Organic Process Research & Development
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MeOH (68.0 mL) at RT then rapidly heated to 80 °C. After
stirring for 2 h it was cooled RT overnight, the white solid was
filtered, and rinsed with MeOH (10.0 mL) to give 2.99 g (87%
filtration and washed with MTBE (30 L). The filtrate was
charged to a clean reactor through a 0.1 μ polishing filter and
cooled to 16 °C. Then 28% NH4OH (35 kg, 576 mol, 10.8
equiv) was added, and the mixture was heated to 30−34 °C.
After 18 h at 30−34 °C, the mixture was cooled to 23 °C. The
layers were separated, and the organic layer was washed with
10% NH4OH (2 × 50 L). The product was crystallized through
a solvent exchange of MTBE to heptane (88 L, 18 3 °C,
100 mmHg) and isolated by filtration after cooling to 20 °C.
The wet cake was washed with heptanes (22 L) and dried
under vacuum (50 °C, 50 mmHg) to yield 12 (6.54 kg, 25.9
1
yield) with 99.3% de by chiral HPLC. H NMR (400 MHz,
DMSO-d6) δ 8.00−7.98 (m, 2H), 7.69−7.65 (m, 1H), 7.56−
7.53 (m, 2H), 6.55 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 7.9 Hz,
1H), 3.64−3.58 (m, 4H), 3.53 (s, 3H), 3.13−3.08 (m, 1H),
2.92−2.87 (m, 1H), 2.74 (m, 4 H), 2.57−2.43 (m, 3H), 2.21−
2.05 (m, 3 H), 1.30−1.19 (m, 2H).
( )-(1S,2S,5R,6R,)-3-Aza-tricyclo[4.2.1.0(2,5)]-non-7-
en-one (8). To a stirred solution of 2,5-norbornadiene (8.0 kg,
86.9 mol) and DCM (41 L) at −15 °C was added over 1.5 h a
solution of chlorosulfonyl isocyanate (12.5 kg, 86.9 mol) in
DCM (16 L) at −15 5 °C. After 0.5 h the batch was warmed
to 15 °C, held for 16 h, and then cooled to <5 °C where DI
water (23 L) was added over 5 min. After the mixture stirred
for 45 min at <5.0 °C and warmed to 20 °C, the layers were
separated. The aqueous was extracted with DCM (24 L), and
the organic phases were combined, washed with brine (20 L),
dried over MgSO4, and filtered. Solids were rinsed with DCM
(10 L), and the filtrate was concentrated to 53.05 kg (760 mm,
37 °C). This was then added over 45 min at 5 5 °C to a
solution of sodium sulfite (8.75 kg, 70.0 mol, 0.8 equiv),
sodium bicarbonate (12.75 kg, 152 mol, 1.8 equiv), and sodium
carbonate (7.55 kg, 70.0 mol, 0.8 equiv) in DI water (120 L).
After stirring for 30 min at 15−20 °C the layers were separated.
The aqueous was extracted with DCM (30 L), and the combined
organics washed with brine (45 L), dried over MgSO4, and
filtered, and the solids were washed with DCM (10 L).
A solvent exchange (760 mm, 37 °C) to heptane (105 L) preci-
pitated the product which was isolated by filtration after cooling
to 20 °C. The wetcake was washed [heptanes (3 × 10 L)],
dried to constant weight at 50 mmHg and 45.0 °C to yield 8.89 kg
(65.7 mol, 75.6%) of 8 as an off-white solid with 96.8 A%.
1H NMR (400 MHz, DMSO-d6) δ 8.02 (s, b, 1H), 6.23 (dd, J =
3.04, 5.64 Hz, 1H), 6.14 (dd, J = 3.24, 5.64 Hz, 1H), 5.75 (s,
1H), 3.33 (d, J = 3.88 Hz, 1H), 2.88 (dt, J = 1.44, 3.04 Hz, 1H),
2.80 (t, J = 1.16 Hz, 1H), 2.75 (s, 1H), 1.60 (d, J = 9.44 Hz,
1H), 1.48 (d, J = 9.44 Hz, 1H).
( )-(1S, 2S, 5R, 6R)-4-Oxo-3-aza-tricyclo[4.2.1.0(2, 5)-
non-7-ene-3-carboxylic acid tert-butyl ester (9). A solution
of 8 (8.5 kg, 62.9 mol, 1.0 equiv) and DMAP (920 g, 7.52 mol,
0.12 equiv) in THF (68 L) was cooled to 2.0 °C, and a solution
of di-tert-butyl dicarbonate (13.73 kg, 62.9 mol, 1.0 equiv) in
THF (25 L) was added over 40 min. After warming to 20 °C
and stirring for 19 h, to the mixture was then added DI water
(68 L), and THF was removed by distillation (21 °C, 50−
80 mmHg). The precipitated solids were filtered, washed
with DI water (17 L), and dried (50 °C, 55 mmHg) to yield
12.68 kg (53.9 mol, 85.8%) of 9 with 97.2A% purity. 1H NMR
(400 MHz, DMSO-d6) δ 6.3 (dd, J = 3.04, 5.60 Hz, 1H), 6.20
(dd, J = 3.24, 5.60 Hz, 1H), 3.78 (d, J = 4.52 Hz, 1H), 3.14
(t, J = 1.24 Hz, 1H), 3.07 (dt, J = 1.32, 4.48 Hz, 1H), 2.94 (s,
1H), 1.55 9d, J = 9.92 Hz, 1H), 1.45 (s, 9H), 1.43 (d, J =
9.90 Hz, 1H).
1
mol, 48%) in 98.3% ee and 94 A% chemical purity. H NMR
(400 MHz, DMSO-d6) δ 7.47 (s, 1H), 7.03 (s, 1H), 6.39 (d, J =
8.64 Hz, 1H), 6.20 (m, 2H), 3.57 (t, J = 8.20 Hz, 1H), 2.7 (s,
1H), 2.53 (s, 1H), 2.36 (d, J = 8.28 Hz, 1H), 2.03 (d, J = 8.72
Hz, 1H), 1.37 (s, b, 10 H), 1.31 (d, J = 8.92 Hz, 1H).
