Cannabinol Probes for CB1 and CB2 Receptors
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 20 3783
extracted (2×) with ether. The combined ether extracts were
washed with water, dried, and concentrated to afford a gum.
Purification of the crude product by flash chromatography on
SiO2 eluting with varying amounts of ethyl acetate in hexanes
(100% hexanes - 1% EtOAc/hexanes) afforded compound 10a
of SeO2 (2.75 g, 24.78 mmol) in EtOH/H2O (43 mL/4.3 mL) over
0.5 h at 25 °C. After the addition was complete, the reaction
mixture was refluxed overnight. The reaction mixture was
then cooled, filtered through a Celite pad, and washed with
MeOH. The filtrate was concentrated, and the residue was
dissolved in ether. The ether layer was then successively
washed with water, sodium bicarbonate solution, and water.
It was then dried and concentrated. Purification of the crude
product by flash chromatography on SiO2 eluting with varying
amounts of ethyl acetate in hexanes (5% EtOAc/hexanes - 7%
EtOAc/hexanes) afforded the intermediate 11-oxo derivative
(1.5 g, 40%) as a yellow solid.
1
as a gum (0.092 g, 82%). H NMR (100 MHz, CDCl3) δ 9.1 (d,
J ) 2.4 Hz, 1 H), 7.9 (dd, J ) 9.5, 2.4 Hz, 1 H), 7.3 (d, J ) 9.5
Hz, 1 H), 6.6 (s, 2 H), 5.3 (m, 1 H), 4.0 (s, 3 H), 1.6 (s, 6 H), 1.4
(m, 6 H), 1.3 (s, 6 H), 1.2-0.85 (m, 13 H). Anal. (C29H40O4) C,
H.
10b: Prepared as described above for 10a using iodohexane,
1
(82%). H NMR (100 MHz, CDCl3) δ 9.1 (d, J ) 2.4 Hz, 1 H),
7.9 (dd, J ) 9.5, 2.4 Hz, 1 H), 7.3 (d, J ) 9.5 Hz, 1 H), 6.6 (s,
2 H), 4.35 (m, 2 H), 4.0 (s, 3 H), 1.65 (s, 6 H), 1.3 (m, 24 H),
0.9 (m, 6 H). Anal. (C32H46O4) C, H.
A three-neck round-bottom flask fitted with a condenser and
nitrogen inlet was charged with the 11-oxo derivative (1.66 g,
4.5 mmol), t-BuOH (69 mL), and 2-methyl-2-butene (68.5 mL;
technical grade). To this was added in portions a solution of
NaClO2 and NaH2PO4 in water (4.69 g, 4.47 g, 45.5 mL) over
0.5 h. The biphasic mixture was then vigorously stirred for
2.5 h. The reaction mixture was then concentrated, and the
residue was partitioned between water and ether. The aqueous
layer was separated and extracted (2×) with ether. The
combined ether extracts were washed with 1 N HCl and water,
dried, and concentrated to afford the corresponding 9-carboxy
derivative (1.72 g, 99%) as a solid which was used in the next
step without further purification.
10c: Prepared as described above for 10a using benzyl
1
bromide, (91%). H NMR (300 MHz, CDCl3) δ 9.15 (d, J ) 1.9
Hz, 1 H), 7.95 (dd, J ) 8.3, 1.9 Hz, 1 H), 7.35 (m, 6 H), 6.6 (d,
J ) 1.6 Hz, 2 H), 5.38 (s, 2 H), 3.93 (s, 3 H), 1.61 (s, 6 H), 1.35
(s, 6 H), 1.2-0.85 (m, 13 H). Anal. (C33H40O4) C, H.
10d : Prepared as described above for 10a using 2-bromo-
methyl naphthalene, (80%). 1H NMR (300 MHz, CDCl3) δ 9.18
(d, J ) 1.9 Hz, 1 H), 7.92 (m, 5 H), 7.51 (m, 3 H), 7.29 (d, J )
8.0 Hz, 1 H), 6.57 (d, J ) 1.9 Hz, 2 H), 5.54 (s, 2 H), 3.92 (s, 3
H), 1.61 (s, 6 H), 1.28 (s, 6 H), 1.15-0.85 (m, 13 H). Anal.
