4878
J. Xie et al. / Tetrahedron 60 (2004) 4875–4878
Harrell, C. M.; Vyas, K. P.; Zhang, K.; Gilbert, J.; Pettibone,
D. J.; Patane, M. A.; Bock, M. G.; Freidinger, R. M.;
Gluchowski, C. J. Med. Chem. 1999, 42, 4778–4793.
3. Efange, S. M.; Kamath, A. P.; Khare, A. B.; Kung, M.-P.;
Mach, R. H.; Parsons, S. M. J. Med. Chem. 1997, 40,
3905–3914.
concentrated to yield a crude solid. The solid was triturated
with 50% ethyl acetate–hexane to give 1a as a white solid
(26 g, 90 mmol, 90%): mp 173–174 8C; H NMR (CDCl3,
1
500 MHz): d 1.49 (s, 9H), 1.71 (d, J¼13.1 Hz, 2H), 1.81 (m,
2H), 2.92 (m, 2H), 3.48 (s, 2H), 4.06 (m, 2H), 6.65 (d,
J¼7.5 Hz, 1H), 6.75 (dd, 1H), 7.03–7.07 (m, 2H); 13C
NMR (CDCl3, 125 MHz): d 28.65, 35.71, 41.20, 44.60,
56.10. 79.69, 109.9, 118.9, 122.8, 128.1, 136.5, 150.7,
155.1; CI-MS m/e 289 (MþH). Anal. Calcd for
C17H24N2O2: C, 70.80; H, 8.39; N, 9.71. Found C, 70.49;
H, 8.11; N, 9.55.
4. Charmbers, M. S.; Baker, R.; Billington, D. C.; Knight, A. K.;
Middlemiss, D. N.; Wong, E. H. J. Med. Chem. 1992, 35,
2033–2039.
5. Bednarek, M. A.; Feighner, S. D.; Pong, S.-S.; McKee, K. K.;
Hreniuk, D. L.; Silva, M. V.; Warren, V. A.; Howard, A. D.;
Van der Ploeg, L. H.; Heck, J. V. J. Med. Chem. 2000, 43,
4370–4376.
2.2.6. 10-Cbz-spiro-[indoline-3,40-piperidine] (1b). To a
solution of 1d (3.0 g, 16 mmol) in anhydrous THF (16 mL)
was slowly added Z–OSu (4.0 g, 16 mmol). The reaction
mixture was stirred at room temperature for 2 h, then
concentrated to dryness. The crude product was partitioned
between ethyl acetate and 1 N NaOH aqueous solution. The
organic layer was then washed with saturated sodium
bicarbonate solution and brine, dried with sodium sulfate,
filtered and concentrated to yield a crude solid. The solid
was triturated with MeOH to give 1b as a white solid. (4.5 g,
14 mmol, 85%): mp 115–117 8C (lit.10 mp 118–120 8C);
1H NMR (CDCl3, 500 MHz): d 1.73–1.82 (m, 4H), 3.01 (m,
2H), 3.50 (s, 2H), 4.13 (m, 2H), 5.16 (s, 2H), 6.71 (d,
J¼7.8 Hz, 1H), 6.80 (dd, 1H), 7.32–7.38 (m, 6H); 13C
NMR (CDCl3, 125 MHz): d 35.56, 41.41, 44.51, 56.06,
67.24, 109.9, 118.9, 122.7, 128.0, 128.1, 128.6, 136.2,
137.0, 150.6, 155.5; CI-MS m/e 323.0 (MþH). Anal. Calcd
for C20H22N2O2: C, 74.51; H, 6.88; N, 8.69. Found C, 74.38;
H, 7.07; N, 8.59.
6. Elliott, J. M.; Broughton, H.; Cascieri, M. A.; Chicchi, G.;
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Stevenson, G. I. Bioorg. Med. Chem. Lett. 1998, 8,
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7. Nargund, R. P.; Sebhat, I.; Ye, Z.; Barakat, K.; Weinberg, D.;
MacNeil, T.; Kalyani, R.; Martin, W.; Cashen, D.; Chen, H.;
Drisko, J.; Mosley, R.; Fong, T.; Stearns, R.; Miller, R.;
Tamvakopoulos, R.; Colwell, L.; Strack, A.; Shen, X.; Tan, C.;
Pong, S. -S.; Howard, A.; Sailer, A.; Hickey, G.; MacIntyre,
E.; Van der Ploeg, L.; Patchett, A. Abstracts of Papers, 222nd
ACS National Meeting, Chicago, IL, US, August 26–30,
2001, MEDI-151.
8. (a) Bondensgaard, K.; Ankersen, M.; Thogersen, H.; Hansen,
B. S.; Wulff, B. S.; Bywater, R. P. J. Med. Chem. 2004, 47,
888–899. (b) Patchett, A. A. J. Med. Chem. 2002, 45,
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Upadhyay, V.; Wells, K. M.; Reamer, R. A.; Lynch, J. E.;
Askin, D.; Volante, R. P.; Reider, P. J. Tetrahedron 1997, 53,
10983–10992.
Acknowledgements
We thank Dr. Val Goodfellow for providing experimental
results for demethylation of 1c and Drs. John Saunders and
Nick Ling for reviewing this paper.
11. Ong, H. H.; Profitt, J. A.; Fortunato, J.; Glamkowski, E. J.;
Ellis, D. B.; Geyer, H. M., III; Wilker, J. C.; Burghard, H.
J. Med. Chem. 1983, 26, 981–986.
12. (a) Dean, D. C.; Nargund, R. P.; Pong, S.-S.; Chaung, L. P.;
Griffin, P.; Melillo, D. G.; Ellsworth, R. L.; Van Der Ploeg,
L. H.; Patchett, A. A.; Smith, R. G. J. Med. Chem. 1996, 39,
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Piteau, M.; Malfroot, T. J. Org. Chem. 1984, 49, 2081–2082.
13. Based on the in-house experiment, the 10-N-demethylation
using a-chloroethyl chloroformate (ACE–Cl) gave a complex
reaction mixture with the desired product in 50% conversion
based on HP LC/MS. The impurities were not identified.
14. Based on the in-house experiment, the 10-N of 1d can
selectively react with acid chloride, acid anhydride, chloro-
formate and sulfonyl chloride. Thus, 1d itself can be used as an
useful template for parallel synthesis.
References and notes
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