Development of In-Water Scalable Process for the Preparation of [2-(3-Bromo-2-methylphenyl)-7-chloro-1,3-benzoxazol-5-yl]methanol, a Key Intermediate in the Synthesis of Potent PD-1/PD-L1 Inhibitors

Abstract

We propose a synthetic process for the preparation of a benzoxazole building block for a programmed death-ligand 1 inhibitor that is a candidate currently under clinical investigation for cancer treatment. Our research focused on searching for mild, scalable, and ecofriendly conditions for the synthesis of benzoxazoles. To reduce the use of toxic reagents or solvents and to minimize the production of organic wastes, the cyclization reaction was performed in an aqueous micellar medium. This in-water benzoxazole synthesis gave comparable yields to previously reported processes, and was applied to a broad range of benzoxazoles with various substitution patterns, showcasing its effectiveness in ecofriendly benzoxazole cyclization reactions.

Key words

benzoxazoles - cyclization - in-water reaction - micelles - surfactants

Publikationsverlauf

Eingereicht: 15. Mai 2024

Angenommen nach Revision: 10. Juni 2024

Artikel online veröffentlicht:
01. Juli 2024

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• 26 Benzoxazole 8–16; General Procedure (Procedure A)A mixture of the appropriate aminophenol 1 (1.0 equiv) and benzaldehyde 5 (1.3 equiv) in 5 wt% aq Triton X-100 (2.0 mL) was stirred at 800 rpm at rt for 1 h, then DDQ (1.2 equiv) was added and the mixture was stirred at rt for a further 5 min. The resulting mixture was concentrated by rotary evaporation, and the crude product was purified by column chromatography (silica gel). 2-(3-Bromo-2-methylphenyl)-1,3-benzoxazole-5-carbonitrile (8) Synthesized according to General Procedure A from 3-amino-4-hydroxybenzonitrile (4b; 134.1 mg, 1.0 mmol) and 3-bromo-2-methylbenzaldehyde (5a; 258.7 mg, 1.3 mmol) to give a white solid; yield: 68%. ¹H NMR (500 MHz, CDCl₃): δ = 8.12 (t, J = 1.2 Hz, 1 H), 8.05 (dd, J = 7.9, 1.3 Hz, 1 H), 7.78 (dd, J = 8.0, 1.3 Hz, 1 H), 7.69 (d, J = 1.2 Hz, 2 H), 7.23 (t, J = 7.9 Hz, 1 H), 2.87 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 164.6, 152.7, 142.4, 138.9, 136.2, 129.8, 129.6, 127.7, 127.4, 127.3, 125.10, 118.8, 112.1, 108.7, 21.5. HRMS (method: Kinetex C18, 1.7 um, LC column 50 x 2.1 mm (phenomenex). Oven temperature 45 °C. Gradient solvent: 0.1% HCOOH in water: 0.1% HCOOH in acetonitrile = 80/20 to 0.1% HCOOH in water: 0.1% HCOOH in acetonitrile = 5/95 run time 10 minutes with flowrate 0.2 mL/min. Sciex exion LCTM and Q-TOF (X500B)): m/z [M + H]⁺ calcd for C₁₅H₁₀BrN₂O: 312.9977; found: 312.9974.