Journal of Medicinal Chemistry
BRIEF ARTICLE
MeOH. The resulting aqueous mixture was extracted with 2-methyl-
tetrahydrofuran (2-Me-THF) (1 ꢀ 6.00 L). The 2-Me-THF layer was
washed with brine (2.00 L, 2.38 kg), concentrated under partial
vacuum with a pot temperature of 40-45 °C to give an oil, which
was collected in a 5 L container (Naljug). The reactor was rinsed with
1 L of acetonitrile, and the rinse was combined with the crude oil
product. After 12 h standing at 10-15 °C, crystallization occurred in
the Naljug. Filtration of the mixture gave 3 (193 g, 98% de). The
filtrate was purified by silica gel chromatography (mobile phase,
toluene/heptane/diethylamine 70/30/5, isocratic), followed by an-
other chromatography using ChiralPak AD (mobile phase, isopropa-
nol/heptane/diethylamine 5/95/0.2) to give additional crop of 3
(86.3 g, 99% de) and 4 (96.5 g, 99% de).
methyl-6-[(2-methylpyridin-3-yl)oxy]pyrimidine (7)10 (164 mg, 0.69
mmol) were dissolved in anhydrous dioxane (4 mL) under an atmosphere
of nitrogen. The solution was heated at 105 °C, and 1 M NaHMDS
(0.85 mL, 0.84 mmol) was added. The red mixture was heated at 102-
110 °C for 1 h, and then the mixture was allowed to cool to room
temperature. Water (1.0 mL) was added, and the solution was transferred
to a bigger flask with 2-Me-THF. The solvents were concentrated under
reducedpressure to giveanoil whichwaspartitionedbetween CH2Cl2 and
saturated aqueous NaHCO3. The layers were separated, and the aqueous
layer was extracted again with CH2Cl2. The organic extracts were
combined and washed with brine and then dried over Na2SO4. The
mixture was filtered and the filtrate concentrated under reduced pressure
to give an oil that was purified via column chromatography twice (0-5%
MeOH/EtOAc and then 0-10% MeOH/CH2Cl2) to give the product as
a clear oil. The oil was dissolved in EtOAc and heptane, and the solution
was concentrated in vacuo to give an oily foam which was dried under
vacuum. Triturating the foam with a solution of EtOAc and heptane
produced 8 as a white solid (106 mg, 36%) after filtration. Compound 8
was crystallized from a cold (4 °C) mixture of toluene and heptane for
X-ray analysis, mp 135 °C. 1H NMR (400 MHz, CDCl3) δ 8.42 (dd, 1H, J
= 1.2, 4.8 Hz), 8.2 (s, 1H), 7.40 (1.2, 8.0Hz), 7.22 (dd, 1H,J= 4.8, 8.0 Hz),
5.38 (dd, 1H, J = 3.4, 3.4 Hz), 5.021-4.97 (m, 1H), 4.65 (d, 1H, J = 13
Hz), 4.48 (d, 1H, J = 13 Hz), 4.16 (dd, 2H, J = 11, 13 Hz), 3.97 (d, 1H, J =
13 Hz), 3.89 (d, 1H, J = 13 Hz), 3.32 (d, 1H, J = 14 Hz), 3.24 (d, 1H, J = 14
Hz), 2.43 (s, 3H), 2.29 (s, 3H), 2.01 (apps, 1H), 1.96 (apps, 1H), 1.28 (d,
3H, J = 3.5 Hz), 1.27 (d, 3H, J = 3.5 Hz). LCMS: 429.0 (M þ 1).
Isopropyl 9-anti-({5-Methyl-6-[(2-methylpyridin-3-yl)oxy]
pyrimidin-4-yl}oxy)-3-oxa-7-azabicyclo[3.3.1]nonane-7-car-
Isopropyl 9-syn-Hydroxy-3-oxa-7-azabicyclo[3.3.1]nonane-
7-carboxylate (5) and Isopropyl 9-anti-Hydroxy-3-oxa-7-
azabicyclo[3.3.1]nonane-7-carboxylate (6). The individual iso-
mers 3 and 4 can be taken through the following two steps separately with
the conditions described. However, the specific experiments below pertain
to the mixture of the syn and anti isomers which are separated as 5 and 6.
