Organic Process Research & Development
Article
125.4, 125.3, 124.8, 122.8, 121.5, 119.3, 119.1, 117.0, 110.9,
109.2, 65.9, 65.05, 65.0, 55.7, 48.6, 42.7, 30.0, 29.6; HRMS
(ESI) m/z calcd for C31H31Cl2FN3O5 [M + H]+ 614.1625,
found 614.1619.
The crude 31 (32.5 mmol in theory) obtained above was
dissolved in a mixture of THF (102 mL) and water (20 mL).
Then 50% NaOH (8.6 mL) was added. The mixture was stirred
at 65 °C for 4 h and then acidified with 6 M HCl (28.2 mL, 169
mmol) to pH ∼2. The organic phase was separated, washed
with brine (3 × 20 mL), and filtered through a pad of Celite.
The filtrate was diluted with water (204 mL), and the resulting
suspension was filtered. The filter cake was washed with water
and dried by suction to give crude 42 (22.0 g, overweight) as a
light-yellow solid, which was directly used in the next step.
The crude 42 (32.5 mmol in theory) from above was dis-
solved in ethyl acetate (80 mL), and then 43 (5.58 g, 37.4 mmol)
was added. The mixture was stirred at 60 °C for 4 h, gradually
cooled to room temperature, and stirred overnight. The resulting
suspension was filtered, and the collected solids were washed with
ethyl acetate (2 × 10 mL) to give crude 42-salt (16.4 g, 97%
chemical purity and 98.5% de). This crude salt was triturated in
methanol (40 mL) to give pure 42-salt (14.8 g, 99% chemical
purity, 99.5% de, and 60% yield) as an off-white solid.
4-{[(2′S,3′R,4′S,5′R)-6-Chloro-4′-(3-chloro-2-fluoro-
phenyl)-2′-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro-
[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-
benzoic Acid Dimethyl-((R)-1-phenylethyl) Amine Salt
(42-Salt). A mixture of 43 (1.12 g, 7.49 mmol) and rac-42
(4.00 g, 6.51 mmol) in ethyl acetate (80 mL) was stirred at
60 °C for 2 h, gradually cooled to room temperature over 5 h,
and stirred at room temperature overnight. The resulting sus-
pension was filtered. The collected solids were washed with
cold ethyl acetate (2 mL) and dried to give 42-salt (2.06 g, 41%
yield, 98% ee) as a white solid. 1H NMR (300 MHz, DMSO-d6)
δ 10.75 (s, 1H), 10.51 (s, 1H), 8.39 (m, 1H), 7.70 (d, J = 7.9
Hz, 1H), 7.62 (m, 1H), 7.60−7.52 (m, 2H), 7.37 (m, 1H),
7.33−7.26 (m, 4H), 7.24 (m, 1H), 7.16 (t, J = 7.9 Hz, 1H),
7.01 (dd, J = 8.3, 1.5 Hz, 1H), 6.69 (d, J = 1.5 Hz, 1H), 4.67 (d,
J = 9.2 Hz, 1H), 4.47 (d, J = 9.2 Hz, 1H), 3.90 (s, 3H), 3.85 (m,
1H), 3.34 (q, J = 6.6 Hz, 1H), 2.12 (s, 6H), 1.31 (m, 1H), 1.28
(d, J = 6.6 Hz, 3H), 0.91 (s, 9H), 0.77 (d, J = 14.0 Hz, 1H).
(2′S,3′R,4′S,5′R)-6-Chloro-4′-(3-chloro-2-fluorophen-
yl)-2′-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro-
[indole-3,3′-pyrrolidine]-5′-carboxylic Acid (4-Carbamo-
yl-2-methoxyphenyl)amide (2). A mixture of 42-salt (30.0 g,
39.3 mmol) and CDI (12.7 g, 78.6 mmol) in THF (300 mL)
was stirred at room temperature for 1.5 h. Ammonium hydroxide
(53.1 mL, 786 mmol) was then added to the resulting suspension
in one portion. The mixture was stirred at room temperature for
30 min and then diluted with water (180 mL) and ethyl acetate
(240 mL). The organic phase was separated, washed suc-
cessively with brine, 1 M HCl, and water, and then concentrated.
The resulting suspension was diluted with n-heptane and filtered.
The filter cake was washed with n-heptane and dried to give 2
(23.3 g, 99% ee, 97% yield) as a white solid, mp 203 °C dec; 1H
NMR (300 MHz, DMSO-d6) δ 10.69 (s, 1H), 10.47 (s, 1H),
8.33 (d, J = 10.3 Hz, 1H), 7.92 (s, 1H), 7.71 (d, J = 8.0 Hz,
1H), 7.61 (m, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.50 (dd, J = 8.5,
1.9 Hz, 1H), 7.38 (m, 1H), 7.29 (s, 1H), 7.17 (t, J = 7.9 Hz,
1H), 7.01 (dd, J = 8.1, 1.9 Hz, 1H), 6.68 (d, J = 1.8 Hz, 1H),
4.66 (t, J = 9.4 Hz, 1H), 4.47 (d, J = 9.4 Hz, 1H), 3.90 (s, 3H),
3.84 (m, 1H), 3.71 (m, 1H), 1.30 (dd, J = 14.0, 9.4 Hz, 1H),
0.91 (s, 9H), 0.76 (d, J = 14.0 Hz, 1H); 13C NMR (100 MHz,
DMSO-d6) δ 176.9, 171.9, 167.2, 156.7, 154.3, 147.4, 143.4,
132.4, 129.9, 129.0, 128.9, 128.4, 126.7, 126.6, 125.8, 125.3,
124.8, 121.4, 120.4, 119.3, 119.1, 116.8, 109.8, 109.2, 65.9, 65.0,
55.7, 48.8, 42.7, 30.0, 29.6; HRMS (ESI) m/z calcd for
C31H32Cl2FN4O4 [M + H]+ 613.1779, found 613.1779.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed procedures for the preparation of 3, 6-TFA, 26, 28,
and 30; 1H, 13C NMR data for 26, 28, 32−39; 1D NOE results
for 26, 32−39, copies of NMR spectra for 2, 3, 6-TFA, 26, 28,
precursor of 30, 30−39, and 42; LC−MS chromatograms for
reactions of 3 with 30, and isomers interconversion experi-
ments. This material is available free of charge via the Internet
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Mr. Gino Sasso for structure identification of
the isomers with NOE experiments, Dr. Hanspeter Michel for
HRMS analysis, and Mr. Joseph Degasperi for analytical
support. We thank Dr. Michelangelo Scalone of Roche Basel
for providing ligands 47 and 48.
REFERENCES
■
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Asymmetric Synthesis. A solution of ligand 48 (676 mg,
0.97 mmol) and AgOAc (131 mg, 0.78 mmol) in MeTHF
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filter cake was washed with n-heptane to give crude 31, which
was directly used in the next step.
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dx.doi.org/10.1021/op3003213 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX