to 11 °C) and then the cooling bath was removed. After allowing
to warm to rt and stirring for 24 h the mixture was washed
with water (2 × 1200 mL). The dichloromethane solution was
distilled at atmospheric pressure until 2060 mL of dichlo-
romethane had been removed. IMS16 (74 O.P., 2000 mL) was
then added, and distillation continued until an additional 1500
mL of distillate had been collected (distillation head temperature
reached 78 °C). The resulting mixture was allowed to cool to
60 °C, and water (290 mL) was added over 10 min with stirring
to give a turbid solution. The mixture was seeded, and stirring
continued for 30 min whilst cooling further during which
crystallisation began at 29 °C. Further water (110 mL) was
added to the mixture over a 15 min period, and stirring
continued for 10 min. A final portion of water (100 mL) was
added over 10 min, and stirring was continued for 16 h. The
stirred suspension was cooled to between 5 and 10 °C, stirred
for 2 h, and then the solid product was collected by filtration
and washed with a mixture of water (300 mL) and IMS (100
mL) then dried in a vacuum oven at 45-50 °C for 24 h to give
18 as a white solid, 545 g (96%). Mp 62 °C. 1H NMR δ 7.87
(s, 1H), 7.40 (d, J ) 4.0 Hz, 1H), 7.29 (d, J ) 4.0 Hz, 1H),
1.17 (s, 9H).
5-(4-Methoxyphenyl)thiophene-2-sulphonic Acid, tert-
Butylamide (20). A mixture of tri(p-tolyl)phosphine (0.716 kg,
2.35 mol), palladium acetate (0.105 kg, 0.47 mol) and IMS16
(74 O.P., 38.75 kg) was stirred at rt for 4 h to give a yellow
solution with some suspended solid. Meanwhile, sulphonamide
18 (14.0 kg, 46.9 mol), 4-methoxybenzeneboronic acid (7.50
kg, 49.4 mol), aqueous sodium carbonate (2 M, 58.07 kg) and
IMS (74 O.P., 63.75 kg) were mixed by stirring at rt (slightly
exothermic). The prepared catalyst solution was added to mixed
substrates and base in IMS, and the reaction mixture was then
heated under reflux (77-83 °C) for 1.25 h, when 1.25 area %
sulphonamide 18 remained. After cooling to 70 °C, water (135
kg) was added, and the thick heterogeneous reaction mixture
was cooled slowly to 20 °C with stirring. After holding
overnight at this temperature, the crude solid product was
isolated on a centrifuge in 3-4 kg portions, washing each with
50% w/w aqueous IMS (3.0 kg) followed by water (3.0 kg).
The portions were then combined to give the title compound
as a damp orange solid, weight 18.8 kg. Assay by HPLC 83.2%
w/w, therefore contained weight 15.6 kg (>100%). HPLC purity
(Waters Symmetry C8, 4.6 mm × 150 mm at 80 °C, eluting
with 10 mM aqueous NH4OAc/MeCN at 1.5 mL/min, 254 nm
detection): 98.0 area % (largest single impurity 1.43 area %).
Spectral data for a purified sample (recrystallised from
aqueous methanol): Mp 120 °C. LC-MS (AP-): m/z 325 (M-).
1H NMR δ 7.76 (1H, s), 7.65 (2H, m), 7.52 (1H, d), 7.40, (1H,
d), 7.02 (2H, m), 3.81 (3H, s), 1.18 (9H, s). Anal. Calcd for
C15H19NO3S2: C, 55.36; H, 5.88; N, 4.30%; S, 19.70%. Found:
C, 55.43; H, 5.88; N, 4.42; S, 19.35%.
