M.-Y. Jang et al. / Bioorg. Med. Chem. 19 (2011) 702–714
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NaOH solution to lead a precipitate. The resulting solid was filtered
off, washed with water and dried over P2O5, furnishing the title
compound as a pale yellow solid (3.3 g, 81%). 1H NMR (300 MHz,
DMSO, 25 °C): d = 5.78 (s, 2H, NH2), 5.59 (s, 2H, NH2), 5.03 (s, 1H,
CH), 3.60 (br s, 4H, O(CH2)2), 3.31 (br s, 4H, N(CH2)2) ppm. 13C
NMR (75 MHz, DMSO, 25 °C): d = 165.2, 164.1, 162.6, 74.1, 65.9,
44.2 ppm. MS: 196.06 [M+H]+
5.2.6. 6-Ethoxy-5-thiocyanatopyrimidine-2,4-diamine (2b)
This compound was synthesized from 1b according to the pro-
cedure for the preparation of compound 2a. The crude residue was
purified by flash chromatography on silica (CH2Cl2/MeOH 50:1) to
yield the title compound as a pale yellow solid (89%). Mp 182 °C.
1H NMR (300 MHz, DMSO, 25 °C): d = 6.88 (s, 2H, NH2), 6.61 (s,
2H, NH2), 4.31 (q, J = 7.1 Hz, 2H, CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3)
ppm. 13C NMR (75 MHz, DMSO, 25 °C): d = 169.1, 165.6, 163.1,
112.1, 66.5, 62.0, 14.6 ppm. HRMS: calcd for C7H10N5OS [M+H]+
212.06061, found 212.05973.
5.2.2. 6-Ethoxypyrimidine-2,4-diamine (1b)
To a solution of NaH (2.77 g, 69.2 mmol) in ethanol (150 ml)
was added 2,6-diamino-4-chloropyrimidine (5.0 g, 34.6 mmol).
The mixture was refluxed for 6 h. After cooling, the solution was
neutralized with a 5–6 N HCl solution in isopropyl alcohol. After
removing the solvents in vacuo, the residue was purified by chro-
matography on silica gel (CH2Cl2/MeOH 40:1), yielding the title
compound as a white solid (4.0 g, 75%). Mp 164–165 °C. 1H NMR
(300 MHz, DMSO, 25 °C): d = 6.00 (s, 2H, NH2), 5.88 (s, 2H, NH2),
5.03 (s, 1H, CH), 4.13 (q, J = 7.1 Hz, 2H, CH2), 1.22 (t, J = 7.1 Hz,
3H, CH3) ppm. 13C NMR (75 MHz, DMSO, 25 °C): d = 170.0, 165.9,
162.9, 76.1, 60.2, 14.7 ppm. HRMS: calcd for C6H11N4O [M+H]+
155.09329, found 155.09260.
5.2.7. 6-(Isopentyloxy)-5-thiocyanatopyrimidine-2,4-diamine
(2c)
This compound was synthesized from 1c, according to the pro-
cedure for the preparation of compound 2a. The crude residue was
purified by flash chromatography on silica (CH2Cl2/MeOH 50:1) to
yield the title compound as a pale yellow solid (76%). Mp 152 °C.
1H NMR (300 MHz, DMSO, 25 °C): d = 6.87 (s, 2H, NH2), 6.59 (s,
2H, NH2), 4.29 (t, J = 6.6 Hz, 2H, OCH2), 1.74 (sixtet, J = 6.6 Hz, 1H,
CH), 1.59 (q, J = 6.7 Hz, 2H, CH2), 0.93 (d, J = 6.6 Hz, 6H, CH3) ppm.
13C NMR (75 MHz, DMSO, 25 °C): 169.1, 165.6, 163.1, 112.1, 66.6,
64.6, 37.2, 24.6, 22.4 ppm. HRMS: calcd for C10H16N5OS [M+H]+
254.10756, found 254.10689.
5.2.3. 6-(Isopentyloxy)pyrimidine-2,4-diamine (1c)
This compound was synthesized according to the procedure for
the preparation of compound 1b, using isoamyl alcohol. The crude
residue was purified by flash chromatography on silica (CH2Cl2/
MeOH 40:1) to yield the title compound as a pale yellow oil
(95%). 1H NMR (300 MHz, CDCl3, 25 °C): d = 5.23 (s, 1H, C@CH),
4.69 (s, 2H, NH2), 4.51 (s, 2H, NH2), 4.18 (t, J = 6.7 Hz, 2H, OCH2),
1.77 (m, 1H, CH), 1.60 (q, J = 6.7 Hz, 2H, CH2), 0.94 (d, J = 6.6 Hz,
6H, CH3) ppm. 13C NMR (75 MHz, CDCl3, 25 °C): d = 170.6, 165.3,
162.3, 76.6, 63.8, 37.1, 24.3, 21.9 ppm. HRMS: calcd for C9H17N4O
[M+H]+ 197.14024, found 197.13955.
5.2.8. 7-Morpholinothiazolo[4,5-d]pyrimidine-2,5-diamine (3a)
6-Morpholino-5-thiocyanatopyrimidine-2,4-diamine 2a (3.5 g,
14.3 mmol) was heated at 140 °C in a DMF/water solution (4:1,
50 ml) for two days. After cooling, the resulting solid was filtered
off, washed with water and ethyl acetate, furnishing the title com-
pound as a yellow solid (2.1 g, 58%). Mp 242 °C. 1H NMR (300 MHz,
DMSO, 25 °C): d = 7.95 (s, 2H, NH2), 6.01 (s, 2H, NH2), 3.66 (br s, 4H,
O(CH2)2), 3.58 (br s, 4H, N(CH2)2) ppm. 13C NMR (75 MHz, DMSO,
25 °C): d = 171.2, 170.6, 160.9, 157.8, 90.8, 65.9, 45.7 ppm. HRMS:
calcd for C9H13N6OS [M+H]+ 253.08715, found 253.08621.
