was concentrated to 3 L, diluted with water (3 L), and
concentrated again to 3 L to remove acetonitrile. This solution
was diluted to 5 L with water and extracted with ethyl acetate
(7.4 L). The organic layer was separated and washed with brine
and then extracted with 2 N hydrochloric acid (5.5 L). This
acidic phase was washed with ethyl acetate and basified to pH
8 with solid sodium bicarbonate. A residue was obtained which
was redissolved in ethyl acetate (7.3 L), washed with brine,
treated with magnesium sulfate-charcoal, filtered on Celite, and
concentrated to 2.8 L. This mixture was added dropwise to
heptane (18 L) under nitrogen. A gummy, brown solid was
obtained and separated by decantation. Methylene chloride (3
L) was added, and the resulting mixture was slowly stirred
overnight at 20-25 °C. The fluffy solid was filtered off, washed
with methylene chloride (1.5 L), and dried under vacuum to
yield a beige amorphous solid (826.5 g, 83%). Mp ) 154-155
°C; 1H NMR (CD3OD, 400 MHz) δ: 7.26 (broad, 1H); 7.13 (t,
J ) 7.8 Hz, 1 H); 6.98 (d, J ) 8.2 Hz, 4H); 6.68 (d, J ) 2.5
Hz, 2H); 3.68 (broad, 2 H); 3.52 (broad, 4H); 2.72 (t, J ) 7.4
Hz, 2H); 1.49 (s, 9H); 13C NMR (CD3OD, 100 MHz) δ: 154.06;
145.36; 139.61; 129.47; 129.31 (3 carbons overlapped); 128.52;
115.85 (4 carbons overlapped); 115.21; 114.57; 112.81; 110.90;
79.54; 61.32; 42.83; 42.43; 35.11; 27.55 (3 carbons overlapped);
LRMS (ESI): m/z 481 (MH+), 503 (MNa+); HPLC: tR ) 1.8
min (purity 100% at 210 and 254 nm).
2-(4-(3-(tert-Butoxycarbonylamino)phenylamino)-6-(4-(4-
(3-(tert-butoxycarbonylamino)phenylamino)-6-chloro-1,3,5-
triazin-2-ylamino)phenethylamino)-1,3,5-triazin-2-ylamino)-
ethanol (6). The alcohol 5 (820.0 g, 1.71 mol) was dissolved in
THF (10.9 L), and a solution of triazine 3 (607.7 g, 1.71 mol) in
acetone (2.9 L) and water (2.9 L) was added over 10 min followed
by a saturated solution of sodium bicarbonate (2.9 L). The mixture
was stirred at 20-25 °C for 24 h and then concentrated to 5 L to
remove volatiles. The solution was diluted with water (2 L) and
concentrated to 4 L. The brown solution was then extracted with
ethyl acetate (9.0 L), washed with water and brine, and treated
with magnesium sulfate-charcoal. The solution was then filtered
and concentrated to 3.0 L. This mixture was added dropwise under
nitrogen to heptane (18.0 L) with stirring. The precipitated beige
solid was filtered, washed with heptane (2 × 1 L), and dried under
vacuum to yield a beige amorphous solid (1.29 kg; 94.7%). Mp
) 146-149 °C; 1H NMR (CD3OD, 400 MHz) δ: 7.75-7.72 (m,
3H); 6.88-7.32 (m, 9H); 3.68 (broad, 2H); 3.60 (broad, 2H); 3.54
(broad, 2H); 2.84 (t, J ) 7.2 Hz, 2H); 1.49 (s, 18H); 13C NMR
(CD3OD, 100 MHz) δ: 171.83; 165.94; 164.52 (2 carbons
overlapped); 154.02; 140.50; 139.55 (2 carbons overlapped);
136.57; 135.22; 128.96 (3 carbons overlapped); 128.71 (3 carbons
overlapped); 128.50; 120.94 (3 carbons overlapped); 114.54; 112.85
(2 carbons overlapped); 110.90; 79.85; 79.57; 61.35; 60.38; 42.85;
42.11; 35.35; 27.59 (3 carbons overlapped); 27.58 (3 carbons
overlapped);19.71; 13.30; LRMS (ESI): m/z 800 (MH+), 822
(MNa+); HPLC: tR ) 3.3 min (purity 100% at 210 and 254 nm).
2-(4-(4-(4-(4-Aminophenethylamino)-6-(3-(tert-butoxycar-
bonylamino)phenylamino)-1,3,5-triazin-2-ylamino)phenyl-
ethylamino)-6-(3-(tert-butoxycarbonylamino)phenylamino)-
1,3,5-triazin-2-ylamino)ethanol (7). The triazine 6 (1.1 kg, 1.39
mol) in acetonitrile (15.5 L) and water (465 mL) was treated with
4-aminophenethylamine hydrochloride (0.8 kg, 3.84 mol) portion-
wise, followed by the addition of triethylamine (0.7 kg, 6.82 mol).
