CHLOMETHOCILLIN

Originator

Clometocillin,Ribbon

Definition

ChEBI: A penicillin that is benzylpenicillin in which the phenylacetyl group has been replaced by a (3,4-dichlorophenyl)(methoxy)acetyl group. It is a mixture of epimers at the methoxy-bearing carbon.

Manufacturing Process

2 Methods of producing of clometocillin:
1. 6-Aminopenicillanic acid (2.16 g) is dissolved in 20 ml of a one molar aqueous solution of potassium bicarbonate and 10 ml of acetone. The resultant solution is cooled in an ice-water bath and to it is added with stirring a solution of 2.7 g of alpha-methoxy-3,4-dichloro-phenylacetyl chloride in 10 ml of acetone. The pH is adjusted to 7-8 and upon completion of the addition the reaction medium is stirred for 15 min at ice bath temperature and then for 2.5 h at room temperature, maintaining the pH range between 7 and 8. The solution is extracted once with ether and then adjusted to pH 2.5 with 20% phosphoric acid. The acidic solution is extracted once with 30 ml of butyl acetate and again with 10 ml of butyl acetate. These combined butyl acetate extracts are thereafter successively washed twice with water and reextracted at pH 7 with 0.5 N aqueous potassium hydroxide solution. The aqueous layer is washed twice with ether and the remaining organic solvent is then removed by evaporation under reduced pressure. The washed aqueous layer is then lyophilized and the residue thus obtained taken up in acetone. The crystal line product is collected by filtration and dried to yield the potassium salt of 6-(α- methoxy-3,4-dichlorophenylacetamido)penicillanic acid. Upon treatment with mineral acid of an aqueous solution of the compound so prepared, there is obtained the free acid, 6-(α-methoxy-3,4-dichlorophenylacetamido)penicillanic acid.
2. A solution of 19.2 g (0.096 mole) of α-methoxy-4-chlorophenyl acetic acid in 200 ml of acetone is cooled in an ice bath to 0°C. To the cooled solution is added 10.2 g (0.1 mole) of triethylamine in 100 ml of acetone. The temperature of the reaction mixture is maintained at 10°C and a solution of 11.0 g (0.1 mole) of ethylchloroformate in 45 ml of acetone is added dropwise with agitation so as to maintain a final reaction temperature of -5°C. To this mixture is then slowly added with stirring a solution of 23.8 g (0.11 mole) of 6-aminopenicillanic acid in 40 ml of water and 15 ml of triethylamine. Upon completion of the addition, the mixture is stirred while attaining room
temperature and then stirred for an additional 1.5 h. The mixture is extracted with three portions of 300 ml, of ether and the resulting aqueous solution adjusted to pH 2.0 with 6 N sulfuric acid, maintaining a temperature of less than 10°C. At pH 2, the solution is extracted with 250 ml, of butyl acetate and then extracted twice with 75 ml each of butyl acetate. To the combined butyl acetate extracts are added 250 ml of water and the pH adjusted to 8.0 by the addition of sodium bicarbonate. The layers are separated and the aqueous layer adjusted to 2.0 by the addition of 6 N sulfuric acid at less than 10°C. This acid aqueous mixture is next extracted with 200 ml of butyl acetate and the organic extract extracted once with water and dried over sodium sulfate. To the butyl acetate solution is added with vigorous stirring a solution of potassium hydroxide in n-butanol (40 g/l) until the pH of the reaction mixture is 8.4. The mixture is then cooled until crystallization occurs. The crystals are collected by centrifugation, washed with a small amount of acetone and dried. These dried crystals are recrystallized from butanol and retried to yield 6-(α- methoxy-4-chlorophenylacetamido)penicillanic acid as the potassium salt. Treatment with acid yields the corresponding free acid 6-(α-methoxy-4-chlorophenylacetamido)penicillanic acid.

Therapeutic Function

Antibiotic