General
Melting points were determined on a Kofler melting point apparatus. 1H- and 13C-NMR-spectra were recorded on a Bruker AC-200 (200 MHz) pulse Fourier-transform NMR spectrometer in CDCl3 or DMSO-d6 using tetramethylsilane as an internal standard. Thin layer chromatography (TLC) was performed on precoated plates (Merck TLC aluminum sheets silica 60 F254) with detection by UV light or with phosphomolybdic acid in aqueous EtOH by heating. All reactions were magnetically stirred under an argon atmosphere. MPLC (medium pressure liquid chromatography) was performed using SiO2 (Baker), a LC-8A pump (Shimadzu), a SPD-6AV UV-detector (Shimadzu) and Büchi glass columns.
2-Bromo-4-methoxy-5-(1-methylethoxy)benzenemethanamine hydrochloride (2). 1-Bromo-2-(chloro-methyl)-5-methoxy-4-(1-methylethoxy)benzene (1) (5.00 g, 17.0 mmol) and potassium phthalimide (3.47 g, 18.7 mmol) were stirred in dry DMF (60 mL) for 12 h at 60 °C. The suspension was filtered and concentrated in vacuo, and the residue was partitioned between water (150 mL) and Et2O (150 mL). The aqueous layer was extracted with Et2O (2 x 100 mL), the combined organic layer was washed with water (3 x 200 mL) and brine (1 x 200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was refluxed with hydrazine hydrate (1.28 g, 25.5 mmol) in dry EtOH (100 mL) for 24 h, cooled to ambient temperature and filtered. The residue was extracted with boiling EtOH (2 x 25 mL), the combined extracts were added to the filtrate and concentrated in vacuo. The residue was dissolved in Et2O (10 mL), cooled to 0 °C and treated with HCl/Et2O (satd. at 0 °C). The precipitated hydrochloride salt was collected by filtration and triturated with dry Et2O (3 x 50 mL). Yield: colorless needles (4.15 g, 79%), mp. 235-237 °C. TLC: Rf = 0.7 (CHCl3 - MeOH - conc. NH3 = 89:10:1); Anal. Calcd for C11H16BrNO2*HCl: C, 42.54; H, 5.52; N, 4.51. Found: C, 42.24; H, 5.40; N, 4.36. 1H‑NMR (DMSO-d6): δ 8.73 (b, 3H), 7.41 (s, 1H), 7.18 (s, 1H), 4.61 (septet, J = 6.3 Hz, 1H), 4.03 (s, 2H), 3.86(s, 3H), 3.47(s, 2H), 1.22 (d, J = 6.3 Hz, 6H); 13C-NMR (DMSO-d6): δ 150.5 (s), 146.4 (s), 124.95 (s), 117.05 (s), 115.85 (d), 113.55 (d), 70.8 (d), 56.1 (q), 41.7 (t), 21.9 (2 q).
4-[[[2-Bromo-4-methoxy-5-(1-methylethoxy)phenylmethyl]amino]methyl]phenol (3). 2-Bromo-4-methoxy-5-(1-methylethoxy)benzenemethanamine (2.28 g. 7.30 mmol, extracted from 2 by partitioning the salt between CHCl3 and conc. NH3) and 4-hydroxybenzaldehyde (0.89 g, 7.30 mmol) in dry EtOH (60 mL) were stirred under reflux for 6 h. The mixture was cooled to 0 °C, then sodium borohydride (1.36 g, 36.5 mmol) was added and stirred for 30 min at this temperature and 1 h under reflux. 2 N HCl (10 mL) was added, the mixture was concentrated to a volume of 5 mL, neutralized with satd. NaHCO3 and extracted with CHCl3 (4 x 50 mL). The combined organic layer was washed with satd. NaHCO3 (2 x 100 mL), water (1 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC (100 g SiO2, CHCl3 : MeOH : conc. NH3 = 89 : 10 : 1). Yield: colorless crystals (2.34 g, 84%). An analytical sample was converted into the hydrochloride salt by treatment with HCl/Et2O to give colorless crystals (mp. 211 - 215 °C). TLC: Rf = 0.55 (CHCl3 - MeOH - conc. NH3 = 89:10:1); Anal. Calcd for C18H22BrNO3*HCl: C, 51.88; H, 5.56; N, 3.36. Found: C, 51.93; H, 5.56; N, 3.31. 1H-NMR (DMSO-d6): δ 9.82 (b, 3H), 7.54 (s, 1H), 7.39 (d, J = 8.9 Hz, 2H), 7.17 (s, 1H), 6.82 (d, J = 8.9 Hz, 2H), 4.61 (septet, J = 6,7 Hz, 1H), 4.10 (s, 2H), 4.06 (s, 2H), 3.80 (s, 3H), 1.26 (d, J = 6,7 Hz, 6H); 13C-NMR (DMSO-d6): δ 158.1 (s), 150.8 (s), 146.3 (s), 131.8 (d), 123.1 (s), 121.5 (s), 117.7 (s), 115.8 (d), 115.4 (d), 114.4 (d), 70.8 (d), 56.0 (q), 49.4 (t), 48.3 (t), 21.9 (q).
N-[[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-N-[(4-hydroxyphenyl)-methyl]form-amide (4). Compound 3 (1.50 g, 3.94 mmol), 4-(dimethylamino)pyridine (50 mg), ethyl formate (1.4 mL), formic acid (0.4 mL) and DMF (1.5 mL) were refluxed in dry dioxane for 6 h. The mixture was concentrated in vacuo, and the residue was partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL), the combined organic layer was washed with 2 N HCl (3 x 50 mL), water (1 x 50 mL), satd. NaHCO3 (2 x 50 mL) and brine (1 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with tert.-butylmethylether (5 mL). Yield: colorless crystals (1.19 g, 74%), mp. 125 - 128 °C. TLC: Rf = 0.5 (CHCl3 - MeOH - conc. NH3 = 89:10:1); Anal. Calcd for C19H22BrNO4: C, 55.89; H, 5.43; N, 3.43. Found: C, 55.91; H, 5.43; N, 3.44. 1H-NMR (DMSO-d6): δ 9.46 and 9.38 (s, 1H), 8.46 and 8.40 (s, 1H), 7.12 and 7.10 (s, 1H), 7.03 and 6.99 (d, J = 13.3 Hz, 2H), 6.78 (s, 1H), 6.73 and 6.99 (d, J = 13.3 Hz, 2H), 4.55 - 4.12 (m, 5H), 3.76 (s, 3H), 1.32 - 1.12 (m, 6H); 13C-NMR (DMSO-d6): δ 163.5 and 163.3 (d), 157.0 and 156.6 (s), 150.4 and 150.0 (s), 146.3 (s), 129.1 (s), 127.0 and 126.7 (d), 126.9 and 126.6 (s), 117.2 and 116.4 (s), 116.2 and 116.1 (d), 115.4 and 115.2 (d), 113.7 and 113 (d), 70.9 (d), 55.9 (q), 49.7 (t), 44.4 and 43.9 (t), 21.8 and 21.7 (q).
N-[(2-Bromo-5-hydroxy-4-methoxyphenyl)methyl]-N-[(4-hydroxyphenyl)methyl]formamide (5). To 4 (1.0 g, 2.45 mmol) in dry CH2Cl2 (5 mL) BCl3 (10 mL, 10 mmol, 1 M in CH2Cl2) was added at -78 °C and stirred for 4 h at ambient temperature. Water (20 mL) was added dropwise, and the mixture was concentrated in vacuo to a volume of 15 mL. The precipitate was collected by filtration and triturated with water (6 x 20 mL) and iPr2O (2 x 10 mL). Yield: colorless crystals (879 mg, 98%), mp. 94 - 96 °C. TLC: Rf = 0.2 (CHCl3 - MeOH - conc. NH3 = 89:10:1); Anal. Calcd for C16H16BrNO4: C, 52.84; H, 4.40; N, 3.82. Found: C, 52.65; H, 4.61; N, 3.67. 1H-NMR (DMSO-d6): δ 9.50 (b, 1H), 9.40 (b, 1H), 8.50 and 8.40 (s, 1H), 7.31 - 6.81 (m, 3H), 6.81 - 6.55 (m, 3H), 4.51 - 4.11 (m, 4H), 3.79 (s, 3H); 13C‑NMR (DMSO-d6): δ 163.5 and 163.3 (d), 157.1 and 156.7 (s), 148.3 and 147.9 (s), 146.5 (s)129.3 and 129.2 (s), 127.2 and 127.1(d), 126.6 and 126.5 (s), 116.7 and 116.3 (s), 116.0 and 115.8 (d), 115.5 and 115.4 (d), 111.1 and 110.6 (d), 56.1 (q), 49.5 and 49.2 (t), 43.7 and 43.6 (t).
