Organic Process Research & Development
ARTICLE
scrubber containing 3 N NaOH were added the crude nitrile 6
(56 wt %, 10.96 kg, 16.8 mol), ZnO (137 g, 1.68 mol), THF
(6.2 L), and water (31 L). Sodium azide (1.20 kg, 18.5 mol)
[CAUTION: sodium azide is extremely toxic and may generate
hydrazoic acid in the presence of acid. Hydrazoic acid is shock-
sensitive, volatile, and toxic (see ref 16 for further details). Ensure
that all aqueous solutions of sodium azide are kept above pH 7,
wash all equipment with copious aqueous base post-use, and
ensure all azide-containing waste is collected separately, kept
basic, and disposed of separately] was dissolved in water (3.1 L)
and added via an addition funnel to the reaction mixture over
20 min. The mixture was then heated to 78 °C for 15 h, cooled to
ambient temperature, and transferred to an extractor charged
with saturated aqueous NaHCO3 (16 L), brine (16 L), and
2-MeTHF (31 L). The organic layer was separated and assayed
by HPLC (6.88 kg, 100% assay yield). The 25 wt % crude
solution was used directly in the next step. 1H NMR (500 MHz,
DMSO-d6) δ 7.60 (dd, J = 8.8, 6.4 Hz, 1 H), 7.23 (dd, J = 11.1, 2.8
Hz, 1 H), 6.77 (td, J = 8.5, 2.7 Hz, 1 H), 6.54 (s, 1 H), 4.79 (s,
1 H), 4.05 (s, 1 H), 3.53À3.47 (m, 2 H), 2.01À1.95 (m, 2 H),
1.77À1.71 (m, 2 H). 13C NMR (126 MHz, DMSO-d6) δ 166.7,
162.2 (d, JCF = 244 Hz), 156.5, 154.2 (d, JCF = 11 Hz), 133.7
(m, 2 H), 6.77 (td, J = 8.5, 2.7 Hz, 1 H), 5.83 (s, 2 H), 4.82À4.78
(m, 1 H), 3.59À3.53 (m, 2 H), 2.03À1.97 (m, 2 H), 1.78À1.71
(m, 2 H). 13C NMR and HRMS data obtained are in complete
accord with literature precedent.5
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: sarah_dolman@merck.com.
’ ACKNOWLEDGMENT
We thank Claude Briand, Richard Desmangles, and Wayne
Mullett for analytical support. Also, we would like to express our
appreciation to Theintu Lam for helpful safety discussions.
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(5-{3-[4-(2-Bromo-5-fluoro-phenoxy)-piperidin-1-yl]-iso-
xazol-5-yl}-tetrazol-2-yl)-acetic Acid tert-Butyl Ester (23). To
the crude solution of tetrazole 7 (25 wt %, 22 kg, 13.4 mol) was
added Et3N (3.3 L, 23.5 mol), and the mixture was heated to
55 °C. tert-Butylbromoacetate (3.0 L, 20.5 mol) was added over
20 min, and the internal temperature rose to 63 °C over the
course of the addition. The mixture was aged for 2 h 30 min at
58 °C and then cooled to 35 °C. It was transferred to an extractor
charged with aqueous HCl (1 N, 30 L). The layers were sepa-
rated, and the organic layer was washed with a mixture of water
and brine (15 L each) and assayed by HPLC (5.03 kg, 71% assay
yield and 1.25 kg of the desired 1-regioisomer). The solution was
filtered through a 1.0 μm inline filter, concentrated under
reduced pressure, flushed with heptane (20 L), and concentrated
to give a thick beige slurry (47 wt %). MTBE (25 L) and heptane
(5.8 L) were added to the slurry, and the resultant suspension
was warmed to 47 °C. After ageing for 16 h, the slurry was cooled
to 39 °C and the precipitate was recovered by filtration, rinsing
with a 3:1 mixture of MTBE/heptane (2.0 L). A light beige solid
was obtained (3.52 kg, 20:1 regioisomers, 70% isolated yield). 1H
NMR (500 MHz, DMSO-d6) δ 7.60 (dd, J = 8.8, 6.3 Hz, 1 H),
7.24 (d, J = 14.8 Hz, 2 H), 6.78 (td, J = 8.5, 2.8 Hz, 1 H), 5.85 (s,
2 H), 4.83À4.79 (m, 1 H), 4.03 (s, 1 H), 3.59À3.52 (m, 2 H),
2.03À1.97 (m, 2 H); 1.79À1.73 (m, 2 H); 1.43 (s, 9 H).13C
NMR (126 MHz, DMSO-d6) δ 166.7, 164.7, 162.3 (d, JCF = 245
Hz), 157.2, 155.3, 154.3 (d, JCF = 10 Hz), 133.7 (d, JCF = 10 Hz),
109.0 (d, JCF = 23 Hz), 107.0 (d, JCF = 2.5 Hz), 103.6 (d, JCF = 26
Hz), 97.0, 83.3, 72.9, 54.3, 43.7, 28.9, 27.5.
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(5-{3-[4-(2-Bromo-5-fluoro-phenoxy)-piperidin-1-yl]-iso-
xazol-5-yl}-tetrazol-2-yl)-acetic Acid (MK-8245). A suspen-
sion of tert-butyl ester 23 in formic acid (17 L) was heated to
95 °C for 2 h. The solution was cooled to 77 °C, and 80 g of seed
was added. The suspension was aged for 1 h, and water (6.5 L)
was added over 1 h. It was allowed to cool to 40 °C, aged for 14 h,
and then filtered. The cake was washed with water (17 L) and
dried in a vacuum oven at 70 °C (2.87 kg, 94% isolated yield,
98.1% pure as measured by HPLC at 210 nm). 1H NMR (500
MHz, DMSO-d6) δ 7.60 (dd, J = 8.8, 6.3 Hz, 1 H), 7.25À7.19
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dx.doi.org/10.1021/op200186d |Org. Process Res. Dev. 2011, 15, 1073–1080