product was washed with 20 mL of water and dried in a
none (9). To a nitrogen-purged ethyl acetate solution of
1-((2R,5S)-(4-(4-fluorobenzyl)-2,5-dimethylpiperazin-1-yl)-
2-(4-chloro-2-(chloromethyl)phenoxy)ethanone (7) (584 L/0.30
M) at 20 °C was added solid potassium thioacetate (30.1
kg/1.50 equiv.). The reaction was heated to 50 °C for 8 h,
and then cooled to 25 °C and washed with water (2 × 150
L). The organic layer was separated and concentrated
atmospherically to approximately 100 L (1.50 M, calculated
from starting benzyl alcohol). Toluene (215 L) was added
to the oil followed by reduced pressure distillation to
approximately 100 L (max. pot temperature not to exceed
40 °C). The toluene dilution/concentration was twice re-
peated. The ethanethioate oil was again diluted with toluene
(150 L) followed by hexane (230 L). Some precipitation was
evident at this point. The resulting mixture was heated to
60 °C and held until a complete solution was achieved. The
heated solution was cooled to 10 °C and stirred for 2 h
following initial precipitation. The precipitate was filtered,
rinsed with hexanes, and dried under vacuum at 50 °C.
vacuum oven for use in the following step. Mp: 152-153
1
°C. H NMR (400 MHz, CD3OD): δ 7.23 (dd, 2H), 6.88
(dd, 2H), 5.21 (s, 1H), 4.62 (s, 2H). 13C NMR (CD3OD): δ
171.26, 159.95, 129.21, 126.16, 116.00, 64.86, 47.92. Anal.
calcd for C8H7ClO3: C, 51.50; H, 3.78. Found: C, 50.33;
H, 3.54.
2-(4-Chloro-2-(chloromethyl)phenoxy)acetic Acid (13).
To a clean, dry 2-L vessel were added 2-(4-chlorophenoxy)-
acetic acid (12) (100 g, 0.536 mol), paraformaldehyde (72.4
g, 0.800 mol), acetic acid (400 mL, 6.98 mol), 37%
concentrated hydrochloric acid (368 mL, 4.29 mol), and
phosphoric acid (59.6 mL, 1.07 mol). The reaction was
heated to 85-95 °C for 18 h. The reaction was cooled to
20-30 °C and then analyzed for reaction completion by
HPLC. Ethyl acetate (500 mL) was added to the reaction
which was then stirred for 20 min. The phases were
separated, the organic layer was concentrated, and the white
product was filtered off and washed with ethyl acetate (20
mL). After drying under vacuum at 40-50 °C for 12 h with
a slight nitrogen bleed, 2-(4-chloro-2-(chloromethyl)phen-
1
Yield: 81% (two steps). H NMR (DMSO-d6): δ 0.92 (d,
3H), 1.22 (d, 3H), 2.22 (d, 1H), 2.31 (s, 3H), 2.70 (dd, 1H),
2.98 (m, 1H), 3.31(bs, 1H), 3.44 (d, 1H), 3.59 (d, 1H), 3.71-
(bs, 1H), 4.10 (s, 2H), 4.26 (bs, 1H), 4.76 (d, 1H), 4.86 (d,
1H), 6.95 (d, 1H), 7.09 (t, 2H), 7.22 (dd, 1H), 7.28 (d, 1H),
7.36 (t, 2H). 13C NMR (DMSO-d6): δ 7.0, 15.9, 20.1, 26.9,
29.7, 42.9, 45.9, 48.3, 51.0, 56.7, 66.9, 113.8, 114.4, 124.1,
126.4, 127.7, 128.2, 129.1, 129.6, 134.7, 154.6, 160.1, 161.7,
165.5.
1
oxy)acetic acid (13) was isolated. Mp: 112-113 °C. H
NMR (400 MHz, CD3OD): δ 7.4 (dd, 1H), 7.26 (qd, 1H),
6.9 (dd, 1H), 4.74 (s, 2H), 4.69 (s, 2H). 13C NMR (CD3-
OD): δ 170.87, 154.75, 130.09, 129.28, 128.72, 126.07,
113.61, 65.31, 39.98. Anal. calcd for C9H8Cl2O3: C, 45.99;
H, 3.43. Found: C, 45.33; H, 3.32.
1-((2R,5S)-4-(4-Fluorobenzyl)-2,5-dimethylpiperazin-
1-yl)-2-(4-chloro-2-(chloromethyl)phenoxy)ethanone (7).
To a concentrated solution of 1-((2R,5S)-4-(4-fluorobenzyl)-
2,5-dimethylpiperazin-1-yl)-2-(4-chloro-2-(hydroxymethyl)-
phenoxy)ethanone (6) in 2-methyltetrahydrofuran (74.0 kg/
75.9 L solution) was added ethyl acetate (214 L). The
resulting solution was concentrated under atmospheric pres-
sure to a minimum stir volume. To the concentrated solution
was added ethyl acetate (214L). Again, the solution was
concentrated to a minimum stir volume. The ethyl acetate
charge/concentration sequence was repeated until the water
content was reduced to 1.0% or less via KF analysis. Upon
completion of drying, ethyl acetate (874 L) was added to
the concentrated solution to create a final dried solution with
a concentration of 0.50 M. To a nitrogen-purged solution of
thionyl chloride (31.4 kg) in ethyl acetate (532 L) at 20 °C
was added the dried ethyl acetate solution of 1-((2R,5S)-4-
(4-fluorobenzyl)-2,5-dimethylpiperazin-1-yl)-2-(4-chloro-2-
(hydroxymethyl)phenoxy)ethanone (6) at a rate to ensure the
temperature did not exceed 35 °C. The reaction mixture was
stirred at 25 °C for 2 h followed by an aqueous quench (361
L). The organic layer was separated, washed with water, and
added to a 1.0 N NaOH solution (381 L) at a rate to ensure
the temperature did not exceed 30 °C. The resulting mixture
was stirred for 30 min at 20 °C, and the organic layer was
separated and dried with several atmospheric ethyl acetate
azeotropic distillations. The product (7) was delivered to the
next step as a dried ethyl acetate solution (0.30 M, calculated
as 100% yield from starting benzyl alcohol).
(2-(2-((2R,5S)-4-(4-Fluorobenzyl)-2,5-dimethylpiperazin-
1-yl)-2-oxoethoxy)-5-chlorophenyl)methanesulfonic Acid
(8). To a nitrogen-purged reactor at 20 °C were added solid
(2-(2-((2R,5S)-4-(4-fluorobenzyl)-2,5-dimethylpiperazin-1-
yl)-2-oxoethoxy)-5-chlorophenyl)methanesulfonic acid (9)
(34.2 kg/71.3 mol) and 96% formic acid (7.20 L/kg
ethanethioate). To the formic acid solution at 20 °C was
added 30% hydrogen peroxide (3.77 L/0.467 equiv). The
exotherm was noted, and the temperature rise was recorded.
The reaction was stirred at 20 °C for 2 h followed by the
addition of a second aliquot of 30% hydrogen peroxide (3.77
L/0.467 equiv). Again, the exotherm was noted, and the
temperature rise was recorded. The reaction was stirred at
20 °C for 2 h. The reaction mixture was sampled and
analyzed by HPLC to monitor starting material consumption
and sulfonic acid formation. (A lack of starting material
consumption and sulfonic acid formation implies a buildup
of hydrogen peroxide, and subsequent additions should be
discontinued.) Upon determination of safe hydrogen peroxide
consumption, the reaction mixture was treated with seven
further aliquots of 30% hydrogen peroxide (3.77 L/0.467
equiv) with 2-h reaction times at 20 °C. Samples for HPLC
analysis were taken following aliquots 5 and 8 to reaffirm
safe peroxide consumption. Upon complete addition of
hydrogen peroxide, the reaction mixture was added to a
suspension of 96% formic acid (39 L) and activated carbon
(Darco G-60) (1.70 kg) at 20 °C under a high-volume
nitrogen sweep over 2 h. A gentle gas evolution was noted
and confirmed a controlled consumption of excess hydrogen
peroxide. The resulting suspension was stirred at 20 °C for
1-((2R,5S)-(4-(4-Fluorobenzyl)-2,5-dimethylpiperazin-
1-yl)-2-(4-chloro-2-(acetoxythiomethyl)phenoxy)etha-
760
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Vol. 11, No. 4, 2007 / Organic Process Research & Development