TreprostinilSodium Chemische Eigenschaften,Einsatz,Produktion Methoden
Originator
Pharmacia/
GSK (USA)
Trademarks
Remodulin
Synthese
The synthesis of treprostinil starts from commercially available 3-methoxybenzyl
alcohol (213). The hydroxyl group in 213 was protected as a
t-butyldimethylsilyl ether via reaction with TBDMS
chloride in DCM at rt. A regiospecific introduction of the
allylic chain and deprotection of the silyl group in situ
provided alcohol 216 in 36% yield in a three-step sequence.
Swern oxidation of alcohol 216 using oxalyl
chloride/DMSO furnished aldehyde 217 in 86% yield.
Acetylene 218 was first treated with magnesium ethyl
bromide and then reacted with aldehyde 217 to provide
adduct 219 in 52% yield. The alcohol functional group in 219 was then transformed into a carbonyl group in 220 via a
PCC-mediated oxidation. Ketone 220 was then reduced
again using chiral boron reagent to give the chiral alcohol
which was protected with TBDMS chloride in situ (221).
Optically pure intermediate 221 underwent cobalt-mediated
Pauson-Khand reaction to furnish tricyclic compound 222 in
excellent yield. Catalytic hydrogenation was employed to
reduce the double bond and the hydroxyl moiety to give
ketone 223. Sodium borohydride mediated reduction of the
carbonyl group in 223 gave single diastereomer 224. The
THP and methyl ether protecting groups were then removed
in a two-step process to give triol 226. The more reactive
hydroxyl group on the phenyl ring was then reacted with
chloroacetonitrile to furnish nitrile 227. A base mediated
hydrolysis of the nitrile provided free acid, treprostinil
(228), which was converted to its sodium salt 26 by titration
with sodium hydroxide (no yield reported).
TreprostinilSodium Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
