A Concise Synthesis of a Key Azabicyclo[2.1.1]hexane Building Block for N-Heteroaryl Indazole LRRK2 Kinase Inhibitors

Abstract

Increasing the fraction of sp³ character in lead compounds has been shown to increase their drug-likeness by improving their potency, selectivity, and physicochemical properties. Azabicyclo[2.1.1]hexanes have recently garnered much interest in the synthetic community as pyrrolidine analogues for their interesting biological properties and stereoelectronic effects. During the course of our optimization of N-heteroaryl LRRK2 inhibitors, we discovered that this unique bicyclic system leads to improvements in solubility and metabolic clearance. Herein, we outline a match-pair analysis showcasing the broad impact of this unique azabicyclo[2.1.1]hexane system on key drug-like properties, as well as a concise and scalable synthesis of this building block, featuring an intramolecular cyclization to forge a strained amide bond.

Key words

amides - bicyclic compounds - drugs - heterocycles - lactams - medicinal chemistry

Publication History

Received: 08 November 2024

Accepted after revision: 09 December 2024

Article published online:
13 January 2025

• References and Notes

• 1 Theodore Martinot is now affiliated to Parabalis Medicines (formerly FogPharma). Thomas Lyons is now affiliated to Takeda Pharmaceutical Company. J. Michael Ellis is now affiliated to Bristol Myers Squibb. Michael J. Ardolino is now affiliated with LifeMine Therapeutics.
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• 10 2-(2-Azabicyclo[2.1.1]hex-4-yl)propan-2-ol (9) A 500 mL three-necked round-bottomed flask was charged with 15 (4.75 g, 0.031 mol, 1 equiv) and THF (150 mL). The solution was cooled to 0 °C (ice–salt bath), and BH₃·Me₂S (16.1 mL, 0.161 mol, 5.3 equiv) was added dropwise over 0.5 h while the temperature was maintained between 0 and 5 °C. When the addition was complete, the mixture was warmed to 25 °C and stirred for 1 h then heated to 50 °C for 15 h. The mixture was cooled to 0 °C, and MeOH (50 mL) was added slowly over 2 h. The resulting mixture was heated to 50 °C for 2 h and then concentrated to give the crude intermediate. A 1 M solution of HCl in MeOH (200 mL) was added dropwise at 20 °C over 0.5 h, and the resulting mixture was stirred at 50 °C for 12 h. The mixture was then concentrated to provide a crude residue. 50 wt% aq K₂CO₃ (200 mL) was added, and the resultant mixture was extracted with 2-methyltetrahydrofuran (4 × 250 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated to give a colorless oil; yield: 3 g (69%). ¹H NMR (400 MHz, MeOD): δ = 3.73–3.72 (m, 1 H), 3.53 (s, 1 H), 2.94 (s, 2 H), 1.84–1.83 (m, 2 H), 1.38–1.36 (m, 2 H), 1.21 (s, 6 H). ¹³C NMR (101 MHz, CD₃CN): δ = 117.9, 70.09, 69.6, 61.0, 55.8, 47.7, 39.8, 26.0. LCMS: m/z [M + H]+ calcd: 142.1; found; 142.4.