A. Gangjee et al. / Bioorg. Med. Chem. 18 (2010) 5261–5273
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4.2.3. 2-Pivaloylamino-4-oxo-6-(2,5-dimethoxybenzyl)-pyrrolo
[2,3-d]pyrimidine (16c)
chloroform. Fractions containing the product (tlc) were pooled
and evaporated to afford pure 4, 7, and 10.
Compound 16c was synthesized from 15c (0.53 g, 1.38 mmol)
using the general procedure described above and was obtained
as a light yellow solid (0.55 g, 81%): Rf 0.45 (CHCl3/CH3OH, 10:1);
mp 250 °C; 1H NMR (DMSO-d6); d 1.20 (s, 9H, C(CH3)3), 3.65 (s,
3H, OCH3), 3.74 (s, 3H, OCH3), 3.86 (s, 2H, CH2), 5.96 (s, 1H, C5-
CH), 6.60–6.93 (m, 3H, Ar-H), 10.75 (br s, 1H, NH, exch), 11.53
(br s, 1H, NH, exch), 11.87 (br s, 1H, NH, exch).
4.4.1. 2-Amino-4-(N-methyl-m-bromoanilino)-6-benzyl-pyrrolo
[2,3-d]pyrimidine (4)
Compound 4 was synthesized from 17a (0.20 g, 0.58 mmol)
using the general procedure described above and was obtained
as a light yellow solid (33 mg, 14%): Rf 0.33 (CHCl3/CH3OH, 10:1);
mp 179.5–180.7 °C; 1H NMR (DMSO-d6) d 3.42 (s, 3H, NCH3),
3.68 (s, 2H, CH2), 4.34 (s, 1H, CH), 5.63 (br s, 2H, NH2, exch), 7.1–
7.4 (m, 5H, Ar-H), 10.77 (br s, 1H, NH, exch). Anal. (C20H18BrN5):
C, H, N, Br.
4.3. General procedure for the synthesis of 17a–c
In a 50 mL round-bottom flask was placed 16a–c and POCl3
(5 mL). The mixture was heated to reflux for 2 h. After evaporation
of the excess of POCl3, ice-cold water was added. The reaction mix-
ture was neutralized with NH3ꢀH2O, and extracted with CHCl3
(3ꢁ50 mL). The organic phase was combined and dried with
Na2SO4. Concentration of the chloroform afforded a brown solid
that was dissolved in chloroform (2–3 mL) again and was placed
to the top of a 15 ꢁ 150 mm chromatographic column and eluted
with 0.1% methanol in chloroform. Fractions containing the prod-
uct were pooled and evaporated to afford pure compounds 17a–c.
4.4.2. 2-Amino-4-(N-methyl-m-bromoanilino)-6-(2-methyl
benzyl)-pyrrolo[2,3-d]pyrimidine (7)
Compound 7 was synthesized from 17b (0.20 g, 0.58 mmol)
using the general procedure described above and was obtained
as a white-off solid (25 mg, 14%): Rf 0.51 (CHCl3/CH3OH, 10:1);
mp 176.6–177.9 °C; 1H NMR (DMSO-d6) d 2.27 (s, 3H, CH3-Ph),
3.66 (s, 3H, NCH3), 4.12 (s, 2H, CH2), 5.72 (br s, 2H, NH2, exch),
6.99 (s, 1H, C5-CH), 7.07–7.41 (m, 7H, Ar-H), 10.79 (br s, 1H, NH,
exch). Anal. (C21H20BrN5): C, H, N, Br.
4.3.1. 2-Pivaloylamino-4-chloro-6-benzyl-pyrolo[2,3-d] pyrimi-
dine (17a)
4.4.3. 2-Amino-4-(N-methyl-m-bromoanilino)-6-(2,5-dime-
thoxybenzyl)-pyrrolo[2,3-d]pyrimidine (10)
Compound 17a was synthesized from 16a (0.30 g, 0.92 mmol)
using the general procedure described above and was obtained
as a yellow solid (0.10 g, 31%): Rf 0.50 (CHCl3/CH3OH, 10:1); mp
131.3–133.1 °C; 1H NMR (DMSO-d6) d 1.20 (s, 9H, C(CH3)3), 4.07
(s, 2H, CH2), 6.17 (s, 1H, C5-CH), 7.23–7.31 (m, 5H, Ar-H), 9.96
(br s, 1H, NH, exch), 12.36 (br s, 1H, NH, exch).
Compound 10 was synthesized from 17c (0.15 g, 0.42 mmol)
using the general procedure described above and was obtained
as a white-off solid (35 mg, 20%): Rf 0.52 (CHCl3/CH3OH, 10:1);
mp 212–214 °C; 1H NMR (DMSO-d6) d 3.39 (s, 3H, NCH3), 3.57 (s,
3H, OCH3), 3.63 (s, 3H, OCH3), 4.24 (s, 2H, CH2), 5.62 (br s, 2H,
NH2, exch), 6.6 (s, 1H, C5-CH), 6.82–6.69 (m, 3H, Ar-H), 7.26–
7.43 (m, 3H, Ar-H), 10.7 (br s, 1H, NH, exch). Anal.
(C22H22BrN5O2ꢀ0.9CH3OH): C, H, N, Br.
4.3.2. 2-Pivaloylamino-4-chloro-6-(2-methylbenzyl)-pyrolo[2,3-
d]pyrimidine (17b)
Compound 17b was synthesized from 16b (0.50 g, 1.48 mmol)
using the general procedure described above and was obtained
as a yellow solid (0.20 g, 38%): Rf 0.65 (CHCl3/CH3OH, 10:1); mp
80–82 °C; 1H NMR (DMSO-d6) d 1.22 (s, 9H, C(CH3)3), 2.37 (s, 3H,
CH3), 4.06 (s, 2H, CH2), 5.98 (s, 1H, C5-CH), 7.17–7.19 (m, 4H, Ar-
H), 10.00 (br s, 1H, NH, exch), 12.37 (br s, 1H, NH, exch).
4.5. General procedure for the synthesis of 18a–c
Compounds 17a–c were dissolved in THF (10 mL) and cooled
down to 0 °C, 1.5 equiv NaH was added into the mixture and stir-
red for 10 min. adding the MeI dropwise to the reaction mixture
and stirring for another 3 h. Water (10 mL) was added slowly to
the reaction solution in an ice-bath, and the solution was extracted
with ethyl acetate (3 ꢁ 50 mL). The organic phase was combined
and dried with anhydrous Na2SO4. Concentration of the ethyl ace-
tate afforded a solid that was dissolved in methanol, and then
250 mg silica gel was added and removed the solvent in vacuo to
4.3.3. 2-Pivaloylamino-4-chloro-6-(2,5-dimethoxybenzyl)-
pyrolo[2,3-d]pyrimidine (17c)
Compound 17c was synthesized from 16c (0.55 g, 1.43 mmol)
using the general procedure described above and was obtained
as a yellow solid (0.45 g, 78%): Rf 0.69 (CHCl3/CH3OH, 10:1); mp
129.0–131.5 °C; 1H NMR (DMSO-d6) d 1.25 (s, 9H, C(CH3)3), 3.83
(s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.12 (s, 2H, CH2), 6.02 (s, 1H,
C5-CH), 6.78–6.94 (m, 3H, Ar-H), 9.96 (br s, 1H, NH, exch), 12.28
(br s, 1H, NH, exch).
afford
a dry plug. This plug was placed on the top of a
15 ꢁ 150 mm column and eluted with chloroform. Fractions con-
taining the product were pooled and evaporated to afford 18a–c.
4.5.1. 2-Pivaloylamino-4-chloro-6-benzyl-7-methyl-pyrrolo
[2,3-d]pyrimidine (18a)
4.4. General procedure for the synthesisofcompounds4, 7, and 10
Compound 18a was synthesized from 17a (0.15 g, 0.42 mmol)
using the general procedure described above and was obtained
as a white-off solid (90 mg, 58%): Rf 0.84 (CHCl3/CH3OH, 10:1);
mp 190.5–192.1 °C; 1H NMR (DMSO-d6) d 1.21 (s, 9H, C(CH3)3),
3.60 (s, 3H, NCH3), 4.22 (s, 2H, CH2), 6.18 (s, 1H, C5-CH), 7.28–
7.35 (m, 5H, Ar-H), 10.04 (br s, 1H, NH, exch).
Compounds 17a–c and 3-bromo-N-methyl aniline (1.5 equiv), i-
PrOH (10 mL), and 2–3 drops of conc HCl were placed in a 50-mL
flask. The mixture was heated to reflux overnight. After evapora-
tion of the solvent, the residue was dissolved in 1,4-dioxane
(10 mL), and 15% KOH aqueous solution (2 mL) was added. The
reaction mixture was heated to reflux for 10 h. The solvent was re-
moved under reduced pressure to give syrup. Water (20 mL) was
added and the solution was extracted with chloroform
(3ꢁ50 mL). The organic phase was combined and dried over anhy-
drous Na2SO4. Evaporation of the chloroform afforded a solid that
was dissolved in methanol, and then 250 mg silica gel was added
and the solvent removed in vacuo to afford a dry plug. This plug
was placed on the top of a 15 ꢁ 150 mm column and eluted with
4.5.2. 2-Pivaloylamino-4-chloro-6-(2-methylbenzyl)-7-methyl-
pyrrolo[2,3-d]pyrimidine (18b)
Compound 18b was synthesized from 17b (0.35 g, 0.98 mmol)
using the general procedure described above and was obtained
as a yellow solid (0.2 g, 56%): Rf 0.86 (CHCl3/CH3OH, 10:1); mp
180.9–182.2 °C; 1H NMR (DMSO-d6) d 1.23 (s, 9H, C(CH3)3), 2.37
(s, 3H, CH3), 3.67 (s, 3H, NCH3), 4.16 (s, 2H, CH2), 5.98 (s, 1H, C5-
CH), 7.17–7.19 (m, 4H, Ar-H), 10.09 (br s, 1H, NH, exch).