PAPER
Improvements to the Synthesis of Psilocybin
937
21.6 g (85.9%). The crude product was recrystallized from MeOH/
EtOAc to give 19.5 g (77%) of 3 with mp 152–155 °C (Lit.4 mp
146–150 °C).
1H NMR (300 MHz, CDCl3): d = 2.88, 2.92 (2s, 6H, NCH3), 5.21
(s, 2H, CH2), 6.60 (d, 1H, J =7.92 Hz, Ar), 6.86 (d, 1H, J = 8.04 Hz,
Ar), 7.27–7.37 (m, 3H, Ar), 7.50 (m, 3H, Ar), 10.07 (br s, 1H, NH).
storage in the freezer. Psilocybin (1) crystallized as long
colorless needles.
As a potential replacement for 1, 4-Acetoxy-N,N-dimeth-
yltryptamine (2) fumarate was conveniently prepared by
shaking under hydrogen a mixture of 4, acetic anhydride,
and sodium acetate in benzene with Pd/C in a Parr low
pressure hydrogenation apparatus. Following uptake of
the required amount of hydrogen corresponding to O-de-
benzylation, the catalyst and insoluble salts were removed
by filtration. One molar equivalent of fumaric acid was
added to the filtrate, and the solution was concentrated to
dryness under vacuum. The resulting solid was recrystal-
lized to afford white crystals of the desired product. This
material was stable when stored in the cold, but slowly
4-Benzyloxy-N,N-dimethyltryptamine (4)
A slurry of LiAlH4 (8.90 g, 0.234 mol) in anhyd THF (100 mL) was
prepared in a 2 L, 3-neck flask, previously dried with a heat gun un-
der an argon purge. The flask was fitted with a reflux condenser,
mechanical stirrer, and addition funnel. Anhyd dioxane (200 mL)
was added, and the mixture was heated to 60 °C on an oil bath. 4-
benzyloxyindol-3-yl-N,N-dimethylglyoxylamide (3) (14.5 g, 0.045
moles) was dissolved in a mixture of dioxane (250 mL) and THF
(150 mL) and, with rapid stirring, this solution was added dropwise
darkened on storage for several months at ambient tem- over 1 h. The oil bath temperature was held at 70 °C for 4 h, fol-
lowed by vigorous reflux overnight (16 h) at an oil bath temperature
perature.
of 95 °C. Thin layer chromatographic analysis (9:1 CH2Cl2/MeOH;
silica plates) showed nearly complete reduction. The reaction was
heated at reflux for an additional 4 h and then cooled to 20 °C. A
solution of distilled H2O (27 mL) in THF (100 mL) was added
dropwise, resulting in a gray flocculent precipitate. Et2O (250 mL)
was added to assist breakup of the complex and improve filtration.
This slurry was stirred for 1 h and the mixture was then filtered with
a Buchner funnel. The filter cake was washed on the filter with
warm Et2O (2 x 250 mL) and was broken up, transferred back into
the reaction flask and vigorously stirred with additional hot Et2O
(500 mL). This slurry was filtered, and the cake was washed on the
filter with Et2O (150 mL) and hexane (2 x 150 mL). All of the or-
ganic filtrates were combined and dried (MgSO4). After the drying
agent was removed by filtration, the filtrate was concentrated under
vacuum at 40 °C and dried under high vacuum at 0.01 mm Hg, lead-
ing to crystallization of the residue as a white waxy solid. Recrys-
tallization from EtOAc yielded 12.57 g, (94.8%) of 4 with mp 124–
126 °C (lit.4 mp 125–126 °C).
Mps were determined on a Thomas-Hoover Meltemp melting point
apparatus and are uncorrected except where indicated. H NMR
1
spectra were recorded on a Bruker ARX 300 MHz spectrometer.
Chemical shifts are reported in d values (ppm) relative to an internal
standard of TMS in CDCl3, except where noted. Abbreviations used
in NMR analysis are as follows: s, singlet; d, doublet; t, triplet; m,
multiplet; br s, broad singlet; dd, doublet of doublets, dt, doublet of
triplets. Microanalyses were obtained from the Purdue Microanalyt-
ical Laboratory. A low pressure Parr apparatus was used for all hy-
drogenations. Solvents and reagents were used as purchased, except
as noted. THF was distilled from potassium metal/benzophenone
ketyl. All other compounds were purchased from commercial
sources.
