Organic Process Research & Development
Article
Preparation of (S)-2,2-Diphenyl-2-(pyrrolidin-3-yl)-
acetonitrile (6). To a cold solution of diphenyl acetonitrile
(19) (124.52 g,0.644 mol) in a mixture of THF (500 mL) and
DMF (500 mL) at 0−5 °C under nitrogen atmosphere was
added potassium tert-butoxide (101.22 g, 0.90 mol) in portions,
and the mixture was stirred for 1 h. A solution of 18 (200 g,
0.59 mol) dissolved in a mixture of THF (100 mL) and DMF
(100 mL)) was added into the reaction mixture, and the
reaction mixture was heated to 50−55 °C for 2 h under
nitrogen atmosphere. After complete conversion, THF was
distilled out under reduced pressure at below 50 °C and the
residue was cooled to 25−30 °C. The residue was then diluted
with water (2.0 L) and extracted with ethyl acetate (1 L × 2).
The combined organic layer was washed with a 3% aqueous
solution of sodium hydrogen sulfate (1.0 L) followed by water
(1 L). The ethyl acetate layer was distilled out under reduced
pressure at below 50 °C to yield 20 (213 g) as a light brown
viscous oil.
To a solution of the above residue in methanol (600 mL) at
20−25 °C was added concentrated HCl (185 mL), and the
reaction mixture was warmed to 25−30 °C and stirred for 7 h.
After complete conversion of the starting material, methanol
was removed under reduced pressure at below 50 °C and a
trace amount was removed by codistilling with toluene (400
mL). The residue was diluted with water (1.0 L) and toluene
(1.0 L), cooled to 25−30 °C and extracted with toluene (500
mL). The pH of the aqueous layer was adjusted to 9−10 by
using sodium bicarbonate (110 g, 1.05 mol). The reaction
mixture was extracted with ethyl acetate (1.0 L × 2). The
combined ethyl acetate layer was evaporated under reduced
pressure to obtain 6 (145 g, 95%) as a yellow colored viscous
oil. 1H NMR (CDCl3, 400 MHz, δ ppm): 7.5 (m, 4H), 7.3 (m,
4H), 7.2 (m, 2H), 3.3 (m, 1H), 3.1 (m, 1H), 3.0−2.9 (m, 3H),
2.0 (m, 1H), 1.7 (m, 1H). ESI-mass: calcd for C18H18N2 (M+)/
z 262.36; found (M + H)/z 263.0.
H2O); obtained [α]d25 +16.6° (c 1.0, H2O). 1H NMR (DMSO-
d6, 400 MHz, δ ppm): 9.0−7.5 (brs, 4H), 7.4−7.3 (m, 11H),
6.8 (brs, 1H), 3.9 (s, 2H), 3.8−3.7 (m, 1H), 3.40 (m,1H), 3.1
(m, 1H), 2.7−2.6 (m, 1H), 2.5 (m, 1H), 2.1 (m, 1H), 1.4−1.3
(m, 1H). 13C NMR (DMSO-d6, 100 MHz, δ ppm): 174.9,
174.4, 141.2, 140.8, 129.8, 129.6, 127.9, 127.0, 126.9, 72.2, 62.0,
46.1, 43.7, 41.7, 38.8, 26.6.
Synthesis of Darifenacine Hydrobromide (1) from
Tartrate Salt (3). Compound 3 (300 g, 0.7 mol) was dissolved
in a biphasic mixture of DM water (900 mL) and cyclopentyl
methyl ether (1.2 L), and potassium carbonate (404.55 g, 2.93
mol) was added slowly at 25−30 °C and stirred for 30 min.
Then compound 4 (185.17, 0.82 mmol) was added into the
reaction mixture at 25−30 °C, and the reaction mixture was
heated to 70−75 °C for 12 h. After complete consumption of
the starting material (monitored by HPLC), the reaction
mixture was cooled to 25−30 °C, diluted with CPME (1.2 L)
and DM water (900 mL) and stirred for 30 min. The reaction
mixture was filtered through a bed of hyflow. The filtrate was
separated, and the aqueous layer was extracted with CPME
(600 mL). Combined CPME layers were washed with DM
water and distilled out to obtain a crude residue. CPME was
removed under vacuum; the traces were removed by
codistilling with toluene (600 mL) two times. The viscous
mass was dissolved in acetone (1.5 L) and cooled to 0−5 °C.
Aqueous hydrobromic acid (117.3 mL, 48% in water) was
slowly added, and the mixture was stirred for 2 h at 0−5 °C and
further for 5 h at room temperature. Acetone was distilled out
under reduced pressure, the solid residue was stirred with fresh
acetone (2.4 L) for 4 h and the solids were filtered. The wet
solid (>99.0% HPLC pure) was redissolved in n-butanol (2.1
L) at reflux temperature and stirred for 3 h at room
temperature. The solids were filtered and washed with acetone.
