smoothly and cleanly. After the reaction mixture stirred at 90
°C for 18 h, the reaction was complete. Quenching the reaction
mixture with methanol followed by water gave the target
molecule 1 in 98% yield as a first drop. Final API recrystalli-
zation using EtOH/H2O gave 1 with 90% recovery and 99.9%
HPLC purity. Moreover, while the starting material 5 had an
ee of 98.5%, the optical purity of API 1 was raised to 100% ee
after the recrystallization.
In summary, we have developed an efficient alternative
synthesis for 6-[(5S,9R)-9-(4-cyanophenyl)-3-(3,5-dichlorophe-
nyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotin-
ic acid1. This new process features an in situ protection of
6-chloronicotinic acid as trimethylsilyl ester 8 followed by
coupling with the spirocyclic hydantoin core (5) to give the
target product 1 in 89% overall yield after a one-pot deprotection
and final API recrystallization.
were collected by vacuum filtration, washed with cold chloro-
form (2 × 5 mL), and dried in Vacuo at 60 °C to give 3 (347
mg, 75% yield, 98% HPLC area purity). LC/MS (ESI) m/z 536
(M + H).
Scale-Up Synthesis. A 2-L three-neck round-bottom flask
was charged with 6-chloronicotinic acid 2 (37.8 g, 0.24 mol),
dichloromethane (360 mL), hexamethyldisilazane (28.61 g,
0.177 mol), and TMSCl (1.11 g, 10 mmol). The slurry was
refluxed under N2 atmosphere for 3 h until a light-brown
solution was obtained. The reaction mixture was cooled to rt,
and the solvent was removed under reduced pressure to afford
a light-brown syrup which solidified upon cooling. To this flask
was added 5 (49.68 g, 0.119 mol), dimethylacetamide (500 mL),
and diisopropylethylamine (38.73 g, 0.299 mmol). After the
reaction mixture was stirred at 90 °C for 18 h under nitrogen,
it was cooled to rt. MeOH (100 mL) was added while stirring.
The temperature was raised from 25 to 35 °C. The resulting
volatile solvents (MeOH and methoxytrimethylsilane) were
removed in Vacuo, and the resulting mixture was slowly added
to H2O (600 mL) with stirring. The resulting white slurry was
filtered by vacuum filtration, and the product was washed with
water (3 × 20 mL) and dried to afford 1 as a white solid (62.88
g, 98% yield). LC/MS (ESI) m/z 536 (M + H).
Experimental Section
All reagents were obtained from Aldrich Chemical Co. and
used without further purification unless otherwise stated. Spi-
rocyclic hydantoin 5 was obtained from Bristol-Myers Squibb
Company. All reactions were performed under a nitrogen
atmosphere. All glassware was dried and purged with nitrogen
or argon before use. All reactions were monitored by HPLC
using the following conditions: Combi-Screen ODS column 5
µm, 4.6 mm × 50 mm. Solvent: A ) 10% methanol/90% water
with 0.2% H3PO4; B ) 90% Methanol/10% water with 0.2%
H3PO4. Gradient: 0-100% B over 4 min. Flow: 1 mL/min,
wavelength: 220 nm). HPLC analyses were performed using a
Recrystallization from EtOH/H2O. Compound 1 (49 g) from
above was dissolved in EtOH (390 mL) at 90 °C, and H2O
(120 mL) was added at this temperature. The mixture was
cooled slowly to room temperature and then at 4 °C for 30
min. The white crystals were collected by vacuum filtration,
washed with EtOH/H2O (1/3 ratio, 2 × 100 mL) and then H2O
(3 × 300 mL). The solid was dried in Vacuo at 60 °C for 16 h
and then at 90 °C for additional 18 h to give 1 (44.5 g, 90%
1
Shimadzu system (model SPD 10AV). All H NMR and 13C
NMR spectra were recorded on a Bruker 400 MHz spectrometer
using DMSO-d6 as the solvent.
1
recovery yield, 99.9% HPLC area purity, and 100% ee). H
6-[(5S,9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-
methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-yl]nicotinic Acid
(1). Direct Coupling. A 250-mL round-bottom flask was
charged with 6-iodonicotinic acid 2′ (373.3 mg, 1.5 mmol), 5
(414 mg, 1 mmol), dimethylacetamide (2 mL), and diisopro-
pylethylamine (320 mg, 2.5 mmol). After the reaction mixture
was stirred at 110 °C for 16 h under nitrogen, it was cooled to
rt and was slowly added to ice water (2 mL) with stirring. The
resulting white slurry was filtered by vacuum filtration, and the
crude product was washed with water (3 × 2 mL). The crude
product was dried in Vacuo at 60 °C for 18 h and was
redissolved in chloroform (25 mL) and stirred overnight at room
temperature and then at 4 °C for 30 min. The white crystals
NMR (DMSO-d6, 500 MHz) δ 8.68 (s, 1H), 8.31 (s, 1H), 8.00
(s, 2H), 7.90 (s, 2H), 7.63 (s, 2H), 6.84 (s, 2H), 4.37 (t, J ) 9.9
Hz, 1H), 4.16 (d, J ) 9.9 Hz, 3H), 4.00 (d, J ) 12.1 Hz, 1H),
3.19 (s, 3H); 13C NMR (DMSO-d6, 500 MHz) δ 170.81, 166.46,
158.01, 152.81, 150.37, 139.08, 137.81, 133.65, 132.88, 132.15,
128.83, 127.64, 124.46, 114.62, 110.73, 105.48, 48.03, 46.75,
45.24, 24.73. Anal. Calcd for C26H19Cl2N5O4 ·0.62 H2O: C,
57.03; H, 3.73; N, 12.79; Cl, 12.95. Found: C, 57.01; H, 3.34;
N, 12.78; Cl, 13.00.
Received for review April 15, 2010.
OP100104Z
938
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Vol. 14, No. 4, 2010 / Organic Process Research & Development