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M. T. Rubino et al.
Arch. Pharm. Chem. Life Sci. 2011, 344, 557–563
Methyl 3,4,5-trimethoxy benzoate (C4) and 3,4,5-trimethoxy
benzoic acid (C10) were prepared according to literature [23].
aqueous layer. The organic solution was washed with saturated
solutions of NaHCO3 and brine, dried over Na2SO4, and evapo-
rated to dryness to give a residue that was purified by column
chromatography on silica gel (eluent EP/CH2Cl2 9.8:0.2) affording
the title compound as a white solid. Yield: 72%. M. p.: 96–998C;
1H-NMR (CDCl3): d 3.80 (s, 6H, CH3), 6.93–7.04, (m, 4H, aromatics)
7.27–7.32, (m, 2H, aromatics), 7.45–7.49, (m, 2H, aromatics). GC–
MS m/z (%): 214 ([M]þ, 100). Anal. calcd. for C14H14O2: C 78.48%,
H 6.59%, found: C 78.35%, H 6.64%.
3,4,5-Trimethoxy benzoic acid C4
White solid. Yield: 96%. M. p.: 171–1738C; 1H-NMR (CDCl3): d 3.92
(s, 6H, OCH3), 3.93 (s, 3H, OCH3), 7.40 (s, 2H, aromatics). MS (ESI)
m/z: 211 [M–H]ꢁ, MS2 m/z (%): 153 ([C8H9O3þ], 100). Anal.
calcd. for C10H12O5: C 56.60%, H 5.70%, found: C 56.77%,
H 5.71%.
Methyl 3,4,5-trimethoxy benzoate C10
1,2-Dihydroxy-3-aminobenzene C8
Yellowish solid. Yield: 98%. M. p.: 83–848C; 1H-NMR (CDCl3): d 3.90
(s, 12H, CH3), 7.29 (s, 2H, aromatics). GC–MS m/z (%): 226 ([M]þ,
100). Anal. calcd. for C11H14O5: C 58.40%, H 6.24%, found:
C 58.77%, H 6.27%.
A solution of 2,3-dihydroxybenzoic acid (12.99 mmol) in MeOH
(17 mL) and H2SO4 (0.7 mL) was held at reflux for 6 h. The solvent
was removed under reduced pressure, the residue was dissolved
in EtOAc (70 mL) and washed with saturated solution of NaHCO3,
brine, and dried over Na2SO4. The organic phase was evaporated
to dryness to afford the corresponding methyl ester as yellowish
solid in quantitative yield. The compound was immediately used
in the next step without further purification. M.p.: 77–808C;
1H-NMR (CDCl3): d 3.95 (s, 3H, CH3), 5.67 (s, 1H, OH), 6.79
(m, 1H, aromatic), 7.09–7.12 (m, 1H, aromatic), 7.35–7.38
(m, 1H, aromatic), 10.99 (s, 1H, OH). GC–MS m/z (%): 168 ([M]þ,
36), 136 ([C7H4O3]þ, 100).
1,2-Dihydroxy-4-aminobenzene C6, 3,4-Dihydroxy-benzyl-
amine C7, and 2,40-Dihydroxybiphenyl D9
BBr3 (1 M CH2Cl2 solution, 5.9 mmol) was carefully added drop-
wise under N2 atmosphere to a cooled (ꢁ708C) red solution of the
suitable dimethoxy derivative (1.96 mmol) in anhydrous toluene
(21 mL). After 5 h at r.t. an excess of frozen MeOH (10 mL) was
added and stirring was continued for additional 30 min. The
organic solvent was removed under reduced pressure, and the
crude solids were crystallized or triturated with hexane/MeOH or
hexane affording the final compounds (C6, C7, D9) as colored
solids in 44–64% yields.
To
a stirred solution of methyl 2,3-dihydroxybenzoate
(12.17 mmol) and K2CO3 (24.34 mmol) in anhydrous DMF
(16 mL), benzyl bromide (24.34 mmol) was added and the reac-
tion mixture was stirred at 858C under Ar atmosphere. After 6 h
the suspension was filtered and the resulted solution was evap-
orated affording a yellowish oil. The unreacted benzyl bromide
was removed by distillation and the solid obtained was crystal-
lized from hexane to afford the methyl 2,3-bis(benzyloxy) benzo-
1,2-Dihydroxy-4-aminobenzene C6
Grey solid. Yield: 64%. M. p.: 256–2598C; 1H-NMR (DMSO-d6):
d 6.58–6.61 (m, 1H, aromatic), 6.75–6.79 (m, 2H, aromatics),
9.26 (br s, 1H, OH), 9.52 (br s, 1H, OH), 9.64 (br s, 2H, NH2).
