Organic Process Research & Development
Article
(m, 2H), 0.83 (t, J = 7.3 Hz, 3H). 19F NMR (376 MHz,
(d, J = 11.5 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.77 (dd, J =
11.7, 6.0 Hz, 2H), 3.82 (dt, J = 10.9, 3.5 Hz, 1H), 2.67 (t, J =
5.8 Hz, 2H), 2.28 (s, 3H), 1.68 (brs, H2O), 1.53 (m, 1H), 1.45
(m, 1H), 1.25 (t. J = 7.1 Hz, 3H), 1.10−0.97 (m, 2H), 0.74 (t, J
= 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) 173.4, 166.8,
150.8, 149.1 (d, J = 250.6 Hz), 148.4, 143.2, 140.2, 135.4 (d, J =
6.4 Hz), 135.0 (d, J = 3.4 Hz), 133.0, 132.9, 129.9, 129.2, 128.6
(d, J = 1.9 Hz), 128.4, 127.5, 126.5, 124.6, 124.4 (d, J = 1.6 Hz),
119.8 (d, J = 11.1 Hz), 115.5 (d, J = 3.2 Hz), 113.3 (d, J = 19.8
Hz), 61.0, 50.2, 47.7, 37.5, 35.6, 34.0, 21.4, 20.4, 14.3, 14.0.
Anal. Calcd for C38H37ClFN3O7S·0.5 H2O: C, 61.41; H, 5.15;
Cl, 4.77; F, 2.56; N, 5.65; O, 16.14; S, 4.31. Found: C, 61.10, H,
C D C l
)
− 1 2 2 . 3 . A n a l . C a l c d f o r
3
C33H28ClFN2O6S·0.5MTBE·0.2heptane: C, 63.38; H, 5.36; N,
4.01; Cl, 5.07; F, 2.72; S, 4.59. Found: C, 63.59; H, 5.36; N,
3.84; Cl, 4.94; F, 2.75; S, 4.61.
N-({4-[(1R,2S)-1-(4-Chlorophenyl)-1-(7-fluoro-5-methyl-
1H-indol-3-yl)pentan-2-yl]phenyl}carbonyl)-β-alanine Hemi-
hydrate (1). Penultimate 31e (30.0 kg of 99.4 wt %, 47.0 mol)
was dissolved in THF (169 L) and degassed using N2/vacuum
purge cycles. N,N-Carbonyldiimidazole (13.1 kg, 98.2%, 79.2
mol) was charged, and degassed using N2/vacuum purge cycles.
The mixture was heated over 60 min to 40 °C and aged for 1 h.
Conversion was determined by a quench of 50 μL of reaction
mixture into 50 μL of pyrrolidine followed by dilution to 25 mL
with acetonitrile to give the pyrrolidine amide, and the ratio of
acid to pyrrolidine amide was determined by HPLC. After
99.5% conversion to the imidazolide, the batch was cooled to
25 °C and β-alanine methyl ester HCl (12.4 kg, 86.8 mol) and
THF (17 L) were charged. After a repurge of the vessel, the
batch was then heated over 1.4 h to 60 °C and aged for 6 h.
After cooling to ambient, HPLC analysis showed 99.6%
conversion to 38. 1.7 N NaOH (198 L, 337 mol) was charged
over 1 h, and the batch was allowed to warm during the charge.
The batch was aged at 40 °C for 9 h (99.6% conversion),
cooled to 25 °C, and MTBE (196 L) charged, followed by 5 wt
% NaCl (200 kg). After agitation and settling, the phases were
separated and the organics washed with 5 wt % NaCl (200 kg),
3 N HCl (50 kg), and finally water (208 kg). The pH of the
final aqueous layer was 6. The organics were concentrated to
∼182 L and solvent switched to IPA using a total of 833 L IPA
via vacuum distillation with a maximum batch temperature of
30 °C. The organic was assayed by HPLC and diluted to ∼110
g/L by charging the appropriate volume of IPA. Water (150 kg)
was then slowly added over 45 min followed by seed (20 g).