(C37H42O4) C, H.
10e: Prepared as described above for 10a using iodopropane,
(100%). 1H NMR (100 MHz, CDCl3) δ 9.15 (d, J ) 2.4 Hz, 1
H), 7.95 (dd, J ) 9.5, 2.4 Hz, 1 H), 7.3 (d, J ) 9.5 Hz, 1 H), 6.6
(s, 2 H), 4.3 (t, 2 H), 4.0 (s, 3 H), 1.65 (s, 6 H), 1.3 (m, 18 H),
0.9 (m, 6 H). Anal. (C29H40O4) C, H.
3-(1′,1′-Dim eth ylh ep tyl)-∆8-tetr a h yd r oca n n a bin ol-1-d i-
eth yl P h osp h a te (12). To a solution of 11 (4.95 g, 13.3 mmol)
in anhydrous acetonitrile (100 mL) was added K2CO3 (16 g,
110 mmol) followed by diethylchlorophosphate (3.4 g, 19.7
mmol).22 The reaction mixture was then stirred at 90 °C under
N2 for 4 h and concentrated, and the residue was partitioned
between water and ether. The aqueous layer was separated
and extracted (2×) with ether. The combined ether extracts
were washed with water, dried, and concentrated to afford 12
(7 g) as a golden gum which was used directly in the next step
without further purification.
To a solution of the 9-carboxy derivative (1.72 g, 4.47 mmol)
in acetone (30 mL) was added K2CO3 (2.47 g, 17.8 mmol),
followed by iodomethane (2.5 mL). The reaction mixture was
then stirred at 60 °C, for 5 h. The reaction mixture was
concentrated, and the residue was partitioned between water
and ether. The aqueous layer was separated and extracted (2×)
with ether. The combined ether extracts were washed with
water, dried, and concentrated to afford 15 (1.82 g, 100%) as
a golden gum. Purification of a portion of the crude product
(0.12 g) by preparative TLC plate (20 × 20 × 2 mm thickness)
eluting with 20% EtOAc/hexanes afforded compound 15 (0.096
1
g) as a golden gum. H NMR (300 MHz, CDCl3) δ 7.2 (d, J )
8.2 Hz, 1 H), 7.05 (m, 1 H), 6.85 (dd, J ) 8.2, 1.9 Hz, 1 H), 6.7
(d, J ) 1.9 Hz, 1 H), 3.8 (s, 3 H), 3.2 (dd, J ) 17.0, 3.0 Hz, 1
H), 2.65 (m, 1 H), 2.4 (m, 1 H), 2.05 (m, 2 H), 1.75 (m, 1 H),
1.55 (m, 2 H), 1.45 (s, 3 H), 1.25-0.85 (m, 20 H). Anal.
(C26H38O3) C, H.
1-Deoxy-3-(1′,1′-d im eth ylh ep tyl)-∆8-tetr a h yd r oca n n a -
bin ol (13). A solution of 12 (7 g) in dry ether (70 mL) was
added to ∼300 mL of liquid NH3. The reaction mixture was
stirred vigorously and small pieces of Li wire (0.16 g) were
added until blue color persisted for >5 min.22 Excess Li was
then decomposed by addition of NH4Cl, and NH3 was allowed
to evaporate using a stream of nitrogen. The residue was
partitioned between water and ether. The aqueous layer was
separated and extracted (2×) with ether. The combined ether
extracts were washed with water, dried, and concentrated to
afford a gum. Purification of the crude product by flash
chromatography on SiO2 eluting with varying amounts of ethyl
acetate in hexanes (100% hexanes - 0.8% EtOAc/hexanes)
afforded 13 (4 g, 85%) as a colorless gum. 1H NMR (300 MHz,
CDCl3) δ 7.1 (d, J ) 8.0 Hz, 1 H), 6.84 (dd, J ) 8.0, 2.0 Hz, 1
H), 6.74 (d, J ) 1.9 Hz, 1 H), 5.45 (m, 1 H), 2.64 (m, 2 H), 1.95
(m, 3 H), 1.7 (m, 3 H), 1.53 (m, 4 H), 1.4 (s, 3 H), 1.23 (s, 6 H),
1.2 (m, 4 H), 1.14 (s, 3 H), 1.06-0.85 (m, 6 H), 0.85 (t, 3 H).
