L. Lang et al.
N 15.97; MS (M11)1 432.2; HRMS calcd. for C21H30O5N5 432.2247, hexane, v/v), which provided 284 mg (0.335 mmol, 52% yield) of
1
obsd. 432.2232.
a white solid. H NMR (CDCl3) d6.70 s), 4.27 (4H, m), 3.75 (4H, t,
J = 6.0 Hz), 3.75 (6H, s), 3.37 (6H, s), 2.35 (3H, s), 2.19 (3H, s), 1.58
Trifluoromethanesulfonic acid 4-f4-[bis(2-methoxyethyl)amino]-2,7- di- (6H, m), 1.35 (6H, m), 1.06 (6H, m), 0.90 (9H, t, J = 7.3 Hz);
methylpyrazolo[1,5-a][1,3,5]triazin-8-ylg -3,5-dimethoxyphenyl ester (11)
elemental analysis calcd. for C33H55N5O4Sn C 56.26, H 7.87, N
9.94, found C 56.44, H 7.89, N 9.69.
To a solution of 4- f4-[bis(2-methoxyethyl)amino]-2,7-dimethyl-
pyrazolo[1,5-a][1,3,5]triazin-8-ylg -3,5-dimethoxyphenol (10) (300 mg,
0.695 mmol) in dry pyridine (1.0mL) was added trifluorometha-
nesulfonic anhydride (129mL, 0.765 mmol) at 01C. The mixture
[8-(4-Bromo-2,6-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[1,5-
a][1,3,5]triazin-4-yl]bis(2-methoxyethyl)amine (13)
was stirred at 01C for 30min and then at rt overnight. The mixture To a solution of f8-[2,6-dimethoxy-4-(trimethylstannyl)-phenyl]-
was partitioned between water (3mL) and ethyl acetate (3mL). 2,7 - dimethylpyrazolo[1,5 - a][1,3,5]triazin - 4 -ylg - bis(2 - methox-
The aqueous layer was extracted with ethyl acetate (3 mLꢁ 2). yethyl)amine (12a) (27.7 mg, 0.0467 mmol) in dry THF (0.3 mL)
Combined ethyl acetate layers were washed with water (5mL), was added NBS (9.1 mg, 0.0514 mmol) and the mixture was
1 N aqueous HCl solution (3mL), water, and brine, dried (over stirred for 1 h at rt. The solvent was removed in vacuo and the
anhydrous MgSO4), and the concentrated crude product was residue was purified on a silica gel chromatographic column
purified on a silica gel chromatographic column (elution with (eluted with hexane–EtOAc 5:1, v/v) to provide 21.0 mg
1
hexane–EtOAc 4:1, v/v) to provide 224 mg (0.397mmol, 57% (0.0425 mmol, 91% yield) of a pale yellow solid. H NMR (CDCl3)
yield) of a white foam. 1H NMR (CDCl3) d 6.54 (2H, s), 4.31 (4H, m), d 6.79 (2H, s), 4.30 (4H, m), 3.76 (4H, t, J = 5.7 Hz), 3.74 (6H, s), 3.38
3.76 (4H, t, J = 5.6 Hz), 3.76 (6H, s), 3.39 (6H, s), 2.38 (3H, s), 2.17 (3H, s), 2.37 (3H, s), 2.17 (3H, s); m.p. 112–1131C; elemental
(3H, s); MS (M11)1 564.2; HRMS (M1) calcd. for C22H28F3N5O7S analysis calcd. for C21H28BrNO4 ꢃ 0.5 acetone C 51.63, H 5.97, N
564.1740, obsd. 564.1730.
13.37, obsd. C 51.95, H 6.01, N 13.52; MS (M11)1 494; HRMS
calcd. for C21H30BrN5O4 494.1403, obsd. 494.1403.
f8 - [2,6 -Dimethoxy-4-(trimethylstannyl)-phenyl]-2,7-dimethylpyra-
zolo[1,5-a][1,3,5]triazin-4-ylg -bis(2-methoxyethyl)amine (12a)
[8-(2,6-Dimethoxyphenyl)-2,7-dimethyl-pyrazolo[1,5-a][1,3,5]tria-
zin-4-yl]bis(2-methoxyethyl)amine (14)
To a solution of trifluoromethanesulfonic acid 4- f4-[bis(2-
methoxyethyl)amino]-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin- To compound 13 (107 mg, 0.216 mmol) in methanol (5.0 mL)
8-ylg-3,5-dimethoxyphenyl ester (11) (216mg, 0.383 mmol) in was added 10 wt% Pd/C (40 mg, Aldrich) and the flask was filled
dioxane (2.5 mL) were added lithium chloride (48 mg, 1.13 mmol), with hydrogen gas. The mixture was stirred under atmospheric
tetrakis(triphenylphosphine)palladium (12 mg, 0.0104 mmol), hydrogen (balloon) for 30 min. The mixture was filtered through
one crystal of 2,6-di-tert-butyl-4-methylphenol, and hexamethyl- a Celite pad (ꢀ2 cm) and the filtrate concentrated under
ditin (180 mg, 0.549 mmol) under argon. The mixture was reduced pressure. The residue was purified on a silica gel
heated to 1101C for 3 h and cooled to rt. It was diluted with column (eluted with hexane–EtOAc 5:1–2:1 and 10% methanol/
ethyl acetate (3 mL) and washed with 10% aqueous ammonium CH2Cl2) to give 83.1 mg (0.200 mmol, 92.6% yield) of compound
hydroxide solution (5 mL) and the organic layer was filtered 14 as a white solid. 1H NMR (CDCl3) d 7.28 (1H, t, J = 8.7 Hz), 6.65
through a bed (1 cm) of Celite. The filtrate was washed with (2H, d, J = 8.7 Hz), 4.30 (4H, br), 3.76 (4H, t, J = 5. Hz), 3.76 (6H, s),
water (5 mL) and brine (5 mL), dried (anhydrous MgSO4), and the 3.39 (6H. s), 2.37 (3H, s), 2.20 (3H, s); HRMS (TOF MS ES1) calcd.
