J. M. Dener et al. / Tetrahedron Letters 47 (2006) 4591–4595
4595
6. (a) Janc, J. W.; Clark, J. M.; Warne, R. L.; Elrod, K. C.;
Katz, B. A.; Moore, W. R. Biochemistry 2000, 39, 4792–
4800; (b) Katz, B. A.; Clark, J. M.; Finer-Moore, J. S.;
Jenkins, T. E.; Johnson, C. R.; Ross, M. J.; Luong, C.;
Moore, W. R.; Stroud, R. M. Nature 1998, 391, 608–612.
7. Mittendorf, J.; Henning, R.; Raddatz, S.; Schlemmer,
K.-H.; Hiraoka, M.; Kadono, H.; Mogi, M.; Moriwaki,
T.; Murata, T.; Sakakibara, S.; Shimada, M.; Yoshida, N.;
Yoshino. T. PCT Int. Appl. WO 0020401, 2000. CRA-
9249 was developed by Bayer as part of an agreement
between Bayer and Arris Pharmaceutical Corporation,
now part of Celera. Celera re-acquired the tryptase
program from Bayer in 2002.
8. Although bis(amide) 12 was not isolated, this intermediate
could be produced as a mixture of regioisomers. The
specific regioisomer shown here is based on the assump-
tion that acylation occurs on the more basic nitrogens
found on each 1,2-diaminobenzene derivative 9 and 11.
9. Sperandio, D.; Gangloff, A. R.; Litvak, J.; Goldsmith, R.;
Hataye, J. M.; Wang, V. R.; Shelton, E. J.; Elrod, K.;
Janc, J. W.; Clark, J. M.; Rice, K.; Weinheimer, S.;
Yeung, K.-S.; Meanwell, N. A.; Hernandez, D.; Staab, A.
J.; Venables, B. L.; Spencer, J. S. Bioorg. Med. Chem. Lett.
2002, 12, 3129–3133.
14. (a) Galat, A.; Elion, G. J. Am. Chem. Soc. 1939, 61, 3585–
3586. For a review of synthetic applications of hexameth-
´
ylenetetramine, including the Delepine reaction, please see
´
the following: (b) Blazˇevic, N.; Kolbah, D.; Belin, B.;
ˇ
´
Sunjic, V.; Kajfezˇ, F. Synthesis 1979, 161–176.
15. Other routes explored in the preparation of 29 included
reduction of nitrile 35 and reaction of bromide 30 with
ammonia. Reaction of 35 using either catalytic [e.g., H2/
PtO2; transformation (a)] or chemical reduction [e.g.,
BH3ÆTHF or LiAlH4, THF, reflux; transformation (b)]
were unsatisfactory, providing either C–O bond cleavage
as the primary reaction pathway or formation of small
amounts of N,N-bis[2-(40-fluorophenoxy)ethyl]amine (36).
The hydrogenolysis of the C–O bond of a-phenoxyaceto-
´
nitriles is a known process: Benarab, A.; Boye, S.; Savelon,
L.; Guillaumet, G. Tetrahedron Lett. 1993, 34, 7567–7568,
Displacement of the bromide in 30 with ammonia in
several solvent combinations and conditions (transforma-
tion c) was also plagued by formation of 36 and the
corresponding trialkylamine which could not be easily
separated from the desired product.
26
+
29
a
b
10. Imidate 17 was prepared in 85% yield on a 1.1 mol scale
from the reaction of ethyl cyanoacetate and HCl gas in a
mixture of toluene and ethanol (ꢁ6:1) at 0–5 °C.
F
NC
O
O
11. The conditions used to produce 19 also afforded small
amounts of the decarboxylated bis(benzimidazole)meth-
ane derivative shown below, whose identity was confirmed
by comparison to an authentic sample.
HN
29
35
30
+
F
2
36
CH3
H
F
c
H
N
N
29
+ 36
N
N
F
16. The 95-g lot of 7 also provided acceptable analysis results
including combustion (CHN), inductively coupled plasma
(ICP), residue on ignition (ROI) and moisture content
(Karl Fischer).
12. The preparation of compound 29 by alkylation of a-
chloroacetamide with 4-fluorophenol followed by LiAlH4
reduction has been described in the literature: Shtacher, G.;
Taub, W. J. Med. Chem. 1966, 9, 197–203. However, we
did not evaluate this process for the work described here.
13. Protection of commercially available 2-bromoethylamine
hydrobromide with di-tert-butyl dicarboxylate and N-
methylmorpholine (NMM), followed by bromide displace-
ment with 4-fluorophenol and cesium carbonate also
provided 27 contaminated with aziridine 28.
LC-MS: m/z 516.0 [M+1]+; 1H NMR (DMSO-d6; 400
MHz) d 8.8 (t, 1H), 8.3 (s, 1H), 7.85 (d, 1H), 7.8 (d, 1H),
7.3 (d, 1H), 7.2 (t, 1H), 7.1 (m, 2H), 7.0 (m, 2H), 4.1
(t, 2H), 4.0 (s, 3H), 3.7 (q, 2H); CHN: calcd: C, 58.26; H,
3.52; N, 13.59; F, 18.43. Found: C, 58.03; H, 3.28; N,
13.62; F, 18.55; ICP results: Zn: <1 ppm; Cu < 1 ppm.
ROI: <0.10%; % moisture (Karl Fischer): <0.10%.