The starting mixture of syn and anti isomers 3 and 4 (3.71 g, 15.9 mmol)
was dissolved in ethanol (120 mL), and Pd(OH)2 (450 mg) was added.
The mixture was shaken for 2.5 h under 50 psi of hydrogen in a Parr shaker
at 23 °C. The mixture was filtered through diatomaceous earth, and the
collected solid was washed three times with MeOH. The filtrate was
concentrated in vacuo to give an oily solid. This oily solid was dissolved in
EtOAc, and heptane was added. The solution was concentrated in vacuo to
give a mixture of syn and anti isomers of 3-oxa-7-azabicyclo[3.3.1]nonan-9-
ol as a white solid (2.08 g, 91%). This material was used in the next step
without further purification. LCMS (ESþ): 144.1 (M þ 1). To a CH2Cl2
(15 mL) solution of the mixture of syn and anti-isomers of 3-oxa-7-
azabicyclo[3.3.1]nonan-9-ol (2.08 g, 14.5 mmol) and N,N-diisopropylethy-
lamine (2.80 mL, 16.0 mmol) at 0 °C was added isopropyl chloroformate
(14.2 mL, 14.2 mmol, 1.0 M in toluene) dropwise. The mixture was allowed
to warm to room temperature over 14 h. The mixture was then diluted with
aqueous 1 M HCl (50 mL) and the aqueous layer separated. The organic
layer was washed sequentially with water (50 mL) and brine (50 mL) and
then dried over Na2SO4. The mixture was filtered, and the filtrate was
concentrated in vacuo to give a colorless oil. This oil was dissolved in EtOAc.
Heptane was added, and the mixture was concentrated. The resulting oil
was driedunder vacuumto give the mixture of5 and 6 asa clear oil (2.74 g,
82%). LCMS (ESþ): 230.1 (M þ 1). A mixture of 5 and 6 (5.04 g, 35.1
mmol) was separated via preparatory high pressure liquid chromatogra-
phy utilizing a Chiralpak AD-H column (21 mm ꢀ 250 mm) with mobile
phase of 85:15 carbon dioxide/MeOH at a flow rate of 65 mL/min. The
wavelength for monitoring the separation was 210 nm. The analytical
purity of each isomer was determined using analytical high pressure
chromatography using a Chiralpak AD-H(4.6 mmꢀ 25 cm) columnwith
a mobile phase of 85:15 carbon dioxide/MeOH at a flow rate of 2.5 mL/
min. The wavelength for monitoring the peaks was 210 nm. The following
two isomers were obtained. 5 (1.34 g): clear oil which solidified on
standing. Retention time (tR) = 2.3 min. 1H NMR (400 MHz, DMSO-
d6): δ 5.12 (d, 1H, J = 2.8 Hz), 4.76-4.71 (m, 1H), 4.20 (d, 1H, J = 13
Hz), 4.16 (d, 1H, J = 13 Hz), 3.96-3.92 (m, 2 H), 3.79 (d, 1H, J = 3 Hz),
3.55 (s, 1H), 3.52 (s, 1H), 3.08 (d, 1H, J = 13 Hz), 2.98 (d, 1H, J = 13 Hz),
1.47 (m, 2 H) 1.16 (d, 3 H, J = 3 Hz), 1.15 (d, 3 H, J = 3 Hz). LCMS
(ESþ): 230.2 (M þ 1). 6 (1.70 g): amber oil, tR = 3.08 min. 1H NMR
(400 MHz, DMSO-d6): δ 5.11 (d, 1H, J = 2.8 Hz), 4.74-4.67 (m, 1H),
3.89 (d, 1H, J = 13 Hz), 3.84-3.78 (m, 2 H, J = 11 Hz), 3.80 (d, 1H, J = 6
Hz), 3.78 (d, 1H, J = 3 Hz), 3.52-3.47 (m, 2 H), 3.35-3.30 (m, 1H),
3.24-3.20 (m, 1H), 1.53 (s, 1H), 1.51 (s, 1H), 1.13 (d, 3 H, J = 1 Hz),
1.16 (d, 3 H, J = 1 Hz). LCMS (ESþ): 230.2 (M þ 1).
boxylate (9). Compounds 6 (180 mg, 0.79 mmol) and 7 (204 mg, 0.86
mmol) were dissolved in anhydrous dioxane (4 mL) under an atmosphere
of nitrogen. The solution was heated at 105 °C, and 1 M NaHMDS
(0.85 mL, 0.84 mmol) was added. The red mixture was heated at 105 °C
for 1.3 h, and then the mixture was allowed to cool to room temperature.
Water (1.0 mL) was added, and the solution was transferred to a bigger
flask with 2-Me-THF. The solvents were concentrated under reduced
pressure to give an oil which was partitioned between CH2Cl2 and
saturated aqueous NaHCO3. The layers were separated, and the aqueous
layer was extracted again with CH2Cl2. The organic extracts were
combined and washed with brine and then dried over Na2SO4. The
mixture was filtered and the filtrate concentrated under reduced pressure
to give an oil that was purified via column chromatography (0-10%
MeOH/EtOAc) to give the product as a clear oil. The oil was dissolved in
EtOAc and heptane, and the solution was concentrated in vacuo to give
the product as an oily foam (174 mg, 51%). A sample of the product was
dissolved in acetonitrile and water and frozen in a dry ice/acetone bath.
Lyophilization under vacuum produced 9 as a white solid. 1H NMR (400
MHz, CDCl3) δ 8.42 (dd, 1H, J = 1.2, 4.8 Hz), 8.2 (s, 1H), 7.41 (dd, 1H, J
= 1.2, 8.0 Hz), 7.22 (dd, 1H, J = 4.8, 8.0 Hz), 5.44 (dd, 1H, J = 3.6, 3.6 Hz),
5.02-4.97 (m, 1H), 4.36 (d, 1H, J = 13.5Hz), 4.21 (m, 2H), 4.14 (d, 1H, J
= 11Hz), 3.86 (dd, 2H, J =11.6Hz), 3.52(d, 1H, J =13Hz), 3.44 (d, 1H, J
= 13 Hz), 2.43 (s, 3H), 2.28 (s, 3H), 2.08 (app s, 1H), 2.03 (app s, 1H),
1.28 (d, 3H, J = 3.5 Hz), 1.27 (d, 3H, J = 3.5 Hz). LCMS: 429.2 (M þ 1).
(1R,5R,8R)-Isopropyl 8-(5-Methyl-6-(2-methylpyridin-3-
yloxy)pyrimidin-4-yloxy)-6-oxa-3-azabicyclo[3.2.1]octane-
3-carboxylate and (1S,5S,8S)-Isopropyl 8-(5-Methyl-6-(2-methyl-
pyridin-3-yloxy)pyrimidin-4-yloxy)-6-oxa-3-azabicyclo[3.2.1]-
octane-3-carboxylate (11, 11a, 11b). Amixtureof1021 (90 mg, 0.42
mmol) and 710 (106 mg, 0.35 mmol) was dissolved in 1,4-dioxane (2.1 mL). A
solution of 1 M LiHMDS (0.42 mL, 0.42 mmol) was added dropwise, and the
mixture was stirred at room temperature for 1 h. The mixture was heated at
85 °C for 16 h. The mixture was cooled to room temperature, diluted with
EtOAc, and saturated aqueous NH4Cl. The layers were separated, and the
aqueous phase was extracted twice with EtOAc. The combined organic phase
was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The
Isopropyl 9-syn-({5-Methyl-6-[(2-methylpyridin-3-yl)oxy]-
pyrimidin-4-yl}oxy)-3-oxa-7-azabicyclo[3.3.1]nonane-7-car-
boxylate (8). Compound 5 (176 mg, 0.76 mmol) and 4-chloro-5-
1951
dx.doi.org/10.1021/jm200003p |J. Med. Chem. 2011, 54, 1948–1952