The wet solid was dried under vacuum at 50−60 °C to afford
darifenacin hydrobromide (1, 265 g, 75%) with >99.7% HPLC
purity. 1H NMR (DMSO-d6, 400 MHz, δ ppm): 9.8 (bs, 0.7H),
9.3 (bs, 0.3 H), 7.4−7.3 (m, 10 H), 7.1−7.0 (m, 1H), 7.0−6.7
(m, 2H), 6.7 (m, 1H), 4.5 (m, 2H), 4.0−3.9 (m, 1.3 H), 3.8−
3.7 (m, 0.7 H), 3.4−3.3 (m, 2H), 3.1 (m, 2H), 2.9 (m, 1.3 H),
2.8−2.7 (m, 2H), 2.6 (m, 0.7H), 2.4−2.3 (m, 0.7H), 2.2 (m,
1.3H), 1.6 (m, 0.7 H), 1.5 (m, 0.3 H). 13C NMR (DMSO-d6,
100 MHz, δ ppm): 174.4, 174.2, 158.5, 141.2, 140.7, 140.6,
129.7, 129.4, 129.5, 128.3, 128.0, 127.9, 127.5, 127.2, 127.1,
125.4, 125.2, 108.7, 70.8, 62.4, 62.1, 56.1, 55.2, 55.1, 54.7, 53.0,
52.2, 40.0, 40.8, 30.3, 30.1, 29.0, 26.9, 25.6. Calcd for
C28H30N2O2·HBr, (M+)/z: 425.56; found (M + H)/z 427.2,
(M + Na)/z 449.3. Anal. Calcd for C28H31BrN2O2: C, 66.27; H,
6.16; N, 5.52. Found: C, 66.36; H, 6.07; N, 5.68.
Preparation of (S)-2, 2-Diphenyl-2-(pyrrolidin-3-yl)-
acetamide (2). To a cold solution of sulfuric acid (376 mL,
90%) at 10−15 °C was added compound 6 (135 g, 0.514 mol)
slowly, and the reaction mixture was heated to 85−90 °C for 12
h. After complete consumption of the starting material, the
reaction mixture was poured slowly into chilled water (1.0 L) at
below 15 °C. The pH of the reaction mixture was then adjusted
to 9−10 by adding an aqueous solution of sodium hydroxide
slowly. The reaction mixture was then stirred at 25−30 °C for
30 min and extracted with ethyl acetate (1.0 L × 2). The
combined ethyl acetate layer was washed with water (1.0 L).
The ethyl acetate layer was evaporated under reduced pressure
to obtain a solid residue. The compound was recrystallized with
1
ethyl acetate to obtain 2 (110 g, 76%). H NMR (CDCl3, 400
Dimeric Impurity (15). Isolated from the Viscous Mass
1
MHz, δ ppm): 7.4−7.3 (m, 10 H), 5.8 (bs, 1H), 5.5 (bs, 1H),
3.5−3.4 (m, 1H), 3.1−3.0 (m, 1H), 3.0 (m, 1H), 2.8−2.7 (m,
2H), 2.0 (m, 1H), 1.7 (m, 1H). ESI-mass: calcd for C18H20N2O
(M+)/z 280.37; found (M + H)/z 281.2, (M + Na)/z 303.0.
Preparation of (S)-2,2-Diphenyl-2-(pyrrolidin-3-yl)-
acetamide L-Tartrate (3). To a solution of 2 (100 g, 0.36
mol) in ethanol (1.0 L) was added a solution of L-(+)-tartaric
acid (54.6 g, 0.36 mol) in warm ethanol (600.0 mL), and the
mixture was stirred for 1 h. The reaction mixture was filtered,
and the solid residue was taken in methanol (500 mL) and
heated to reflux for 1 h. Reaction mixture was allowed to cool at
room temperature and stirred for 3 h. The solid crystals were
filtered and dried to obtain 3 (123 g, 80% yield) as colorless
Left in the Reactor. H NMR (CDCl3, 400 MHz, δ ppm):
7.4−7.3 (m, 11H), 7.0 (d, 1H, J = 8.0, Hz), 6.9 (s, 1H), 6.7 (d,
1H, J = 8.0 Hz), 6.7 (m, 2H), 6.0 (m, 2H), 4.6−4.4 (m, 6H),
4.1 (m, 1H), 3.9−3.8 (m, 2H), 3.6−3.5 (m, 1H), 3.4 (m, 1H),
3.3−3.0 (m, 7H), 3.0−2.9 (m, 1H), 2.8−2.7 (m, 3H), 2.2−2.1
(m, 1H). 13C NMR (CDCl3, 100 MHz, δ ppm): 175.2, 159.5,
159.5, 141.2, 140.6, 129.6, 129.4, 128.8, 128.5, 128.2, 128.1,
128.0, 127.7, 126.7, 126.3, 125.9, 125.3, 109.5, 109.5, 71.4, 71.3,
65.8, 63.3, 62.6, 62.2, 61.6, 42.4, 29.6, 29.6, 29.5, 29.0, 27.0.
ESI-mass: calcd for C38H41BrN2O3 (M+)/z 572.74; found
(M+)/z 572.8. Anal. Calcd for C38H41BrN2O3: C, 69.83; H,
6.32; N, 4.29. Found: C, 68.96; H, 6.12; N, 4.19.
1
Bromo Phenol Impurity (12). H NMR (DMSO-d6, 400
crystals. Specific rotation: lit.11 value [α]d +16.3° (c 1.0,
MHz, δ ppm): 9.8 (bs, 1H), 9.5 (bs, 1H), 9.2 (bs, 1H), 7.4−7.3
25
1596
dx.doi.org/10.1021/op300119s | Org. Process Res. Dev. 2012, 16, 1591−1597