Organic Process Research & Development
Article
Next, CuI (0.084 kg, 0.020 equiv, 0.442 mol) was charged in a
single portion. The mixture was degassed by evacuating and
refilling via nitrogen bleed three times. Pd(PPh3)2Cl2 (0.16 kg,
0.010 equiv, 0.221 mol) was charged in a single portion, and
the mixture was heated to 35 °C. Next, ammonium hydroxide
(28% solution) (12.6 kg, 8 equiv) was charged via pressure can,
carefully maintaining an internal temperature in the range of 35
− 40 °C. The addition time was approximately 45 min. The
reaction was held in this range for 1 h and deemed complete by
LC analysis (NMT 1% starting material). Next, a solution of L-
cysteine (0.5 kg, 0.167 equiv, 3.69 mol) in water (3.0 kg, 3.0 L)
and 28% ammonium hydroxide (0.7 kg) was added to the
reaction and held for 2 h. The mixture was cooled to 20 °C to
effect crystallization. Water (47.3 kg, 47.3 L) was added over a
period of 45 min, and the suspension was cooled to 5 °C. After
N,N-diisopropylethylamine (DIPEA) (2.9 kg, 22.4 mol, 3.9 L).
This material was stored at ambient temperature. Into a 100 L
fixed vessel at 25 °C was charged NMP (12.4 kg, 12.1 L)
followed by 1,1-carbonyldiimidazole (CDI) (3.5 kg, 1.10 equiv,
21.6 mol). This mixture was stirred to dissolve. The solution of
(6) was charged at 25 °C to the fixed vessel over a period of 60
min. The transfer line was washed with an additional amount of
NMP (1.4 kg, 1.4 L). The vessel was aged at 25 °C for 1 h.
Generation of the activated intermediate was checked by
quenching a small aliquot into a 1 M methylamine solution in
THF (HPLC retention time of methylamine adduct: 6.11 min).
The reaction was deemed complete when the area percent of
acid 6 was less than 3% of the corresponding methyl amide.
Into a 200 L vessel was charged NMP (11.5 kg, 11.2 L)
followed by 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine dihydrobro-
mide (7) (5.7 kg, 1.05 equiv, 20.3 mol). To this was charged
DIPEA (4.6 kg, 35.5 mol, 6.2 L) over a period of 25 min,
keeping the temperature below 35 °C. The contents from the
100 L vessel were transferred at ambient temperature to the
200 L vessel over a period of 45 min. The reaction was held at
25 °C for a minimum of 4 h. The reaction progress was again
checked by quenching a small aliquot into methylamine. Once
deemed complete, water (84.0 kg, 84.0 L) was added over a
period of 2 h to the mixture at 30 °C. If needed, an additional
charge of water (28 kg, 28 L) may be added to aid in
crystallization if crystals are not observed after 1h. The mixture
was held at 25 °C overnight and filtered. The cake was washed
with water (33.6 kg, 33.6 L) followed by MTBE (20.7 kg, 28.0
L), and allowed to dry on the filter overnight. The solids were
weighed to provide 1 as a white powder (6.59 kg, 86.5% yield,
99.5% purity, form I mp = 140 °C). HPLC retention time: 6.44
1 h at this temperature, the solids were filtered on a Nutsche
̈
filter and washed consecutively with water (30.9 kg), two 28%
ammonium hydroxide solution portions (14.2 kg each), and
water (23.5 kg). To effect further residual Pd removal, the cake
was washed with a 2:1 MeOH:water solution (28.6 kg). Finally,
the crystals (6.34 kg, 86.1% yield, 98.5% purity, mp = 109 °C)
were dried under positive nitrogen flow. HPLC retention time:
1
8.33 min. H NMR (300 MHz, DMSO-d6) δ 8.65 (dt, J = 4.0,
0.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 8.8, 2.2 Hz,
1H), 7.90 (td, J = 7.8, 1.8 Hz, 1H), 7.70 (d, J = 4.5 Hz, 1H),
7.52 (t, J = 72.6 Hz, 1H), 7.45−7.49 (m, 2H), 3.89 (s, 3H); 13
C
NMR (100 MHz, DMSO-d6) δ 164.7, 154.7, 150.3, 141.7,
136.9, 134.6, 132.0, 127.7, 126.5, 124.0, 117.9, 116.0 (t, J = 260
Hz), 113.7, 94.1, 82.0, 52.5. HRMS calculated for
C16H11F2NO3: 304.07798 [M + H]; found: 304.07793.
