Manufacturing Process
9.9 g (0.031 mole) of cis-4-phenylthio-L-proline is suspended in 100 ml of
water (pH 5.6) and the pH is adjusted to 10.2 by the addition of about 20 ml
of 10% sodium bicarbonate to provide a clear solution. The pH is then
adjusted to 9.5 by the addition of about 4.5 ml of concentrated HCl. The
solution is kept at 30°C while 8.1 g (0.033 mole) of (D)-3-(benzoylthio)-2-
methylpropanoic acid chloride in 30 ml of toluene is added simultaneously
with 100 ml of 10% sodium bicarbonate to keep the pH at 9.3. After about
1/4 of the acid chloride is added, a slimy precipitate begins to form which
persists throughout the reaction. After stirring the reaction mixture at pH 9.3
for 2.5 h, it is made strongly acidic by adding 20% HCl in the presence of
ethyl acetate. The aqueous layer is extracted twice with 350 ml portions of
ethyl acetate and the combined organic layers are washed with 300 ml of
saturated brine and dried (MgSO 4 ). The solvent is removed to yield 11.8 g of
foamy solid cis-1-[D-3-(benzoylthyo)-2-methyl-1-oxopropyl]-4-(phenylthio)-L-proline hydrochloride.
To a solution of this cis-1-[D-3-(benzoylthyo)-2-methyl-1-oxopropyl]-4-
(phenylthio)-L-proline hydrochloride 11.8 g (0.027 mole) in 70 ml of
acetonitrile there is added about 6.0 g of dicyclohexylamine in 25 ml of ether.
A white crystalline precipitate forms immediately. After standing overnight in
the cold room, the solid is filtered and washed with ether to yield (cis)-1-[D-
3-(benzoylthio)-2-methyl-1-oxopropyl]-4-(phenylthio)-L-proline,
dicyclohexylamine salt (1:1).
he slightly moist (cis)-1-[D-3-(benzoylthio)-2-methyl-1-oxopropyl]-4-
(phenylthio)-L-proline dicyclohexylamine salt is stirred for 2.5 h in a mixture
of 300 ml of ethyl acetate and 200 ml of 10% potassium bisulfate. Two clear
layers form. The aqueous layer is extracted with two 200 ml portions of ethyl
acetate and the combined organic layers are dried (MgSO 4 ). The solvent is
removed to yield 10.1 g of foamy solid (cis)-1-[D-3-(benzoylthio)-2-methyl-1-
oxopropyl]-4-(phenylthio)-L-proline; melting point 42-44°C.
In practice it is usually used as calcium salt (2:1).
