7816 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 24
Bookser et al.
methanol. The compound 4-amino-1-(5-deoxy-2,3-diacetoxy-â-
D-ribofuranosyl)-3-phenylpyrazolo[3,4-d]pyrimidine (4.70 g,
11.4 mmol) was dissolved in 30 mL of methanol, and 2.3 mL
of 1 M sodium methoxide in methanol was added. After stirring
for 2 h at room temperature, the mixture was diluted with
200 mL of CH2Cl2, washed with water and brine, dried
(MgSO4), and evaporated to provide 3.11 g of 4-amino-1-(5-
deoxy-â-D-ribofuranosyl)-3-phenylpyrazolo[3,4-d]pyrimidine,
which was used in the next reaction without further purifica-
tion: 1H NMR (DMSO-d6) δ 1.11 (d, 3H, J ) 6 Hz, 5′-CH3),
3.85 (quintet, 1H, J ) 6, 4 Hz, H4′), 3.98 (q, 1H, J ) 6 Hz,
H3′), 4.46 (dt, 1H, J ) 6, 3 Hz, H2′), 4.99 (d, 1H, J ) 6 Hz,
3′-OH), 5.30 (d, 1H, J ) 6 Hz, 2′-OH), 6.04 (d, 1H, J ) 3 Hz,
H1′), 7.3-7.5 (m, 5H, Ph), 8.16 (s, 1H, H6).
Step 5. To a solution of 4-amino-1-(5-deoxy-â-D-ribofuran-
osyl)-3-phenylpyrazolo[3,4-d]pyrimidine (3.00 g, 10.2 mmol)
and dimethoxypropane (12.6 mL, 102 mmol) in 30 mL of DMF
was added methanolic HCl until the solution pH was equal to
1. After stirring at room temperature for 2 h, the mixture was
diluted with CH2Cl2; washed with aqueous sodium carbonate,
water, and brine; dried (MgSO4); and evaporated. The residue
was subjected to flash chromatography eluting with hexane/
EtOAc mixtures of 2:1 and 1:1 to provide 2.2 g of compound
18c as an amorphous solid: 1H NMR (DMSO-d6) δ 1.14 (d,
3H, J ) 6 Hz, 5′-CH3), 1.19 and 1.39 (s each, 3H each, IP-
CH3s), 4.19 (dq, 1H, J ) 2, 6 Hz, H4′), 4.66 (dd, 1H, J ) 2, 6
Hz, H3′), 5.32 (dd, 1H, J ) 2, 6 Hz, H2′), 6.24 (d, 1H, J ) 2
Hz, H1′), 7.4-7.6 (m, 5H, Ph), 8.17 (s, 1H, H6).
4-Amino-1-(5-O-tert-butyldimethylsilyl-2,3-O-isopropy-
lidenyl-â-d-ribofuranosyl)-3-phenylpyrazolo[3,4-d]pyri-
midine (18d). A mixture of 4-amino-1-(2,3-O-isopropylidenyl-
â-D-ribofuranosyl)-3-bromopyrazolo[3,4-d]pyrimidine21,23 (15.00
g, 42.8 mmol), TBS-Cl (6.78 g, 51.4 mmol), and imidazole (3.65
g, 53.5 mmol) in 250 mL of DMF was stirred at room
temperature for 16 h. Then the mixture was diluted with ether,
washed with water and brine, dried (MgSO4), and evaporated
to provide 21.15 g (106%) of compound 17 as a solid which
was used without further purification: 1H NMR (CDCl3) δ 0.01
(s, 6H, Me2Si), 0.87 (s, 9H, t-Bu), 1.40 (s, 3H, IP-CH3), 1.59 (s,
3H, IP-CH3), 3.60 (dd, 1H, J ) 10, 6 Hz, H5′), 3.70 (dd, 1H, J
) 10, 6 Hz, H5′), 4.31 (dt, 1H, J ) 6H, 2 Hz, H4′), 4.98 (dd,
1H, J ) 6H, 2 Hz, H3′), 5.41 (dd, 1H, J ) 6H, 2 Hz, H2′), 6.11
(br s, 2H, NH2), 6.51 (d, 1H, J ) 2 Hz, H1′), 8.36 (s, 1H, H2).