4-(Difluoromethoxy)-3-(pyridin-2-ylethynyl)benzoic
Acid (6). Water (31.5 kg, 31.5 L) and methanol (27.8 kg, 38.6
L) were charged at 20 °C. Next, 5 (6.33 kg, 1.00 equiv, 21.8
mol) was added as a solid, and the suspension was heated to
the range of 35−40 °C. To this suspension was added a
solution of 50% NaOH (2.10 kg, 26.2 mol, 1.2 equiv) via a
pressure can, keeping the temperature in the range of 35−40
°C. Addition time was approximately 30 min. The pressure can
and transfer line were rinsed with 1.7 kg of water. The reaction
was allowed to react until deemed complete by HPLC analysis
(NMT 1% starting material). Typical reaction time was
approximately 1 h. The reaction was diluted with water (32.5
kg, 32.5 L) and warmed to 45 °C. A solution of HOAc (6.80
kg, 6.48 L) in water (13.7 kg, 13.7 L) was slowly charged from a
pressure can over a period of 3 h. After addition of the acetic
acid solution, the mixture was cooled to 20 °C and held for one
1
min. H NMR (300 MHz, DMSO-d6, rotomeric mixture) δ
8.65 (d, J = 6.0 Hz, 1H), 8.49 (dd, J = 8.8, 4.7 Hz, 1H), 7.98 (t,
J = 2.3 Hz, 1H), 7.90 (td, J = 7.8, 1.8 Hz, 1H), 7.79−7.84 (m,
2H), 7.65−7.68 (m, 1H), 7.43−7.48 (m, 2H), 7.47 (t, J = 73.0
Hz, 1H), 7.28−7.34 (m, 1H), 4.90 (d, J = 14.3 Hz, 2H), 4.85
(d, J = 16.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6,
rotomeric mixture) δ 167.3, 157.4, 156.6, 150.3, 149.0, 141.8,
136.9, 134.5, 132.7, 131.3, 130.0, 127.6, 123.9, 122.5, 118.5,
117.9, 116.3 (t, J = 260 Hz), 113.7, 93.9, 82.6, 54.3, 52.8.
HRMS calculated for C22H15F2N3O2: 391.1132 [M+]; found:
391.1137.
Conversion to Form II. Due to volume restrictions, the
clarification process was split into two equal batches. Crude 1
(3.2 kg, 8.2 mol) was dissolved in EtOAc (86.1 kg, 97.0 L) at
reflux (77 °C). The solution was allowed to cool to 50 °C in
preparation for filtration. The solution was filtered through a
hour, and the solids were collected on a Nutsche filter. The
̈
solids were washed with water (78.0 kg, 78.0 L) and dried
under positive nitrogen flow. The solids were weighed to
provide 6 as a white powder (5.86 kg, 99.1% yield, 98.8%
pad of Darco G-60 (1.2 kg) and Celite (0.7 kg) on a Nutsche
̈
filter and through a 5-μm in-line filter into a fixed vessel. The
reactor, filter, and lines were washed with additional EtOAc
(9.51 kg, 10.7 L). The procedure was repeated for the second
3.2 kg portion of 1. The combined solution of 1 was
concentrated at atmospheric pressure to a final volume of
approximately 50 L and cooled to 55 °C. A 75 mL portion of
the batch was removed and sonicated for 10 min at ambient
temperature to generate the desired form II seeds. The seeds
were added back to the batch at 55 °C. Next, heptane (44.1 kg,
64.0 L) was added to the mixture over a period of 1 h. The
mixture was held at 55 °C for 30 min before being cooled to 0
°C over a minimum of 4 h. The contents of the reactor were
held at 0 °C for 8 h. 1 was isolated as the desired form II (mp =
142 °C) (5.51 kg, 87.1% yield, 100% purity) by filtration.
1
purity, mp = 240 °C). HPLC retention time: 4.24 min. H
NMR (300 MHz, DMSO-d6) δ 8.64 (d, J = 6.0 Hz, 1H), 8.18
(d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.5, 2.3 Hz, 1H), 7.90 (td, J =
7.8, 1.8 Hz, 1H), 7.69 (dd, J = 10.0, 1.7 Hz, 1H), 7.49 (t, J =
73.0 Hz, 1H), 7.44−7.49 (m, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 165.7, 154.3, 150.3, 141.8, 136.9, 134.7, 132.1,
128.0, 127.6, 124.0, 117.9, 116.1 (t, J = 260 Hz), 113.5, 93.9,
82.3. HRMS calculated for C15H9F2NO3: 290.06233 [M + H];
found: 290.06264.
(4-Difluoromethoxy-3-pyridin-2-ylethynyl-phenyl)-
(5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone, 1
(1). Into a Hastelloy pressure can was charged 6 (5.61 kg,
1.00 equiv, 19.4 mol) followed by NMP (11.5 kg, 11.2 L) and
F
dx.doi.org/10.1021/op3002728 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX