H. Xiong et al. / Tetrahedron Letters 53 (2012) 5833–5836
5835
Table 1
Thiazole formation from aniline 10
S
H2N
N
N
N
H2N
N
N
N
N
1
10
+
S
N
N
HN
R
N
H
N
N
N
S
N
N
H2N
1b
11
: R = COPh
12: R = COCF3
13: R = H
Entries
Conditions
Result
1
2
3
4
5
6
KSCN, CuSO4, MeOH
KSCN, CuSO4, MeOH, AcOH
NH4SCN, TFA, NBS
NH4SCN, TFA
(a) PhCONCS; (b) NBS, TFA; (c) HBr, H2O
(a) PhCONCS, MeOH; (b) NaOMe, MeOH; (c) NBS, TFA/MsOH
30% of 1 and 1b
Low conversion
No desired product
Formation of trifluroacetamide 12
1 (16%)
1 (50%)
Bioorg. Med. Chem. Lett. 2001, 11, 2345; (h) Johnson, D. S.; Choi, C.; Fay, L. K.;
Favor, D. A.; Repine, J. T.; White, A. D.; Akunne, H. C.; Fitzgerald, L.; Nicholls, K.;
Snyder, B. J.; Whetzel, S. Z.; Zhang, L.; Serpa, K. A. Bioorg. Med. Chem. Lett. 2011,
21, 2621; (i) Favor, D. A.; Johnson, D. S.; Repine, J. T.; White, A. D. WO
200,61,03,559, 2006.; (j) Blackwell, W. C., III; Hulsizer, J.; Liu, J.; Steelman, G.;
Urbanek, R.; Widzowski, D.; Wu, Y. WO 200,91,05,026, 2009.
However, numerous attempts to separate 1 from 1b through
recrystallization of the isolated mixture were not successful. Ulti-
mately, we were able to recrystallize and isolate compound 1 di-
rectly from the crude reaction mixture. After removal of the
volatiles from the reaction, the residue was diluted with CH3CN
and then treated with an excess of aqueous 5N NaOH. Addition
of seed crystals of 1 resulted in selective precipitation and clean
isolation of 1 in 50% yield.13
In conclusion, we have demonstrated an efficient and scalable
synthesis of the D2 partial agonist 1 from tetrahydrobenzazepine
2, in four steps and 30% overall yield. Regioselective nitration, fol-
lowed by reductive amination, hydrogenation, and oxidative cycli-
zation and in situ recrystallization afforded more than 60 g of 1 in
good yield, without the need of chromatography in the entire syn-
thetic sequence.
5. (a) Koshio, H.; Asai, N.; Takahashi, T.; Shimizu, T.; Nagai, Y.; Kawabata, K.; Thor,
K. B. WO 2011111817, 2011.; (b) Gribble, A. D.; Forbes, I. T.; Lightfoot, A.;
Payne, A. H.; Walker, G. WO 200,30,99,792, 2003.; (c) Bonanomi, G.; Damiani,
F.; Gentile, G.; Hamprecht, D. W.; Micheli, F.; Tarsi, L.; Tedesco, G.; Terreni, S.
WO 200,51,18,549, 2005.; (d) Pooni, P.; Merchant, K. J.; Buffham, W. J. WO
201,10,83,314, 2011.; (d) Pooni, P. K.; Merchant, K. J.; Buffham, W. J. WO
201,10,83,314, 2011.; (e) Adam, G.; Binggeli, A.; Maerki, H.-P.; Mutel, V.;
Wilhelm, M.; Wostl, W. EP 10,74,549, 2001.; (f) Bhatti, B. S.; Cuthbertson, T. J.;
Mazurov, A.; Mitchener, J. P., Jr.; Munoz, J. A.; Murthy, V. S.; Xiao, Y.-D.;
Yohannes, D. WO 201,00,96,384, 2010.; (g) Busch-Petersen, J.; Cooper, A. W. J.;
Laine, D. I.; Palovich, M. R.; Davis, R. S.; Fu, W. WO 200,50,94,834, 2005.
6. Purchased from Ramidus AB.
7. Kaye, I. A.; Roberts, I. M. J. Am. Chem. Soc. 1951, 73, 4762.
8. (a) Wood, J. L. Org. React. 1946, 3, 240; (b) Ismail, I. A.; Sharp, D. E.; Chedekel, M.
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Acknowledgments
9. 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine monosulfate 6. To
a stirred
solution of 840 mL of TFA in 12 L 3-neck RB flask, equipped with
a
a
The authors are grateful to all members of the excellent drug
discovery and development community that once thrived at Astra-
Zeneca-Wilmington. We would like to thank Jennifer Van Anda,
James Hall, Xiaomei Ye, Timothy Blake, Don Pivonka, and Russ
Spreen for analytical chemistry support; many thanks to the biol-
ogists and DMPK staff who supported this effort. We also thank
James Muir, ThomasSimpson, Chad Elmore, Dean Brown, and Mar-
tin Hentemann for helpful discussions.
thermometer, mechanical stirring, and dropping funnel with N2 inlet, in an
ice bath was added 2,3,4,5-tetrahydro-1H-benzo[d]azepine 2 (200 g, 1.36 mol)
dropwise over ꢀ0.5 h, followed by the addition of 98% sulfuric acid (296 mL,
5.44 mol) over 15 min. The mixture was then cooled to <5 °C, before the
addition of 70% nitric acid (96 mL, 1.49 mol) over ꢀ2 h while maintaining the
internal temp lower than 10 °C. The mixture was then stirred in the ice bath for
2 h. 2 L of EtOAc was then added over 0.5 h, followed by the addition of 4 L
EtOAc in a single portion and the mixture was stirred overnight in the ice bath.
The white precipitate was collected by filtration, washed with EtOAc (2 Â 1 L)
and dried in vacuo at 50 °C to afford the title compound (356 g, 90%). 1H NMR
(500 MHz, d6-DMSO) d ppm 3.23 (m, 8H), 7.52 (d, J = 8.2 Hz, 1H), 8.06 (dd,
J = 8.2, 2.4 Hz, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.91 (br. s., 2H).
References and notes
10. 3-((1-methyl-1H-pyrazol-4-yl)methyl)-7-nitro-2,3,4,5-tetrahydro-1H-benzo-
[d]azepine, 9. To a 22 L 3-neck RB flask in an ambient temperature water bath
was charged with 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine monosulfate
6 (400 g, 1.38 mol) and sodium acetate (237 g, 2.89 mol) as solids, followed by
5 L MeOH. 1-methyl-1H-pyrazole-4-carbaldehyde (176 g, 1.60 mol) was then
added in a single portion. The mixture was stirred for ꢀ1 h, before the addition
of sodium cyanoborohydride (143 g, 2.27 mol) in three portions over 15 min.
After 2 h, additional sodium cyanoborohydride (13 g) was added, and it was
stirred for another 4 h. Sarcosine (19 g, 0.21 mol) was then added and it was
stirred at rt overnight. The solution was cooled to ꢀ10 °C, before the addition of
8 L water over 0.5 h while cooling in an ice bath. Then 2.5 L of 2N NaOH
solution was added over 2.5 h (pH > 12). Additional 1.5 L water was added in a
single portion. It was cooled in an ice bath and stirred overnight. The
precipitate was collected by filtration, washed with water (2 Â 1 L), and dried
in vacuum at 50–60 °C to afford the title compound (381.7 g, 97%). 1H NMR
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