The mixture was then heated at 60 °C for 24 h. The solvent was
concentrated under vacuum to 3.0 L, coevaporated with ethyl
acetate (3 × 2 L), and diluted with ethyl acetate to 8.0 L. The
solution was washed with water and brine, treated with magnesium
sulfate-charcoal, and filtered. The filtrate was acidified with 2 N
hydrochloric acid (1.5 L) to afford a brown, oily residue which
was separated with the aqueous phase from the organic layer. The
aqueous mixture was basified to pH 8 with solid sodium bicarbon-
ate. The solid was separated, dissolved in ethyl acetate (9 L), treated
with magnesium sulfate-charcoal, filtered, and concentrated to 3.5
L under vacuum. This solution was added dropwise to heptane
(18.6 L) to form a solid. The precipitate was filtered, washed with
heptane (2 × 750 mL), and dried under vacuum to yield a beige
amorphous solid (1.24 kg, 97%). Mp ) 104-107 °C; 1H NMR
(CD3OD, 400 MHz) δ: 7.48-8.14 (m, 4H); 7.06-7.34 (m, 7H);
6.90-7.06 (m, 3H); 6.66 (d, J ) 8.2 Hz, 2H); 3.68 (broad, 2H);
3.53 (broad, 6H); 2.82 (broad, 2H); 2.74 (t, J ) 7.6 Hz, 2H); 1.48
(s,18H); 13C NMR (CD3OD, 100 MHz) δ: 171.13; 166.07; 165.99;
165.63; 165.00; 164.66; 164.33; 154.08; 154.02; 145.14; 140.43;
140.19; 139.60; 139.51; 138.11; 137.73; 133.91; 133.53; 129.60;
129.47; 129.35 (2 carbons overlapped); 129.23; 128.82 (2 carbons
overlapped); 128.58; 120.89; 120.27; 115.94 (2 carbons over-
lapped); 115.05; 114.67; 112.95; 111.31; 110.93; 79.61; 61.30;
60.38; 42.91; 42.56; 42.20; 36.25; 35.15; 34.67; 34.60; 34.56;
34.51; 31.58; 27.60 (6 carbons overlapped); 27.59 (3 carbons
overlapped); 25.13; 25.03; 22.53; 21.83; 19.86; 19.76; 19.71; 17.98;
13.30; 13.29; 10.62. (mixture of rotamers); LRMS (ESI): m/z 901
(MH+) 923 (MNa+); HPLC: tR ) 2.7 min (purity 100% at 210
and 254 nm).
2-(4-(4-(4-(4-Aminophenethylamino)-6-(3-aminopheny-
lamino)-1,3,5-triazin-2-ylamino)phenylethylamino)-6-(3-ami-
nophenylamino)-1,3,5-triazin-2-ylamino)ethanol pentahy-
drochloride salt (2). The protected triazine 7 (1.24 kg, 0.7 mol)
was dissolved in a mixture of 4 N hydrochloric acid/dioxane (7.9
L) and water (0.73 L). This mixture was stirred at 20-25 °C for
60 min, diluted with acetonitrile (23 L), and stirred 15 min to afford
a beige solid. The material was filtered and washed with methanol
(12 L), tetrahydrofuran (6 L), and TBME (6 L) and then dried for
24 h. The solid was dissolved in water (58 L). The clear, pale-
yellow solution was filtered on a 0.22 µm membrane, frozen and
lyophilized. A light beige fluffy solid was obtained (1.11 kg, 90%).
1
Mp ) 220-222 °C; H NMR (D2O, 400 MHz) δ: 6.80-7.80
(m, 16H); 3.00-3.70 (m, 8H); 2.60 (broad, 4H); 13C NMR
(CD3OD, 100 MHz) δ: 161.27; 155.04; 154.22; 151.99; 139.28;
137.88; 137.48; 135.47; 134.27; 130.26 (8 carbons overlapped);
128.92 (3 carbons overlapped); 128.36; 123.14 (3 carbons over-
lapped); 120.17; 118.91; 114.64 (2 carbons overlapped); 59.53;
42.95; 42.43 (2 carbons overlapped); 34.28 (2 carbons overlapped);
LRMS (ESI): m/z 700 (MH+) 350 ((M + 2 H+)/2); HPLC: tR )
3.6 min (purity 100% at 210 and 254 nm).
Acknowledgment
We thank Shaun D. Abbott for reading the manuscript and
Joe¨l Lechasseur for technical assistance.
Received for review August 3, 2009.
OP900202B
1160
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Vol. 13, No. 6, 2009 / Organic Process Research & Development