Synthesis of a Vanilloid Receptor-1 Antagonist
charged to a glass-lined reactor and the reaction mixture was heated
to 55 °C; the reaction progress was monitored by HPLC. Complete
consumption of 2 (<0.5%) was observed after 2 h. The reaction
mixture was cooled to 10 °C. Deionized water (8.8 L) was charged
while maintaining a temperature of <20 °C. The product appeared
as crystalline material during this addition. The contents of the
reactor were cooled to 10 °C and aged at this temperature for 2 h.
The solids were isolated by vacuum filtration. The reactor as rinsed
with deionized water (1 × 4.4 L and 4 × 2.2 L) and the rinse was
transferred to the filter as a cake wash. The material was dried on
the filter under a stream of nitrogen for 1 h and then transferred to
a vacuum oven. The material was dried at 60 °C for 36 h. The
product is obtained as an off-white crystalline solid (2.54 kg, 90%
yield, 98.47% purity by HPLC). The isolated solids contained
<0.5% of N-{4-[6-(2-acetylaminobenzothiazol-4-yloxy)pyrimidin-
4-yloxy]benzothiazol-2-yl}acetamide (26) and 4-(6-chloropyrimi-
din-4-yloxy)benzothiazol-2-ylamine (27). Mp 260 °C. IR 1541,
1446, 1419, 1339, 1294, 1268, 1251, 1227, 1177, 1096, 984, 957,
N-[4-(6-{4-[(R)-1-(4-Fluorophenyl)ethyl]piperazin-1-yl}pyrimidin-
4-yloxy)benzothiazol-2-yl]acetamide Phosphate (1 ·H3PO4). N-[4-
(6-{4-[(R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl}pyrimidin-4-yloxy)-
benzothiazol-2-yl]acetamide (1, 2900 g, 5.88 mol), isopropyl alcohol
(25.6 L), and deionized water (4.4 L) were charged to a glass-
lined reactor. Efficient stirring was established. The reaction mixture
was heated to 65 °C and a solution of phosphoric acid (410.3 mL,
7.05 mol) in isopropyl alcohol (1.5 L) was charged at this
temperature. The solids dissolved completely and after approxi-
mately 30 min the salt precipitated as a crystalline solid. The mixture
was held at 65 °C for 2 h and then cooled to 20 °C.
The solids were isolated by vacuum filtration after aging for 2 h.
The reactor was rinsed with isopropyl alcohol (2 × 5.8 L) and the
rinse was transferred to the filter as a cake wash. The material was
dried on the filter for 1 h and transferred to a vacuum oven. The
material was dried at 60 °C for 19 h. The product is obtained as a
white crystalline solid (3.28 kg, 94% yield, 99.56% pruity by HPLC,
ee 99.5%, 3800 ppm isopropyl alcohol). Mp 243 °C. IR 1596, 1566,
1548, 1292, 1227, 1197, 1180, 1110, 1095, 1069, 1014, 994, 976,
1
894, 865, 845, 792, 754, 745, 721 cm-1. H NMR (400 MHz,
DMSO-d6) δ ppm 12.43 (s, 1H), 8.59 (s, 1H), 7.93 (dd, J ) 7.4,
1.4 Hz, 1H), 7.49 (s, 1H), 7.37 (dd, J ) 8.0, 7.6 Hz, 1H), 7.32 (dd,
J ) 8.0, 1.4 Hz, 1H), 2.14 (s, 3H). 13C NMR (100 MHz, DMSO-
d6) δ ppm 169.9, 169.7, 160.9, 158.9, 158.6, 143.0, 141.1, 133.7,
124.0, 119.9, 118.8, 107.7, 22.7. Anal. Calcd for C13H9ClN4O2S:
C, 48.68; H, 2.83; N, 17.47. Found: C, 48.39; H, 2.91; N, 17.24.
N -[4-(6-{4-[(R)-1-(4-Fluorophenyl)ethyl]piperazin-1-yl}pyrimidin-
4-yloxy)benzothiazol-2-yl]acetamide (1). Dimethylformamide (9.47
L), N-[4-(6-chloro-pyrimidin-4-yloxy)benzothiazol-2-yl]acetamide
(4, 2.374 kg, 7.40 mol), and 1-[(R)-1-(4-fluorophenyl)ethyl]pip-
erazine (6, 1.695 kg, 8.14 mol) were charged to a glass-lined reactor.
Efficient stirring was established and triethylamine (1.240 L, 8.89
mol) was added at room temperature. The reaction mixture was
heated to 75 °C, and the reaction progress was monitored by HPLC.
Complete consumption of 4 (<0.5%) was observed after 3 h. The
reaction mixture was cooled to rt and a polish filtration through a
glass frit (porosity M) was performed, then the reactor and the filter
were rinsed with dimethylformamide (1.2 L). The crude reaction
mixture was transferred back into the reactor and 3.6 L of solvent
was removed by vacuum distillation. Isopropyl alcohol (19.0 L)
was charged to the reactor while maintaining a temperature of >60
°C. The product appeared as crystalline material during this addition.
