Preparation method of azepano[4,5-b]indole compound

Abstract

The invention discloses a preparation method of an azepano[4,5-b]indole compound, which comprises the following steps: by taking tryptamine or a derivative thereof as an initial raw material, protecting an NH2 group of a side chain alkyl group, protecting an NH group on an indole ring, and allylating the NH group on the side chain alkyl group to obtain an allyl derivative; then carrying out metathesis reaction on olefin of an allyl derivative to prepare a corresponding allylaldehyde compound, and carrying out intramolecular Michael addition reaction on the allylaldehyde compound in form under the action of a Lewis acid catalyst to generate the azepano[4,5-b]indole compound. The raw materials which are low in cost and easy to obtain are adopted, so that the whole reaction route is mild, operation is easy and harsh reaction conditions are not needed; besides, most of the reaction processes are carried out at room temperature, and the yield of the product is high, and the azepano[4,5-b]indole structure has multiple derivatization sites and has good application prospects.

Description

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of an azepano[4,5-b]indole compound. Background technique

[0002] The backbone structure of azepano[4,5-b]indole (azepino[4,5-b]indole) exists in a variety of active natural product structures, such as ibogaine, ibogamine ), coronaridine, 18-MC (18-OMe-coronaridine) and noribogaine all contain azepan[4,5-b]indole (azepino[4, 5-b] indole) backbone structure, which have significant anti-drug addiction activity (cf. a) Maillet, E.L.; Milon, N.; Heghinian, M.D.; Fishback, J.; Schürer, S.C.; Garamszegi, N.; Mash ,D.C.Neuropharmacology 2015,99,675-688.b)Glue,P.;Lockhart,M.;Lam,F.;Hung,N.;Hung,C.-T.;Friedhoff,L.J.Clin.Pharmacol. 194. et al.).

[0003] The construction of the azepano[4,5-b]indole structure is of great significance for the synthesis of intermediates related to such active pharmaceutical molecules. The reported synthetic methods mainly us...

Examples

preparation example Construction

[0034] Preparation of compound 2: NH on the side chain alkyl of the tryptamine or its derivatives 2 The protection of the group is to use TsCl and NH on the side chain 2 It is realized by sulfonamidation reaction, and its reaction equation is:

[0035]

[0036] Among them, the structural formula of TsCl is TEA is triethylamine.

[0037] Under the protection of an inert gas, at 0°C, sequentially add tryptamine compound 1, triethylamine and 4-toluenesulfonyl chloride (TsCl) compound to the organic solvent to keep the reaction temperature. Return to room temperature and continue the reaction. After the disappearance of the tryptamine substrate is monitored by thin-layer chromatography, saturated ammonium chloride aqueous solution is added to the reaction solution to quench the reaction, and then water is added to dilute the reaction solution, and CH 2 Cl 2 Extract, combine the organic phases, remove the organic solvent after drying, and purify the concentrated reaction pr...

Embodiment 1

[0052] 1) Preparation of Compound 2a: Under the protection of an inert gas, at 0°C, tryptamine 1a (8.0 g, 50 mmol), triethylamine (20.8 mL, 150 mmol) and 4 -Toluenesulfonyl chloride (11.4g, 60mmol), keep the reaction temperature, after reacting for 0.5 hours, make the reaction temperature return to room temperature and continue the reaction, after the thin-layer chromatography monitors that the tryptamine substrate disappears, add saturated ammonium chloride to the reaction solution Aqueous solution (100mL) quenched the reaction, then added water (200mL) to dilute the reaction solution and washed with CH 2 Cl 2 (2×200mL, that is, use 200mL CH 2 Cl 2 two extractions) were extracted, the organic phases were combined, washed with water (2×300mL) and saturated brine (100mL), washed over anhydrous Na 2 SO 4 After drying, the organic solvent was removed, and the concentrated reaction product was purified by silica gel column chromatography (the eluent was petroleum ether: ethyl ...

