
Preparation of Tryptamine and 5-MeO-Tryptamine

Tryptamine
----------

Ethyl tryptamine-2-carboxylate, method A:

6.4 g. (0.11 moles) of potassium hydroxide are dissolved in 70 ml. of dry
ethanol, and the solution is added dropwise, within one hour to the
solution of 23.7 g. (0.1 moles) of chloropropyl-malonic acid diethyl ester
in 70 ml. of dry ethanol. The addition is carried out at room temperature
under constant stirring and exclusion of moisture. When the addition is
complete the mixture is stirred for additional two hours, thereafter it is
cooled to -5°C, and a diazotized solution of aniline is added.
Diazotization is carried out by dissolving 9.3 g. (0.1 moles) of freshly
distilled aniline in a mixture of 27 ml. of concentrated hydrochloric acid
and 100 ml. of water, cooling the solution to 0° to 3°C, and treating the
mixture dropwise with a solution of 7.0 g. (0.11 moles) of sodium nitrite
in 15 ml. of water.) The pH of the obtained solution is adjusted to 6 by
the addition of a 10% sodium hydroxide solution, taking care, that the
temperature of the mixture should not rise above 0°C. Thereafter the pH of
the mixture is adjusted to 7.4 to 7.5 by adding further amounts of 10%
sodium hydroxide solution to the mixture. The mixture is left to stand in
nitrogen atmosphere for 1 hour at -2 to 0°C, acidified to pH 6 with acetic
acid, and left to stand in nitrogen atmosphere at room temperature
overnight. Next day the mixture is diluted with water, whereupon the
obtained ethyl-2-oxo-5-chloro-valerate-phenylhydrazone separates in the
form of a dark oil. The phases are separated from each other, and the oily
phase is extracted with dichloromethane. The dichloromethane solution is
washed with 2n sodium hydroxide solution, thereafter three times with
water, dried over magnesium sulphate, and evaporated to dryness in vacuo.
24 g. of ethyl-2-oxo-5-chlorovalerate-phenylhydrazone are obtained in the
form of a cis-trans isomeric mixture. 

The above product is dissolved in 160 ml. of n-butanol containing 4 drops
of water, and the mixture is refluxed for 24 hours under nitrogen
atmosphere. The reaction mixture is cooled to 0°C, and the separated 9.6 g.
of ethyl-tryptamine-2-carboxylate hydrochloride is isolated by filtration,
and washed with a few amount of n-butanol. Upon evaporating the butanol
solution to 50% of its original volume, an additional 0.4 g. of the product
are obtained. Total yield: 10.0 g. (37 %). The crude product melts at
238°C, while the melting point raises to 243°-245°C after recrystallization
from ethanol. 

Ethyl tryptamine-2-carboxylate, method B:

4.6 g. (0.05 moles) of aniline are dissolved in 42.5 ml. of 4n hydrochloric
acid, and the solution is diazotated at 0° to 3°C with a solution of 3.5 g.
(0.005 moles) of sodium nitrite in 8.5 ml. of water. In the same time 10.3
g. (0.05 moles) of chloropropyl-acetoacetate are dissolved in 38 ml. of
ethanol, the solution is cooled to -15°C, and 38.5 ml. of a cold 20 %
sodium hydroxide solution are added. The diazotated aniline solution is
added dropwise to this solution at -50° to -10°C, under stirring. The pH of
the obtained solution amounts to 9. The reaction mixture is left to stand
at the same temperature for 35 minutes, whereupon the cis-trans isomeric
mixture of the obtained ethyl-2-oxo-5-chlorovalerate-phenylhydrazone
separates in the form of a dark oil. The two phases are separated from each
other, and the oily phase is extracted with dichloromethane. The
dichloromethane solution is washed with 2n sodium hydroxide solution,
thereafter three times with water, dried over magnesium sulphate, and
evaporated to dryness in vacuo. 14.0 g. of the obtained product are
dissolved in 80 ml. of n-butanol, and the solution is refluxed for 24 hours
under nitrogen atmosphere. The reaction mixture is cooled to 0°C, the
separated ethyl-tryptamine-2-carboxylate hydrochloride is filtered off,
washed with a few amount of n-butanol and then with ethanol, and dried.
Yield: 5.0 g. (37.0 %); m.p.: 235°C. 

