C. Mamat, B. Mosch, et al.
MED
3
Hdioxole), 6.75 (d, J=8.3 Hz, 1H; Hpyr), 6.80 (br. s, 1H; NH), 6.98 (d,
3J=8.3 Hz, 1H; HPyr), 8.19 ppm (d, 3J=5.8 Hz; Hdioxole); 13C NMR
(101 MHz, CDCl3): d=102.6, 103.3 (Ar-H), 117.3 (quart. C), 122.7 (Ar-
H), 123.0, 143.1, 147.8 (quart. C), 158.4 (Ar-H), 160.7, 161.9
194.3 ppm (quart. C); MS (ESI+): m/z (%): 288 (12) [M+ +H, 37Cl],
286 (66) [M+ +H, 35/37Cl], 284 (100) [M+ +H, 35Cl]; elemental analy-
sis calcd (%) for C11H7Cl2N3O2 (284.10): C 46.50, H 2.48, N 14.79;
found: C 46.51, H 2.52, N 14.91.
trate was removed, and the crude product was purified by column
chromatography (PE/EtOAc, 1:1) to yield 17 as a pale-yellow solid
1
(210 mg, 77%): Rf =0.48 (PE/EtOAc, 1:2); H NMR (400 MHz, CDCl3):
3
d=2.23–2.31 (m, 2H; CH2CH2I), 3.22 (t, J=7.4 Hz, 2H; CH2S), 3.24
3
3
(dt, J=6.6 Hz, 2H; CH2CH2I), 6.02 (d, J=5.7 Hz, 1H; Hdioxole), 6.02
3
(s, 2H; OCH2O), 6.39 (s, 1H; NH), 6.74 (d, J=8.4 Hz, 1H; HPyr), 6.98
(d, 3J=8.4 Hz, 1H; Hpyr), 7.17 (s, 1H; NH), 7.46 (t, 3J=7.8 Hz, 1H;
HAr), 7.51 (dt, 3J=7.8 Hz, J=1.6 Hz, 1H; HAr), 7.89 (dt, 3J=7.8 Hz,
4
4J=1.6 Hz, 1H; HAr), 8.13 (d, 3J=5.7 Hz, 1H; Hdioxole), 8.21 ppm (t,
4J=1.8 Hz, 1H; HAr); 13C NMR (101 MHz, CDCl3): d=26.7 (CH2CH2I),
31.1 (CH2CH2I), 56.9 (CH2S), 98.1, 102.5 (CH2), 107.1, 117.8, 118.5,
120.9, 122.4, 123.3, 123.9, 130.0, 139.5, 141.2, 143.5, 147.8, 157.4,
159.2, 161.1 ppm; MS (ESI+): m/z (%): 573 (23) [M+ +H, 35Cl], 575
(10) [M+ +H, 37Cl]. An incomplete conversion from starting materi-
N-4-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-2-(3-(3-fluoropropylsul-
fonyl)-phenyl)pyrimidine-2,4-diamine (15): Compound 14
(110 mg, 0.39) and freshly prepared amine 13 (92 mg, 0.42 mmol)
were dissolved in anhydrous dioxane (3 mL), p-TsOH (2 mg) was
added, and the mixture was heated for two days at 1008C. After-
ward, the mixture was cooled to room temperature, half-saturated
bicarbonate solution (10 mL) was added, the mixture was extracted
with EtOAc (3ꢁ10 mL), the combined organic layers were dried
over Na2SO4, and the solvent was removed in vacuo. Purification
was carried out by column chromatography (PE/EtOAc, 1:1) to
yield compound 12 as a colorless oil (138 mg, 76%): Rf =0.29 (PE/
EtOAc, 1:2); 1H NMR (400 MHz, CDCl3): d=2.06–2.21 (m, 2H;
1
al 16 to iodo compound 17 was observed via H NMR. Due to the
identical Rf values, the separation of product from starting material
was impossible using column chromatography, and the mixture of
16 and 17 was used instead for the following reaction.
3-(3-(4-(5-Chlorobenzo-[d][1,3]dioxol-4-ylamino]pyrimidin-2-yla-
mino)-phenylsulfonyl)propyl-4-methylbenzenesulfonate
(18):
3
2
3
CH2CH2F), 3.22 (t, J=7.8 Hz, 2H; CH2S), 4.50 (dt, JH,F =46.9 Hz, J=
5.9 Hz, 2H; CH2CH2F), 5.99 (s, 2H; OCH2O), 6.01 (d, 3J=5.9 Hz;
Compound 17 (300 mg, 0.52 mmol) was dissolved in CH3CN (7 mL),
silver p-toluenesulfonate (454 mg, 1.63 mmol) was added, and the
mixture was allowed to stir at room temperature in the dark for
two days. Afterward, the precipitate was filtered, the solvent from
the filtrate was removed, and the crude product was purified by
column chromatography (PE/EtOAc, 1:1!:2) to yield 18 as a pale-
yellow viscous liquid (198 mg, 61%): Rf =0.42 (PE/EtOAc, 1:3);
1H NMR (400 MHz, CDCl3): d=2.04–2.12 (m, 2H; CH2CH2O), 2.41 (s,
3H; CH3), 3.11 (t, 3J=7.7 Hz, 2H; CH2S), 4.09 (dt, 3J=6.6 Hz, 2H;
3
3
Hdioxole), 6.60 (s, 1H; NH), 6.73 (d, J=8.4 Hz, 1H; Hpyr), 6.97 (d, J=
8.4 Hz, 1H; HPyr), 7.44 (t, 3J=7.8 Hz, 1H; HAr), 7.49 (d, 3J=7.8 Hz,
3
3
1H; HAr), 7.72 (s, 1H; NH), 7.90 (d, J=7.8 Hz, 1H; HAr), 8.13 (d, J=
5.6 Hz, 1H; Hdioxole), 8.18 ppm (t, 4J=1.8 Hz, 1H; HAr); 13C NMR
(101 MHz, CDCl3): d=24.3 (d, 2JC,F =20.6 Hz, CH2CH2F), 52.5 (d,
3JC,F =4.4 Hz; CH2S), 81.8 (d, 1JC,F =167.5 Hz, CH2CH2F), 97.9, 102.5
(CH2), 107.1, 118.0, 118.5, 120.8, 122.3, 123.4, 124.0, 129.8, 139.3,
141.3, 143.6, 147.7, 157.5, 159.4, 161.2 ppm; 19F NMR (376 MHz,
CDCl3): d=ꢀ221.0 ppm; MS (ESI+): m/z (%): 487 (47) [M+ +Na,
35Cl], 465 (31) [M+ +H, 35Cl]; Anal. calcd for C20H18ClFN4O4S
(464.90): C 51.67, H 3.90, S 6.09, found: C 51.69, H 4.36, S 6.25.
3
CH2CH2O), 5.96 (s, 2H; OCH2O), 6.02 (d, J=5.9 Hz, 1H; Hdioxole), 6.59
3
3
(s, 1H; NH), 6.71 (d, J=8.4 Hz, 1H; Hpyr), 6.93 (d, J=8.4 Hz, 1H;
3
Hpyr), 7.24 (d, J=8.2 Hz, 2H; HOTs), 7.35–7.40 (m, 3H; HAr), 7.64 (s,
1H; NH), 7.72 (d, 3J=8.2 Hz, 2H; HOTs), 7.88 (dt, 3J=7.2 Hz, 4J=
2.1 Hz, 1H; HAr), 8.07 (d, J=5.9 Hz, 1H; Hdioxole), 8.12 ppm (s, 1H;
3
N-4-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-2-(3-(3-chloropropylsul-
fonyl)-phenyl)pyrimidine-2,4-diamine (16): Compound 14
(136 mg, 0.48 mmol) and freshly prepared amine 12 (143 mg,
0.61 mmol) were dissolved in anhydrous dioxane (3 mL), p-TsOH
(2 mg) was added, and the mixture was heated for two days at
1008C. The mixture was then cooled to room temperature, half-sa-
turated bicarbonate solution (10 mL) was added, the mixture was
extracted with EtOAc (3ꢁ10 mL), the combined organic layers
were dried over Na2SO4, and the solvent was removed in vacuo.