The vessel was repurged and 160 kg water was charged over
1.25 h. After aging for 4.5 h, the batch was filtered, and washed
with 190 kg 2/1 (v/v) IPA/water. The cake was blown dry for
4 h and then dried in the tray dryer for 39 h at 60 °C to give
21.8 kg of 1 (98.6 LCWP, 99% ee) in 87.3% corrected yield. 1:
1H NMR (400 MHz, CDCl3) 8.20 (br s, NH), 7.46 (d, J = 8.1
Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 7.25 (d, J = 8.5 Hz, 2H),
7.17 (d, J = 8.1 Hz, 2H), 6.94 (s, 1H), 6.83 (d, J = 2.1 Hz, 1H),
6.72 (t, J = 6.0 Hz, -CONH), 6.60 (d, J = 11.9 Hz, 1H), 4.37 (d,
J = 10.7 Hz, 1H), 3.58 (m, 2H), 3.37 (dt, J = 10.7, 3.2 Hz, 1H),
2.57 (m, 2H), 2.35 (s, 3H), 1.50 (m, 1H), 1.40 (m, 1H), 0.98
(m, 2H), 0.71 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz,
CDCl3) 176.6, 168.2, 149.2 (d, JCF = 243.8 Hz), 149.0, 142.6,
132.1, 131.7, 130.9 (d, JCF = 5.5 Hz), 130.0, 129.6 (d, JCF = 5.6
Hz), 128.8, 128.5, 127.1, 122.8, 122.6 (d, JCF = 13.3 Hz), 118.6
(d, JCF = 1.2 Hz), 114.3 (d, JCF = 2.5 Hz), 108.6 (d, JCF = 15.7
Hz), 50.3, 48.2, 37.3, 35.5, 34.0, 21.8, 20.5, 14.1. 19F NMR (376
MHz, CDCl3) −136.3. Anal. Calcd for C30H31ClFN2O3.5: C,
67.98; H, 5.90; Cl, 6.69; F, 3.58; N, 5.29. Found: C, 68.11; H,
5.84; Cl, 6.70; F, 3.54; N, 5.33.
1
5.54, N, 5.29. Syn diastereomer 40: H NMR (400 MHz,
CDCl3) 8.31 (m, 2H), 8.07 (m, 2H), 7.71 (s, 1H), 7.60 (d, J =
8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 7.06 (s, 1H), 7.03 (m,
2H), 6.97 (m, 2H), 6.81 (d, 13.7 Hz, 1H), 6.79 (t, J = 5.9 Hz,
-NH), 4.25 (d, J = 10.9 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.71
(dd, J = 11.8, 6.0 Hz, 2H), 3.41 (dt, J = 10.9, 3.0 Hz, 1H), 2.64
(t, J = 5.9 Hz, 2H), 2.37 (s, 3H), 1.85 (m, 1H), 1.62 (m, 1H),
1.61 (br s, H2O), 1.28 (t, J = 7.1 Hz, 3H), 1.12 (m, 2H), 0.81
(t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) 173.2, 167.2,
150.8, 149.4 (d, J = 250.1 Hz), 146.5, 143.9, 140.1, 135.6 (d, J =
6.3 Hz), 135.3 (d, J = 3.8 Hz), 132.7, 132.4, 129.7, 129.5 (d, J =
1.3 Hz), 128.8, 128.6, 127.2, 125.2, 124.9, 124.7, 120.5 (d, J =
10.1 Hz), 115.8 (d, J = 2.5 Hz), 113.6 (d, J = 18.9 Hz), 61.0,
50.7, 48.6, 37.1, 35.5, 34.2, 21.5, 20.8, 14.4, 14.2.
ASSOCIATED CONTENT
* Supporting Information
Alternative synthesis of 2, crystallographic information files for
1, and NMR NOE for 39 and 40. This material is available free
■
S
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Yanfeng Zhang and Laura Artino for their work on
the crystal form characterizations. We thank Robert Reamer
and Peter G. Dormer for NMR analyses, and Mirlinda Biba and
Xiaoyi Gong for chiral chromatography analyses. We thank
PRPL and Rahway CPDC for pilot plant scale up efforts. We
thank both Wuxi Pharmatech and SAFC for providing the pilot
plant facilities for the production efforts.
REFERENCES
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Ethyl N-({4-[(1R,2S)-1-(4-chlorophenyl)-1-{7-fluoro-5-
methyl-1-[(4-nitrophenyl)sulfonyl]-1H-indol-3-yl}pentan-2-
yl]phenyl}carbonyl)-β-alaninate hemihydrate (39). Compound
39 was prepared similarly as for 38 except that the β-alanine
ethyl ester was used instead of the β-alanine methyl ester and
the product was not hydrolyzed but isolated and purified. 39:
1H NMR (400 MHz, CDCl3) 8.16 (m, 2H), 7.72 (m, 2H), 7.49
(d, J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.36−7.31 (m, 6H), 6.94 (t, J
= 5.9 Hz, -NH), 6.87 (s, 1H), 6.67 (d, J = 12.8 Hz, 1H), 4.30
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1843
dx.doi.org/10.1021/op300249q | Org. Process Res. Dev. 2012, 16, 1832−1845