Organic Process Research & Development
ARTICLE
until HPLC analysis indicated complete reaction, and then was
cooled to 5 ꢀC. Water (1560 kg) was added over one hour, and
the slurry was stirred for 2 h at 5 ꢀC before filtering and washing
with further water (500 kg). The wet cake was dissolved in ethyl
acetate (1077 kg). DARCO G60 (44.6 kg) was added and the
mixture heated to 75 ꢀC and stirred for 2 h. The batch was cooled
to 55 ꢀC, filtered, and then concentrated to a volume of 250 L.
The resulting slurry was cooled to 5 ꢀC and stirred for 5 h then
filtered and washed with a further 80 L of ethyl acetate. The solids
were dried to afford 76.9 kg of aldehyde 4 (86%).
THF (11 L) and water (0.6 L), p-toluene sulphonic acid (536 g)
was added, and the vessel was inerted with nitrogen. The mixture
was heated to 65ꢀ67 ꢀC and aged for 16 h to generate a tan-
coloured slurry. Once the reaction had reached >99% comple-
tion, the slurry was cooled to room temperature, filtered, and
washed with THF (2 L). The solid was collected and dried
in vacuo at 40 ꢀC to afford 1 as the tosylate monohydrate salt
(797 g, 86%, >99 wt %, >99%ee) as a tan-coloured solid.
Mp = 144 ꢀC. 1H NMR (600 MHz, CD3OD) δ 8.95 (1H, s),
8.15 (1H, dd, J = 7.1, 1.2 Hz), 8.02 (2H, m), 8.00 (1H, dd, J = 8.3,
1.2 Hz), 7.72 (2H, m), 7.49 (2H, m), 7.25 (1H, dd, J = 8.3, 7.1
Hz), 7.22 (2H, d, J = 8.0 Hz), 3.49ꢀ3.43 (2H, m), 3.16ꢀ3.04
(3H, m), 2.34 (3H, s), 2.09ꢀ2.05 (2H, m), 1.96ꢀ1.82 (2H, m).
13C NMR (150.9 MHz, CD3OD) δ 169.7, 148.1, 143.7, 143.0,
141.9, 140.5, 131.8, 130.0, 129.8, 127.3, 127.1, 125.4, 124.2,
123.3, 122.4, 50.2, 45.2, 41.1, 30.9, 24.0, 21.4.
Separation of rac-18-Nitrobenzylideneamino)phenyl)pi-
peridine-1-carboxylate (5). Amine 17 (3.64 kg), aldehyde 4
(2.92 kg), and MTBE (24.3 kg) were charged to a vessel that
was inerted and heated to 50 ꢀC for 20 h. The batch was seeded
(386 g), and heptane (27.4 kg) was charged over 1 h. The slurry
was cooled to 15 ꢀC over 1 h and filtered, washing with a
premixed wash (MTBE 0.9 kg, heptane 3.3 kg) and dried by
nitrogen sweep to give 5 as an off-white solid (6.04 kg, 92%).
Spectroscopic data in accord with previously published.3a,c
(S)-tert-Butyl 3-(4-(7-carbamoyl-2H-indazol-2-yl)phenyl)-
piperidine-1-carboxylate 16. Imine 5 (5.84 kg), sodium azide
(812 g), and DMF (44.1 kg) were charged to an inerted vessel
followed by 2,6-lutidine (1.34 kg), and the batch was heated to
110 ꢀC for 20 h. The batch was cooled to 20 ꢀC, THF (51.7 kg)
was added followed by 25 wt % LiCl(aq) (58 L, precooled to
5 ꢀC), and the layers were separated. The aqueous layer was re-
extracted with THF twice (2 ꢁ 36 kg). The three organics were
combined and washed with 25 wt % LiCl(aq) (2 ꢁ 30 L). The
THF solution was returned to the vessel (which had been rinsed
out with water) and concentrated in vacuo (T < 35 ꢀC) to a
volume of ∼60 L. It was then cooled to 20 ꢀC, and 2 N NaOH
(58.4 L) was added. The biphasic mixture was agitated and
heated to 35 ꢀC overnight. After the mixture was checked for
complete ester hydrolysis, the phases were separated. Twenty-
nine liters of 25 wt % NaCl(aq) and 29 L of 2 M HCl were added
to the organic layer, and the phases were separated. The organic
layer was washed with 25 wt % NaCl(aq) (15 L) and then distilled
in vacuo to a volume of ∼9 L.
’ ASSOCIATED CONTENT
S
Supporting Information. Procedures for resolution of
b
rac-2 via DBT salt and ee upgrade of low ee 1. 1H and 13C NMR
spectra for 1 tosylate salt.This material is available free of charge
’ AUTHOR INFORMATION
Corresponding Author
*debra_wallace@merck.com.
’ ACKNOWLEDGMENT
We thank Sophie Strickfuss, Andy Kirtly, Jeremy Scott, Dave
Waterhouse, John Edwards, and Bob Reamer for analytical and
experimental support.
’ REFERENCES
(1) (a) Hassa, P. O.; Hottiger, M. O. Front. Biosci 2008, 13, 3046.
(b) Hagtao, P.; Szabo, C. Nat. Rev. Drug Discovery 2005, 4, 421.
(2) (a) Bryant, H. E.; Schultz, N.; Thomas, H. D.; Parker, K. M.;
Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N. J.; Helleday, T.
Nature (London) 2005, 434, 913. (b) Farmer, H.; McCabe, N.; Lord,
C. J.; Tutt, A. N. J.; Johnson, D. A.; Richardson, T. B.; Santarosa, M.;
Dillon, K. J.; Hickson, I.; Knights, C.; Martin, N. M. B.; Jackson, S. P.;
Smith, G. C. M.; Ashworth, A. Nature (London) 2005, 434, 913.
(3) (a) Jones, P.; Altamura, S.; Boueres, J. K.; Ferrigno, F.; Fonsi, M.;
Giomini, C.; Lamartina, S.; Monteagudo, E.; Ontoria, J. M.; Orsale,
M. V.; Palumbi, M. C.; Pesci, S.; Roscilli, G.; Scarpelli, R.; Schultz-
Fademrecht, C.; Toniatti, C.; Rowley, M. J. Med. Chem. 2009, 52, 7170.
(b) Scarpelli, R.; Boueres, J. K.; Cerretani., M.; Ferrigna, F.; Ontoria,
J. M.; Rowley, M.; Schultz-Fademrecht, C.; Toniatti, C.; Jones, P. Bio.
Org. Med. Chem. Lett. 2010, 20, 488. (c) Jones, P; Ontoria, J. M; Scarpelli,
R; Schultz-Fademrecht, C. PCT Int. Appl. WO 2008/084261, 2008.
(4) For some synthetic approaches to 2H-indazoles see: (a) Shirtcliff,
L. D.; Weakly, T. J. R.; Haley, M. M.; Kohler, F.; Herges, R. J. Org. Chem.
2004, 69, 6979. (b) Shirtcliff, L. D.; Rivers, J.; Haley, M. M. J. Org. Chem.
2006, 71, 6619. (c) Shirtcliff, L. D.; Hayes, A. G.; Haley, M. M.; Kohler, F.;
Hess, K.; Herges, R. J. Am. Chem. Soc. 2006, 128, 9711. (d) Mills, A. D.;
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70, 1060.
Dichloromethane (46.6. kg) was added, followed by a solution
of di-tert-butyl carbonate (3.54 kg) in DCM (∼6 L) and pyridine
(0.99 kg), and the batch was aged at 20ꢀ25 ꢀC for 30 min.
Ammonium bicarbonate (1.28 kg) was then added in one
portion, and the batch was aged at 20ꢀ25 ꢀC for 20 h. After
checking for complete reaction, 1 M HCl (26.5 L) was added
slowly, and the layers were separated. The organic phase was
washed with water (13 kg) and reduced in vacuo to a volume of
∼7 L. This was loaded onto ∼17 kg of silica in a small oyster filter
which had been prewetted with cold DCM. The filter was then
eluted with DCM (∼37 L) followed by a 50/50 mixture (by
volume) of DCM/MTBE (∼150 L). Once product had stopped
coming off the silica, elution was stopped. The product-contain-
ing fractions were reduced by vacuum distillation to a volume of
∼60ꢀ80 L, T ≈ 45 ꢀC. Seed (10 g) was then charged, and
distillation continued to a volume of ∼20 L. Once the product
had crystallized, the slurry was cooled to 15 ꢀC and aged for >1 h,
then was filtered and washed with MTBE (5 L). The product was
dried on the filter using a nitrogen sweep to give amide 16 as a
tan-coloured solid (2.76 kg, 49%).
Spectroscopic data in accord with previously published
(5) Kuvshinov, A. M.; Gulevskaya, V. I.; Rozhkov, V. V.; Shevelev,
S. A. Synthesis 2000, 1474.
reports.3a,c
(S)-2-(4-(Piperidin-3-yl)phenyl)-2H-indazole-7-carboxamide-
Tosylate Monohydrate 1. Amide 16 (789 g) was dissolved in
(6) Fu, X-L; Wu, L-L; Fu, H-Y; Chen, H; Li, R-Xi. Eur. J. Org. Chem.
2009, 13, 2051.
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dx.doi.org/10.1021/op2000783 |Org. Process Res. Dev. 2011, 15, 831–840