Tryptamine from ethyl tryptamine-2-carboxylate hydrochloride:

10.00 g. (0.037 moles) of ethyl-tryptamine-2-carboxylic acid hydrochloride
is dissolved in 100 ml. of ethanol, and 100 ml. of 4n sodium hydroxide
solution are added. The mixture is boiled for 2 hours, thereafter cooled to
0°C and acidified with glacial acetic acid. The separated tryptamine-
2-carboxylic acid is filtered off and washed with water. 7.6 g (99%) of the 
product are obtained; m.p.: 244°C (recrystallized from a mixture of H2O/EtOH). 

5.00 g. (0.024 moles) of tryptamine-2-carboxylic acid are dissolved in 100
ml. of 15% sulphuric acid, and the solution is boiled for 4 hours.
Thereafter the pH of the solution is adjusted to 9 by adding concentrated
sodium hydroxide solution under ice cooling, and the separated 2.5 g. of
crystalline tryptamine base are filtered off and washed with water. The
mother liquor is extracted with chloroform, and the chloroform solution is
evaporated to yield further 0.30 g. of crystalline tryptamine. Total yield:
2.8 g. (72 %) M.p.: 118°-120°C.

When acidifying the mother liquor with acetic acid, 0.50 g. of tryptamine-
2-carboxylic acid can be isolated. 

 
5-MeO-Tryptamine
----------------

3.2 g. of potassium hydroxide are dissolved in 35 ml. of dry ethanol, and
the solution is added dropwise, within 1 hour to the solution of 11.9 g.
(0.05 moles) of chloropropyl-malonic acid-diethyl ester in 35 ml. of dry
ethanol at room temperature. The mixture is stirred for additional 2 hours,
thereafter cooled to -5°C, and a diazotated solution of p-anisidine is
added to the stirred mixture. Diazatization is carried out by dissolving
6.15 g (0.05 moles) of freshly distilled p-anisidine in a mixture of 19.5
ml. of concentrated hydrochloric acid and 50 ml. of water, cooling the
solution to 0° to 3°C, and treating the mixture dropwise with a solution of
3.5 g. (0.055 moles of sodium nitrite in 8.5 ml. of water). The pH of the
obtained solution is adjusted to 6 with 10 % aqueous sodium hydroxide
solution (about 38 ml. are required), taking care, that the temperature of
the mixture should not rise above 0°C. Thereafter the pH of the mixture is
adjusted to 7.4 to 7.5 with a further amount of 10% aqueous sodium
hydroxide solution (about 7.5 ml. of the solution are required). The
mixture is left to stand under nitrogen atmosphere for 1 hour at -2 to 0°C.
acidified to pH 6 with acetic acid, and left to stand under nitrogen
atmosphere at room temperature overnight. Next day the mixture is diluted
with water, whereupon the obtained ethyl-2-oxo-5-chloro-valerate-
4'-methoxyphenylhydrazone separates in the form of a dark oil. The phases
are separated from each other, and the oily phase is extracted with
dichloromethane. The dichloromethane solution is washed with 2n sodium
hydroxide solution, thereafter three times with water, dried over magnesium
sulphate, and evaporated to dryness in vacuo. 9.8 g. of ethyl-2-oxo-5-chloro-
valerate-4'-methoxyphenylhydrazone are obtained in the form of a cistrans
isomeric mixture. The isomers are separated from each other by preparative
layer chromatography as described in Example 1, and their structures are
characterized by NMR spectroscopy.

The above product is dissolved in 80 ml. of n-butanol, and the solution is
refluxed for 24 hours under nitrogen atmosphere. The solution is cooled,
the separated ethyl-5-methoxy-tryptamine-2-carboxylate hydrochloride is
filtered off, washed with a few amount of n-butanol and dried. Yield: 2.5
g. (17 %); m.p.: 226°C (after recrystallization from ethanol).

1.00 g. (3.35 mmoles) of ethyl-5-methoxy-tryptamine-2-carboxylate
hydrochloride is dissolved in a mixture of 10 ml. of ethanol and 10 ml. of
4n sodium hydroxide, and the mixture is boiled for 2 hours. The solution is
cooled to 0°C and acidified with glacial acetic acid. The separated
5-methoxy-tryptamine-2-carboxylic acid is washed with water. Yield: 0.77 g.
(99 %); m.p.: 247°-248°C. The product is decarboxylated in the usual way to
form 5-methoxy-tryptamine with a yield of 75 %; m.p.: 120°-121°C.

