An Alternate Synthesis of Bosentan Monohydrate, an Endothelin Receptor Antagonist^[1]

Abstract

An alternate synthesis of an endothelin receptor antagonist bosentan monohydrate is reported. This new synthetic route involves the coupling of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)(2,2′-bipyrimidin)-4-yl]benzene sulfonamide with commercially available raw material (2,2-dimethyl-1,3-dioxolan-4-yl)methanol as the key step. Attractive features of this approach are its versatileness, commercial availability of raw materials, usage of eco-friendly reagents, and it efficiently provides the desired bosentan monohydrate free from reported impurities such as dimer, N-alkylated, and pyrimidinone impurities.

Key words

alternate synthesis - bosentan monohydrate - eco-friendly reagents - dimer impurity - N-alkylated - pyrimidinone

• References and Notes

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• 13 HPLC Method Column: BDS Hypersil C₁₈, 250 × 4.6 mm, 5 μm; UV, λ = 220 nm; temp: 30 °C; load: 20 μL; elution: gradient; buffer: dipotassium hydrogen orthophosphate; diluent: mobile phase A + mobile phase-B; mobile phase A: 95% buffer + 5% MeOH; mobile phase B: 95% MeOH + 5% H₂O.
• 14 GC Method for Residual Solvents Column: DB-624; length: 30 m; film thickness: 30 μm; injector temp: 140 °C; split: 1:5; detector temp: 260 °C (FID); carrier gas: helium; load: 1.0 μL; diluent: DMSO; oven temp: 40 °C; program to 130 °C at 6 °C per min; hold for 5 min; then again raised to 240 °C at 35 °C per min.