Author Topic: Synth. of 5-halo-tryptamine derivatives  (Read 722 times)

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Synth. of 5-halo-tryptamine derivatives
« on: February 07, 2003, 03:09:00 PM »

Patent WO03000252



(E)-5-Bromo-2-methyl-3-(2-nitroethenyl)-lH-indole

To a solution of 0.58 g of 1- (dimethylamine)-2-nitroethylene (5 mmol) in 5 mL of trifluoroacetic acid, stirred and cooled to 0 C, 1.05 g (5 mmol) of 5-bromo-2-methyl-indole is added and the resulting mixture is left to react at room temperature, under nitrogen, for 30 minutes. The reaction mixture is then placed into an ice-water bath. The aqueous solution is extracted with ethyl acetate and the organic phases combined, then washed with a saturated bicarbonate solution, and then water and finally dried over anhydrous sodium sulphate. After filtration, the solvent is removed at low pressure, leaving a solid, orange-coloured residue, which is then suspended in an ethyl acetate-ether mixture and filtered.

Yield: 89%

TLC: Rf = 0.3 (cyclohexane/EtOAc : 1)

M. p.: 196-198 C (dec.)


5-bromo-2-methyltryptamine hydrochloride

A solution of nitroethenylindole (2) (1.7 g, 6 mmol), in 25 mL of anhydrous THF, is added dropwise to a suspension, under nitrogen at 0 C, of LiAlH4 (1.2 g, 36 mmol) in THF (6.5 mL) and the resulting mixture is stirred for 5 hours at room temperature. After cooling to 0 C, the excess LiAlH4 is destroyed by the careful addition of water and the resulting suspension filtered through celite. The solvent is evaporated under vacuum, the residue acidified with 2N HC1 and then partitioned with water and ethyl acetate. The aqueous phase is then alkalinized with 6N NaOH and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The resulting free amine is then transformed into the hydrochloride salt by the addition of a solution of HC1 in anhydrous methanol. The salt is then purified by crystallization in ethyl acetate.

Yield: 69%


5-bromo-2-methyl-N, N-dimethyltryptamine (ST 1938)

A 40% solution of HCHO (0. 95 mL) in 16 mL of MeOH, is added dropwise to a stirred solution of 5-bromo-2-methyltryptamine (0. 8 g, 3.16 mmol), AcOH (0.47 mL) and NaCNBH4 (0.35 g). This is let to react for 2.5 hours at room temperature under stirring; 5 mL of an aqueous saturated solution of K2CO3 is then added; methanol is evaporated under vacuum and the aqueous phase extracted with ethyl acetate.

The organic phases are dried over anhydrous sodium sulphate, and after evaporation of the solvent under vacuum an orange coloured oil is obtained, which is purified by filtration through silica gel and subsequent crystallisation from dichloromethane-hexane.

Yield: 56%

M. p.: 135-136 C

TLC: Rf = 0,52 (CH2Cl2/MeOH/TEA 9: 0,4 : 0,4)


The following compounds were prepared:

(E)-5-chloro-2-methyl-3-(2-nitroethenyl)-1H-indole

Orange solid

Yield: 85%

M. p. 191-193 C

5-chloro-2-methyltryptamine hydrochloride

Beige solid crystalline precipitated from EtOH/Et2O.

Yield: 72%

5-chloro-2-methyl-N, N-dimethyltryptamine (ST 1936)

White solid

Yield: 75%

M. p. = 126-127 C

__________ ______ ___ _

This might serve as an excellent pre-cursor to fully active 2-alkylated (5-subst.) tryptamines such as:

http://www.erowid.org/library/books_online/tihkal/tihkal45.shtml



Also the last step can be adapted to tryptamine as pre-cursor in order to obtain DMT.

Alkylation on position 2 when it comes to tryptamines seems to be getting in the way for enzymatic degradation just as for instance mathylation (alkylation) on alpha position...

Other interesting publications on ths subject:

JOC 1994, 59, 6372-6377
J. Med. Chem. 1993, 36, 4069