Journal of Medicinal Chemistry
Article
6-[(1S)-1-Hydroxyethyl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihy-
dro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11b). (1S)-2-Chloro-1-
methyl-2-oxoethyl acetate (30 g, 199 mmol) was added to a
suspension of 5b (38.1 g, 181 mmol) in dry dioxane (1000 mL).
The mixture was heated at reflux for 2 h amd then concentrated in
vacuo to provide (1S)-2-{[4-carbamoyl-1-(tetrahydro-2H-pyran-4-yl)-
1H-pyrazol-5-yl]amino}-1-methyl-2-oxoethyl acetate, which was sus-
pended in water (700 mL) and treated with anhydrous potassium
carbonate (100 g). The mixture was heated at 45 °C for about 18 h
and then neutralized with acetic acid and extracted with chloroform (4
× 1 L). The combined organic layers were washed with saturated
aqueous sodium chloride solution and dried over sodium sulfate.
Filtration and removal of solvents in vacuo provided 11b as an off-
white solid. Yield: 43.1 g, 163 mmol, 90% over 2 steps. LCMS m/z
filtered, concentrated, and chromatographed (eluant 50:1 CHCl3/
CH3OH) to give 2.0 g of 13a. LCMS m/z 304.4 (M + 1). H NMR
(400 MHz, CDCl3) δ 1.31 (d, 3H, J = 6.6), 1.64−1.74 (m, 2H), 1.90−
2.15 (m, 6H), 3.14−3.17 (br m, 1H), 3.25−3.27 (br m, 1H), 3.48−
3.62 (m, 3H), 4.39−4.44 (m, 1H), 5.15 (apparent quintet, 1H, J =
7.6), 8.08 (s, 1H).
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6-[(1R)-1-(3-Hydroxyazetidin-1-yl)ethyl]-1-(tetrahydro-2H-pyran-
4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (13b). The
title compound was prepared in a manner analogous to 13a with
the substitution of starting material 12b in place of 12a to afford 1.6 g
1
(72% yield) of 13b. MS (APCI) m/z 320.0 (M + 1). H NMR (400
MHz, CDCl3) δ 1.34 (d, J = 6.8 Hz, 3H), 1.91 (m, 2H), 2.38 (dddd,
apparent qd, J = 12, 12, 12, 4.6 Hz, 2H), 3.17 (br s, 1H), 3.28 (br s,
1H), 3.52−3.68 (m, 5H), 4.14 (dd, J = 11.3, 3.6 Hz, 2H), 4.46 (m,
1H), 4.85 (tt, J = 11.6, 4.2 Hz, 1H), 8.10 (s, 1H).
1
265.2 (M + 1). H NMR (400 MHz, CDCl3) δ 1.67 (d, J = 6.6 Hz,
(R)-1-{1-[4-Oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-6-yl]ethyl}azetidin-3-yl methanesulfo-
nate, (14b). The title compound was prepared in a manner analogous
to that of 9 to afford 1.72 g (77% yield) of 14b. LCMS m/z 398.3 (M
3H), 1.92 (br d, J = 13 Hz, 2H), 2.39 (m, 2H), 3.62 (br dd, apparent
br t, J = 12, 12 Hz, 2H), 4.15 (br dd, J = 11.7, 4 Hz, 2H), 4.84 (tt, J =
11.6, 4.3 Hz, 1H), 4.90 (q, J = 6.7 Hz, 1H), 8.08 (s, 1H), 10.65 (br s,
1H).
1
+ 1). H NMR (400 MHz, CD3OD) δ 1.36 (d, J = 6.6 Hz, 3H), 1.90
(1S)-1-[4-Oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-6-yl]ethyl Methanesulfonate (12b). A
solution of 11b (20.0 g, 75.7 mmol) in dichloromethane (400 mL)
was treated with triethylamine (15.8 mL, 113 mmol), cooled to 0 °C,
and stirred for 30 min. Methanesulfonyl chloride (99%, 5.92 mL, 75.7
mmol) was added dropwise to the cold reaction, which was allowed to
warm to room temperature over the next 18 h. Solvents were removed
in vacuo, and the residue was purified by silica gel chromatography
(gradient 0−5% methanol in dichloromethane). Rechromatography of
mixed fractions provided additional product to afford 12b as a solid.
(m, 2H), 2.29 (m, 2H), 3.10 (s, 3H), 3.39 (dd, J = 8.3, 5.4 Hz, 1H),
3.44 (dd, J = 8.4, 5.3 Hz, 1H), 3.62 (m, 3H), 3.76 (br dd, J = 7.4, 7.4
Hz, 1H), 3.84 (br dd, J = 7.4, 7.4 Hz, 1H), 4.10 (br d, J = 11.6 Hz,
2H), 4.97 (tt, J = 11.6, 4.2 Hz, 1H), 5.15 (m, 1H), 8.03 (s, 1H).
6-{1-[3-(4-Fluorophenoxy)azetidin-1-yl]ethyl}-1-(tetrahydro-2H-
pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (10a).
Step 1: 3-(4-Fluorophenoxy)azetidine. Palladium hydroxide (500
mg) and 1-(diphenylmethyl)-3-(4-fluorophenoxy)azetidine (500 mg,
1.50 mmol) were combined in ethanol (50 mL) and hydrogenated at
50 psi for 18 h. The reaction mixture was then filtered through Celite
and concentrated in vacuo. The residue was purified via silica gel
chromatography (eluant 100:5:2 chloroform/methanol/concentrated
aqueous ammonium hydroxide) to provide titled compound (188 mg,
75%). LCMS m/z 168.1 (M + 1). 1H NMR (400 MHz, CDCl3) δ 2.44
(br s, 1H), 3.76 (m, 2H), 3.89 (m, 2H), 4.91 (m, 1H), 6.66 (m, 2H),
6.93 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 54.55, 70.81, 115.43,
115.51, 115.76, 115.99, 152.96, 156.15, 158.53.
Step 2: 6-{1-[3-(4-Fluorophenoxy)azetidin-1-yl]ethyl}-1-(tetrahy-
dro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one,
(10a). A mixture of 6-(1-bromoethyl)-1-(tetrahydro-2H-pyran-4-yl)-
1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (6b, 100 mg/0.306
mmol), 3-(4-fluorophenoxy)azetidine (102 mg/0.611 mmol), and
potassium carbonate (92.9 mg/0.672 mmol) in acetonitrile (10 mL)
was stirred at room temperature for 2 h and refluxed overnight. The
mixture was cooled, concentrated, diluted with brine (25 mL) and 1N
NaOH (25 mL), and extracted with CH2Cl2. The combined extracts
were concentrated, dissolved in DMSO (3.0 mL), and filtered through
an Acrodisc syringe filter (0.2 um). The filtrate was concentrated and
purified with a Shimadzu HPLC (Xterra 30 mm × 100 mm; 30−70%
water/acetonitrile gradient elution with 0.1% NH4OH). The resulting
material was further purified by dissolving it in MeOH (3 mL) and
passing through an Oasis MCX LP extraction cartridge (1 g) with
MeOH, and then the product was eluted with ammonia in MeOH and
concentrated to provide 29 mg of 10a. LCMS m/z 414.4 (M + 1). 1H
NMR (400 MHz, CDCl3) δ 1.36 (d, J = 6.6 Hz, 3H), 1.91 (br d, J =
12.6 Hz, 2H), 2.37 (m, 2H), 3.23 (br s, 1H), 3.40 (m, 1H), 3.61 (m,
3H), 3.88 (br s, 2H), 4.14 (dd, J = 11.5, 4.0 Hz, 2H), 4.75−4.88 (m,
2H), 6.71 (m, 2H), 6.97 (m, 2H), 8.06 (s, 1H).
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Total yield: 10.6 g, 31.0 mmol, 41%. LCMS m/z 341.1 (M − 1). H
NMR (400 MHz, CDCl3) δ 1.86 (d, J = 6.6 Hz, 3H), 1.93 (br d, J = 12
Hz, 2H), 2.39 (m, 2H), 3.23 (s, 3H), 3.61 (ddd, apparent td, J = 12,
12, 2.1 Hz, 2H), 4.16 (br dd, J = 11.4, 3.5 Hz, 2H), 4.86 (tt, J = 11.7,
4.2 Hz, 1H), 5.70 (q, J = 6.7 Hz, 1H), 8.08 (s, 1H).
6-[(1R)-1-(3-Phenoxyazetidin-1-yl)ethyl]-1-(tetrahydro-2H-pyran-
4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (7). Step 1: 3-
Phenoxyazetidine. Commercial 3-phenoxyazetidine hydrochloride
(5.57 g, 30.0 mmol) and sodium hydroxide (1.44 g, 36.0 mmol)
were stirred at room temperature in dichloromethane (150 mL) and
water (50 mL). The mixture was stirred at room temperature for 5 h.
