Organic Process Research & Development
Communication
was filtered under vacuum to get compound 6 446 g (88%
yield) as a white to off-white solid with >98.5% HPLC purity
(2.2:1.3:1 dr).
ACKNOWLEDGMENTS
■
We thank the management of Dr. Reddy’s Laboratories Ltd. for
supporting this work. We also thank to Mahesh Kumar Y. Joshi,
K. Siva Kumari and K. Rama Seshaiah for analytical support, N.
M. Sekhar, Dr. MSM Mujeebur Rahuman, and Dr. Abhishek
Sud for providing valuable suggestions.
Synthesis of (1R,2S,5S)-N-(4-Amino-1-cyclobutyl-3,4-
dioxobutan-2-yl)-3-((S)-2-(3-(tert-butyl)ureido)-3,3-di-
methylbutanoyl)-6,6-dimethyl-3-azabicylo[3.1.0]-
hexane-2-carboxamide 7. To a stirred solution of 6 (200 g,
0.38 mol, 1.0 equiv) in ethyl acetate (2.0 L) was added Dess−
Martin periodinane (DMP) (260 g, 0.61 mol, 1.6 equiv) in
three lots at equal intervals of 45 min at 5−10 °C, and the
reaction mass was stirred at 12−18 °C for 3 h. After the
completion of the reaction (based on TLC), the reaction mass
was filtered through a Celite bed under vacuum. The filtrate
was washed with the water (2.0), and 40% sodium bisulfite
solution (256 g sodium bisulfite in 640 mL water) was added to
the organic layer. The solution was stirred at 25−30 °C for 12−
15 h. The layers were separated, and the organic layer was
concentrated under vacuum up to 80%, and cyclohexane (0.8
L) was added to this. The heterogeneous mass was stirred for 1
h at 25−30 °C, and the bisulfite adduct was filtered under
vacuum. The bisulfite adduct was dissolved in water (0.5 L) and
EtOAc (1.0 L) and cooled to 0−3 °C. The reaction mass was
stirred at 0−3 °C for 10−15 min, and layers were separated.
The aqueous layer was washed with ethyl acetate (0.5 L) at 0−
3 °C. MTBE (1.0 L) was added to the aqueous layer, and the
reaction mass was stirred at 25−30 °C for 2−3 h and the layers
separated. The MTBE layer was concentrated under vacuum up
to 80% and added to the precooled solution of heptane at 0−5
°C and stirred at that temperature for 30−45 min. The solid
material was filtered under vacuum to get 80 g (40% yield) as a
white solid with >99% purity (1.1:1 dr). Caution: We completed
all the DMP related operations at cooling conditions and did not
have any accidents. It was reported that it could be explosive under
impact or heating at >130 °C.13 1H NMR (400 MHz, DMSO-
d6) δ 8.00−8.27 (m, 1H), 7.99 (m, 1H), 7.75 (m, 1H), 5.96 (s,
1H), 5.88 (m, 1H), 5.83−8.00−8.27 (m, 1H), 4.82−4.99 (m,
1H), 4.27 (d, 1H), 4.10−4.14 (m, 1H), 3.96−3.99 (m, 1H),
3.74−3.78 (m, 1H), 2.49−2.51 (m, 1H), 1.91−1.99 (m, 2H),
1.71−1.81 (m, 3H), 1.55−1.66 (m 3H), 1.41−1.45 (m, 2H),
1.26−1.29 (m, 9H), 0.90−1.19 (m, 3 H), 0.82−0.89 (m, 12 H).
13C NMR (100 MHz, DMSO-d6) δ 198.3, 197.3, 171.6, 171.4,
171.3, 171.2, 163.5, 163.3, 157.8, 157.8, 59.9, 59.6, 57.3, 52.6,
52.3, 49.4, 49.4, 47.9, 37.2, 37.1, 34.5, 32.6, 32.6, 31.1, 31.0,
29.6, 28.4, 28.2, 27.9, 27.5, 27.4, 27.3, 26.8. IR (KBr, cm−1):
3383, 2961, 1665, 1547, 1436, 1214. MS (m/z): 520 [M + H]+,
542 [M + Na]+. Mp 118−125 °C.
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ASSOCIATED CONTENT
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S
* Supporting Information
1
Copies of H NMR, 13C NMR, IR, mass spectra, and HPLC
data. This material is available free of charge via the Internet at
(6) Diaz, D. J.; Darko, A. K.; White, L. M. Eur. J. Org. Chem. 2007,
4453−4465.
AUTHOR INFORMATION
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Corresponding Author
(7) (a) Wu, C.; Cheng, H.; Liu, R.; Wang, Q.; Hao, Y.; Yu, Y.; Zhao,
F. Green Chem. 2010, 12, 1811−1816. (b) Paz, J.; Balado, C. P.;
Iglesias, B.; Munoz, L. J. Org. Chem. 2010, 75, 3037−3046. (c) Shi, F.;
Deng, Y.; Sima, T.; Peng, J.; Gu, Y.; Qiao, B. Angew. Chem., Int. Ed.
2003, 42, 3257−3260.
*Telephone: +91 4044346417. Fax: +91 4044346285. E-mail:
Notes
DRL-IPD Communication No.: IPDO-IPM-00397.
The authors declare no competing financial interest.
(8) Saksena, A. K.; Girijavallabhan, V. M.; Lovey, R. G.; Jao, E.;
Bennett, F.; Mc Cormick, J. L.; Wang, H.; Pike, R. E.; Bogen, S. L.;
H
dx.doi.org/10.1021/op500065t | Org. Process Res. Dev. XXXX, XXX, XXX−XXX