temperature of 165-170 °C. A solution of thiophenol (12.75
kg, 116 mol) in N-methylpyrrolidone (23.0 kg) was then added
and the mixture held at 162-168 °C for 4 h when 0.48 area %
starting material remained. After being cooled to 15 °C and
held overnight, to the reaction mixture was added a solution of
potassium hydroxide (10.2 kg, 181.8 mol) in water (117.9 kg)
(exothermic). The resulting solution was washed three times
with dichloromethane (233.9 kg, 137.9 kg, 134.7 kg), and then
the aqueous layer was acidified to pH 8-8.5 with dilute
hydrochloric acid (prepared from 123 kg of water and 20.3 kg
of concentrated hydrochloric acid) with cooling to maintain the
temperature at around 15 °C. After stirring at 20 °C for 2 h,
the solid was collected on a centrifuge and washed with water
(25 kg) to leave the crude product as a damp grey solid, weight
24.2 kg. Loss on drying of a sample 36.9%, therefore 15.3 kg
dry weight equivalent. Purity by HPLC (Waters Symmetry C8,
4.6 mm × 150 mm at 40 °C, eluting with 10 mM aqueous
NH4OAc/MeCN at 1.5 mL/min, 254 nm detection): 84.5 area
% (8.90 area % 21). Pd level 165 ppm.
Damp crude biaryl 15 prepared above (24.0 kg actual weight,
15.1 kg dry weight equivalent) was dissolved in methanol (113.7
kg), by warming to 60 °C and then was passed through a
cartridge filter to remove insoluble material. The filter was
washed with further hot (60 °C) methanol (39.7 kg), and the
filtrates were combined and then cooled to 50 °C. Water (139.7
kg) was added, the mixture was cooled to 20 °C and held at
this temperature with stirring overnight. The resulting solid was
collected on a centrifuge, washed with toluene (30.0 kg)
followed by water (24.0 kg), and then dried at 45 °C/-950
mbar to afford biaryl 15 as pale-yellow crystals 11.60 kg (48%
yield from sulphonamide 18). HPLC purity (conditions as
above): 95.6% area % (3.22 area % impurity 22 or 23).
Palladium content: 57 ppm. Mp 186 °C. LC-MS (AP-): m/z
310 (M - 1). 1H NMR δ 9.86 (s, 1H), 7.71 (s, 1H), 7.56-7.47
(m, 3H), 7.31, (d, J ) 4.0 Hz, 1H), 6.84 (dd, J ) 11.6, 3.0 Hz,
2H), 1.18 (s, 9H).
5-(4-Hydroxyphenyl)-thiophene-2-sulphonic Acid, tert-
Butylamide (15). Method 2 (Telescoped Process). Sulpho-
namide 18 was prepared from 175 g (0.67 mol) of 5-bro-
mothiophene-2-sulphonyl chloride in a similar manner to the
process given above, with appropriate scaling of quantities. For
the work up, after the reaction mixture had been washed twice
with water, it was concentrated by distillation at atmospheric
pressure until 700 mL of solvent had been collected. After
cooling to 30 °C, IMS (680 mL) was added and a further 600
mL of solvent removed by distillation at atmospheric pressure
leaving a solution of 18 in IMS (volume ∼300 mL, assumed
quantitative yield, 199.5 g). This was converted to methoxy-
biaryl 20 using the procedure described above, with appropriate
scaling of quantities, to afford the damp crude product, weight
386.5 g (assumed quantitative yield for the purposes of
calculating the reagent charges for the next step). Purity by
HPLC 97.3 area %. This was converted to hydroxy biaryl 15
using the procedure given above, with appropriate scaling of
quantities, except that the reaction was carried out at 168 °C
for 7 h. After work up, the crude solid product was dried on
the filter for 30 min to afford crude damp biaryl 15, weight
258.3 g. This material was recrystallised as described above,
5-(4-Hydroxyphenyl)thiophene-2-sulphonic Acid, tert-
Butylamide (15). Method 1. A mixture of damp methoxy
biaryl 20 (30.3 kg, weight corrected for assay 25.1 kg, 77.1
mol) and potassium carbonate (0.80 kg, 5.79 mol) in N-
methylpyrrolidone (108 kg) was heated with stirring until the
mixture started boiling (130 °C). Water was allowed to distill
out, and heating continued until the reaction mixture reached a
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Vol. 13, No. 4, 2009 / Organic Process Research & Development