Organic Process Research & Development
Communication
1
eluent. E-isomer (12) (1.3 g, 16.5%): H NMR (CDCl3, 400
Preparation of Cyclic Impurity-6 [(Z)-6-(4-Fluorophen-
yl)-1,2,3,4-tetrahydro-2,2-dimethylbenzo(c)azoline-9-
carbonitrile Mesylate]. To a solution of Z-intermediate (13)
(3.2 g, 10.0 mmol) in DCM (15 mL) were added triethyl amine
(1.2 g, 12.0 mmol) and methane sulfonylchloride (1.3 g, 11.0
mmol) respectively at 20 to 25 °C. After complete addition, the
reaction mixture was stirred for 10 min followed by addition of
saturated sodium bicarbonate solution (50 mL). After the
biphasic mixture was stirred for 30 min, the layers were
separated and the aqueous layer was washed with DCM (20
mL). Water was distilled out completely, and the remaining
residue was stirred with acetone (25 mL) and filtered. The
MHz, δ ppm): 2.08 (s, 6H), 2.36−2.44 (m, 2H), 2.50−2.54 (m,
2H), 4.63 (s, 2H), 5.73 (t, J = 7.1 Hz, 1H), 6.98−7.03 (m, 3H),
7.12−7.17 (m, 2H), 7.46 (dd, J = 7.9 Hz, 1.6 Hz, 1H), 7.65 (d,
J = 1.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz, δ ppm): 27.0,
44.5, 58.6, 62.9, 110.5, 115.0, 115.2, 118.7, 130.7, 130.7, 130.9,
131.0, 131.7, 133.1, 134.7, 134.7, 138.4, 141.4, 148.3, 160.6,
163.1. ESI-Mass: For C20H21FN2O, (M + H)/z: 325.4. Found:
(M + H)/z: 325.3. A small sample was further purified by
preparative TLC for elemental analysis. Anal. for C20H21FN2O,
Calcd C, 74.05; H, 6.53; N, 8.64. Found: C, 74.1; H, 6.49; N,
1
8.32. Z-isomer (13) (4.1 g, 51.8%): H NMR (CDCl3, 400
1
filtrate was concentrated to yield Impurity-6 (2.4 g 60%). H
MHz, δ ppm): 2.01 (s, 6H), 2.06−2.17 (m, 2H), 2.25−2.30 (m,
1H), 2.44−2.51 (m, 1H), 4.22 (d, J = 12.6 Hz, 1H), 4.38 (d, J =
12.6 Hz, 1H), 5.17 (bs, 1H), 6.21 (dd, J = 7.0 Hz, 8.6 Hz, 1H),
6.93−6.98 (m, 2H), 7.10−7.13 (m, 2H), 7.27 (d, J = 8.9 Hz,
1H), 7.64 (dd, J = 8.9 Hz, 1.5 Hz, 1H), 7.81 (d, J = 1.5 Hz,
1H), 13C NMR (CDCl3, 100 MHz, δ ppm): 27.9, 45.3, 58.8,
61.3, 111.7, 115.2, 115.4, 118.6, 127.4, 127.5, 128.6, 130.8,
130.9, 132.3, 135.8, 135.8, 138.6, 141.7, 142.6, 160.9, 163.3.
ESI-Mass: For C20H21FN2O, (M + H)/z: 325.4. Found: (M +
H)/z: 325.2. A small sample was further purified by preparative
TLC for elemental analysis. Anal. for C20H21FN2O: C, 74.05;
H, 6.53; N,8.64. Found: C, 73.97; H, 6.55; N, 8.67.
NMR (400 MHz, CDCl3, δ ppm): 2.0 (s, 3H), 2.1−2.2 (m,
1H), 2.7−2.8 (m, 1H), 3.5−3.5 (m, 4H), 3.9 (s, 3H), 3.9−4.0
(m, 1H), 4.4 (d, J = 12.9 Hz, 1H), 5.6 (d, J = 12.9 Hz, 1H), 6.4
(t, J = 7.8 Hz, 1H), 7.0−7.1 (m, 4H), 7.2−7.3 (m, 1H), 7.7 (dd,
J = 8.1, 0.6 Hz, 1H), 8.9 (s, 1H); 13C NMR (100 MHz, CDCl3
δ ppm): 23.4, 39.6, 48.7, 56.5, 62.5, 63.5, 112.1, 115.4, 115.6,
117.8, 128.6, 129.5, 129.5, 130.0, 131.4, 133.2, 136.4, 138.6,
139.7, 145.8, 161.3, 163.8. ESI-Mass: For C20H21FN2 (M+)/z:
307.40. Found: (M+)/z: 307.2. Anal. for C20H21FN2·CH3O3S:
Calcd C, 62.66; H, 6.01; N,6.96. Found: C, 62.60; H, 5.99; N,
7.13.
Preparation of Impurity-7. To a solution of E-
intermediate 12 (1.0 g, 15.3 mmol) in DCM (5.0 mL) were
added triethyl amine (0.4 g, 3.8 mmol), Citalopram free base
(5.0 g, 49.0 mmol), and methane sulfonyl chloride (0.4 g, 3.4
mmol) respectively at 20 to 25 °C. After complete of addition,
the reaction mixture was stirred for 24 h at reflux temperature.