The organic layer was separated, and the water layer was extracted
with dichloromethane. The combined organic phases were dried over
MgSO4, filtered, and concentrated to give 4.4 g of 3-phenoxyazetidine
as the free base, which was used without further purification.
Step 2: 6-[(1R)-1-(3-Phenoxyazetidin-1-yl)ethyl]-1-(tetrahydro-
2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one, (7).
Mesylate 12b (4.6 g, 13.4 mmol) and 3-phenoxyazetidine (3.01 g, 20.2
mmol) were combined with triethylamine (9.36 mL, 67.2 mmol),
acetonitrile (50 mL), and toluene (50 mL). The mixture was heated at
90 °C for 5 h with stirring and then concentrated. The residue was
purified by silica gel chromatography (1% methanol in chloroform) to
provide 4.93 g (93% yield) of 9 as a solid. LCMS m/z 396.4 (M + 1).
1H NMR (400 MHz, CDCl3) δ 1.38 (d, J = 6.8 Hz, 3H), 1.89 (m,
2H), 2.29 (m, 2H), 3.28 (dd, assumed, partially obscured by solvent
peak, J = 8.1, 5.2 Hz, 1H), 3.34 (dd, assumed, partially obscured by
solvent peak, J = 7.9, 5.4 Hz, 1H), 3.61 (m, 3H), 3.85 (dd, J = 7.0, 7.0
Hz, 1H), 3.93 (dd, J = 6.9, 6.9 Hz, 1H), 4.08 (m, 2H), 4.87 (m, 1H),
4.98 (tt, J = 11.7, 4.2 Hz, 1H), 6.80 (d, J = 8.2 Hz, 2H), 6.93 (t, J = 7.8
Hz, 1H), 7.26 (dd, J = 7.8, 7.8 Hz, 2H), 8.03 (s, 1H).
1-Cyclopentyl-6-{(1R)-1-(3-hydroxyazetidin-1-yl)ethyl}-1,5-dihy-
dro-4H-pyrazolo[3,4-d]pyrimidin-4-one (13a). N-Boc-3-hydroxyaze-
tidine (2.50 g, 14.4 mmol) was treated with trifluoroacetic acid (3.7
mL) in dichloromethane (20 mL). The mixture was stirred at room
temperature overnight and then concentrated. To the resulting residue
was added acetonitrile (20 mL) and toluene (20 mL), followed by
potassium carbonate (finely ground, 13.3 g, 96.0 mmol). Mesylate 12a
(3.13 g, 9.60 mmol) was then added, and the mixture was heated to 90
°C for 5 h with stirring. The mixture was concentrated to remove all
solvents, diluted with water, and extracted with methylene chloride.
The combined extracts were washed with brine, dried over MgSO4,
4-[(1-{1-[4-Oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-6-yl]ethyl}azetidin-3-yl)oxy]benzonitrile
(10d). Step 1: 1-(Diphenylmethyl)azetidin-3-ol Hydrochloride. A
solution of 2-(chloromethyl)oxirane (260 g, 2.81 mol) and
diphenylmethanamine (500 g, 2.73 mol) in MeOH (1 L) was heated
at reflux for 4 days. Solvent was removed under reduced pressure to
provide a white precipitate, which was collected by filtration. The solid
was washed with acetone and dried to provide title compound, which
was used in the next step without further purification.
Step 2: 1-(Diphenylmethyl)azetidin-3-yl Methanesulfonate.
Methanesulfonyl chloride (180 g, 1.57 mol) was added to a solution
of 1-(diphenylmethyl)azetidin-3-ol hydrochloride (360 g, 1.31 mol)
and triethylamine (330 g, 3.26 mol) in dichloromethane (3 L) at 0 °C.
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dx.doi.org/10.1021/jm3009635 | J. Med. Chem. 2012, 55, 9055−9068