Organic Process Research & Development
Article
filtered. The solvent was removed under vacuum to give the
title compound 34 as a light brown solid (672 g, 97%). This
product had spectroscopic properties consistent with those
described above.
project. We also thank Richard Ward from Almac (formerly
CSS) for managing the scale-up of the final route.
REFERENCES
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Preparation of SB-649915 or 6-[(1-{2-[(2-Methyl-5-
quinolinyl)oxy]ethyl}-4-piperidinyl)methyl]-2H-1,4-ben-
zoxazin-3(4H)-one (1). Sodium hydrogen carbonate (310.5 g,
3.68 mol) was added to a stirred slurry of quinoline 34 (345 g,
1.23 mol) and piperidine 5 (302 g, 0.88wt) in 1,2-dimethoxy-
ethane (1.38 L) under a nitrogen atmosphere. Once gas
evolution had ceased, the mixture was heated to 85 °C, and this
was maintained until the reaction was complete (16−20 h).
Water (8.6 L) was added into the vessel portionwise
maintaining an internal temperature greater than 70 °C. The
reaction mixture was heated to 85 °C, held for one hour and
left to cool slowly overnight. The reaction mixture was further
cooled in an ice/water bath to below 5 °C and was held at this
temperature for a one hour. Filtration, washing with water (1.38
L) and drying under vacuum at 50 °C gave the crude title
compound 1 (592 g, 98%). Further purification of this material
was achieved by recrystallisation from ethanol (20 vol),41 using
a hot filtration to remove insoluble inorganic residues, and gave
pure title compound 1 as a cream solid (499 g, 84%).42 1H
NMR (400 MHz, DMSO): δ 1.28 (2H, m), 1.51 (1H, m), 1.62
(2H, m), 2.39 (4H, m), 2.64 (3H, s), 3.08 (2H, s), 3.15 (2H,
m), 4.34 (2H, m), 4.52 (2H, s), 6.68 (1H, s), 6.71 (1H, d), 6.85
(1H, d), 7.00 (1H, d), 7.40 (1H, d), 7.49 (1H, d), 7.61 (1H,
m), 8.42 (1H, d), 10.63 (1H, s) (1H NMR comparable to
reported data1). 13C NMR (100 MHz, DMSO): δ 24.8, 31.8,
37.4, 41.7, 53.7, 56.9, 66.7, 66.8, 105.1, 115.8, 116.1, 118.2,
120.3, 121.2, 123.5, 126.9, 129.6, 130.3, 134.5, 141.4, 148.2,
153.9, 158.9, 165.0.
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Alternative Conditions. A mixture of piperidine 5 (1.0 g, 4.0
mmol) and quinoline 34 (1.1 g, 4.0 mmol) in 3-pentanone (11
mL) was treated with diisopropylamine (1.68 mL, 1.21 g, 11.99
mmol), heated to 85 °C and then stirred at this temperature for
36 h. The mixture was cooled to ambient, diluted with 1.0 M
sodium hydrogen carbonate (aqueous) (10 mL) and stirred for
30 min. Filtration, washing with water (10 mL) and drying gave
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C. V. R.; Rao, K. S.; Rastogi, K.; Jain, M. L. Indian J. Chem. 1988, 27B,
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1990, 33, 380−386.
(10) For Friedel−Crafts reactions of isonicotinoyl chloride 13, see:
(a) Qin, Z.; Mu, C.; Mao, S.; Dong, Y.; Li, N.; Zhang, S. Faming
Zhuanli Shenqing Gongkai Shuomingshu 2005, 9 pp. CN 1566095 A
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(12) The reduction of aroyl pyridines to the corresponding
arylmethyl piperidines is known: Strupczewski, J. T.; Allen, R. C.;
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1
the crude title compound 1 (1.44 g, 83%) as a cream solid. H
NMR data was comparable to those described above and those
reported.1
ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
AUTHOR INFORMATION
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Corresponding Author
(13) (a) Alinezhad, H.; Tavakkoli, S. M.; Salehian, F. Synth. Commun.
2010, 40, 3226−3232. (b) Pourmousavi, S. A.; Salehi, P. Acta Chim.
Slov. 2009, 56, 734−739. (c) Adibi, H.; Hajipour, A. R.; Hashemi, M.
Tetrahedron Lett. 2007, 48, 1255−1259. (d) Rajagopal, R.; Jarikote, D.
V.; Lahoti, R. J.; Daniel, T.; Srinivasan, K. V. Tetrahedron Lett. 2003,
44, 1815−1817. (e) Narender, N.; Srinivasu, P.; Prasad, M. R.;
Kulkarni, S. J.; Raghavan, K. V. Synth. Commun. 2002, 32, 2313−2318.
(14) Buckley, G. M., Morgan, T.; Sabin, V. M. PCT Int Appl. WO
2008/044022 A1.
Notes
The authors declare no competing financial interest.
†Formerly from Synthetic Chemistry, GlaxoSmithKline Phar-
maceuticals, Old Powders Mills, Nr. Leigh, Tonbridge, Kent,
TN11 9AN, U.K.
ACKNOWLEDGMENTS
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We thank John Warren, Pritpal Slaich and Alec Simpson for
spectroscopy support, David Childs for analytical support and
Dave Grimshaw for process safety support throughout this
(15) Monobromination of aniline using conversion to acetanilide,
bromination to 4-bromoacetanilide and subsequent hydrolysis to 4-
bromoaniline: Furniss, B. S.; Hannaford, A. J.; Rogers, V.; Smith, P.
H
dx.doi.org/10.1021/op300185s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX