Decagram-Scale Synthesis of N-{2-[4-(β-d-Glucopyranosyloxy)-2-methylphenyl]-1,1-dimethyl-2-oxoethyl}-3-methylthiophene-2-carboxamide (GPTC), a Metabolite of the Fungicide Isofetamid

Abstract

A decagram-scale synthesis of N-{2-[4-(β-d-glucopyranosyloxy)-2-methylphenyl]-1,1-dimethyl-2-oxoethyl}-3-methylthiophene-2-carboxamide (GPTC), a metabolite of the fungicide isofetamid, has been achieved in a highly straightforward manner from the known compound 1-(4-hydroxy-2-methylphenyl)-2-methylpropan-1-one in eight steps with a 20% overall yield to provide a standard certified reference material for residue analysis in food.

Key words

isofetamid - GPTC - large-scale synthesis - certified reference materials

• References and Notes

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• 8 The high β-selectivity probably results from β-attack of the phenol moiety in 2 on the corresponding oxonium intermediate of pentaacetyl-β-d-glucose (8), avoiding the steric hindrance of the neighboring α-oriented acetate group.
• 9 Glucoside 15 To a cooled (0 °C) solution of 4-HP (2; 18.02 g, 56.77 mmol) in CH₂Cl₂ (500 mL) were added pentaacetyl-β-d-glucose (8; 44.32 g, 113.5 mmol), Et₃N (15.83 mL, 113.5 mmol), and BF₃·OEt₂ (35.05 mL, 283.9 mmol) and the resulting mixture was stirred for 12 h at r.t. The reaction was quenched with sat. aq NaHCO₃, and the layers were separated. The aqueous layer was extracted with CH₂Cl₂ and the combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexanes–EtOAc (3:1 to 1:1)] to give a white solid; yield: 23.04 g (90%); [α]_D ²⁵ ‒9.24 (c 1.00, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.47 (d, J = 8.6 Hz, 1 H), 7.23 (d, J = 5.0 Hz, 1 H), 6.86–6.82 (m, 2 H), 6.74 (dd, J = 8.6, 2.5 Hz, 1 H), 6.70 (s, 1 H), 5.33–5.20 (m, 2 H), 5.14 (dd, J = 10.1, 9.0 Hz, 1 H), 5.09 (d, J = 7.6 Hz, 1 H), 4.26 (dd, J = 12.3, 5.5 Hz, 1 H), 4.15 (dd, J = 12.3, 2.4 Hz, 1 H), 3.87 (ddd, J = 10.0, 5.5, 2.4 Hz, 1 H), 2.41 (s, 3 H), 2.35 (s, 3 H), 2.05 (s, 3 H), 2.04 (s, 6 H), 2.02 (s, 3 H), 1.72 (s, 6 H). ¹³C NMR (150 MHz, CDCl₃): δ = 205.9, 170.5, 170.2, 169.35, 169.23, 162.3, 157.3, 140.7, 139.6, 132.5, 131.9, 131.3, 127.6, 126.5, 119.4, 112.5, 98.5, 72.6, 72.1, 71.0, 68.2, 62.6, 61.9, 25.23, 25.20, 20.63, 20.58, 20.56, 20.54, 15.5. HRMS (EI-magnetic sector); m/z [M⁺] calcd for C₃₁H₃₇NO₁₂S: 647.2036; found: 647.2033.
• 10 GPTC (1) LiOH (35.93 g, 1.50 mol) was added to a solution of β-glucoside 15 (19.43 g, 30.00 mmol) in 2:1:1 THF–MeOH–H₂O ( mL) at r.t., and the resulting mixture was stirred for 18 h at r.t. The reaction was then quenched with sat. aq NH₄Cl. The solvent was evaporated until about 100 mL remained, and the residue was diluted with CH₂Cl₂ and H₂O. The layers were separated and the aqueous layer was extracted with CH₂Cl₂. The combined organic layers were dried (MgSO₄) and concentrated in vacuo. The residue was purified by column chromatography [silica gel, EtOAc–MeOH (10:1)] to give a white solid; yield: 10.84 g (75%); [α]_D ²⁵ ‒33.7 (c 0.75, CHCl₃). ¹H NMR (600 MHz, DMSO-d6): δ = 8.53 (s, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.49 (d, J = 4.9 Hz, 1 H), 6.91–6.83 (m, 2 H), 6.77 (dd, J = 8.7, 2.6 Hz, 1 H), 5.29 (d, J = 5.1 Hz, 1 H), 5.08 (d, J = 4.9 Hz, 1 H), 5.01 (d, J = 5.3 Hz, 1 H), 4.86 (d, J = 7.6 Hz, 1 H), 4.55 (dd, J = 6.3, 5.3 Hz, 1 H), 3.66 (ddd, J = 11.8, 5.3, 2.1 Hz, 1 H), 3.45 (dt, J = 11.8, 6.1 Hz, 1 H), 3.32 (ddd, J = 9.9, 5.5, 2.1 Hz, 1 H), 3.26 (td, J = 8.8, 4.9 Hz, 1 H), 3.21 (td, J = 7.6, 5.0 Hz, 1 H), 3.16 (td, J = 8.6, 5.2 Hz, 1 H), 2.32 (s, 3 H), 2.17 (s, 3 H), 1.570 (s, 3 H), 1.567 (s, 3 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ = 205.1, 162.9, 158.5, 140.6, 139.9, 131.69, 131.47, 131.27, 128.6, 127.4, 119.4, 111.8, 100.6, 77.6, 77.1, 73.7, 70.1, 61.6, 61.0, 26.51, 26.45, 21.3, 15.2. HRMS (FAB-magnetic sector): m/z [M + H]⁺ calcd for C₂₃H₃₀NO₈S: 480.1691; found: 479.1691.