4-(Phenylamino)pyrrolopyrimidines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 12 2291
4-((3-Cya n op h en yl)a m in o)-5,6-d im et h yl-7H -p yr r olo-
[2,3-d]pyr im idin e (20): FABMS m/ z 264 (M + H)+ (C15H13N5);
1H NMR (DMSO-d6) δ 11.50 (s, NH), 8.26 (d, NH), 8.21 (s,
pyrimidine H), 8.25 (s, aromat H), 8.06 (d, aromat H), 7.48
(tr, aromat H), 7.41 (d, aromat H), 2.42 (s, CH3), 2.27 (s, CH3).
4-((3,5-Dich lor oph en yl)am in o)-5,6-dim eth yl-7H-pyr r olo-
[2,3-d ]p yr im id in e (27): colorless crystals of mp >250 °C;
FABMS m/ z 253 (M + H)+ (C15H16N4); 1H NMR (DMSO-d6) δ
11.38 (s, NH), 8.12 (s, pyrimidine H), 7.83 (s, NH), 7.57 (d,
aromat H), 7.50 (s, aromat H), 7.18 (tr, aromat H), 6.81 (d,
aromat H), 2.38 (s, CH3), 2.27 (s, CH3).
4-((3-Hyd r oxyp h en yl)a m in o)-5,6-d im eth yl-7H-p yr r olo-
[2,3-d ]p yr im id in e (15): colorless crystals of mp 230-234 °C;
1
FABMS m/ z 255 (M + H)+; H NMR (DMSO-d6) δ 11.38 (s,
1
FABMS m/ z 307 (M + H)+ (C14H12Cl2N4); H NMR (DMSO-
NH), 9.25 (s, NH), 8.14 (s, pyrimidine H), 7.80 (s, OH), 7.30
(s, aromat H), 7.08 (d, 2 aromat H), 6.42 (m, aromat H), 2.36
(s, CH3),2.25 (s, CH3). Anal. (C14H14N4O) C, H, N.
d6) δ 11.54 (s, pyrrole NH), 8.26 (s, NH), 8.23 (s, pyrimidine
H), 7.91 (s, 2 aromat H), 7.12 (m, aromat H), 2.39 (s, CH3),
2.19 (s, CH3).
4-((3-Ch lor op h en yl)a m in o)-5-m eth yl-6-p h en yl-7H-p yr -
r olo[2,3-d ]p yr im id in e (28): crystals of mp 275-280 °C (HCl
salt); FABMS m/ z 335 (M + H)+ (C19H15ClN4); 1H NMR
(DMSO-d6) δ 12.27 (s, pyrrole NH), 9.05 (s, NH), 8.31 (s,
pyrimidine H), 7.85 (m, aromat H), 7.62 (m, 3 aromat H), 7.56
(m, 2 aromat H), 7.43 (m, 2 aromat H), 7.23 (d, aromat H),
2.61 (s, CH3).
4-((3-Ch lor op h en yl)a m in o)-5-p h en yl-6-m eth yl-7H-p yr -
r olo[2,3-d ]p yr im id in e (29): colorless crystals of mp 257-
261 °C; FABMS m/ z 335 (M + H)+ (C19H15ClN4); 1H NMR
(DMSO-d6) δ 10.49 (s, pyrrole NH), 8.50 (s, pyrimidine H), 7.78
(s, aromat H), 7.53 (m, 2 aromat H), 7.50 (m, 3 aromat H),
7.16 (m, 2 aromat H), 6.97 (d, aromat H), 6.81 (s, NH), 2.56 (s,
CH3).
4-((3-Meth oxyp h en yl)a m in o)-5,6-d im eth yl-7H-p yr r olo-
[2,3-d ]p yr im id in e (16): colorless crystals of mp 211-214 °C;
1
FABMS m/ z 269 (M + H)+; H NMR (DMSO-d6) δ 11.46 (s,
NH), 8.17 (s, pyrimidine H), 7.93 (s, NH), 7.44 (d, aromat H),
7.33 (d, aromat H), 7.21 (tr, aromat H), 6.61 (dd, aromat H),
2.40 (s, CH3), 2.28 (s, CH3). Anal. (C15H16N4O) C, H, N.
4-((3-Ca r boxyp h en yl)a m in o)-5,6-d im eth yl-7H-p yr r olo-
[2,3-d ]p yr im id in e (18): pale-yellow crystals of mp >260 °C;
1
FABMS m/ z 283 (M + H)+; H NMR (DMSO-d6) δ 12.47 (s,
NH), 9.55 (s, NH), 8.25 (s, pyrimidine H), 8.11 (s, aromat H),
7.87 (d, aromat H), 7.82 (d, aromat H), 7.60 (tr, aromat H),
2.41 (s, CH3), 2.33 (s, CH3). Anal. (C15H14N4O2) C, H, N.
4-((3-Eth oxyca r bon yl)a m in o)-5,6-d im eth yl-7H-p yr r olo-
[2,3-d ]p yr im id in e (19): beige crystals of mp 186-190 °C dec;
1
FABMS m/ z 311 (M + H)+; H NMR (DMSO-d6) δ 11.42 (s,
4-((3-Ch lor op h en yl)a m in o)-5,6-d ip h en yl-7H -p yr r olo-
[2,3-d ]p yr im id in e (30): White amorphous powder; FABMS
m/ z 396 (M + H)+ (C24H17ClN4).
4-((3-Ch lor op h en yl)-N-m eth yla m in o)-5,6-d im eth yl-7H-
p yr r olo[2,3-d ]p yr im id in e (31): orange-colored crystals of
mp 191-196 °C; FABMS m/ z 287 (M + H)+; 1H NMR (DMSO-
d6) δ 11.68 (s, pyrrole NH), 8.41 (s, pyrimidine H), 7.28 (m,
aromat H), 7.04 (m, 2 aromat H), 6.86 (m, aromat H), 3.48 (s,
NCH3), 2.30 (s, CH3),1.48 (s, CH3). Anal. (C15H15ClN4) C, H,
N, Cl.
pyrrole NH), 8.29 (m, aromat H), 8.23 (s, NH), 8.14 (s,
pyrimidine H), 8.02 (m, aromat H), 7.58 (d, aromat H), 7.43
(tr, aromat H), 4.33 (ester CH2), 2.40 (s, CH3), 2.17 (s, CH3),
1.17 (ester CH3). Anal. (C17H18N4O2) C, H, N.
4-(Cycloh exyla m in o)-5,6-d im et h yl-7H -p yr r olo[2,3-d ]-
p yr im id in e (46). Reaction of 9a with cyclohexylamine gave
46 as colorless crystals of mp >260 °C: FABMS m/ z 245 (M
+ H)+ (C14H20N4); 1H NMR (DMSO-d6) δ 12.35 (s, pyrrole NH),
8.18 (s, pyrimidine H), 7.19 (d, NH), 3.95 (m, cyclohexyl H),
2.34 (s, CH3), 2.26 (s, CH3), 1.93 (d, 2 cyclohexyl H), 1.75 (m,
2 cyclohexyl H), 1.60 (m, 3 cyclohexyl H), 1.42 (m, 2 cyclohexyl
H), 1.17 (m, cyclohexyl H). Anal. (C14H20N4) C, H, N.
Reaction of 4-chloro-5,6-tetramethylene-7H-pyrrolo[2,3-d]-
pyrimidine (9b) with the corresponding substituted aniline as
described for 7a gave the following products.
4-((3-Meth ylph en yl)am in o)-5,6-tetr am eth ylen e-7H-pyr -
r olo[2,3-d ]p yr im id in e (35): colorless crystals of mp 258-
261 °C; FABMS m/ z 279 (M + H)+; 1H NMR (DMSO-d6) δ
11.37 (s, pyrrole NH), 8.12 (s, pyrimidine H), 7.71 (s, NH), 7.57
(d, aromat H), 7.50 (s, aromat H), 7.17 (tr, aromat H), 6.81 (d,
aromat H), 2.92 (s, 2 cyclohexyl H), 2.68 (s, 2 cyclohexyl H),
1.81 (s, 4 cyclohexyl H). Anal. (C17H18N4) C, H, N.
4-((3-H yd r oxyp h en yl)a m in o)-5,6-t et r a m et h ylen e-7H -
p yr r olo[2,3-d ]p yr im id in e (38): colorless crystals of mp
231-235 °C dec; FABMS m/ z 281 (M + H)+; 1H NMR (DMSO-
d6) δ 11.50 (s, pyrrole NH), 9.51 (s, NH), 8.49 (s, pyrimidine
H), 7.87 (m, aromat H), 7.44 (s, OH), 7.35 (m, aromat H), 7.12
(tr, aromat H), 6.75 (m, aromat H), 2.77 (s, 2 cyclohexyl H),
2.60 (s, 2 cyclohexyl H), 1.62 (s, 4 cyclohexyl H). Anal.
(C16H16N4O) C, H, N.
4-((3-Met h oxyp h en yl)a m in o)-5,6-t et r a m et h ylen e-7H -
p yr r olo[2,3-d ]p yr im id in e (39): colorless crystals of mp
239-241 °C; FABMS m/ z 295 (M + H)+; 1H NMR (DMSO-d6)
δ 11.46 (s, pyrrole NH), 8.18 (s, pyrimidine H), 7.81 (s, NH),
7.42 (m, aromat H), 7.34 (d, aromat H), 7.20 (tr, aromat H),
6.58 (m, aromat H), 3.76 (s, OCH3), 2.94 (s, 2 cyclohexyl H),
2.68 (s, 2 cyclohexyl H), 1.81 (s, 4 cyclohexyl H). Anal.
(C17H18N4O) C, H, N.
4-(3-Ch lor op h en oxy)-5,6-d im et h yl-7H -p yr r olo[2,3-d ]-
p yr im id in e (33): colorless crystals of mp 214-216 °C;
1
FABMS m/ z 274 (M + H)+; H NMR (DMSO-d6) δ 12.62 (s,
pyrrole NH), 8.97 (s, pyrimidine H), 8.27 (tr, aromat H), 8.18
(m, aromat H), 8.13 (m, aromat H), 8.03 (dd, aromat H), 3.12
(s, 2 CH3). Anal. (C14H12ClN3O) C, H, N, Cl.
4-((3-Ch lor oph en yl)am in o)-5,6-tetr am eth ylen e-7H-pyr -
r olo[2,3-d ]p yr im id in e (36): colorless crystals of mp 246-
249 °C; FABMS m/ z 299 (M + H)+; 1H NMR (DMSO-d6) δ
11.47 (s, pyrrole NH), 8.20 (s, pyrimidine H), 8.00 (s, NH), 7.93
(m, aromat H), 7.68 (m, aromat H), 7.30 (tr, aromat H), 7.02
(m, aromat H), 2.92 (s, 2 cyclohexyl H), 2.67 (s, 2 cyclohexyl
H), 1.81 (s, 4 cyclohexyl H). Anal. (C16H15ClN4) C, H, N, Cl.
4-((3-Br om oph en yl)a m in o)-5,6-tetr a m eth ylen e-7H-p yr -
r olo[2,3-d ]p yr im id in e (37): colorless crystals of mp 240-
245 °C; FABMS m/ z 343 (M + H)+; 1H NMR (DMSO-d6) δ
11.35 (s, pyrrole NH), 8.18 (s, pyrimidine H), 8.06 (m, aromat
H), 7.93 (s, NH), 7.72 (m, aromat H), 7.23 (tr, aromat H), 7.12
(m, aromat H), 2.91 (s, 2 cyclohexyl H), 2.67 (s, 2 cyclohexyl
H), 1.80 (s, 4 cyclohexyl H). Anal. (C16H15BrN4) C, H, N, Br.
4-((3-(Tr iflu or om et h yl)p h en yl)a m in o)-5,6-t et r a m et h -
ylen e-7H-p yr r olo[2,3]p yr im id in e (40): pale-yellow crystals
of mp 259-261 °C; FABMS m/ z 333 (M + H)+; 1H NMR
(DMSO-d6) δ 11.50 (s, pyrrole NH), 8.21 (s, pyrimidine H), 8.18
(m, NH + aromat H), 8.06 (m, aromat H), 7.53 (tr, aromat H),
7.31 (d, aromat H), 2.96 (s, 2 cyclohexyl H), 2.68 (s, 2 cyclohexyl
H), 1.82 (s, 4 cyclohexyl H). Anal. (C17H15F3N4) C, H, N, F.
Removal of the N-benzyl protecting group from the chlorides
7a and 7b in a similar way gave the deprotected chlorides 9a
and 9b which were used without further purification:
4-Ch lor o-5,6-d im et h yl-7H -p yr r olo[2,3-d ]p yr im id in e
(9a ): mp 247-250 °C; FABMS m/ z 182 (M + H)+ (C8H8-
ClN3).33
4-((3-Ca r b oxyp h en yl)a m in o)-5,6-t et r a m et h ylen e-7H -
p yr r olo[2,3-d ]p yr im id in e (41): colorless amorphous com-
pound of mp >260 °C; FABMS m/ z 309 (M + H)+ (C17H16N2O2);
1H NMR (DMSO-d6) δ 12.85 (s, COOH), 11.44 (s, pyrrole NH),
8.30 (m, aromat H), 8.16 (s, pyrimidine H), 8.10 (s, NH), 8.00
(m, aromat H), 7.57 (m, aromat H), 7.42 (tr, aromat H), 2.95
(s, 2 cyclohexyl H), 2.67 (s, 2 cyclohexyl H), 1.82 (s, 4 cyclohexyl
H).
4-Ch lor o-5,6-tetr a m eth ylen e-7H-p yr r olo[2,3-d ]p yr im i-
d in e (9b): mp >220 °C dec; FABMS m/ z 208 (M + H)+
(C10H10ClN3).
Reaction of 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimi-
dine (9a ) with the corresponding substituted aniline gave the
following products.
4-((3-Met h ylp h en yl)a m in o)-5,6-d im et h yl-7H -p yr r olo-
[2,3-d ]p yr im id in e (11): colorless crystals of mp 230-234 °C;
4-((3-Ch lor op h en yl)a m in o)p yr im id o[4,5-b]in d ole (44).
A solution of 12.1 g (31 mmol) of 4-((3-chlorophenyl)amino)-
5,6-tetramethylene-7-benzylpyrrolo[2,3-d]pyrimidine (8b) and
14.1 g (62 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in 260 mL of toluene was refluxed for 30 min.
A