Embodiment 2

[0063] 1) Preparation of compound 2b: under the protection of inert gas, 6-methyltryptamine 1a (1.74g, 10mmol), triethylamine (4.2mL, 30mmol) and 4-toluenesulfonyl chloride (2.28g, 12mmol), keep the reaction temperature, after reacting for 0.5 hours, make the reaction temperature return to room temperature and continue the reaction, after the thin-layer chromatography monitors that the tryptamine substrate disappears, add Saturated aqueous ammonium chloride solution (20 mL) quenched the reaction, then added water (40 mL) to dilute the reaction solution, and washed with CH 2 Cl 2 (2×40mL, that is, use 40mL CH 2 Cl 2 two extractions) were extracted, the organic phases were combined, washed with water (2×60mL) and saturated brine (20mL), washed over anhydrous Na 2 SO 4 After drying, the organic solvent was removed, and the concentrated reaction product was purified by silica gel column chromatography (the eluent was petroleum ether: ethyl acetate=5:1) to obtain the tryptamine...

technical field

[0001] The invention relates to the technical field of organic synthesis, in particular to a preparation method of an azepano[4,5-b]indole compound. Background technique

[0002] The backbone structure of azepano[4,5-b]indole (azepino[4,5-b]indole) exists in a variety of active natural product structures, such as ibogaine, ibogamine ), coronaridine, 18-MC (18-OMe-coronaridine) and noribogaine all contain azepan[4,5-b]indole (azepino[4, 5-b] indole) backbone structure, which have significant anti-drug addiction activity (cf. a) Maillet, E.L.; Milon, N.; Heghinian, M.D.; Fishback, J.; Schürer, S.C.; Garamszegi, N.; Mash ,D.C.Neuropharmacology 2015,99,675-688.b)Glue,P.;Lockhart,M.;Lam,F.;Hung,N.;Hung,C.-T.;Friedhoff,L.J.Clin.Pharmacol. 194. et al.).

[0003] The construction of the azepano[4,5-b]indole structure is of great significance for the synthesis of intermediates related to such active pharmaceutical molecules. The reported synthetic methods mainly us...

Examples

preparation example Construction

[0034] Preparation of compound 2: NH on the side chain alkyl of the tryptamine or its derivatives 2 The protection of the group is to use TsCl and NH on the side chain 2 It is realized by sulfonamidation reaction, and its reaction equation is:

[0035]

[0036] Among them, the structural formula of TsCl is TEA is triethylamine.

[0037] Under the protection of an inert gas, at 0°C, sequentially add tryptamine compound 1, triethylamine and 4-toluenesulfonyl chloride (TsCl) compound to the organic solvent to keep the reaction temperature. Return to room temperature and continue the reaction. After the disappearance of the tryptamine substrate is monitored by thin-layer chromatography, saturated ammonium chloride aqueous solution is added to the reaction solution to quench the reaction, and then water is added to dilute the reaction solution, and CH 2 Cl 2 Extract, combine the organic phases, remove the organic solvent after drying, and purify the concentrated reaction pr...

Embodiment 1

[0052] 1) Preparation of Compound 2a: Under the protection of an inert gas, at 0°C, tryptamine 1a (8.0 g, 50 mmol), triethylamine (20.8 mL, 150 mmol) and 4 -Toluenesulfonyl chloride (11.4g, 60mmol), keep the reaction temperature, after reacting for 0.5 hours, make the reaction temperature return to room temperature and continue the reaction, after the thin-layer chromatography monitors that the tryptamine substrate disappears, add saturated ammonium chloride to the reaction solution Aqueous solution (100mL) quenched the reaction, then added water (200mL) to dilute the reaction solution and washed with CH 2 Cl 2 (2×200mL, that is, use 200mL CH 2 Cl 2 two extractions) were extracted, the organic phases were combined, washed with water (2×300mL) and saturated brine (100mL), washed over anhydrous Na 2 SO 4 After drying, the organic solvent was removed, and the concentrated reaction product was purified by silica gel column chromatography (the eluent was petroleum ether: ethyl ...

Embodiment 2

[0063] 1) Preparation of compound 2b: under the protection of inert gas, 6-methyltryptamine 1a (1.74g, 10mmol), triethylamine (4.2mL, 30mmol) and 4-toluenesulfonyl chloride (2.28g, 12mmol), keep the reaction temperature, after reacting for 0.5 hours, make the reaction temperature return to room temperature and continue the reaction, after the thin-layer chromatography monitors that the tryptamine substrate disappears, add Saturated aqueous ammonium chloride solution (20 mL) quenched the reaction, then added water (40 mL) to dilute the reaction solution, and washed with CH 2 Cl 2 (2×40mL, that is, use 40mL CH 2 Cl 2 two extractions) were extracted, the organic phases were combined, washed with water (2×60mL) and saturated brine (20mL), washed over anhydrous Na 2 SO 4 After drying, the organic solvent was removed, and the concentrated reaction product was purified by silica gel column chromatography (the eluent was petroleum ether: ethyl acetate=5:1) to obtain the tryptamine...

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