Syntheses of Melatonin and its Derivatives Masanori Somei, Yoshikazu Fukui, Masakazu Hasegawa, Naoki Oshikiri, and Toshikatsu HayashiHeterocycles 53(, 1725-1736 (2000)
(
http://www.heterocycles.jp/data/pdffiles/COM-00-8930.pdf)
Abstract: Two simple synthetic methods for melatonin are newly developed from tryptamine through intermediates, which are promising lead compounds for drug developing research. Novel chemical reactivities of melatonin in its bromination, lithiation, and acylation are also reported.
ExperimentalN b-Methoxycarbonyl-2,3-dihydrotryptamine (4b) from N b-Methoxycarbonyltryptamine (3b)Et
3SiH (7.50 mL, 46.9 mmol) was added to a solution of
3b (5.03g, 23.0 mmol) in
CF
3COOH (100 mL) and the mixture was heated at 60°C for 3 h with stirring. After evaporation of the solvent, H
2O was added to the residue. The whole was made basic by adding 2N aqueous NaOH under ice cooling and extracted with CHCl
3-MeOH (95:5, v/v). The extract was washed with brine, dried over Na
2SO
4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO
2 with CHCl
3-MeOH (95:5, v/v) to give
4b (4.93g, 97%).
4b: mp 64-65°C (colorless prisms, recrystallized from AcOEt-hexane).
N b-Methoxycarbonyl-1-hydroxytryptamine (5b) from 4b30% Aq. H
2O
2 (1.0 mL, 9.18 mmol) was added to a solution of
4b (201.9mg, 0.92 mmol) and Na
2WO
4×2H
2O (63.2mg, 0.18 mmol) in MeOH-H
2O (1:1, v/v, 22.0 mL) at 0°C with stirring. Stirring was continued at rt for 30 min and then the whole was extracted with CHCl
3. The extract was washed with brine, dried over Na
2SO
4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO
2 with AcOEt-hexane (1:2, v/v) to give
5b (237.4mg, 65%).
5b: mp 114—115°C (colorless needles, recrystallized from CH
2Cl
2-hexane).
5-Methoxy-N b-methoxycarbonyltryptamine (6) from 5b50% BF
3-methanol complex (180.0 mL) was added to a solution of
5b (9.64g, 41.2 mmol) in MeOH (500 mL) and the mixture was refluxed for 30 min with stirring. After addition of ice and H
2O, the whole was made neutral by adding 40% aq. NaOH and extracted with CHCl
3. The extract was washed with brine, dried over Na
2SO
4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO
2 with CHCl
3 to give
6 (8.52g, 83%).
5-Methoxytryptamine (7) from 620% Aq. NaOH (1.0 mL) was added to a solution of
6 (51.2 mg, 0.20 mmol) in MeOH (1.0 mL) and the mixture was refluxed for 4 h with stirring. After addition of ice and H
2O, the whole was extracted with CHCl
3-MeOH (95:5, v/v). The extract was washed with brine, dried over Na
2SO
4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO
2 with CHCl
3-MeOH-28% aq. NH
3 (46:5:0.5, v/v) to give
7 (38.8 mg, 99%).
7: mp 124-126°C (lit.,4f mp 120°C, colorless prisms, recrystallized from CHCl
3-hexane).
Melatonin (1) from 7Ac
2O (3.0 mL, 31.7 mmol) was added to a solution of
7 (918.0mg, 4.83 mmol) in pyridine (6.0 mL) and the mixture was stirred at rt for 40 min. After evaporation of the solvent under reduced pressure, the whole was made alkaline by adding 2N aq. NaOH under ice cooling and extracted with CHCl
3-MeOH (95:5, v/v). The extract was washed with brine, dried over Na
2SO
4, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO
2 with CHCl
3-MeOH (99:1, v/v) to give
1 (1.03g, 92%).