1-Deoxy-3-(1′,1′-dim eth ylh eptyl)-can n abin ol (14). A mix-
ture of 13 (0.45 g, 1.3 mmol) and sulfur (0.83 g, 2.6 mmol)
was heated at 250 °C under N2 for 0.5 h, in a flask fitted with
condenser (no water) and connected to a dilute NaOH trap.
Purification of the crude product by flash chromatography on
SiO2 eluting with varying amounts of ethyl acetate in hexanes
(100% hexanes - 1.5% EtOAc/hexanes) afforded 14 (0.236 g,
1-Deoxy-3-(1′,1′-d im eth ylh ep tyl)-9-ca r bom eth oxy-ca n -
n a bin ol (16). This was prepared from 15 in a similar manner
as described for the synthesis of 14. The ester 16 was obtained
in 73% yield. 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J ) 1.6
Hz, 1 H), 7.9 (dd, J ) 8.2, 1.6 Hz, 1 H), 7.72 (d, J ) 8.2 Hz, 1
H), 7.3 (d, J ) 8.0 Hz, 1 H), 7.02 (dd, J ) 8.2, 1.6 Hz, 1 H), 6.9
(d, J ) 1.9 Hz, 1 H), 3.95 (s, 3 H), 1.65 (s, 6 H), 1.6 (m, 2 H),
1.28 (s, 6 H), 1.2-0.82 (m, 11 H). Anal. (C26H34O3) C, H.
1-Deoxy-3-(1′,1′-d im et h ylh ep t yl)-11-h yd r oxy-ca n n a -
bin ol (17).21 A three-neck round-bottom flask equipped with
addition funnel and nitrogen inlet was charged with LiAlH4
(0.379 g, 10 mmol) and dry ether (30 mL). To this was added
dropwise a solution of 16 (0.35 g, 0.88 mmol) in dry ether (10
mL). After the addition was complete, the reaction mixture
was stirred at 25 °C for 3 h. Excess LiAlH4 was then
decomposed by dropwise addition of EtOAc followed by addi-
tion of a saturated solution of NH4Cl. The aqueous layer was
separated and extracted (2×) with ether. The combined ether
extracts were washed with aqueous NH4Cl and water, dried,
and concentrated. Purification of the crude product by flash
chromatography on SiO2 eluting with varying amounts of ethyl
acetate in hexanes (100% hexanes - 5% EtOAc/hexanes - 10%
EtOAc/hexanes) afforded 17 (0.28 g, 86%) as a colorless gum.
1H NMR (300 MHz, CDCl3) δ 7.7 (brs, 1 H), 7.64 (d, J ) 8.2
Hz, 1 H), 7.24 (m, 2 H), 7.0 (dd, J ) 8.2, 1.6 Hz, 1 H), 6.9 (d,
J ) 1.6 Hz, 1 H), 4.74 (m, 2 H), 1.6 (m, 10 H), 1.32 (s, 6 H),
1.15-0.85 (m, 9 H). Anal. (C25H34O2) C, H.
1
53%) as an oily solid. H NMR (100 MHz, CDCl3) δ 7.65 (d, J
) 9.0 Hz, 1 H), 7.5 (s, 1 H), 7.15 (s, 2 H), 7.05 (m, 2 H), 2.4 (s,
3 H), 1.6 (s, 6 H), 1.5 (m, 2 H), 1.3 (s, 6 H), 1.15-0.83 (m, 11
H). Anal. (C25H34O) C, H.
1-Deoxy-3-(1′,1′-d im et h ylh ep t yl)-9-ca r b om et h oxy-∆8-
tetr a h yd r oca n n a bin ol (15). To a solution of 13 (3.65 g, 10.29
mmol) in ethanol (43 mL) was added dropwise a solution
3-(1′,1′-Dim eth ylh ep tyl)-ca n n a bin ol (18a ). 1-Acetoxy-3-
(1′,1′-dimethylheptyl)-cannabinol was prepared (84%) from
1-acetoxy-3-(1′,1′-dimethylheptyl)-∆8-tetrahydrocannabinol in
a similar manner as described for the synthesis of 14.