over 30 min. MS m/z 205 [M + 1] (free base).
(100 mL) over a period of 45 min. The resulting light-yellow
solution was heated to 85 °C and stirred for 3 h until only
trace amounts of 4,4′-difluorobenzhydrol were detected by
TLC analysis in 80:20 heptane/ethyl acetate. The reaction
mixture was cooled to 15-25 °C, diluted with toluene (100
mL), and neutralized with potassium bicarbonate (powder)
to pH 6-7. The mixture was filtered, and the filtrate was
washed with water (3 × 300 mL) and concentrated under
reduced pressure at <40 °C to afford 102.3 g (98% yield)
of compound 4 as a yellow oil in 99% purity by HPLC
(AUC). 1H NMR (300 MHz, CDCl3) δ 7.32-7.21 (m, 4H),
7.05-6.97 (m, 4H), 5.36 (s, 1H), and 3.71-3.62 ppm (m,
4H). HPLC method: Waters Symmetry C8, 5 µm, 3.9 mm
× 150 mm, 1.0 mL/min, 267 nm, 30% CH3CN with 0.1%
TFA:70% water to 90% CH3CN with 0.1% TFA:10% water
over 30 min.
Final preparation of N-(3-Phenylpropyl)piperazine
Dihydrochloride Salt (2). To a solution of piperazine (500.0
g, 5.5 mol) in acetonitrile (1 L) at 75-80 °C was added
1-bromo-3-phenylpropane (85 mL, 0.56 mol) over a period
of 8 h. The mixture was then cooled to 15-25 °C and filtered
to remove piperazine. The filter cake was washed with
acetonitrile (250 mL), and the filtrate was concentrated under
vacuum at <40 °C to furnish a thick, mobile slurry. The
concentrate was diluted with ethyl acetate (500 mL) and
water (500 mL). The organic phase was separated, and the
aqueous layer was back-extracted with ethyl acetate (3 ×
200 mL). The combined organic extracts were washed with
saturated aqueous sodium chloride (250 mL) and then
concentrated under vacuum at <40 °C to afford the free base
as a thick oil. The concentrate was dissolved in ethanol (250
mL), treated with concentrated hydrochloric acid (110 mL),
at 20-30 °C, and stirred for 1 h. The batch was diluted with
acetone (700 mL) at 20-30 °C, and the resultant slurry was
stirred for 2 h. The batch was cooled to 0-5 °C and then
filtered; the filter cake was washed with acetone (150 mL)
and then dried under vacuum at 40 °C to constant weight to
afford 111.5 g (72% yield) of compound 2 in 98.4% purity
Initial Scale-Up of 1-[2-[Bis(4-fluorophenyl)methoxy]-
ethyl]-4-(3-phenylpropyl) Piperazine Dihydrochloride
(GBR-12909). A mixture of compound 4 (1948 g, 6.89 mol),
sodium iodide (2782 g, 18.5 mol), and MEK (17 L) was
heated at 80 °C for 24 h, at which point less than 5% residual
chloroether 4 was detected by HPLC analysis. The reaction
mixture was cooled to 25 °C and filtered through a Celite
pad to remove the inorganic salts. To the filtrate was added
potassium carbonate (5217 g) and salt 2 (1739 g, 6.27 mol).