2-[4-(1-Methylethoxy)phenylmethyl]propandioic acid dimethylester (7). 1-(Chloromethyl)-4-(1-methylethoxy)benzene (6) (20.5 g, 111 mmol), dimethyl malonate (102.5 g, 776 mmol) and potassium carbonate (46.5 g, 332 mmol, anhydrous, freshly ground) in dry DMF (250mL) were stirred for 24 h at 70 °C. The suspension was filtered and concentrated, and the residue was partitioned between water (250 mL) and Et2O (250 mL). The aqueous layer was extracted with Et2O (2 x 50 mL), the combined organic layer was washed with water (3 x 200 mL) and brine (1 x 150 mL), dried over Na2SO4, filtered and concentrated in vacuo. The excess of dimethylmalonate was removed by distillation (160 °C/15 mbar), and the crude product was purified by kugelrohr distillation (130 °C/0.001 mbar). Yield: colorless oil (23.6 g, 78%). TLC: Rf = 0.8 (petroleum ether - EtOAc = 9:1); Anal. Calcd for C15H20O5: C, 64.27; H, 7.19. Found: C, 64.28; H, 7.07. 1H-NMR (CDCl3): δ 7.07 (d, J = 7.6 Hz, 2H), 6.76 (d, J = 7.6 Hz, 2H), 4.48 (septet, J = 6.0 Hz, 1H), 3.67 (s, 6H), 3.61 (t, J = 8.0 Hz, 1H), 3.12 (d, J = 8.0 Hz, 2H), 1.29 (d, J = 6.0 Hz, 6H); 13C-NMR (CDCl3): δ 169.1 (s), 156.6 (s), 129.6 (d), 129.4 (s), 115.8 (d), 69.6 (d), 53.7 (d), 52.3 (q), 33.8 (t), 21.9 (q).
2-[[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-2-[[4-(1-methylethoxy)phenyl]methyl]-propanedioic acid dimethylester (8). Compound 7 (2.50 g, 8.92 mmol), 1-bromo-2-chloromethyl-5-methoxy-4-(1-methylethoxy)benzene (1) (2.62 g, 8.92 mmol) and potassium carbonate (3.71 g, 26.8 mmol, anhydrous, freshly ground) in dry acetonitrile (100 mL) were stirred for 24 h at 60 °C. The suspension was filtered and concentrated, and the residue was partitioned between water (100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (1 x 50 mL), the combined organic layer was washed with water (3 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by kugelrohr distillation (180 °C/0.01 mbar). Yield: colorless oil (3.93 g, 82%). TLC: Rf = 0.5 (petroleum ether - EtOAc = 9:1); 1H-NMR (CDCl3): δ 7.02 (d, J = 8.1 Hz, 2H), 7.00 (s, 1H), 6.89 (s, 1H), 6.78 (d, J = 8.1 Hz, 2H), 4.58 - 4.31 (m, 2H), 3.78 (s, 3H), 3.59 (s, 6H), 3.37 (s, 2H), 3.26 (s, 2H), 1.37 - 1.26 (m, 12H); 13C-NMR (CDCl3): δ 171.2 (s), 156.8 (s), 149.5 (s), 146.1 (s), 130.9 (d), 128.1 (s), 127.8 (s), 118.0 (s), 116.1 (s), 115.8 (d), 115.5 (d), 71.3 (d), 69.7 (d), 60.2 (s), 56.0 (q), 52.2 (q), 39.9 (t), 38.6 (t), 22.0 (q), 21.9 (q).
