ナトリウム 2-{[(1R,2R,3aS,9aS)-2-ヒドロキシ-1-[(3S)-3-ヒドロキシオクチル]-1H,2H,3H,3aH,4H,9H,9aH-シクロペンタ[b]ナフタレン-5-イル]オキシ}アセタート

ナトリウム 2-{[(1R,2R,3aS,9aS)-2-ヒドロキシ-1-[(3S)-3-ヒドロキシオクチル]-1H,2H,3H,3aH,4H,9H,9aH-シクロペンタ[b]ナフタレン-5-イル]オキシ}アセタート 化学特性,用途語,生産方法

• Originator

  Pharmacia/ GSK (USA)

• brand name

  Remodulin

• 合成

  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).

  

ナトリウム 2-{[(1R,2R,3aS,9aS)-2-ヒドロキシ-1-[(3S)-3-ヒドロキシオクチル]-1H,2H,3H,3aH,4H,9H,9aH-シクロペンタ[b]ナフタレン-5-イル]オキシ}アセタート 生産企業

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