The batch was heated at 80 °C for 68 h, at which point there
was <10% residual iodoether 5 by HPLC (AUC). The
reaction mixture was cooled to <35 °C, quenched with water
(3.5 L) and saturated aqueous sodium bicarbonate (7 L). The
organic layer was separated, and the aqueous layer was back-
extracted with MEK (3 × 3.5 L). The combined organic
extracts were washed with saturated aqueous sodium chloride
solution (5 L) and then treated with concentrated hydrochloric
acid (1.5 L) and stirred at 20-30 °C for 2 h. The reaction
mixture was then cooled to 0-5 °C and stirred for an
additional 4 h to afford a thick slurry. The crude GBR-12909
was isolated by filtration in reasonable yield (2800 g wet)
and purity 99.0% (AUC by HPLC analysis). The crude
product was purified by dissolution in 5% aqueous ethanol
(25 L) at 80 °C. The solution was cooled to 50-60 °C,
clarified by filtration (to remove extraneous matter), and then
diluted with acetone (34 L). The resultant slurry was cooled
to 0-5 °C and filtered. The filter cake was dried at 45 °C
until the residual ethanol and acetone levels were <0.5%
by GC analysis, to afford 1470 g (45% yield) of GBR-12909
dihydrochloride as a white solid with 99.8% purity by HPLC
1
by HPLC (AUC). H NMR (300 MHz, CD3OD) δ 7.30-
7.16 (m, 5H), 3.69-3.51 (b, 5H), 3.30-3.21 (m, 3H), 2.79-
2.69 (m, 3H), and 2.20-2.08 ppm (m, 3H). HPLC method:
Waters Symmetry C18, 3.5 µm, 2.1 mm × 150 mm, 0.25
mL/min, 267 nm, 15% CH3CN:85% water to 90% CH3CN:
10% water over 30 min.
MS m/z 205 [M + 1] (free base).
Initial Scale-Up of 1-[Bis(4-fluorophenyl)methoxy]-2-
chloroethane (4). A mixture of 4,4′-difluorobenzhydrol
(2100 g, 9.5 mol), 2-chloroethanol (19 L), p-toluenesulfonic
acid (1800 g), and molecular sieves (4 Å) (125 g) was heated
at 85 °C for 10 h. At this point no 4,4′-difluorobenzhydrol
was detected by TLC analysis in 80:20 heptane/ethyl acetate.
The reaction mixture was cooled to 25 °C, diluted with
heptane (12 L), and filtered through a Celite pad to remove
solids. The resulting filtrate was washed with saturated
aqueous sodium bicarbonate solution (3 L) and stirred for
30 min. The aqueous layer was separated and back-extracted
with heptane (3 L). The combined organic extracts were
washed with saturated aqueous sodium chloride solution (3
L), dried over sodium sulfate (500 g), filtered, and concen-
trated under reduced pressure to afford 2511 g (93% yield)
of ether 4 as a yellow oil in 97% purity by HPLC (AUC).
1H NMR (300 MHz, CDCl3) δ 7.32-7.21 (m, 4H), 7.05-
6.97 (m, 4H), 5.36 (s, 1H), and 3.71-3.62 ppm (m, 4H).
HPLC method: Waters Symmetry C8, 5 µm, 3.9 mm × 150
mm, 1.0 mL/min, 267 nm, 30% CH3CN with 0.1% TFA:
70% water to 90% CH3CN with 0.1% TFA:10% water over
30 min.
1
(AUC): mp ) 228-233 °C; H NMR (300 MHz, DMSO-
d6): δ 7.42-7.05 (m, 13H), 5.56 (s, 1H), 3.82-3.54 (m,
10H), 3.3-3.29 (m, 4H), 2.75-2.71 (m, 2H), and 2.11-
2.09 (m, 2H); 13C NMR (300 MHz, DMSO-d6): δ 163.4,
160.2, 140.9, 138.3, 138.2, 129.1, 129.0, 128.8, 128.6, 126.5,
115.7, 115.5, 81.9, 63.1, 55.6, 48.9, 48.3, 40.7, 40.4, 40.2,
39.9, 39.3, 39.0, 32.3, 25.1; IR (KBr) 3433, 2947, 2390,
1603, 1507, 1453, 1222, 1155, 1098, and 1014 cm-1. Anal.
Calcd for C28H34Cl2F2N2O: C, 64.24; H, 6.55; N, 5.35.
Found: C, 63.91; H, 6.47; N, 5.27. HPLC method: Waters
Symmetry C8, 5 µm, 3.9 mm × 150 mm, 1.0 mL/min, 267
nm, 30% CH3CN with 0.1% TFA:70% water to 90% CH3-
Final Preparation of 1-[Bis(4-fluorophenyl)methoxy]-
2-chloroethane (4). A mixture of 2-chloroethanol (37.0 mL,
555 mmol), toluene (60 mL), and sulfuric acid (6.5 mL, 131.0
mmol) was gently heated to 40 °C and treated with a solution
of 4,4′-difluorobenzhydrol (81.26 g, 369 mmol) in toluene
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