A mixture of compound 17 (21.15 g, 42.8 mmol), phenyl-
boronic acid (20.9 g, 171.2 mmol), and (Ph3P)4Pd (4.9 g, 4.3
mmol) was dissolved in 130 mL of diglyme and this was
combined with 65 mL of 1 M aqueous Na2CO3. The resulting
mixture was stirred for 4 h at 100 °C and then cooled and
diluted with ether and water. The yellow solid that formed
was filtered, and the layers were separated. The aqueous layer
was extracted with ether. The combined ether extracts were
washed with brine, dried (MgSO4), and concentrated, which
produced a white solid. The solid was collected by filtration
and washed with ether to provide 12.7 g of compound 18d
contaminated by ca. 10 mol % of diglyme (ca. 58% yield). It
was used without further purification: 1H NMR (CDCl3) δ 0.01
(s, 6H, Me2Si), 0.82 (s, 9H, t-Bu), 1.40 (s, 3H, IP-CH3), 1.62 (s,
3H, IP-CH3), 3.67 (dd, 1H, J ) 10, 6 Hz, H5′), 3.84 (dd, 1H, J
) 10, 6 Hz, H5′), 4.34 (dt, 1H, J ) 6, 2 Hz, H4′), 5.01 (dd, 1H,
J ) 6, 2 Hz, H3′), 5.52 (dd, 1H, J ) 6, 2 Hz, H2′), 6.10 (br s,
2H, NH2), 6.65 (d, 1H, J ) 2 Hz, H1′), 7.5-7.6 (m, 3H, Ph),
7.6-7.8 (m, 2H, Ph), 8.46 (s, 1H, H2).
SiO2 eluting with hexane/EtOAc mixtures of 8:1 and 5:1, which
provided 399 mg (39%) of 19a as a light yellow solid: 1H NMR
(DMSO-d6) δ 1.29 (d, 3H, J ) 7 Hz, 5′-CH3), 1.31 and 1.53 (s
each, 3H each, IP-CH3s), 3.63 (s, 3H, ester CH3), 4.15 (dq, 1H,
J ) 7, 4 Hz, H4′), 4.25 (d, 2H, J ) 6 Hz, ester R-CH2), 4.74
(dd, 1H, J ) 7, 4 Hz, H3′), 5.34 (dd, 1H, J ) 7, 3 Hz, H2′), 6.03
(t, 1H, J ) 6 Hz, C4 NH), 6.25 (d, 1H, J ) 3 Hz, H1′), 7.3-7.5
(m, 5H, Ar Hs), 7.57 (s, 1H, H6), 8.26 (s, 1H, H2).
4-N-(Carbomethoxymethyl)amino-5-phenyl-7-(tert-
butyldimethylsilyloxyethoxymethyl)pyrrolo[2,3-d]pyri-
midine (19b) was prepared as an amorphous solid from 18b
and methyl bromoacetate as described for 19a. 19b (23% yield):
1H NMR (CDCl3) δ 0.04 (s, 6H, TBDMS-CH3s), 0.86 (s, 9H,
t-Bu), 3.59 (t, 2H, J ) 5 Hz, OCH2), 3.55 (s, 3H, ester CH3),
3.75 (t, 2H, J ) 5 Hz, OCH2), 4.32 (d, 2H, J ) 5 Hz, ester
R-CH2), 5.59 (t, 1H, J ) 5 Hz, C4 NH), 5.68 (s, 2H, NCH2O),
7.10 (s, 1H, H6), 7.3-7.6 (m, 5H, Ar Hs), 8.40 (s, 1H, H2).
4-N-(Carbomethoxymethyl)amino-7-(5-deoxy-2,3-O-iso-
propylidenyl-â-d-ribofuranosyl)-5-phenylpyrazolo[3,4-d]-
pyrimidine (19c) was prepared as an amorphous solid from
18c and methyl bromoacetate as described for 19a. 19c (53%
1
yield): H NMR (DMSO-d6) δ 1.28 (d, 3H, J ) 7 Hz, 5′-CH3),
1.32 and 1.52 (s each, 3H each, IP-CH3s), 3.64 (s, 3H, ester
CH3), 4.34 (dq, 1H, J ) 7, 2 Hz, H4′), 4.28 (d, 2H, J ) 6 Hz,
ester R-CH2), 4.81 (dd, 1H, J ) 6, 2 Hz, H3′), 5.46 (dd, 1H, J
) 6, 2 Hz, H2′), 6.39 (d, 1H, J ) 2 Hz, H1′), 6.89 (t, 1H, J )
6 Hz, C4 NH), 7.5-7.8 (m, 5H, Ar Hs), 8.39 (s, 1H, H6).
7-(5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidenyl-
â-d-ribofuranosyl)-4-N-(carbomethoxymethyl)amino-5-
phenylpyrazolo[3,4-d]pyrimidine (19d) was prepared as
an amorphous solid from 18d and methyl bromoacetate as
described for 19a. 19d (ca. 40% yield): 1H NMR (CDCl3) δ 0.05
(s, 6H, TBDMS-CH3s), 0.82 (s, 9H, t-Bu), 1.40 (s, 3H, IP-CH3),
1.61 (s, 3H, IP-CH3), 3.62 (dd, 1H, J ) 10, 6 Hz, H5′), 3.77
(dd, 1H, J ) 10, 6 Hz, H5′), 3.78 (s, 3H, ester CH3) 4.33 (dt,
1H, J ) 6, 2 Hz, H4′), 4.35 (d, 2H, J ) 5 Hz, ester R-CH2),
5.02 (dd, 1H, J ) 6, 2 Hz, H3′), 5.53 (dd, 1H, J ) 6, 2 Hz, H2′),
6.00 (t, 1H, J ) 5 Hz, C4 NH), 6.64 (d, 1H, J ) 2 Hz, H1′),
7.5-7.8 (m, 5H, Ar Hs), 8.46 (s, 1H, H6).
4-N-(N-(n-Propyl)carbamoylmethyl)Amino-5-phenyl-
7-(5-deoxy-2,3-O-isopropylidenyl-â-d-ribofuranosyl)pyr-
rolo[2,3-d]pyrimidine (16f). General Method for AlMe3-
Mediated Preparation of Amides. To a solution of n-propyl-
amine (0.20 mL, 2.4 mmol) in 5 mL of benzene at 0 °C was
added a 2 M solution of AlMe3 in THF (1.3 mL, 2.6 mmol) and
the resulting mixture stirred at room temperature for 30 min,
during which gas evolution occurred. The methyl ester 19a
(1.00 g, 2.36 mmol), as a solution in 5 mL of benzene, was
cannulated into this solution. The resulting mixture was
refluxed for 1 h and then cooled to 10 °C. Then 5 g of SiO2
was added and the solvent evaporated. The resulting material
was subjected to chromatography on SiO2 eluting with hexane/
EtOAc mixtures of 1:1 and 1:1.5, which provided 517 mg (49%)
of compound 16f as a white amorphous solid: 1H NMR (CDCl3)
δ 0.88 (t, 3H, J ) 7 Hz, CH3), 1.39 (s, 3H, IP-CH3), 1.42 (d,
3H, J ) 7 Hz, 5′-CH3), 1.49 (sextet, 2H, J ) 7 Hz, CH2), 1.64
(s, 3H, IP-CH3), 3.20 (q, 2H, J ) 7 Hz, N-CH2), 4.14 (d, 2H, J
) 6 Hz, amide R-CH2), 4.29 (dq, 1H, J ) 7, 4 Hz, H4′), 4.69
(dd, 1H, J ) 7, 4 Hz, H3′), 5.30 (dd, 1H, J ) 7, 3 Hz, H2′), 5.59
(t, 1H, J ) 7 Hz, C4 NH), 6.26 (d, 1H, J ) 3 Hz, H1′), 6.49 (br
s, 1H, C4 NH), 7.04 (s, 1H, H6), 7.4-7.5 (m, 5H, Ar Hs), 8.41
(s, 1H, H2).
This method was applied using an appropriate amine and
methyl ester to prepare the precursors of the following
compounds: 16g-j, 26, 28, 32-41, 43-46, and 52-54.
4-N-(Carbomethoxymethyl)amino-5-phenyl-7-(5-deoxy-
2,3-O-isopropylidenyl-â-d-ribofuranosyl)pyrrolo[2,3-d]-
pyrimidine (19a). General Method for Alkylation of an
Amino Nucleoside with Methyl Bromoacetate. To a
solution of compound 18a (930 mg, 2.4 mmol) in 10 mL of THF
at 0 °C was added a 1 M solution of potassium tert-butoxide
in THF (2.7 mL, 2.7 mmol) and the mixture stirred for 5 min.
Then methyl bromoacetate (0.25 mL, 2.7 mmol) was added and
the mixture stirred for 1.5 h at room temperature. The mixture
was concentrated by rotary evaporation; diluted with EtOAc;
washed with 4 M NH4Cl, water, and brine; dried (MgSO4); and
evaporated. The residue was subjected to chromatography on
4-N-(N-Cyclopropylcarbamoylmethyl)amino-5-phenyl-
7-(hydroxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (16h).
General Method for Desilylation. A mixture of 4-N-(N-
cyclopropylcarbamoylmethyl)amino-5-phenyl-7-(tert-butyldi-
methylsilyloxyethoxymethyl)pyrrolo[2,3-d]pyrimidine (obtained
from 19b) (375 mg, 0.76 mmol) and 1 M tetrabutylammonium
fluoride in THF (1.1 mL, 1.1 mmol) and 2.5 mL of CH3CN was
stirred at room temperature for 4 h. Then it was diluted with
EtOAc, washed with water and brine, dried (MgSO4), and