NO138884B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE ESTERS OF ALFA-CARBOXYBENZYLPENICILLIN - Google Patents

Description

This invention relates to an analogue process

method for the preparation of orally administrable 4-(2-carbomethoxyethyl)phenyl- or 2-biphenylyl esters of α-carboxybenzylpenicillin.

Acylation of 6-aminopenicillanic acid using (1) acid chlorides and (2) simple or mixed acid anhydrides is described in U.S. Pat. patents 3,270,009, 3,142,673 and 3,173,916, and (3) using active derivatives of a substituted malonic acid to form various esters of α-carboxy-aryl-methylpenicillins is described in British patent 1,004,670. The production of certain penicillins by acylation of 6-aminopenicillanic acid using aryl carboxyketene esters is also described in a Norwegian patent'

- application 28/69.

It has now been found that acylation of 6-aminopenicillanic acid

with a reactive derivative of a phenyl-substituted malonic acid occurs smoothly and allows the economical production of valuable esters of α-carboxy-benzylpenicillin which are valuable as orally administrable antibiotics and have very high activity against various bacteria.

According to the invention, an analogous method for the production of therapeutically active esters of α-carboxybenzylpenicillin is provided with the formula:

where M is hydroaene, sodium, potassium or tri(lower alkylamine, and X5 is 4-(3-carbomethoxyethyl) or 2-phenyl. The method is characterized in that a compound of the formula: is reacted with an acylating agent of the formula:

where X 5 and M have the meanings given above, and X is chlorine, bromine or -OCOR^ where R^ is benzyl or lower alkyl, in a reaction-initiated solvent system at a temperature from o to 50°C

and at a pH from 5 to 8.

The degree of purity of the 6-aminopenicillanic acid is not of decisive importance for a successful implementation of the method. The 6-aminopenicillanic acid can be used in pure form, partially pure form or in the unpurified form such as that which is present in a fermentation liquid. When water is used as solvent, fermentation liquids containing 6-aminopenicillanic acid are also preferred from an economic point of view.

Reaction-inert solvent is to be understood as a solvent which, under the conditions of the method, does not participate in any significant reaction with any of the reaction components or products. Aqueous and non-aqueous solvents can be used. Using water as a solvent will of course result in some hydrolysis of the acid chloride reaction component. However, under the appropriate conditions with respect to temperature, pH value and time, the hydrolysis takes place relatively slowly compared to the desired N-acylation reaction. Suitable solvents for the method according to the invention include methylene chloride, benzene, chloroform, dioxane, water, acetone, tetrahydrofuran, diethyl ether and dimethyl ether. Aqueous solvent systems, including those in which an emulsion is formed, e.g. water-water-immiscible solvent, can also be used. Solvents that readily form emulsions with water include the water-immiscible solvents such as benzene, n-butanol, methylene chloride, chloroform, methyl isobutyl ketone and lower alkyl acetates (eg ethyl acetate). The preferred water-immiscible solvents are methyl isobutyl ketone and ethyl acetate.

The reaction is carried out over a pH range from 5 to 8, and preferably over the pH range from 6 to 7. The pH value is maintained at approximately the neutrality point by the addition of a suitable acid acceptor such as an alkali metal or alkaline earth metal hydroxide. Alternatively and preferably, the pH value is maintained at the desired value by using a salt of 6-aminopenicillanic acid with a tri-(lower alkylamine, preferably triethylamine. Such bases have the advantage that they form a salt of 6-aminopenicillanic acid which is -soluble in: many of the solvents listed above They are particularly useful when a non-aqueous solvent system such as methylene chloride is used.

The reaction is carried out over a temperature range from 0 to 50°C. However, it is preferred to use temperatures from 0 to 30°C to prevent degradation of the products.

The preferred form of the phenylmalonic acid esters as acylating agents are the acid monochlorides because of their relative ease of preparation compared to the preparation of the anhydrides.

in

The esters produced according to the invention are effective antibiotics both in vivo and in vitro. They are e.g. remarkably effective in the treatment of a variety of susceptible Gram-positive and Gram-negative infections in animals, including humans. For this purpose, one can use the pure materials or mixtures thereof with other antibiotics.

They can be administered alone or together with a pharmaceutical carrier selected on the basis of the desired route of administration and standard pharmaceutical practice.

The new penicillin ester compounds show improved absorption upon oral administration compared to that obtained for the corresponding free acids or alkali metal salts.

They therefore represent suitable and effective dosage forms for the α-carboxybenzylpenicillins.

Although the esters described here are partly inactive

or relatively little active against gram-negative organisms as such, they are converted by metabolism to the starting acid, i.e. a-carboxybenzylpenicillin, when injected parenterally into animals, including humans.

PD[.q (the dose which causes approx. 50% of the experimental animals to survive) has been determined on mice after intraperitoneal inoculation with a standardized E. coli 266 culture, with the following result:

Comparative biological data for compounds prepared according to the invention and known compounds against Staphylococcus aureus 400 (an antibiotic-resistant strain), Escherichia coli 266 and Pseudomonas 1049 are reproduced below as minimum inhibitory concentrations (MIC, mg/kg):

Known compounds: Percentage protection of mice against E. coli 266

The following example shall serve to further illustrate the method according to the invention.

