Example 2:
4-Amino-3-(4-(dimethylαmino)phenyl)-2-(4-methoxyphenyl)-furo[2,3-d]pyrimidine
Example 2 was prepared according to procedures similar to those shown in Scheme 3.
2(A) 2-Amino-3-cyano-5-(4-methoxyphenyl)furan
To a suspension of
α-((4-methoxybenzoyl)methyl)malononitrile (9.66g, 45.1 mmol) in acetic
acid (50ml) was added cone, hydrogen chloride (11,3 ml). The mixture was
stirred at room temperature for 2 hours, and then poured into water.
The resultant precipitation was filtrated, washed with water and
ethanol, and dried under reduced pressure to give the Intermediate of
Example 2(A) ( 5.54g, 56%) as a solid. 1 H NMR (400MHz, CDCI3) ppm 3.83
(s, 3H), 4.74 (brs, 2H), 6.39 (s, 1 H), 6.90 (m, 2H), 7.42 (m, 2H).
2(B) 4-Amino-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (Example 14)
A solution of the Intermediate of Example 2(A) ( 5.54g,
25.9mmol) in formamide (100ml) was heated at 200°C for 1 hour. The
mixture was cooled with an ice bath, and then poured into cold water.
The precipitated material was filtrated, washed with water and ethanol,
and dried under reduced pressure to give the Intermediate of Example
2(B) (5.61 g, 69<y
0) as a solid. 1 H NMR (400MHz, CDCI3) ppm
3.87 (s, 3H), 5.14 (s, 2H), 6.72 (s, 1 H), 6.99 (m, 1 H), 7.78 (m, 2H), 8.38 (s, 1 H). LC/MS: m/z 242 (M+l)
+;
2(C) 4-Amino-3-bromo-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (Example 33)
To a suspension of the Intermediate of Example 2(B)
(4.02g, 16.7mmol) in carbon tetrachloride (100ml), NBS (3.42g, 19.2mmol)
was added. The mixture was refluxed for 4 hours, and then concentrated
in vacuo. The residual material was suspended in ethanol, refluxed for
20 minutes, and cooled to 0°C. The precipitated material was filtrated,
washed with ethanol, and dried under reduced pressure to afford the
Intermediate of Example 2(C) (4.71g, 88%). 1 H NMR (400MHz, DMSO-d6) ppm
3.84 (s, 3H), 7.13 (m, 2H), 7.95 (m, 2H), 8.24 (s, 1 H). LC/MS: m/z 320
(M)
+, 322 (M+2)
+.
2(D) 4-Amino-3-(4-(dimethylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3- d]pyrimidine
A mixture of the Intermediate of Example 2(C) (62.4 mg,
0.195 mmol), (4- dimethyl amino)phenyl-boronic acid (101 mg, 0.61
mmol), tetrakis(triphenyl phosphine)-palladium(O) (15.5 mg, 0.013 mmol)
was suspended in the mixture of DME (2.0 ml), DMF (0.5 ml), and 2M
aqueousNa_C03 (1.0 ml) under argon atmosphere. The
mixture was refluxed over night, diluted with dichloromethane, and
washed with aqueous Na
2CU3. The organic phase was separated,
concentrated in vacuo, and purified by chromatography on a silica gel
column using hexane / ethyl acetate (3:1- 1 :1) as an eluant to afford
the title compound of Example 2 (37 mg) as a solid. 1 H NMR (400MHz,
CDCI3) ppm 3.05 (s, 6H), 3.80 (s, 3H), 4.94 (brs, 2H), 6.82 (m, 4H),
7.31 (m, 2H), 7.56 (m, 2H), 8.34 (s, 1 H). LC/MS: m/z 361 (M+1)
+.
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