concentrated crude product was purified on silica gel column for C21H30N5O4 416.2298, obsd. 416.2280.
chromatography (elution with 4:1 hexane–EtOAc, v/v) to provide
194 mg (0.335 mmol, 88% yield) of a white solid. 1H NMR (CDCl3) [8-(3-Bromo-2,6-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[1,5-
a][1,3,5]triazin-4-yl]bis(2-methoxyethyl)amine (15)
d 6.75 (2H, s), 4.32 (4H, m), 3.76 (4H, t, J = 6.0Hz), 3.76 (6H, s), 3.39
(6H, s), 2.36 (3H, s), 2.21 (3H, s), 0.32 (9H, s); m.p. 153–1551C; MS
(M11)1 578, 580; elemental analysis calcd. for C24H37N5O4Sn C
49.85, H 6.45, N 12.11, obsd. C 50.06, H 6.53, N 11.70.
To a magnetically stirred solution of [8-(2,6-dimethoxyphenyl)-2,7-
dimethyl-pyrazolo[1,5 - a][1,3,5]triazin - 4 -yl]bis(2-methoxyethyl)amine
(14) (50.0 mg, 0.120 mmol) in THF (2.0 mL) was added NBS
(29 mg, 0.163 mmol) and the mixture was stirred for 15 min at rt.
The solvent was evaporated under reduced pressure and the
mixture was purified on a silica gel chromatographic column
(eluted with hexane–EtOAc 7:1–4:1) to provide compound 15
(56.0 mg, 95% yield) as a white solid. 1H NMR (CDCl3, 300MHz) d 7.49
(1H, d, J= 8.7 Hz), 6.66 (1H, d, J= 8.7 Hz), 4.32 (4H, br s), 3.77
(4H, t, J= 5.7 Hz), 3.73 (3H, s), 3.54 (3H, s), 3.39 (6H, s), 2.38 (3H, s), 2.19
(3H, s); HRMS (TOF MS ES1) calcd. for C21H29N5O4Br 494.1403, obsd.
494.1405.
f8 - [2,6-Dimethoxy-4-(tributylstannyl)-phenyl]-2,7-dimethylpyrazo-
lo[1,5-a][1,3,5]triazin-4-ylg -bis(2-methoxyethyl)amine (12b)
To a solution of trifluoromethanesulfonic acid 4-f4-[bis(2-
methoxyethyl)amino]-2,7-dimethylpyrazolo[1,5-a][1,3,5]triazin-8-
ylg-3,5-dimethoxyphenyl ester (438 mg, 0.777 mmol) in dioxane
(4.5 mL) were added lithium chloride (99 mg, 2.33 mmol),
tetrakis(triphenylphosphine)palladium (27 mg, 0.0233 mmol),
one crystal of 2,6-di-tert-butyl-4-methylphenol, and hexabutyl-
ditin (506 mL, 1.01 mmol) under argon. The mixture was heated
to 1101C for 22 h and then cooled to rt. It was diluted with ethyl
acetate (20 mL) and washed with 10% aqueous ammonium
hydroxide solution (10 mL) and the organic layer was filtered
through a bed (2 cm) of Celite. The filtrate was washed with
water (20 mL) and brine (20 mL), dried (over anhydrous MgSO4),
Radiolabeling
[8-(4-[76Br]bromo-2,6-dimethoxyphenyl)-2,7-dimethyl-pyrazolo[1,5-
a][1,3,5]triazin-4-yl]bis(2-methoxyethyl)amine
and the concentrated crude product was purified on silica gel An aliquot of the aqueous solution of [76Br] ammonium
Chromatotrons (4 mm plate, elution with 5, 7, and 10% EtOAc in bromide (10–20 mL, 20.0–40.0 MBq) was added to a 1 mL
J. Label Compd. Radiopharm 2009, 52 394–400
Copyright r 2009 John Wiley & Sons, Ltd.