An Improved Iodine-Catalyzed Aromatization Reaction and Its Application in the Synthesis of a Key Intermediate of Cannabidiol

Abstract

In this study, the development of an improved process for the synthesis of a key cannabidiol intermediate, methyl olivetolate, is described. The process involves an improvement of the iodine-catalyzed aromatization of cyclohexanone using potassium persulfate as an oxidant. This approach enabled for the efficient synthesis of methyl olivetolate with a 90% yield and 99.84% HPLC purity on a 5 kg scale. Additionally, a total of 19 cyclohexanone substrates afforded higher yields (71–92%) of m-diphenol compounds compared to the established methods.

Key words

methyl olivetolate - potassium persulfate - aromatization - oxidation - iodine-catalyst - cannabidiol

Publication History

Received: 12 March 2024

Accepted after revision: 06 April 2024

Accepted Manuscript online:
09 April 2024

Article published online:
22 April 2024

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• 19 General Procedure To a solution of 2 (10.4 mmol, 1 equiv) in acetonitrile (10 mL) was added potassium persulfate (12.5 mmol, 1.2 equiv) and iodine (1 mmol, 0.1 equiv). Then the reaction mixture was warmed over 16 h at 80 ℃ under nitrogen atmosphere. It was then cooled reaction mixture to 25 °C followed by the addition of ethyl acetate (30 mL) and 0.2 M sodium thiosulfate (20 mL). Afterward, the residues were washed sequentially with water (30 mL) and quenched with hydrogen chloride acid (0.5 M, 10 mL). The organic phase was dried and concentrated in a vacuum at 40–50 °C to afford the crude product. The crude product was purified by silica gel column chromatography to give compound 1.
• 20 Synthesis of Methyl 2,4-dihydroxy-6-pentylbenzoate (1a) Cyclic diketo ester compound 2a (5.7 kg, 24 mol, 1 equiv), potassium persulfate (7.5 kg, 28 mol, 1.2 equiv), and iodine (590 g, 2.3 mol, 0.1 equiv) in CH₃CN (50 L) were charged to a 100 L glass reactor that had been purged with nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The disappearance of starting material 2a was confirmed via TLC analysis and then the reaction mixture was cooled to 25 °C followed by the addition of ethyl acetate (30 L) and 0.2 M sodium thiosulfate (20 L). The water solution was collected and concentrated to 10 L under vacuum conditions, then treated with potassium persulfate (1.5 kg, 5.6 mol) at room temperature, and the catalyst was recovered after the filtration step. The reaction vessel, the filter, and the cake (I₂ catalyst) were washed with additional water (3 × 1 L), and the catalyst was reused for another batch of oxidation and aromatization reaction. The ethyl acetate phase was concentrated and dried under vacuum at 40–50 °C to afford the crude product. The crude product was crystallized with cyclohexane (7.5 L) to obtain a 4.98 kg white solid of methyl olivetolate 1a (90% of yield and 99.84% purity by HPLC); mp 105–106 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 10.26 (s, 1 H), 9.80 (s, 1 H), 6.26–6.04 (m, 2 H), 3.77 (s, 3 H), 2.57–2.49 (m, 5 H), 1.53–1.38 (m, 2 H), 1.27 (td, J = 8.2, 7.0, 4.8 Hz, 5 H), 0.87 (t, J = 6.9 Hz, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 171.9, 165.2, 160.2, 148.9, 110.7, 105, 101.3, 51.87, 36.76, 32.01, 31.42, 22.45, 14.02. HRMS (ESI): m/z [M – H]^– calcd for C₁₃H₁₇O₄: 237.1; found: 237.3.