GC–MS m/z (%): 125 ([M]þ, 100). Anal. calcd. for C6H7NO2 ꢂ HBr:
C 34.98%, H 3.91%, N 6.80%, found: C 35.18%, H 4.06%, N 6.78%.
1
ate as a white solid. Yield: 71%. M. p.: 64–678C; H-NMR (CDCl3):
d 3.85 (s, 3H, CH3), 5.11 (s, 2H, CH2Ph), 5.14 (s, 2H, CH2Ph), 7.10–
7.16 (m, 2H, aromatics), 7.30–7.46 (m, 11H, aromatics).
To a stirred solution of methyl 2,3-bis(benzyloxy) benzoate
(8.64 mmol) in dioxane/MeOH (2:1, 33 mL), 8 N NaOH
(173 mmol) was added. The reaction mixture was heated for
2.5 h at 858C, then evaporated. 2 N HCl was added to the residue
stirring for 10 min. This aqueous phase was extracted with
CHCl3 (100 mL). The organic phase was washed with brine, dried
over Na2SO4, filtered, and evaporated to dryness to obtain the 2,3-
bis(benzyloxy) benzoic acid as a white solid. Yield: 97%. M. p.:
122–1248C; 1H-NMR (CDCl3): d 5.19 (s, 2H, CH2Ph), 5.27 (s, 2H,
CH2Ph), 7.16–7.50 (m, 12H, aromatics), 7.73–7.76 (m, 1H,
aromatic).
To a solution of 2,3-bis(benzyloxy) benzoic acid (4.19 mmol)
in anhydrous THF (15.5 mL) were added diphenylphosphoryl
azide (4.40 mmol), absolute ethanol (2.5 mL), and anhydrous
Et3N (5.03 mmol). After 6 h at 808C, the mixture was concen-
trated under reduced pressure in order to remove most ethanol,
and then it was diluted with EtOAc (50 mL); the organic phase
was washed with saturated aqueous NaHCO3 solution, 1 N HCl,
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The crude solid was purified by column chromatography
on silica gel (eluent EP/EtOAc 9.5:0.5) affording the ethyl 2,3-
bis(benzyloxy)phenylcarbamate as a white solid. Yield: 84%.
M. p.: 67.5–708C; 1H-NMR (CDCl3): d 1.28 (s, 3H, CH3), 1.28
(s, 2H, CH3CH2), 5.05 (s, 2H, CH2Ph), 5.15 (s, 2H, CH2Ph), 6.69–
6.73, (m, 1H, aromatic), 6.98–7.04, (m, 1H, aromatic), 7.13
(br s, 1H, NH) 7.31–7.44, (m, 8H, aromatics), 7.45–7.48, (m, 2H,
aromatics), 7.68–7.71, (m, 1H, aromatic).
3,4-Dihydroxy-benzyl-amine C7
Brownish solid. Yield: 44%. M. p.: 186–1888C; 1H-NMR (DMSO-d6):
d 3.80 (s, 2H, CH2), 6.65–6.74 (m, 2H, aromatics), 6.79–6.80
(m, 1H, aromatic), 7.80–9.20 (br, 4H, OH, NH2). Anal. calcd.
for C7H9NO2 ꢂ HBr:
C 38.20%, H 4.58%, N 6.63%, found:
C 38.21%, H 4.58%, N 6.37%.
2,40-Dihydroxybiphenyl D9
Yellowish solid. Yield: 63%. M. p.: 165–1668C; 1H-NMR (DMSO-d6):
d 6.73–6.88, (m, 4H, aromatics) 7.03–7.09, (m, 1H, aromatic), 7.14–
7.17, (m, 1H, aromatic), 7.31–7.36 (m, 2H, aromatics), 9.33 (br s,
2H, OH). GC–MS m/z (%): 186 ([M]þ, 100). Anal. calcd. for C12H10O2:
C 77.40%, H 5.41%, found: C 77.02%, H 5.42%.
2,40-Dimethoxy-biphenyl D8
A solution of 1-bromo-2-methoxybenzene (2.14 mmol), 4-meth-
oxybenzeneboronic acid (4.28 mmol), and Cs2CO3 (3.21 mmol) in
anhydrous toluene (22 mL) was stirred at room temperature
under N2 atmosphere for 20 min. [Pd(PPh3)4] was added
(0.054 mmol) and the resulting mixture was heated at 908C.
After stirring overnight, the reaction mixture was cooled to
room temperature, diluted with 1 N HCl and EtOAc (1:1,
7.5 mL), stirred for 15 min and filtered through a pad of
Celite, followed by separation of the organic phase from the
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