Organic Process Research & Development
Article
mbar) at 75 °C to afford crude 1 (53.6 g, 75% yield as is).
Headspace-GC: HOBt (500 ppm), DMF (1000 ppm) and
EtOAc (10,000 ppm). HPLC for 11 (tR = 5.9 min); 12 (tR =
2.3 min); 1 (tR = 14.9 and 15.3 min; two atropisomers) purity
99.6%: Synergi Polar-RP 5 μm C-18 150 mm × 4.6 mm, flow
rate = 1 mL/min, 25 °C, gradient elution from 12:88 A/B for
10 min to 40:60 A/B over 14 min; A = acetonitrile; B = 0.1%
TFA in water; UV λ = 254 nm.
37.0, 36.4, 36.3, 35.6, 35.5, 31.3, 18.5, 18.4, 17.8, 17.6, 15.2,
15.1. ICP-MS Pd 0.6 ppm; Headspace-GC: HOBt, 38 ppm;
EtOAc, 3000 ppm; DMF, not detected. HPLC for 1 (tR = 14.9
and 15.3 min; two atropisomers) purity 99.9%: Synergi Polar-
RP 5 μm C-18 150 mm × 4.6 mm, flow rate = 1 mL/min, 25
°C, gradient elution from 12:88 A/B for 10 min to 40:60 A/B
over 14 min; A = acetonitrile; B = 0.1% TFA in water; UV λ =
254 nm.
Recrystallization of (2,4-Dimethyl-1-oxypyridin-3-yl)-
[4′-methyl-4-(phenylpyridin-3-ylamino)-[1,4′]-
bipiperidinyl-1′-yl]-methanone (1, Laboratory-Scale
Process). A suspension of crude 1 (50 g, 100 mmol as is)
and absolute EtOH (500 mL) was heated to 70−80 °C and
stirred for 10 min to obtain a clear solution. The solution was
cooled to 45−55 °C, filtered, and rinsed with EtOH (50 mL).
The filtrates were combined and concentrated at 30−60 °C
under reduced pressure (160−60 mbar) until ∼480 mL of
solvents was collected. The remaining residue was heated to
65−75 °C, and ethyl acetate (500 mL) was added over 30 min.
The mixture was cooled to 40−55 °C and concentrated at 40−
60 °C under reduced pressure (60−160 mbar) until ∼200 mL
of solvents was collected. The solution was seeded with 1 (35
mg, 93:7 atropisomeric ratio) and cooled to 25 °C over 1 h.
The mixture was stirred for 16 h. The resulting suspension was
heated to 70 °C and stirred for 6 h. The suspension was cooled
to 25 °C over 1 h and stirred for 12 h. The precipitate was
filtered, rinsed with a mixture of EtOAc and EtOH (9:1 v/v,
100 mL), and dried under reduced pressure (15−40 mbar) at
75 °C to afford 1 (44.0 g, 88% yield) as an off-white solid: mp
AUTHOR INFORMATION
Corresponding Authors
■
Notes
The authors declare no competing financial interest.
REFERENCES
(1) Horuk, R. Nature 2009, 8, 23−24.
(2) Thoma, G.; Beerli, C.; Bigaud, M.; Bruns, C.; Cooke, N. G.;
Streiff, M. B.; Zerwes, H.-G. Bioorg. Med. Chem. Lett. 2008, 18, 2000−
2005.
(3) For recent reviews on reductive amination of aldehydes and
ketones with acetoxyborohydride, see: (a) Abdel-Magid, A. F.;
Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971−1031. (b) Gribble,
G. W. Org. Process Res. Dev. 2006, 10, 1062−1075.
(4) For recent reviews on Buchwald−Hartwig aryl amination
reactions, see: (a) Mauger, C. C.; Mignani, G. A. Aldrichimica Acta
2006, 39, 17. (b) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004,
■
346, 1599. (c) Frost, C. G.; Mendonca
1998, 2615.
̧ , P. J. Chem. Soc., Perkin Trans. 1
1
209−213 °C; H NMR (300 MHz, DMSO-d6) 8.17−7.96 (m,
(5) For amination reactions using t-Bu3P as a ligand, see
(a) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998,
39, 2367−2370. (b) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.;
Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5575−5580. (c) Lee, M.; Jorgensen, J.; Hartwig, J. F. Org. Lett. 2001,
3, 2729−2732.
3H), 7.41−6.93 (m, 8H), 3.86 (m, 1H), 3.72 (m, 1H), 3.38 (m,
1H), 3.09 (m, 1H), 2.95−2.83 (m, 3H), 2.25 (m, 2H), 2.13 (s,
3H), 2.12 (s, 3H), 1.92 (m, 2H), 1.80 (m, 1H), 1.62 (m, 1H),
1.40 (m, 1H), 1.32−1.12 (m, 3H), 0.91 (s, 3H); 1H NMR (300
MHz, CDCl3) 8.15−8.12 (m, 3H), 7.41−6.91 (m, 8H), 4.05
(m, 1H), 3.81 (m, 1H), 3.43 (m, 1H), 3.22 (m, 1H), 2.97−2.83
(m, 3H), 2.38 (s, 3H), 2.26 (m, 2H), 2.25 (s, 3H), 2.05 (m,
3H), 1.16 (m, 1H), 1.47−1.22 (m, 4H), 0.97 (s, 3H); 13C
NMR (75 MHz, CDCl3) 164.8, 145.0, 143.7, 143.5, 140.8,
140.7, 138.2, 135.0, 132.5, 129.6, 126.6, 125.5, 124.9, 124.7,
123.5, 55.7, 53.8, 44.5, 44.4, 42.1, 37.1, 36.4, 35.5, 31.3, 18.4,
17.6, 15.1; MS (ESI) m/z 500.3 (M + H+); Anal. Calcd for
C30H37N5O2: C, 72.12; H, 7.46; N, 14.02. Found: C, 72.10; H,
7.64; N, 13.97. The following NMR data were acquired for 1,
initially with an atropisomeric ratio of 93:7, after heating its
DMSO-d6 solution at 90 °C for a few minutes and cooled to 25
(6) Prashad, M.; Mak, X. Y.; Liu, Y.; Repic,
1163−1164.
