Development of a two-step route to 3-PBC and βCCt, two agents active against alcohol self-administration in rodent and primate models

Abstract

To gain access to 3-propoxy-β-carboline hydrochloride (3-PBC·HCl) (1·HCl) and β-carboline-3-carboxylate-tert-butyl ester (βCCt) (2), potential clinical agents active against alcohol self-administration, a two-step route was developed. This process involves a palladium-catalyzed Buchwald-Hartwig coupling and an intramolecular Heck reaction. This two-step route provides rapid access to multigram quantities of 3-PBC (1) and βCCt (2), as well as analogues for studies of alcohol self-administration. The overall yield of 3-PBC (1) was improved from 8% to 50% by this route.

Figure 1

Structures of 3-PBC (1) and βCCt (2)

Scheme 1

Retrosynthetic analysis of 1 and 2

Scheme 2

Synthesis of intermediates 5a and 5b Reagents and conditions: (a) 5 mol% Pd(OAc)₂, 7.5 mol% X-Phos, 1.5 eq. Cs₂CO₃, toluene, 100°C, 15 h

Scheme 3

Synthesis of substituted carboline analogs Reagents and conditions: (a) 5 mol% Pd(OAc)₂, 7.5 mol% X-Phos, 1.5 eq. Cs₂CO₃, toluene, 100°C, 15 h; (b) Pd(OAc)₂, (t-Bu)₃P.HBF₄, K₂CO₃, DMA, 120°C, 16 h

Scheme 4

Large-scale synthesis of 3-PBC (1) and βCCt (2) using the new route Reagents and conditions: (a) 5 mol% Pd(OAc)₂, 7.5 mol% X-Phos, 1.5 eq. Cs₂CO₃, toluene, 100°C, 15 h; (b) Pd(OAc)₂, (t-Bu)₃P.HBF₄, K₂CO₃, DMA, 120°C, 16 h