A new synthesis of treprostinil is described using a plug flow reactor in two of the key steps. First, a Claisen rearrangement reaction is described in scaled flow at multigram amounts. Yields and selectivity of this step are sharply improved compared to those from previous syntheses. Second, the key Pauson–Khand reaction in flow is described under catalytic conditions with 5 mol% of cobalt carbonyl and only 3 equiv. of CO. Scaling up of this reaction safely ensures a good yield of an advanced intermediate which is transformed into treprostinil in three steps. Other improvements are the introduction of the carboxymethyl chain into the phenol from the beginning to reduce the protection–deprotection steps. The synthesis is completed in 14% global yield after 12 linear steps from (S)-epichlorhydrin.

• Universidad San Pablo CEU. Urb. Montepríncipe
• CSFlowChem SL

• API

1. API
2. Claisen rearrangement
3. Pauson–Khand reactions
4. Plug flow reactor
5. protection–deprotection step
6. Research Article
7. treprostinil