̌
O. J. Org. Chem. 2003, 68,
(7) (a) Kalir, A.; Edery, H.; Pelah, Z.; Balderman, D.; Porath, G. J.
Med. Chem. 1969, 12, 473−477. (b) Bruylants, P. Bull. Soc. Chim. Belg.
1924, 33, 467. (c) Yoshimura, J.; Ohgo, Y.; Sato, T. Bull. Chem. Soc.
Jpn. 1965, 28, 1809−1813. (d) Maddox, V. H.; Godefroi, E. F.; Parcell,
R. F. J. Med. Chem. 1965, 8, 230−235. (e) Hermans, B.; Daele, P. V.;
Westeringh, C. V. D.; Eycken, C. V. D.; Boey, J.; Janssen, P. A. J. J.
Med. Chem. 1965, 8, 851−855. (f) Yoshimura, J.; Ohgo, Y.; Sato, T. J.
Am. Chem. Soc. 1964, 86, 3858−3862. (g) Kudzma, L. V.; Spencer, H.
K.; Severnak, A. Tetrahedron Lett. 1988, 29, 6827−6830. (h) Agami,
C.; Couty, F.; Evano, G. Org. Lett. 2000, 2, 2085−2088.
(8) Prashad, M.; Liu, Y.; Har, D.; Repic,
Tetrahedron Lett. 2005, 46, 5455−5458.
̌
O.; Blacklock, T. J.
1
°C: H NMR (300 MHz, DMSO-d6) 8.17−7.96 (m, 3H),
7.41−6.93 (m, 8H), 3.86−3.72 (m, 3H), 3.42 (m, 1H), 3.06
(m, 1H), 2.93−2.82 (m, 3H), 2.21 (s, atropisomer B, 1.5H),
2.13 (s, atropisomer A, 1.5H), 2.12 (s, atropisomer A, 1.5H),
2.04 (s, atropisomer B, 1.5H), 2.26−1.64 (m, 5H), 1.43−1.20
(m, 4H), 0.91 (s, 3H). In addition, a CDCl3 solution of 1 with
13:1 atropisomeric ratio was allowed to stand at 25 °C for 16 h
(9) For recent reviews on atropisomers in organic synthesis, see:
(1) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 4, 525−
558. (2) Bringmann, G.; Mortimer, A. J. P.; Keller, P. A.; Gresser, M.
J.; Garner, J.; Breuning, M. Angew. Chem., Int. Ed. 2005, 44, 5384−
5427. (3) Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc.
Rev. 2009, 38, 3193−3207. (4) Bringmann, G.; Gulder, T.; Gulder, T.
A. M.; Breuning, M. Chem. Rev. 2011, 111, 563−639.
1
and recorded: H NMR (300 MHz, CDCl3) 8.15−8.12 (m,
(10) Palani, A.; Shapiro, S.; Clader, J. W.; Greenlee, W. J.; Blythin,
D.; Cox, K.; Wagner, N. E.; Strizki, J.; Baroudy, B. M.; Dan, N. Bioorg.
Med. Chem. Lett. 2003, 13, 705−708.
3H), 7.41−6.92 (m, 8H), 4.15−4.02 (m, 1H), 3.81 (m, 1H),
3.44−3.19 (m, 2H), 3.00−2.83 (m, 3H), 2.45 (s, atropisomer
B, 1.5H), 2.38 (s, atropisomer A, 1.5H), 2.25 (s, atropisomer A,
1.5H), 2.19 (s, atropisomer B, 1.5H), 2.35−1.92 (m, 5H), 1.17
(m, 1H), 1.47−1.22 (m, 4H), 0.97 (s, 3H); 13C NMR (75
MHz, CDCl3): 164.8, 164.7, 145.0, 144.9, 144.0, 143.7, 143.5,
143.4, 141.2, 141.1, 140.8, 140.7, 138.2, 135.0, 132.8, 132.5,
129.6, 129.5, 126.6, 126.1, 126.0, 125.5, 124.9, 124.8, 124.7,
124.4, 123.5, 55.7, 55.6, 53.9, 53.8, 44.5, 44.4, 42.1, 42.0, 37.1,
(11) Clayden, J.; Moran, W. J.; Edwards, P. J.; LaPlante, S. R. Angew.
Chem., Int. Ed. 2009, 48, 6398−6401.
(12) Chan, V.; Kim, J. G.; Jimeno, C.; Carroll, P. J.; Walsh, P. J. Org.
Lett. 2004, 6, 2051−2053.
(13) Warner, J. and Anastas, P. In Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998.
G
dx.doi.org/10.1021/op400250s | Org. Process Res. Dev. XXXX, XXX, XXX−XXX