Organic Process Research & Development
Technical Note
whereas, with 2.5 vol concentrated HCl, complete conversion
was achieved with 94.79% product formation at 45 °C. Under
these conditions 3b was obtained in 78% overall yield in
formamide reaction against 54−55% in NMP.
In a typical experiment 5 was suspended in formamide (5
vol) and a solution of sodium methoxide in methanol was
slowly added at room temperature (rt). After stirring for 1 h at
rt, the reaction mixture was quenched with water (10 vol) and
filtered to give 6. The wet compound thus obtained was directly
deprotected with concentrated HCl (2.5 vol) at 45−50 °C to
give 3b in 78% overall yield with chromatographic purity
The precipitated solid was filtered, washed with water (2 L)
and dried at 55−60 °C under vacuum to furnish the titled
product 3b (510 g, 77.86%). HPLC analysis: 99.5% ; IR(KBr)
−1
+
1
cm 3200,2820, 1654, 1572: . MS (m/z): 246.2 [M + H] ;
H NMR (DMSO-d ) δ: 2.84−2.86 (m, 4H), 3.00−3.02 (m,
6
4H), 7.14−7.16 (dd, J = 2.3 Hz, 1H), 7.40−7.41 (s, 1H), 7.45-
7.47 (dd, J = 9.9 Hz, 2H), 7.58 (bs, 1H), 8.01 (bs, 1H).
AUTHOR INFORMATION
4011832.
■
9
9.5%. Thus, after considerable efforts, the optimized process
proved robust and reliable and was successfully scaled to
provide kilograms of intermediate 3b. Besides, the present
process had the advantage of replacing NMP with the use of
amidating reagent formamide as the solvent and simplified the
work up procedure.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to Dr. Neera Tewari for informative discussions
and the Analytical Division of Ranbaxy Research Laboratories
for their analytical and spectral support.
CONCLUSION
■
An improved scalable process for the preparation of 5-(1-
piperazinyl)benzofuran-2-carboxamide (3b) has been devel-
oped. A process impurity formed during the reaction was
controlled by optimizing the reaction conditions, resulting in
better yield and quality of product.
REFERENCES
■
(
(
1) Owen, R. T. Drugs Today 2011, 47, 531−537.
2) Robinson, D. S.; Kajdasz, D. K.; Gallipoli, S.; Whalen, H.; Wamil,
A.; Reed, C. R. J. Clin. Psychopharmacol. 2011, 31, 643−646.
(
(
3) Citrome, L. Int. J. Clin. Pract. 2012, 66, 356−358.
4) (a) Sorbera, L. A.; Rabasseda, X.; Silvestre, J.; Castaner, J. Drugs
EXPERIMENTAL SECTION
Future 2001, 26, 247−252. (b) Bottcher, H.; Seyfried, C.; Bartoszyk,
̈
■
G.; Greiner, H. (Merck KGaA) U.S. 5532241, 1996. (c) Heinrich, T.;
Boettcher, H.; Gericke, R.; Bartoszyk, G. D.; Anzali, S.; Seyfried, C.;
Greiner, H.; van Amsterdam, C. J. Med. Chem. 2004, 47, 4684−4692.
General. Reagents were used as such without purification.
Water content of NMP and formamide was determined by Karl
Fischer titration and was controlled below 0.15%. H NMR
1
(
5) Hu, B.; Song, Q.; Xu, Y. Org. Process Res. Dev. 2012, 16, 1552−
557.
6) Bathe, A.; Helfert, B.; Bottcher, H.; Schuster, K. (Merck KGaA).
spectra was recorded using a Bruker 400 MHz spectrometer.
The chemical shift data are reported as δ (ppm) using
tetramethyl silane as internal standard. Mass spectra were
recorded using an API 2000 (MPS SCIEX) instrument.
Infrared spectra were recorded using PerkinElmer FTIR
1
(
U.S. Patent 5723614, 1996.
(7) Ramierz, A.; Mudryk, B.; Rossano, L.; Tummala, S. J. Org. Chem.
2012, 77, 775−779.
(
Spectrum One) instrument. HPLC analysis was performed
on a Waters/Agilent instrument with a UV detector (235 nm)
using a Kromosil C18 (250 mm × 4.6 mm, 3 μm) column and
mobile phase [0.174% (w/v) dipotassium hydrogen ortho-
phosphate solution (adjust pH to 5. 0 ± 0.05 with 0.1% v/v
orthophosphoric acid): acetonitrile, gradient 90:10 (0−5 min),
5
0:50 (5−30 min), 30:70 (30−55 min), 90:10 (55−57 min)
and 90:10 (57−65 min) ] with flow rate 1 mL/min. (Column
oven temperature 30 °C) Retention times: 3b, 5 min; 5, 48
min; 7, 23.6 min.
Preparation of 5-(1-Piperazinyl)benzofuran-2-carbox-
amide (3b). Step 1: Preparation of 6. To a suspension of 5
(
(
3
1
1.0 kg, 2.67 mol) in formamide (5 L), methanolic solution
30% w/w) of sodium methoxide (0.963 kg, 5.34 mol) in 20−
0 min at 20−30 °C. The reaction mixture was stirred at RT for
h and monitored by HPLC. Then cooled the reaction mixture
to 0−5 °C, added water (10 L) at 5−25 °C (addition is slightly
exothermic) and stirred at rt for 1 h. The precipitate was
filtered and washed with water (2 L). The wet solid of 6 (∼1.0
kg) is used as such for next step.
Step 2: Preparation of 3b. The above wet solid of 6 was
added portion wise to concentrated HCl (2.50 L) at 35−45 °C
and stirring continued for 1 h at 45−50 °C. The reaction
mixture was then cooled to 10 °C, water (7 L) added and
adjusted pH to 4−4.5 with 10% (w/v) aqueous sodium
hydroxide solution and added activated carbon (100 g). The
resulting mixture was stirred for 15 min, filtered and adjusted
pH to 9.5−10 using sodium hydroxide solution (10% w/v).
6
67
dx.doi.org/10.1021/op500070t | Org. Process Res. Dev. 2014, 18, 665−667