4-Benzyloxyindol-3-yl-N,N-dimethylglyoxylamide (3)
A solution of 4-benzyloxyindole (17.5 g, 0.078 mol) (Biosynth) in
anhyd Et2O (500 mL) was mechanically stirred in a 1 L, 3 necked
flask and cooled in an ice–salt bath to an internal temperature of
0 °C. Oxalyl chloride (20.3 g, 0.16 moles) was added dropwise at a
rate that maintained an internal temperature between 0–5 °C. Stir-
ring was continued for 3 h at a temperature between 5–10 °C with a
gentle argon sparge to remove evolved HCl. The argon sparge was
replaced by a gas inlet tube and a dry ice/acetone condenser. Anhyd
dimethylamine was then bubbled into the reaction with cooling and
vigorous stirring until a pH (determined by moist pH paper) be-
tween 9 and 11 was achieved. At this time, the orange color of the
initial solution had been mostly discharged, and the reaction had the
appearance of a slightly off-white slurry with a few flecks of yellow
unreacted starting material. CH2Cl2 (20 mL) was added to assist sol-
ubilization of the unreacted material and the reaction was stirred for
an additional 6 h to yield finally an off-white slurry. Et2O (150 mL)
was added, and the mixture was cooled to 10 °C. The white solids
were collected by suction filtration on filter paper in a Buchner fun-
nel and then were suspended in distilled H2O (250 mL) and stirred
for 1 h to remove dimethylamine hydrochloride. The slurry was fil-
tered, and the collected solids were washed on the filter with dis-
tilled H2O (3 x 75 mL) and hexane (75 mL) and dried overnight in
a vacuum oven. The dried product weighed 18.3 g. The organic fil-
trates and washes were combined and the solvent was removed by
rotary evaporation. The residue was dissolved in CH2Cl2 (100 mL)
and the organic solution was washed with distilled H2O (2 x 50 mL)
and brine (2 x 50 mL). After drying (MgSO4) the volume was re-
duced by rotary evaporation. The concentrated residual solution
was subjected to flash chromatography over silica gel, first eluting
with CH2Cl2 to recover unreacted indole (1.3 g, 7.4%), followed by
elution with 10% MeOH in CH2Cl2 to recover 3.3 g of 3. The latter
was combined with the initial product to provide a total weight of
1H NMR (300 MHz, CDCl3): d = 2.14 (s, 6H, NCH3), 2.58 (t, 2H, J
= 8.0 Hz, CH2), 3.04 (t, 2H, J = 8.0 Hz, CH2), 5.17 (s, 2H, CH2),
6.52 (d, 1H, J = 7.6 Hz, Ar), 6.87 (s, 1H, Ar), 6.93 (d, 1H, J = 8.0
Hz, Ar), 7.04 (t, 1H, J = 7.9 Hz, Ar), 7.29–7.39 (m, 3H, Ar), 7.49
(br d, 2H, J = 7.0 Hz, Ar), 8.06 (br s, 1H, NH).
4-Hydroxy-N,N-dimethyltryptamine (Psilocin; 5):
A solution of 4 (4.0 g, 0.0135 moles) in 95% EtOH (250 mL) was
added to 1.5 g Pd/C (10% w/w) in a 500 mL Parr low pressure hy-
drogenation bottle. The mixture was shaken under 60 psig of H2
pressure for 2 h. The catalyst was removed by vacuum filtration
through Celite and was washed on the filter with EtOH (3 x 50 mL).
The filtrate was concentrated by rotary evaporation. The clear resid-
ual oil was placed under high vacuum and induced to crystallize by
seeding. The white crystalline powder (2.68 g, 97.0%) was used in
the next step without further purification.
1H NMR (300 MHz, CDCl3): d = 2.36 (s, 6H, NCH3), 2.68 (m, 2H,
CH2),10 2.93 (m, 2H,CH2),10 6.54 (d, 1H, J =7.6, Ar), 6.83 (br d, 2H,
J =12.2 Hz, Ar), 7.03 (t, 1H, J = 7.8 Hz, Ar), 7.86 (br s, 1H, NH),
13.2 (br s, 1H, OH; observed only by integration).
4-O-Monobenzylphosphoryloxy-N,N-dimethyltryptamine (6)
A solution of 0.45 g (2.2 mmol) of psilocin (5) and 0.073 g (0.73
mmol) of diisopropylamine in anhyd THF (50 mL) was magnetical-
ly stirred in a 100 mL 3-necked flask and was cooled to –78 °C in a
dry ice–acetone bath. A 2.5 M solution (1.14 mL, 2.85 mmol) of
BuLi in hexane was added dropwise using a syringe. After complete
addition, the reaction was stirred for
3
min and
tetrabenzylpyrophosphate8 (1.50 g, 2.8 mmol) was added all at
once. The dry ice–acetone bath was replaced by an ice–salt bath,
Synthesis 1999, No. 6, 935–938 ISSN 0039-7881 © Thieme Stuttgart · New York