2-Bromo-4-methoxy-5-(1-methylethoxy)-α-[[4-(1-methylethoxy)phenyl]methyl]-benzenepropan-amide (9). Compound 8 (3.93 g, 7.31 mmol) and KOH (1.50 g, 26.8 mmol) were stirred in EtOH (50 mL)/water (5 mL) under reflux for 12 h. The solution was concentrated to 5 mL in vacuo, a pH < 1 was adjusted by dropwise addition conc. HCl, and the mixture was partitioned between water (100 mL) and Et2O (100 mL). The aqueous layer was extracted with Et2O (2 x 50 mL), the combined organic layer was washed with water (3 x 100 mL) and brine (1 x 100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was decarboxylated using a kugelrohr apparatus (160 °C, 30 min), and the formed carboxylic acid was purified by subsequent distillation (165 °C/0.01 mbar). The distillate was dissolved in thionyl chloride (10 mL), then DMF (100 µL) was added and stirred for 6 h at ambient temperature. The mixture was concentrated in vacuo, dissolved in dry formamide, cooled to 0 °C and treated with a solution of NH3 in formamide (20 mL, saturated at 0 °C). The mixture was stirred for 1 h and poured into water (500 mL). The precipitate was collected by filtration and triturated with water (5 x 100 mL). Yield: colorless crystals (2.58 g, 76%), mp. 129 - 131 °C. TLC: Rf = 0.7 (CH2Cl2 - MeOH = 9:1); Anal. Calcd for C23H30BrNO4: C, 59.49; H, 6.51; N, 3.02. Found: C, 59.22; H, 6.24; N, 2.90. 1H‑NMR (DMSO-d6): δ 7.22 (b, 1H), 7.10 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H), 6.88 (s, 1H), 6.80 (d, J = 8.1 Hz, 2H), 6.71 (b, 1H), 4.76 - 4.46 (m, 2H), 3.39 (s, 3H), 2.98 - 2.34 (m, 5H), 1.38 - 1.07 (m, 12H); 13C-NMR (DMSO-d6): δ 175.5 (s), 155.8 (s), 149.1 (s), 145.8 (s), 131.4 (s), 131.0 (s), 129.9 (d), 118.1 (s), 115.9 (d), 115.4 d), 114.1 (d), 70.7 (d), 69.0 (d), 55.8 (q), 48.0 (d), 37.6 (t), 37.0 (t), 22.0 (q), 21.9 (q), 21.8 (q).
2-Bromo-5-hydroxy-α-[(4-hydroxyphenyl)methyl]-4-methoxypropanamide (10). To 9 2.00 g, 4.31 mmol) in dry CH2Cl2 (30 mL) BCl3 (10 mL, 16 mmol, 1.6 M in CH2Cl2) was added at -78 °C and stirred for 1 h at this temperature and for additional 2 h at ambient temperature. Water (100 mL) was added dropwise, and the mixture was concentrated in vacuo to a volume of 80 mL. The precipitate was collected by filtration and triturated with water (6 x 50 mL) and iPr2O (2 x 10 mL). Yield: colorless crystals (1.52 g, 93%), mp. 174 - 176 °C. TLC: Rf = 0.4 (CH2Cl2 - MeOH = 9:1); Anal. Calcd for C17H18BrNO4: C, 53.70; H, 4.77; N, 3.68. Found: C, 53.48; H, 4.66; N, 3.50. 1H-NMR (DMSO-d6): δ 9.21 (b, 2H), 7.21 (b, 1H), 7.13 - 6.89 (m, 3H), 6.87 - 6.51 (m, 4H), 3.72 (s, 3H), 2.93 - 2.30 (m, 5H); 13C-NMR (DMSO-d6): δ 175.9 (s), 155.6 (s), 147.1 (s), 145.8 (s), 131.4 (s), 130.0 (d), 129.9 (s), 118.0 (s), 115.9 (d), 115.1 (d), 112.0 (d), 56.0 (q), 48.2 (d), 37.7 (t), 37.1 (t).