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.