Subsequently, deionized water (13.1 L) was charged while main-
taining the temperature at >60 °C. The contents of the reactor were
cooled to 10 °C and aged at this temperature for 30 min. The solids
were isolated by vacuum filtration. The reactor was rinsed with
isopropyl alcohol (2 × 4.8 L) and the rinse was transferred to the
filter as a cake wash. The material was dried on the filter under a
stream of nitrogen for 14 h and then transferred to a vacuum oven.
The material was dried at 60 °C for 48 h. The product is obtained
as an off-white crystalline solid (3.15 kg, 86% yield, 98.98% purity
by HPLC). Mp 249 °C. IR 1695, 1600, 1566, 1540, 1506, 1452,
1287, 1274, 1264, 1219, 1201, 1185, 1154, 1014, 1002, 836, 820,
1
952, 845, 808, 741, 523, 515, 487, 447, 416 cm-1. H NMR (400
MHz, DMSO-d6) δ ppm 12.44 (s, 1H), 8.08 (s, 1H), 7.85 (d, J )
7.8 Hz, 1H), 7.35–7.42 (m, 2H), 7.29–7.33 (m, 1H), 7.13–7.20 (m,
3H), 6.34 (s, 1H), 3.61 (m, 5H), 2.49–2.58 (m, 2H), 2.34–2.47 (m,
2H), 2.16 (s, 3H), 1.36 (d, J ) 6.6 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6) δ ppm 169.9, 169.5, 163.6, 161.3 (1JCF ) 244 Hz),
158.0, 157.3, 144.1, 141.7, 138.3, 133.4,129.5 (3JCF ) 8 Hz), 124.0,
119.2, 118.9, 115.0 (2JCF ) 20 Hz), 85.8, 62.9, 49.3, 43.5, 22.6,
18.8. Anal. Calcd for C25H28FN6O6PS: C, 50.84; H, 4.78; N, 14.23.
Found: C, 50.55; H, 4.81; N, 13.98. HRMS m/e calcd for
C25H26FN6O2S (M + H) 493.1817, found 493.1807.
Acknowledgment. The authors would like to thank Dr. P. J.
Reider and Dr. M. J. Martinelli for continuous support of this
project. J. Katon, Dr. H.-L. Wang, and Dr. M. Norman are
thanked for the discovery of 1 and valuable discussions
regarding this synthesis. Dr. J. Preston, Dr. J. Brice, Dr. T.
Correll, Dr. K. Turney, T. Soukup, C. Bolcato, D. Manley, Dr.
D. Smith, Dr. R. Jensen, R. DeBlanc, Dr. J. Cheetham, H. Tan,
M. Wacker, Dr. P. Schnier, Dr. J. Tan, B. Lee, N. Holcomb,
and L. Blue are thanked for analytical support. Dr. A. Bak, D.
Hoffmann, S. Krueger, and D. Daurio are thanked for participa-
tion in salt selection and solid state characterization. Dr. J.
Tedrow is thanked for participating in the catalyst screen for
the metal-catalyzed piperazine formation. R. Price, M. Diaz-
Vasquez, and Dr. M. Bhupathy are thanked for organization of
outsourced campaigns. J. Manley, A. Maheshwari, T. Benkovics,
T. Rippley, and G. Sukay are thanked for support and valuable
input during scale up.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for compounds 1, 1·H3PO4, 2, 4, 6, 10, 14,
16, 23–29, and 31, copies of 1H NMR for compounds 8, 9 and
17, experimental procedures and characterization data for
compounds 2, 8–10, 14, and 16, and characterization data for
compounds 24–31. This material is available free of charge via
1
746, 552 cm-1. H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (s,
1H), 8.06 (s, 1H), 7.85 (d, J ) 7.8 Hz, 1H), 7.30–7.40 (m, 3H),
7.12–7.22 (m, 3H), 6.32 (s, 1H), 3.57 (m, 4H), 3.50 (q, J ) 6.8
Hz, 1H), 2.41–2.49 (m, 2H), 2.32–2.39 (m, 2H), 2.15 (s, 3H), 1.31
(d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz, DMSO-d6) δ ppm 169.8,
169.4, 163.6, 161.0 (1JCF ) 242 Hz), 157.9, 157.3, 144.1, 141.7,
139.1 (4JCF ) 3 Hz), 133.3,129.2 (3JCF ) 8 Hz), 124.0, 119.2, 118.9,
114.8 (2JCF ) 20 Hz), 85.7, 62.7, 49.4, 43.9, 22.6, 19.1. HRMS
m/e calcd for C25H26FN6O2S (M + H) 493.1817, found 493.1803.
JO8002216
J. Org. Chem. Vol. 73, No. 9, 2008 3515