((1S,2S,3R,4R)-3-Amino-bicyclo[2.2.1]hept-5-ene-2-
carboxylic Acid Amide Trifluoroacetate Salt (13). To a
solution of 12 (5.50 kg, 21.8 mol, 1.0 equiv) in DCM (44 L) at
13 °C was added over 1 h trifluoroacetic acid (12.5 kg, 8.1 L,
109 mol, 5.0 equiv). The batch was then warmed to 20 °C and
stirred for 18.5 h. A solvent exchange to MTBE (55 L, 10 vols,
1 atm, max 56 °C) caused the product to precipitate as a white
solid which was isolated by vacuum filtration after cooling to
25 °C. The wetcake was washed with MTBE (11 L) then dried
to constant weight (50 mmHg, 50 °C) to yield 12 (4.63 kg,
17.4 mol, 80%) of 99 A% purity. 1H NMR (400 MHz, DMSO-
d6) δ 7.94 (s, b, 3H), 7.86 (s, 1H), 7.31 (s, 1H), 6.33 (dd, J =
2.8, 5.56 Hz, 1H), 6.20 (dd, J = 3.04, 5.48 Hz, 1H), 3.08 (d, J =
7.72 Hz, 1H), 2.89 (s, b, 2H), 2.40 (d, J = 7.72 Hz, 1H), 2.13
(d, J = 9.32 Hz, 1H), 1.39 (d, J = 9.40 Hz, 1H).
(1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-
bicyclo[2.2.1]hept-5-ene-2-carboxylic Acid Amide, BC-
ring (15). To a mixture of sodium bicarbonate (4.2 kg, 50 mol,
3 equiv) in DI water (22.5) was charged 13 (4.55 kg, 17.1 mol,
1.0 equiv), methanol (45 L), and 2,4,5-trichloropyrimidine
(3.1 kg, 16.9 mol, 0.99 equiv). The batch was stirred at 40 °C
for 22 h and then heated to 60 °C where DI water (29.6 L) was
charged over 0.5 h. The batch was cooled to 55 °C, seeded
(3.7 g), and then cooled to 30 °C. After the mixture stirred 18 h
at RT and cooled to 8 °C, the solids were filtered, washed with
6:7 MeOH/DI water (10 L), and dried under vacuum (50−
100 mmHg, 50−55 °C) to constant weight, yielding 3.82 kg
(12.8 mol, 77.6%) of 15 as a white solid with 99.2 A% purity.
1H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 7.40 Hz, 1H),
8.21 (s, 1H), 7.89 (s, b, 1H), 7.34 (s, b, 1H), 6.34 (dd, J = 2.88,
5.60 Hz, 1H), 6.30 (dd, J = 2.96, 5.60 Hz, 1H), 3.99 (t, J =
7.20 Hz, 1H), 2.89 (s, 1H), 2.75 (s, 1H), 2.54 (s, b, 1H), 2.04
(d, J = 8.92 Hz, 1H), 1.40 (d, J = 8.96 Hz, 1H).
(1S,2S,3R,4R)-3-[5-Chloro-2-(S)-1-methoxy-7-morpho-
lin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yla-
mino)-pyrimidin-4-ylamino]bicycle[2.2.1]hept-5-ene-2-
carboxylic Acid Amide Methanesulfonic Acid Hydro-
chloride Salt (CEP-28122). To a solution of 15 (1.55 kg,
5.03 mol) in 1-methoxy-2-propanol (6 L) was charged 21 (1.46 kg,
5.02 mol, 1.0 equiv) in 1-methoxy-2-propanol (4 L), and the
mixture was then heated to 100 °C, after which methane-
sulfonic acid (350 mL, 518 g, 5.4 mol) was added dropwise
over 50 min at 104−109 °C. Solids were precipitated after
approximately 100 mL of acid had been added. After heating
the batch at 115 °C for 19 h an additional 15 mL (22.2 g, 23 mmol,
4.6%) of methanesulfonic acid was added, and then the mixture
was heated 5 h. The slurry was cooled to <10 °C, and the
((1R,2R,3S,4S)-3-Carbamoyl-bicyclo[2.2.1]hept-5-en-2-
yl)-carbamic Acid tert-Butyl Ester (12). To a mixture of 9
(12.5 kg, 53 mol, 1.0 equiv) and Novozyme 435 resin-
immobilized C. antarctica lipase (8.8 kg, 75 wt %) in MTBE
(112 L) was added DI water (956 g, 53 mol, 1.0 equiv); the
mixture was heated to 50 5 °C and held for 6 d, keeping the
solids just suspended. After the batch was cooled to 25 °C,
MTBE (13 L) was added, and the beads were removed by
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dx.doi.org/10.1021/op200313v | Org. ProcessRes. Dev. 2012, 16, 148−155