5.2.4. 1-(4-(2,6-Diaminopyrimidin-4-yl)piperazin-1-yl)
ethanone (1d)
5.2.9. 7-Ethoxythiazolo[4,5-d]pyrimidine-2,5-diamine (3b)
This compound was synthesized from 2b according to the pro-
cedure for the preparation of compound 3a. The crude residue was
purified by flash chromatography on silica (CH2Cl2/MeOH 20:1) to
yield the title compound as a pale yellow solid (76%). Mp 224 °C.
1H NMR (300 MHz, DMSO, 25 °C): d = 8.05 (s, 2H, NH2), 6.28 (s,
2H, NH2), 4.37 (q, J = 7.1 Hz, 2H, CH2), 1.30 (t, J = 7.1 Hz, 3H, CH3)
ppm. 13C NMR (75 MHz, DMSO, 25 °C): d = 172.7, 171.6, 162.6,
162.2, 92.4, 61.4, 14.6 ppm. HRMS: calcd for C7H10N5OS [M+H]+
12.06061, found 212.05993.
To a solution of 2,6-diamino-4-chloropyrimidine (3.0 g, 20.8
mmol) in water (100 ml) was added N-acetylpiperazine (10.64 g,
83.0 mmol). The mixture was refluxed for 21 h. The orange solu-
tion was cooled down and made alkaline with a 10 M NaOH solu-
tion. The white precipitate was filtered off, washed with cold water
and dried over P2O5 in a vacuum desiccator to yield the title com-
pound as a white solid (3.3 g, 67%). Mp 274 °C 1H NMR (300 MHz,
DMSO, 25 °C): d = 5.74 (s, 2H, NH2), 5.51 (s, 2H, NH2), 5.04 (s, 1H,
CH), 3.33–3.46 (m, 8H, N(CH2)2, CON(CH2)2), 2.02 (s, 3H, CH3)
ppm. 13C NMR (75 MHz, DMSO, 25 °C): 168.3, 165.2, 163.5, 162.7,
74.1, 45.2, 43.7, 43.3, 40.5, 21.2 ppm. HRMS: calcd for C10H17N6O
[M+H]+ 237.1464, found 237.1454.
5.2.10. 7-(Isopentyloxy)thiazolo[4,5-d]pyrimidine-2,5-diamine
(3c)
This compound was synthesized from 2c in a yield of 91%,
according to a procedure for the preparation of compound 3a.
Mp 212 °C. 1H NMR (300 MHz, DMSO, 25 °C): d = 8.06 (s, 2H,
NH2), 6.30 (s, 2H, NH2), 4.35 (t, J = 6.7 Hz, 2H, OCH2), 1.69 (sixtet,
J = 6.5 Hz, 1H, CH), 1.59 (q, J = 6.6 Hz, 2H, CH2), 0.92 (d, J = 6.5 Hz,
6H, CH3) ppm. 13C NMR (75 MHz, DMSO, 25 °C): d = 172.5, 171.6,
162.7, 162.1, 92.4, 64.1, 37.2, 24.7, 22.4 ppm. HRMS: calcd for
5.2.5. 6-Morpholino-5-thiocyanatopyrimidine-2,4-diamine (2a)
A solution of 6-morpholinopyrimidine-2,4-diamine 1a (5.0 g,
25.6 mmol) and potassium thiocyanate (14.9 g, 0.15 mol) in DMF
(120 ml) was heated at 65 °C. Pyridine (4.14 ml, 51.2 mmol) was
added and the solution cooled to 5 °C. Bromine (1.31 ml,
25.6 mmol) was added slowly and the reaction mixture stirred
for 2 h at 5–10 °C. The reaction mixture was poured into ice-water
(100 ml) and stirred for 1 h. The volatiles were removed under re-
duced pressure and the resulting solid was diluted with water, fil-
tered and dried. The crude solid was purified by flash
chromatography on silica gel (CH2Cl2/MeOH 30:1) to yield the title
compound as white solid (3.61 g, 56%). Mp 161 °C. 1H NMR
(300 MHz, DMSO, 25 °C): d = 6.78 (s, 2H, NH2), 6.36 (s, 2H, NH2),
3.69 (br s, 4H, O(CH2)2), 3.41 (br s, 4H, N(CH2)2) ppm. 13C NMR
(75 MHz, DMSO, 25 °C): d = 168.1, 166.5, 162.6, 112.3, 69.1, 66.1,
49.2 ppm. HRMS: calcd for C9H13N6OS [M+H]+ 253.08715, found
253.08637.
C
10H16N5OS [M+H]+ 254.10756, found 254.10675.
5.2.11. 1-(4-(2,5-Diaminothiazolo[4,5-d]pyrimidin-7-yl)
piperazin-1-yl)ethanone (3d)
This compound was synthesized from 1d according to the pro-
cedure for the preparation of compound 2a. The crude residue was
triturated with hot methanol to yield the title compound as a pale
yellow solid (52%). Mp 263 °C. 1H NMR (300 MHz, DMSO, 25 °C):
d = 7.85 (s, 2H, NH2), 5.90 (s, 2H, NH2), 3.53–3.64 (m, 8H,
N(CH2)2, CON(CH2)2), 2.03 (s, 3H, CH3) ppm. 13C NMR (75 MHz,
DMSO, 25 °C): 172.2, 170.2, 168.5, 161.6, 157.5, 90.9, 45.3, 45.2,