene ring.

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The quantitative analysis of C, H, N, S and Cl confirms this Composition identity.

The following examples for the preparation of ° C- (p-chlorophenoxy) -isobutyryl-ampicillin and its salts serve to further illustrate the invention.
example 1

To a solution of 20.2 g (0.0625 mol) ampicillin, trihydrate, in 300 ml of water containing 26.2 g (0.312 mol) of sodium bicarbonate a solution of 18.7 g (0.081 mol) of (p-chlorophenoxy) isobutyryl chloride is added with stirring and cooling in the course of 1 minute in 25 ml of dry acetone.

The mixture is vigorously stirred for 20 minutes at a temperature between 10 and 15 ° C.

The clear solution is extracted twice with methyl isobutyl ketone. I The aqueous solution is covered with 125 ml of methyl isobutyl ketone, ^{cooled to 5 to 10 °} C. and acidified to pH 2 with a 5m sulfuric acid solution.

The extracts are separated off, washed with water and dried with sodium sulfate for 10 minutes.

The acidic solution is mixed with a solution of a salt of a liquid ; neutral organic acid or with a sodium bicarbonate solution.

The "ir-Cp-chlorophenoxy / isobutyryl-ampicillin is produced by precipitation ι obtained the solution with acetone or by lyophilization.

! Example 2

j To a cold solution of 0.083 mol «* .- (p-chlorophenoxy) -isobutyryl-

: Chloride in chloroform or other inert solvent

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add 0.083 mol of ampicillin, trihydrate, j in chloroform or another inert solvent with a Content of 0.083 mol of triethylamine too.

When the addition is complete, the mixture is left to stand until it becomes; has warmed to room temperature and then continues stirring for some time. j

When the reaction has ended, the triethylamine is removed by adding 0.87 N hydrochloric acid up to pH 1. The chloroform layer is extracted, washed with water and treated with MgSO ₁ . dried.

The desired product is obtained by removing the solvent. ^!

Example 3

To a mixture of 1 ml of a solution of 10 mg N, N'-dicyclohexylcarbodiimide per ml in tetrahydrofuran or another mixture suitable solvent and 1 ml of a suspension of 10 mg p-chlorine ι phenoxyisobutyric acid per ml in an inert solvent a suspension of 20 mg ampicillin, sodium salt, in 1 ml water / Tetrahydrofuran (1: 1) added. ;

The mixture is stirred for 2 hours at room temperature.

It is then diluted with water and filtered in order to remove the dicyclohexyl- 'urea and the unchanged dicyclohexylcarbodiimide. >

Then the solution is acidified to pH 2, quickly extracted with butanol and washed with water.

The aqueous solution is lyophilized. The plague substance obtained is oi / - (p-chlorophenoxy) -isobutyryl-ampioillin.

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Example 4

^: A water-free solution of 0.15 mol of a- (p-chlorophenoxy) isobutyric acid and 0.15 mol of triethylamine in 330 ml of dioxane and 65 ml of acetone is cooled to ^{0 ° C.} Then a solution of 0.15 mol of isobutyl chloroformate is added, and the temperature is kept between 0 and 4 ^° C. A mixture of 0.1 mol of ampicillin, trihydrate and 0.1 mol of triethylamine in 30 ml of water is added dropwise to this solution.

It is stirred for 1 hour at 5 ⁰ C and then a solution of 0.13 mol NaHCO- was added in 700 ml of ice water.

S The solution is extracted twice with 550 ml of ether. The water- ^! ge solution is with ön-HpSOj. acidified to pH 2 and extracted with methyl isobutyl ketone.

; The ketone extracts are washed with water and dried with MgSOh.

Evaporation of the solution gives the desired product. Example 5

In a 1 l three-necked flask, which is equipped with a stirrer, a thermometer, a supply line for nitrogen and a drying tube are equipped with 0.12 moles of ampicillin an aliphatic amine with a molecular weight above 185 in 640 cnr methyl chloride or other inert solvent.

8.3 g (0.08 mol) of triethylamine and 17.5 g (0.144 mol) of Ν, Ν-dimethylaniline are added to this solution.

The mixture is cooled and 26.0 g (0.24 mol) of trimethylchlorosilane are added dropwise ^{at 12 ° C.} The mixture is kept under reflux for 1 hour and cooled ^{to 20 ° C.} then

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a solution of 0.75 mol of N, N-dimethylaniline dihydrochloride in 20 cnr. (p-chlorophenoxy) isobutyryl chloride is added. ■ The reaction mixture is stirred at -10 ⁰ C for 30 minutes and heated for 1/2 hour at 10 ^0C.

The reaction mixture is then poured into 900 en of water at 90 ^° C., stirred, and the two-phase mixture is filtered.

After decanting the aqueous layer, remove this from the filtrate To separate the methylene chloride layer is extracted twice with 900 cnr cold water each time, each time the mixture is adjusted to pH 1.8 to 2.6 with dilute hydrochloric acid.

The aqueous layer is extracted with methyl isobutyl ketone, washed with water and washed with MgSO ₁ . dried.

The solvent is removed by distillation under reduced pressure at low temperature and the desired product is thus obtained. . !

The following is the equation for the reaction of Ot- (p-chlorophenoxy) -isobutyryl chloride with ampicillin:

-CH-CONH-CH-HC ' I 1 .C N

Cl "

NH,

CH-COOH

^CH 3 CH-COOH

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Claims (7)

- 7 claims t <«• - (p-Chlorophenoxy / isobutyryl-ampicillin and its salts. 2. Process for the preparation of «- (p-Chlorophenoxy) -isobutyrylampicillin according to claim 1, characterized in that ampicillin, sodium salt, and <* - (p-chlorophenoxy) isobutyryl chloride in sodium bicarbonate medium be reacted at temperatures between 5 and 15 ° C. 3. Process for the preparation of «c- (p-chlorophenoxy) -isobutyrylampicillin according to claim 1, characterized in that ampicillin and «(.- (p-chlorophenoxy-risobutyryl chloride in inert solvents using triethylamine or other amines as blocking agents. 4. The method according to claim 3, characterized in that the inert solvent used is acetone, chloroform or dioxane. 5. Process for the preparation of ° t- (p-chlorophenoxy) -isobutyrylampicillin according to claim 1, characterized in that ampicillin and p * chlorophenoxyisobutyric acid using Dicyclohexylcarbodiimide or another imide as a condensing agent implements. 6. Process for the preparation of oc- (p-chlorophenoxy) -isobutyrylampicillin according to claim 1, characterized in that one of a mixed anhydride of p-chlorophenoxyisobutyric acid and Ampicillin is running out. 7. A process for the preparation of <* - (p-chlorophenoxy) -isobutyrylampicillin according to claim 1, characterized in that one of a silane derivative of ampicillin and oc- (p-chlorophenoxy) -isobutyi ryl chloride using an aliphatic amine with a I starting from molecular weight over 185, t 209837/1227