The Vespiary

Syntheses of Melatonin and its Derivatives
Masanori Somei, Yoshikazu Fukui, Masakazu Hasegawa, Naoki Oshikiri, and Toshikatsu Hayashi

Heterocycles 53(8), 1725-1736 (2000) (http://www.heterocycles.jp/data/pdffiles/COM-00-8930.pdf)

(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.


Experimental

N b-Methoxycarbonyl-2,3-dihydrotryptamine (4b) from N b-Methoxycarbonyltryptamine (3b)
Et₃SiH (7.50 mL, 46.9 mmol) was added to a solution of 3b (5.03g, 23.0 mmol) in
CF₃COOH (100 mL) and the mixture was heated at 60°C for 3 h with stirring. After evaporation of the solvent, H₂O was added to the residue. The whole was made basic by adding 2N aqueous NaOH under ice cooling and extracted with CHCl₃-MeOH (95:5, v/v). The extract was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO₂ with CHCl₃-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 4b
30% Aq. H₂O₂ (1.0 mL, 9.18 mmol) was added to a solution of 4b (201.9mg, 0.92 mmol) and Na₂WO₄×2H₂O (63.2mg, 0.18 mmol) in MeOH-H₂O (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 CHCl₃. The extract was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO₂ with AcOEt-hexane (1:2, v/v) to give 5b (237.4mg, 65%). 5b: mp 114—115°C (colorless needles, recrystallized from CH₂Cl₂-hexane).

5-Methoxy-N b-methoxycarbonyltryptamine (6) from 5b
50% BF₃-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 H₂O, the whole was made neutral by adding 40% aq. NaOH and extracted with CHCl₃. The extract was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO₂ with CHCl₃ to give 6 (8.52g, 83%).

5-Methoxytryptamine (7) from 6
20% 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 H₂O, the whole was extracted with CHCl₃-MeOH (95:5, v/v). The extract was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO₂ with CHCl₃-MeOH-28% aq. NH₃ (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 CHCl₃-hexane).

Melatonin (1) from 7
Ac₂O (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 CHCl₃-MeOH (95:5, v/v). The extract was washed with brine, dried over Na₂SO₄, and evaporated under reduced pressure to leave an oil, which was column-chromatographed on SiO₂ with CHCl₃-MeOH (99:1, v/v) to give 1 (1.03g, 92%).

Synthesis of 5-Substituted Indole Derivatives. I. An Improved Method for the Synthesis of Sumatriptan
Béla Pete, István Bitter, Csaba Szántay, Jr. , István Schön and László Töke

Heterocycles 48(6), 1139-1149 (1998) (https://www.thevespiary.org/rhodium/Rhodium/pdf/sumatriptan.fischer.pdf)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/sumatriptan.fischer.pdf)

Abstract
An improved synthesis of sumatriptan (1b) via Fischer cyclization was achieved by introducing the ethoxycarbonyl group on the N-atom of the sulphonamide moiety in N-methyl-4-hydrazinobenzenemethanesulphonamide (7). As a result, substitution on the benzylic carbon of the indole nucleus could be avoided; however, formation of 1,1-bis-(indol-2-yl)-4-dimethylaminobutane-type by-product (19) was observed. The indolization procedure was optimized to suppress the unwanted side reaction. The N-protection of the sulphonamide moiety was found to be beneficial regarding the purification of the 3-[2-(dimethylamino)ethyl]-N-ethoxycarbonyl-N-methyl-1H-indole-5-methanesulphonamide (18).

How about rating Demorol's post a "good read" (at least) too - it can well compete (in terms of given information) with your two posts on the topic, Rhod!

(cmon chief, you post on melatonine synthesis - "good read", demorol posts gives another ref, posts several procedures - not rated, then you post something else - again "good read"... Do you think this encourages demorol in making articles available to other bees? Just meant as constructive critics  :-[ )

A

Very good point, that post definitely deserves a rating. The lack of rating was definitely due to an oversight, not a conscious desicion.

Note to everyone: If you feel that a good post lacks a rating, then PM me about it - it is not on topic in any thread.

Also, I do not appreciate any flaming or unkind words in PM if I have failed to rate a post (yes, people actually do that from time to time), as it's not particularly surprising if I or any other moderator fail to remember to press the rating buttons from time to time when wading through the over ~250 daily posts at this site.