Purification was carried out by column chromatography (PE/EtOAc,
1:1) to yield compound 13 as a colorless oil (190 mg, 82%); Rf =
0.48 (PE/EtOAc, 1:2); 1H NMR (400 MHz, CDCl3): d=2.20–2.28 (m,
2H; CH2CH2Cl), 3.27 (t, 3J=7.6 Hz, 2H; CH2S), 3.63 (dt, 3J=6.2 Hz,
2H; CH2CH2Cl), 6.01 (d, 3J=5.8 Hz; Hdioxole), 6.02 (s, 2H; OCH2O),
HAr); 13C NMR (101 MHz, CDCl3): d=21.8 (CH3), 22.9 (CH2CH2O), 52.2
(CH2S), 68.1 (CH2CH2O), 97.9, 102.5 (CH2), 107.2, 117.9, 118.4, 120.8,
122.3, 123.5, 124.2, 128.0 (OTs), 129.8, 130.1 (OTs), 132.6 (OTs),
139.0, 141.2, 143.7, 145.3 (OTs), 147.7, 156.6, 159.0, 161.4 ppm; MS
(ESI+): m/z (%): 641 (12) [M+ +Na, 37Cl], 639 (19) [M+ +Na, 35Cl],
619 (25) [M+ +Na, 37Cl], 617 (46) [M+ +H, 35Cl]; Anal. calcd for
C27H25ClN4O7S2 (617.09): C 52.55, H 4.08, N 9.08, S 10.39, found: C
52.79, H 3.97, N 9.06, S 10.58.
N-4-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-2-(3-(3-
[18F]fluoropropyl-sulfonyl)phenyl)pyrimidine-2,4-diamine
([18F]15): An anion-exchange cartridge (Waters, Sep-Pak Light
Accell Plus QMA) was activated by rinsing with 5 mL of a 1m
NaHCO3 solution and 10 mL of deionized H2O. It was charged with
[18F]fluoride (~2 GBq) and eluted with 1.5 mL of a solution of Kryp-
tofix 2.2.2 (10 mgmLꢀ1) and K2CO3 (13 mm) in 7 mL CH3CN and
43 mL H2O. The solvents were evaporated azeotropically by subse-
quent addition of three portions of 1 mL each of anhydrous CH3CN
under a stream of nitrogen at 1108C. Precursor 18 (~6–7 mg) was
dissolved in 300 mL of anhydrous CH3CN, and the mixture was
added to the [18F]fluoride-containing sealed vial. The resulting solu-
tion was heated at 908C for 15 min. Afterward, the mixture was
treated with 15 mL deionized H2O and then passed through a C18
cartridge (LiChrolut RP-18E/Merck). Samples for analytical radio-TLC
and radio-HPLC were taken. Analytical radio-TLC: Rf =0.33 (PE/
EtOAc, 1:2). Analytical radio-HPLC: tR =4.11 min (eluent: CH3CN/
H2O, 50:50 + 0.1% TFA).[31] The mixture was treated with H2O
(1 mL), and the precipitate was filtered using a 5 mL PP-reactor
with a PE frit and washed twice with H2O (300 mL). Purification was
3
3
6.40 (s, 1H; NH), 6.74 (d, J=8.4 Hz, 1H; Hpyr); 6.98 (d, J=8.4 Hz,
3
3
1H; Hpyr), 7.22 (s, 1H; NH), 7.46 (t, J=7.8 Hz, 1H; HAr), 7.50 (dt, J=
7.8 Hz, 4J=1.4 Hz, 1H; HAr), 7.88 (dt, 3J=7.8 Hz, 4J=1.4 Hz, 1H;
HAr), 8.12 (d, 3J=5.8 Hz, 1H; Hdioxole), 8.21 ppm (t, 4J=1.8 Hz, 1H;
HAr); 13C NMR (101 MHz, CDCl3): d=26.1 (CH2CH2Cl), 42.9 (CH2S),
53.7 (CH2CH2Cl), 98.1, 102.5 (CH2), 107.1, 117.9, 118.4, 121.0, 122.4,
123.3, 124.0, 130.0, 139.5, 141.2, 143.5, 147.8, 157.4, 159.3,
161.1 ppm; MS (ESI+): m/z (%): 483 (76) [M+ +H, 37Cl], 481 (100)
[M+ +H, 35Cl]; Anal. calcd for C20H18Cl2N4O4S (481.35): C 49.90, H
3.77, S 6.66, found: C 49.76, H 3.79, S 6.56.
N-4-(5-Chlorobenzo[d][1,3]dioxol-4-yl)-N-2-(3-(3-iodopropylsul-
fonyl)-phenyl)pyrimidine-2,4-diamine (17): Compound 16
(190 mg, 0.48 mmol) was dissolved in acetone (5 mL), NaI (234 mg,
1.56 mmol) was added, and the mixture was heated at 608C for
three days. The precipitate was filtered, the solvent from the fil-
2000
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2012, 7, 1991 – 2003