Stereoselective Lithiation and Carboxylation of Boc-Protected Bicyclopyrrolidine: Synthesis of a Key Building Block for HCV Protease Inhibitor Telaprevir

Abstract

A stereoselective process for the manufacture of bicyclopyrrolidine 7 to 2 has been developed. The process utilizes a stereoselective lithiation/carboxylation sequence. The achiral diamine ligand DPBP induces excellent diastereocontrol, and resolution with ( S )-THNA provides the corresponding salt of 8 in high er and dr. Subsequent processing of 8 gives 2 as the oxalate salt in an overall yield of 27% from 7 (based on total molar charge of 7). Compound 2 was obtained with high chemical and chiral purities. The process was successfully demonstrated on >100 kg scale.

Gram‐Scale Synthesis of the (−)‐Sparteine Surrogate and (−)‐Sparteine

“…The main issue with all of these sources of sparteine/sparteine surrogate is that they rely on natural product extractions and this can lead to supply issues (as observed for (−)‐ and (+)‐sparteine over the last few years) . Indeed, during the development of the hepatitis C drug, Telaprevir, researchers at Vertex rejected a process‐scale route that used the (+)‐sparteine surrogate since “inquiries about long‐term, high‐volume supply of (−)‐cytisine had been met with concerns about production variability, due mainly to reliance on (−)‐cytisine isolation from natural sources” …”

Organocatalytic Asymmetric Conjugate Additions to Cyclopent‐1‐enecarbaldehyde: A Critical Assessment of Organocatalytic Approaches towards the Telaprevir Bicyclic Core

“…1 HNMR (CD 3 OD, 400 MHz): d = 4.22 (d, J = 6.5 Hz, 1H), 3.42 (s, 3H), 3.37 (s, 3H), 2.80 (dd, J = 12.2, 5.3 Hz, 1H), 2.59 (dd, J = 12.4, 6.9 Hz, 1H), 1.90-1.70 (m, 4H), 1.74-1.55 (m, 3H), 1.40-1.30 ppm (m, 1H); 13 CNMR (CD 3 OD, 100 MHz): d = 109. 7, 55.8, 53.2, 47.3, 47.2, 44.6, 32.2, 29.4, 25.6 (3aS,6aR)- 1,3a,4,5,6,pyrrole and (3aS,5aR,8aS,10aR,13aS,15aR)-octadecahydro-1 H, 5 H,10 H-cyclopenta[3,4]pyrrolo [1,2-a]cyclopenta [3,4]pyrrolo [1,2-c]cyclopenta [3,4]pyrrolo [1,2-e] [1,3,5]triazine (12):I nat est tube equipped with am agnetic stirring bar compound 11 (42 mg, 0.24 mmol) was dissolved in 2M HCl (500 mL, 0.96 mmol). The solution was stirred and heated at 70 8Cf or 20 min, then the reaction mixture was allowed to cool to RT.W ater and CH 2 Cl 2 were then added, the phases separated and the aqueous phase was washed with CH 2 Cl 2 (2 2 mL).…”

“…Subsequent approaches, some of which are reported at the top of Scheme , involved resolution of a racemate through crystallisation, or chiral auxiliary methodology. In particular, the racemic N ‐protected amino acid for resolution was obtained by deprotonation of an N ‐protected 3‐azabicyclo[3.3.0]octane7 with sec ‐ or tert ‐butyl lithium in the presence of a suitable chelating agent, followed by quenching with carbon dioxide 3b,c. Whereas by using 3,3‐dipropyl‐3,7‐diazabicyclo[3.3.1]nonane as chelating agent the desired trans isomer was selectively obtained; with simpler diamines [e.g., N , N , N ′, N ′‐tetramethylethylenediamine (TMEDA)] a further equilibration step favouring the trans isomer was required.…”

New and Efficient Synthesis of HCV NS3/4 A Protease Inhibitor Telaprevir

“…Tripeptide acid 3 is another key intermediate for the synthesis of Telaprevir 1 , Tanuory J et al . and Schinazi et al .…”