Example

g- carbo( 2- biphenyloxy) benzylpenicillin- potassium salt g- carbo( 2- biphenyloxy) phenyl- acetic acid

Phenylmalonic acid (90.0 g, 0.5 mol), g<->phenylphenol (85 g,

0.5 mol), N,N-dimethylformamide (0.8 mL), isopropyl ether (725 mL) and thionyl chloride (59.5 g, 0.5 mol) are mixed, stirred and heated under reflux on a steam bath for 2 hours. The mixture is cooled to room temperature and then washed with water (3 x 50 ml) and extracted with a saturated aqueous sodium bicarbonate solution (3 x 100 ml). The combined aqueous extracts are washed with ether (2 x 25 ml), then acidified to pH 3.0 with 6N hydrochloric acid and extracted again with ether (3 x 50 ml). The ether extracts are washed with water (2 x 15 mL), followed by saturated aqueous saline (2 x 15 mL), then dried over anhydrous sodium sulfate and evaporated to dryness to give 90.3 g of α-carbo(2-biphenyloxy)phenyl- acetic acid.

Acid chloride of g-carbo(2-biphenyloxy)phenyl-acetic acid

A dry flask equipped with a condenser and drying tube is filled

with g<->carbo(2-biphenyloxy)phenylacetic acid (45.0 g, 0.135 mol), methylene chloride (450 mL), anhydrous N,N-dimethylformamide (0.1 mL)

and thionyl chloride (16.66 g, 0.140 mol), and the mixture is refluxed for 3 hours. The methylene chloride solvent is removed under reduced pressure, and then a further 200 ml of solvent is added, and the evaporation is repeated to give a yellow oil (48.0 g).

g- carbo(2- biphenyloxy) benzylpenicillin

A slurry of 6-aminopenicillanic acid (29.16 g, 0.135 mol) in methylene chloride (800 mL) is stirred rapidly while triethylamine, 27.27 g, 0.27 mol) is added at room temperature. The mixture is filtered after stirring for 2 hours, cooled to 5°C, and the acid chloride of g<->carbo(2-biphenyloxy)phenylacetic acid (48.0 g, 0.135 mol) in methylene chloride (200 ml) is added at such a rate that the temperature does not rise above 10°C. The mixture is then stirred for 1 hour, diluted with water (400 ml), adjusted to pH 2.0 and stirred thoroughly. The methylene chloride phase is separated, dried over sodium sulphate and evaporated to dryness. The residue is taken up in ethyl acetate (300 ml), the solution is washed with water (3 x 150 ml) and extracted with saturated aqueous sodium bicarbonate (3 x 150 ml). The aqueous extract is washed with ethyl acetate and then acidified to pH 2.0

in the presence of fresh ethyl acetate (300 ml).

The suspension is carefully mixed, the ethyl acetate phase is separated and washed successively with water (3 x 150 ml) and saturated saline (3 x 150 ml). It is then dried (anhydrous sodium sulfate) and evaporated to dryness under reduced pressure.

The residue is dissolved in ethyl acetate (400 ml), and N-ethylpiperidine (12.0 g) is added. Seed of crystallization is added to the mixture and it is allowed to stand overnight. The product is filtered, washed with ethyl acetate and air-dried, 37.5 g, m.p. 131-133°C, split.

It is converted to the potassium salt by adding potassium 2-ethylhexanoate (16 ml of an ethyl acetate solution containing 0.283 g/ml) to a slurry of the N-ethylpiperidine salt (10 g) in dry benzene (100 ml). The mixture becomes clear, heated to 45°C

in a steam bath, crystal seeds are added, and the mixture is kept at room temperature. The product is filtered off and washed with ether (5.97 g).

Claims (1)

The above procedure is repeated, but using 4-(2-carbomethoxyethyl)phenol instead of o-phenylphenol. Thus is prepared as its N-ethylpiperidine salt (NEP): α-carbo[4-(2-carbomethoxyethyl)phenoxy]benzylpenicillin, m.p. 94-96.6°C (dec.). The esters are converted to their sodium or potassium salts using sodium or potassium 2-ethyl hexanoate. Patent claim Analogous process for the preparation of therapeutically active esters of α-carboxybenzylpenicillin with the formula: where M is hydrogen, sodium, potassium or tri(lower alkyl)amine, and X(. is 4-(2-carbomethoxyethyl) or 2-phenyl, characterized in that a compound with the formula: is reacted with an acylating agent of the formula: where Xj. and M has the meanings given above, and X is chlorine, bromine or -OCOR^ where R. is benzyl or lower alkyl, in a reaction-inert solvent system at a temperature from 0 to 50°C and at a pH from 5 to 8, and optionally, a prepared compound is converted into a desired salt.