Concise Synthesis of Potential 4-Hydroxy-5-fluoropentyl Side-Chain Metabolites of Four Synthetic Cannabinoids

Abstract

Synthetic cannabinoids are a group of compounds that act on the CB1 receptor and are used illicitly as substitutes for cannabis. Given the rapid and extensive metabolism of synthetic cannabinoids, urinary biomarkers are essential if proof of drug intake is to be obtained in forensic laboratories. To identify good biomarker candidates, the metabolism of synthetic cannabinoids must be studied and reference standards need to be acquired. Studies on the metabolism of synthetic cannabinoids containing a terminally fluorinated pentyl side chain have shown that hydroxylation can occur at the four position of the side chain. This makes the 4-hydroxy-5-fluoropentyl side-chain metabolite a good urinary biomarker for proving intake of the corresponding parent drug, as this compound cannot be formed from its nonfluorinated analogue. Here, a concise synthetic route to the 4-hydroxy-5-fluoropentyl side-chain metabolites of the synthetic cannabinoids STS-135, MAM-2201, AM-2201, and XLR-11 is reported.

Key words

synthetic cannabinoids - forensic science - reference standards - metabolites - biomarkers - psychoactive substances

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• 21 Ring Opening of Epoxides; General Procedures Method A: In a microwave vial, compound 3 or 7b (1 equiv) was dissolved in anhyd THF (1 mL) or toluene (2.2 mL), together with dry solid TBAF (4–6 equiv) obtained by azeotropic drying of TBAF·3 H₂O with toluene and MeOH until no further loss of mass could be observed. The mixture was heated by microwave irradiation at 165 °C for 45–60 min. The mixture was then diluted with H₂O and extracted with EtOAc (×3). The organic layers were combined, concentrated, and purified by flash column chromatography and preparative HPLC. Method B: A mixture of 7a, 7b, or 7c (1 equiv) with 1 M TBAF (4–4.5 equiv) in THF was heated at 70–80 °C for 4–16 h. The procedure for workup and purification was the same as that described in Method A. N-2-Adamantyl-1-(5-fluoro-4-hydroxypentyl)-1H-indole-3-carboxamide (4) (Method A) White sticky yellow; yield: 20 mg (49%). ¹H NMR (300 MHz, CDCl₃): δ = 7.90–7.83 (m, 1 H), 7.65 (s, 1 H), 7.40–7.32 (m, 1 H), 7.27–7.19 (m, 2 H), 5.72 (br s, 1 H), 4.44–4.12 (m, 4 H), 3.93–3.76 (m, 1 H), 2.21–2.15 (m, 7 H), 2.15–2.11 (m, 3 H), 2.09–1.87 (m, 2 H), 1.80–1.64 (m, 6 H), 1.50–1.39 (m, 2 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 164.6, 136.7, 131.4, 125.4, 122.5, 121.4, 120.1, 112.5, 110.4, 86.8 (d, J _CF = 169.2 Hz), 70.1 (d, J _CF = 19.5 Hz), 52.3, 46.6, 42.3, 36.6, 29.7, 29.1 (d, J _CF = 6.9 Hz), 26.2. ¹⁹F NMR (282.2 MHz, CDCl₃): δ = –227.8 (td, J _HF = 47.7, 16.9 Hz). [1-(5-Fluoro-4-hydroxypentyl)-1H-indol-3-yl](2,2,3,3-tetramethylcyclopropyl)methanone (8c) (Method B) White sticky yellow; yield: 112.3 mg (40%). ¹H NMR (300 MHz, CDCl₃): δ = 8.43–8.36 (m, 1 H), 7.67 (s, 1 H), 7.37–7.27 (m, 2 H), 7.26–7.24 (m, 1 H), 4.48–4.28 (m, 1 H), 4.28–4.11 (m, 3 H), 3.98–3.81 (m, 1 H), 2.23–1.96 (m, 3 H), 1.57–1.44 (m, 2 H), 1.35 (s, 6 H), 1.31 (s, 6 H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 194.9, 136.7, 133.5, 126.5, 123.2, 122.9, 122.3, 120.0, 109.7, 86.8 (d, J _CF = 169.3 Hz), 70.1 (d, J _CF = 19.5 Hz), 46.9, 41.9, 31.9, 29.0 (d, J _CF = 6.9 Hz), 26.2, 24.2, 17.2. ¹⁹F NMR (282.2 MHz, CDCl₃): δ = –228.0 (td, J _HF = 47.4, 17.8 Hz).