Solvent was distilled out, and Impurity-7 was isolated by HPLC
preparative column chromatography using potassium phos-
phate as buffer and a Phenomenex Luna C18 column to yield
0.8 g (45%). 1H NMR (400 MHz, CDCl3): δ 1.5−1.4 (m, 4H),
2.2 (m, 2H), 2.5 (s, 6H), 2.7 (s, 3H), 2.7 (s, 3H), 3.2 (m, 4H),
4.0 (bs, 2H), 5.2 (ABq, J = 13.5 Hz, 2 H), 5.8 (t, J = 3.1 Hz,
1H), 7.5 (m, 5H), 7.6−7.5 (m, 3H), 7.7 (d, J = 7.8 Hz, 2H), 7.8
(d, J = 8.6 Hz, 1H), 7.8 (s, 1H), 8.0 (s, 1H), 8.1 (d, J = 8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): 17.4, 24.7, 29.0, 36.6, 42.2,
49.3, 49.4, 55.6, 62.9, 64.7, 71.1, 90.1, 110.8, 111.3, 115.4,
115.7, 116.0, 118.0, 118.7, 123.0, 125.8, 126.8, 126.9, 127.1,
128.8, 130.9, 131.0, 131.5, 132.1, 133.5, 133.7, 134.3, 138.0,
140.0, 140.0, 148.7, 150.3, 160.2, 160.4, 162.6, 162.8. ESI-Mass:
For C40H42F2N4O (M+)/z 631.80. Found: (M+)/z 631.3.
Alternative Preparation of Intermediates 12 and
13. Preparation of 4-(4-(Dimethylamino)-1-(4-fluorophen-
yl)-1-hydroxybutyl)-3-(tert-butyldimethylsiloxymethyl)-
benzonitrile (8). To a solution of diol 3 (10 g, 29.0 mmol) in
DCM (60 mL) were added imidazole (4.0 g, 59.0 mmol) and
TBDMSCl (5.5 g, 36.0 mmol) portionwise at 10−15 °C,
respectively. The reaction mixture was stirred for 30 min at 10−
15 °C and quenched by adding water (40 mL). Layers were
separated, and the organic layer was washed with water (50 mL
× 2). DCM was distilled out completely, and product was
washed with hexane (50 mL) to get desired O-TBDMS
1
protected 8 (10.9 g, 82%) as a white solid. H NMR (CDCl3,
400 MHz, δ ppm): −0.16 (s, 3H), −0.12 (s, 3H), 0.8 (s, 9H),
1.5−1.6 (m, 2H), 2.14−2.2 (m, 7H), 2.3−3.0 (m, 1H), 2.34−
2.39 (m, 1H), 2.49−2.55 (m, 1H), 4.40 (d, J = 15.5 Hz, 1H),
4.83 (d, J = 15.5 Hz, 1H), 6.91−6.96 (m, 2H), 7.24−7.28 (m,
2H), 7.53−7.60 (m, 2H), 7.97 (s, 1H), 8.9 (bs, 1H); 13C NMR
(CDCl3, 100 MHz, δ ppm): −5.7, −5.6, 18.2, 22.3, 25.8, 43.3,
44.7, 59.9, 62.4, 110.7, 114.4, 114.7, 119.3, 126.5, 127.6, 127.7,
129.3, 131.2, 142.6, 142.6, 143.1, 148.3, 160.3, 162.7; ESI-Mass:
For C26H37FN2O2Si, (M + H)/z: 457.68. Found: (M + H)/z:
457.4. Anal. for C26H37FN2O2Si: Calcd C, 68.38; H, 8.17; N,
6.13. Found: C, 68.32; H, 8.13; N, 6.19.
Preparation of Intermediate 4-(E/Z)-4-(Dimethylamino)-1-
(4-fluorophenyl)but-1-enyl)-3-(hydroxymethyl)benzonitrile
(12 and 13). To a solution of 8 (10 g, 22.0 mmol) in DCM (50
mL) were added triethyl amine (3.3 g, 33.0 mmol) and
methane sulfonyl chloride (2.6 g, 23.0 mmol) respectively at 0−
5 °C. After complete addition, the reaction mixture was
warmed at 25 °C and stirred for 1 h. Reaction was quenched by
adding water (50 mL), layers were separated, and the organic
layer was dried over anhydrous sodium sulfate and solvent was
distilled out completely. The crude reaction mixture was
dissolved in THF, 1.0 M TBAF solution (70 mL) was added to
it, and the reaction mixture was stirred for 2 h. Reaction
mixture was concentrated to leave a crude residue. E and Z
isomer (12/13) were purified by silica gel column chromatog-
raphy using methanol and chloroform (1:99) as eluent.
ASSOCIATED CONTENT
* Supporting Information
■
S
Spectral data of selected intermediates and final compound.
This material is available free of charge via the Internet at
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank Mr. Samit Mehta, our management,
and the ARD group of Emcure Pharmaceuticals Ltd. for their
willing support and constant encouragements.
828
dx.doi.org/10.1021/op300039c | Org. Process Res. Dev. 2012, 16, 824−829