Originator
Estracyt,Bastian Werk,W. Germany,1973
Definition
ChEBI: A steroid phosphate which is the 17-O-phospho derivative of estramustine.
Manufacturing Process
A solution in dry benzene of 82 grams of bis(β-chloroethyl)amine freshly
liberated from its hydrochloride is added gradually to a solution of 36 grams of
carbonyl chloride (phosgene) in benzene at a temperature below 10°C. The
mixture is mechanically stirred for 3 hours, the precipitate of bis(β-
chloroethyl)amine hydrochloride is removed by filtration and the benzene is
distilled off on a water bath. The residue is distilled in vacuo and the Nchloroformyl-bis(β-chloroethyl)amine is obtained as a pale yellow oil with a BP
of 114° to 116°C at 1 mm Hg.
To a solution of 16.35 grams of estradiol in 75 ml of dry pyridine, 21.00
grams of the abovementioned chloroformyl-bis(β-chloroethyl)amine are added
while stirring and cooling with ice-water.
The reaction mixture is allowed to stand at room temperature for 60 to 70
hours under the exclusion of air humidity. Then the excess of the chloroformyl
compound is hydrolyzed with crushed ice. Ethyl acetate is added and after
shaking, the ethyl acetate solution is separated and washed with water, dried
over sodium sulfate and evaporated in vacuo to dryness.
The residue is the 3-N-bis(beta-chloroethyl)carbamate of estradiol. The
compound melts at 101° to 103°C after recrystallization from isopropyl ether
plus hexane (1:1).
To a solution of 2.3 ml of phosphorus oxychloride in 50 ml of dry pyridine is
added a solution of 2.2 grams of 3-N-bis(β-chloroethyl)carbamate of estradiol
while stirring and at a temperature of about -10°C. The reaction mixture is
allowed to stand at about 0°C for 1? hours, whereupon it is hydrolyzed by
pouring it into ice-water. The main part of the pyridine is evaporated in vacuo,
whereupon the residue is poured into 100 ml of cold 3.5 N hydrochloric acid
with stirring. The precipitate thus obtained is isolated and washed with 0.1 N
hydrochloric acid and water.
The compound, which consists of the 17-phosphate of estradiol-3-N-bis(β-
chloroethyl)carbamate, melts under decomposition at about 155°C. It is
soluble in an aqueous solution of alkali.
Therapeutic Function
Cancer chemotherapy
Clinical Use
Alkylating agent:Prostate cancer
Drug interactions
Potentially hazardous interactions with other drugsAntipsychotics: avoid concomitant use with
clozapine (increased risk of agranulocytosis).Bisphosphonates: concentration increased by sodium
clodronate
Metabolism
Estramustine sodium phosphate is absorbed from the
gastrointestinal tract and rapidly dephosphorylated in the
intestine and prostate to estramustine and its oxidised
isomer estromustine. Some hydrolysis of the carbamate
linkage occurs in the liver, releasing estradiol, estrone, and
the normustine group. Estramustine and estromustine are
excreted with their metabolites mainly in the faeces.
