Methyltriazene Prodrugs
Journal of Medicinal Chemistry, 2004, Vol. 47, No. 27 6881
its dimer.28 Monomer δ 8.65 (s, 1H), 7.30-7.50 (m, 5H), 5.76
(s, 2H), 1.76 (s, 9H); dimer δ 8.35, 5.48. Anal. (C17H17N5O4) C,
H, N.
7.50 (m, 3H), 5.73 (s, 2H), 4.49 (q, 2H, J ) 7.1 Hz), 3.61 (s,
3H), 1.70 (s, 9H), 1.44 (t, J ) 7.1 Hz, 3H)
2-(3-Phenyloxycarbonyl-3-methyltriazen-1-yl)-6-ben-
zyloxy-9-Boc-purine 18. Prepared from hydrazide 12f: yield
74%, mp140-141 °C (dec); 1H NMR δ 8.39 (s, 1H), 7.30-7.60
(m, 10H), 5.73 (s, 2H), 3.71 (s, 3H), 1.67 (s, 9H)
2-(3-p-Nitrophenyloxycarbonyl-3-methyltriazen-1-yl)-
6-benzyloxy-9-Boc-purine 19. Prepared from hydrazide
12g: yield 77.%, mp 193-196 °C (dec); 1H NMR δ 8.39 (s, 1H),
8.33 (1/2 AB, 2H, J ) 9.0 Hz), 7.59 (m, 2H), 7.47 (1/2 AB, 2H,
J ) 9.0 Hz), 7.30 (m, 3H), 5.73 (s, 2H), 3.71 (s, 3H), 1.68 (s,
9H).
General Procedure for the Synthesis of 1-Methylhy-
drazides 12a-g. Acylating agent (10 mmol) was added to an
efficiently stirred mixture of methylhydrazine (1.06 mL, 20
mmol) and anhydrous DCM (20 mL) at -60 °C. The cooling
bath was removed, and the suspension was stirred at room
temperature for 3 h. The resulting mixture was extracted once
with water and twice with dilute NaHCO3. The organic layer
was dried (Na2SO4), and the solvent was evaporated, producing
almost pure hydrazide.
1-Acetyl-1-methylhydrazide 12a. Hydrazide 12a was
obtained from acetic anhydride as an oil (87%), 1H NMR δ 4.73
(broad, 2H), 2.99 (s, 3H), 2.03 (s, 3H).
1-Benzoyl-1-methylhydrazine 12b. Benzhydrazide 12b
was obtained from benzoyl chloride as an oil in 90% yield, 1H
NMR δ 7.45-7.55 (m, 5H), 4.64 (broad, 2H), 3.20 (s, 3H).
1-p-Nitrobenzoyl-1-methylhydrazine 12c. Obtained from
p-nitrobenzoyl chloride as an oil in 90% yield, 1H NMR δ 7.40-
7.55 (m, 4H), 4.88 (broad, 2H), 3.34 (s, 3H).
1-Nicotinyl-1-methylhydrazine 12d. Obtained from nico-
tinoyl chloride as an oil in 40% yield after chromatographic
purification (silica, 5-10% MeOH in EtOAc),1H NMR NMR
(DMSO-d6) δ 8.75 (s, 1H), 8.56 (m, 1H), 7.94 (m, 1H), 7.41 (m,
1H), 4.91 (broad, 2H), 3.21 (s, 3H).
1-Ethylcarbamoyl-1-methylhydrazine 12e. Prepared from
ethyl chloroformate: oil, 82% yield, 1H NMR (DMSO-d6) δ 4.59
(broad, 2H), 4.05 (q, 2H, J ) 7.2 Hz), 3.35 (s, 3H), 1.99 (t, J )
7.2 Hz, 3H).
Boc-Deprotection with Piperidine. To a solution of Boc-
protected triazene (0.1 mmol) in DCM (3 mL) was added
dropwise a 0.2 M solution of piperidine in DCM (0.5 mL, 0.1
mmol). After stirring for 18 h, the DCM was evaporated and
the residue was triturated with EtOAc. The product was
obtained by filtration and dried in vacuo.
Boc-Deprotection with Acetonitrile/Water. Water (0.5
mL) was added to a solution of Boc-protected triazene (0.1
mmol) in acetonitrile (2 mL). After 30 min reflux, crystalliza-
tion was induced by the addition of 0.5 mL water and cooling
in ice. The product was obtained by filtration, washed with
acetonitrile/water 1/1, and dried in vacuo.
2-(3-Acetyl-3-methyltriazen-1-yl)-6-benzyloxypurine 20.
From 13 by deprotection with piperidine, yield 82%, mp 200-
202 °C (dec); 1H NMR (DMSO-d6) δ 13.62 (s, 1H), 8.44 (s, 1H),
7.58 (m, 2H), 7.40 (m, 3H), 5.68 (s, 2H), 3.40 (s, 3H); [found
M+ + 1, 326.1362; C15H16N7O2 requires, 326.1365]. Anal.
(C15H15N7O2) C, H, N.
1-Phenylcarbamoyl-1-methylhydrazine 12f. Prepared
from diphenyl carbonate: 92% yield, oil which solidified in the
refrigerator, 1H NMR (DMSO-d6) δ 7.10-7.40 (m, 5H), 4.89
(broad, 2H), 3.35 (s, 3H).
2-(3-Benzoyl-3-methyltriazen-1-yl)-6-benzyloxypu-
rine 21. From 14 by deprotection with piperidine, yield 83%,
mp 176-180 °C (dec); 1H NMR (DMSO-d6) δ 13.60 (broad, 1H),
8.43 (s, 1H), 7.83 (m, 2H), 7.30-7.60 (m, 8H), 5.52 (s, 2H), 3.62
(s, 3H); [found M+ + 1, 388.1520; C20H18N7O2 requires,
388.1522]. Anal. (C20H17N7O2‚2.0H2O) C, H, N.
2-(3-p-Nitrobenzoyl-3-methyltriazen-1-yl)-6-benzyloxy-
purine 22. From 15 by deprotection with piperidine, yield
68%, mp 212-213 °C; 1H NMR (DMSO-d6) δ 13.58 (broad, 1H),
8.43 (broad, 1H), 8.26 (1/2 AB, 2H, J ) 8.8 Hz), 8.04 (1/2 AB,
2H, J ) 8.8 Hz), 7.36 (s, 5H), 5.46 (s, 2H), 3.66 (s, 3H); [found
M+ + 1, 433.1375; C20H17N8O4 requires, 433.173]. Anal.
(C20H16N8O4) C, H.
1-p-Nitrophenylcarbamoyl-1-methylhydrazine 12g.34
Prepared from p-nitrophenyl chloroformate. Workup proce-
dure: After stirring at room temperature for 3 h, diethyl ether
(10 mL) was added and the precipitated salts were removed
by filtration. The solvents were evaporated, and the residue
was crystallized from EtOAc, 79% yield, 1H NMR (DMSO-d6)
δ 8.27 (1/2 AB, 2H, J ) 9.0 Hz),7.32 (1/2 AB, 2H, J ) 9.0 Hz),
4.29 (broad, 2H), 3.32 (s, 3H).
General Procedure for the Synthesis of Boc-protected
Triazenes 13-19 (Method A). To a solution of 2-nitrosopu-
rine 11 (103.5 mg, 0.30 mmol) in a mixture of DCM (1.5 mL)
and acetic acid (0.5 mL) was added hydrazide 12a-g (0.36
mmol). The reaction mixture was stirred at room temperature
for 18 h, diluted with diethyl ether (10 mL), and stirred with
aqueous NaHCO3 (5%, 20 mL) for 30 min. Extractive workup
(small amounts of solid side products were removed by
filtration, together with the drying agent Na2SO4), and after
evaporation and crystallization of the residue (ethanol, 0 °C),
triazenes 13-19 were obtained.
2-(3-Nicotinyl-3-methyltriazen-1-yl)-6-benzyloxypu-
rine 23. From 16 by deprotection with piperidine, yield 42%,
1
mp 148-150 °C; H NMR (DMSO-d6) δ 13.60 (s, 1H), 9.05 (s,
1H), 8.67 (d, 1H, J ) 3.2 Hz), 8.46 (broad, 1H), 8.23 (m, 1H),
7.35-7.51 (m, 6H), 5.53 (s, 2H), 3.63 (s, 3H); [found M+ + 1,
389.1498; C19H17N8O2 requires, 389.1474]. Anal. (C19H16N8O2)
C, H, N.
2-(3-Ethoxycarbonyl-3-methyltriazen-1-yl)-6-benzyl-
oxypurine 24. From 17 by deprotection with piperidine, yield
74%, mp 160-164 °C; 1H NMR (DMSO-d6) δ 13.58 (broad, 1H),
8.45 (s, 1H), 7.61 (m, 2H), 7.40 (m, 3H), 5.66 (s, 2H), 4.42 (q,
2H, J ) 7.1 Hz), 3.48 (s, 3H), 1.33 (t, 3H, J ) 7.1 Hz); [found
M+ + 1, 356.1476; C16H18N7O4 requires, 356.1471]. Anal.
(C16H17N7O3) C, H, N.
2-(3-Phenyloxycarbonyl-3-methyltriazen-1-yl)-6-ben-
zyloxypurine 25. From 18 by deprotection with piperidine,
yield 83%, mp 206-207 °C (dec); 1H NMR (DMSO-d6) δ 13.13
(broad, 1H), 8.45 (s, 1H), 7.30-7.70 (m, 10H), 5.67 (s, 2H), 3.58
(s, 3H); [found M+ + 1, 404.1461; C20H18N7O3 requires,
404.1471]. Anal. (C20H17N7O3) C, H, N.
2-(3-p-Nitrophenyloxycarbonyl-3-methyltriazen-1-yl)-
6-benzyloxypurine 26. From 13 by deprotection with aceto-
nitrile/water, yield 81%, mp 146-149 °C; 1H NMR (DMSO-
d6) δ 13.65 (broad, 1H), 8.45 (s, 1H), 8.39 (1/2 AB, 2H, J )
9.0), 7.70 (1/2 AB, 2H, J ) 9.0), 7.61 (m, 2H), 7.37 (m, 3H),
5.67 (s, 2H), 3.59 (s, 3H); [found M+ + 1, 449.1316; C20H17N8O5
requires, 449.1322]. Anal. (C20H16N6O5) C, H, N.
General Procedure for the Synthesis of Triazenes 28-
30 (Method B). Potassium phenolates were prepared by
addition of potassium tert-butoxide (33.6 mg, 0.30 mmol) to a
solution of a para-substituted phenol (0.30 mmol) in anhydrous
2-(3-Acetyl-3-methyltriazen-1-yl)-6-benzyloxy-9-Boc-
purine 13. Prepared from hydrazide 12a: yield 67%, mp 132-
1
146 °C (dec); H NMR δ 8.39 (s, 1H), 7.55 (m, 2H), 7.30-7.50
(m, 3H), 5.73 (s, 2H), 3.54 (s, 3H), 2.62 (s, 3H), 1.70 (s, 9H).
2-(3-Benzoyl-3-methyltriazen-1-yl)-6-benzyloxy-9-Boc-
purine 14. Prepared from hydrazide 12b: yield 63%, mp 145-
1
147 °C (dec); H NMR δ 8.35 (s, 1H), 7.92 (m, 2H), 7.30-7.50
(m, 8H), 5.55 (s, 2H), 3.76 (s, 3H), 1.67 (s, 9H).
2-(3-p-Nitrobenzoyl-3-methyltriazen-1-yl)-6-benzyloxy-
9-Boc-purine 15. Prepared from hydrazide 12c: yield 28%,
1
mp 193-196 °C (dec); H NMR δ 8.35 (s, 1H), 8.28 (1/2 AB,
2H, J ) 8.8 Hz), 8.12 (1/2 AB, 2H, J ) 8.8 Hz), 7.43 (m, 2H),
7.33 (m, 3H), 5.63 (s, 2H), 3.78 (s, 3H), 1.70 (s, 9H).
2-(3-Nicotinyl-3-methyltriazen-1-yl)-6-benzyloxy-9-Boc-
purine 16. Prepared from hydrazide 12d: yield 27%, mp 143-
145 °C;1H NMR δ 9.16 (d, 1H, J ) 1.9 Hz), 8.66 (m, 1H), 8.36
(s, 1H), 8.28 (m, 1H), 7.30-7.50 (m, 6 H), 5.61 (s, 2H), 3.75 (s,
3H), 1.69 (s, 9H).
2-(3-Ethoxycarbonyl-3-methyltriazen-1-yl)-6-benzyloxy-
9-Boc-purine 17. Prepared from hydrazide 12e: yield 77%,
1
mp130-133 °C; H NMR δ 8.36 (s, 1H), 7.61 (m, 2H), 7.30-