Organic Process Research & Development
was <0.05% in all batches with a purity range of 99.72−99.83
Article
9
(4aS,7aS)-7a-(5-Amino-2-fluorophenyl)-4a,5,7,7a-tetrahy-
dro-4H-furo[3,4-d][1,3]thiazin-2-amine (21). To 17·TsOH
(95 kg, 22.2 mol) and LiOH·H O (21.8 kg, 71.5 mol, 3.2
equiv) in a glass-lined reactor was added 376 kg of MeOH. The
mixture was heated at reflux for 2−3 h and allowed to cool to
50 °C. 37% aqueous HCl (160 kg, 222 mol, 10 equiv) was
added over 30 min, and the mixture was heated at reflux for 2−
4 h. MeOH was distilled at 50 °C until the mixture was <25%
w/w MeOH by GC (distillate approximately 380 L). The
HPLC area %. Assay = 98.8−99.3% based on HCl salt. mp 275
1
°
C. HPLC Method A t = 3.17 min. H NMR (D O) 7.65−
R
2
2
7
.62 (m, 1H), 7.46−7.42 (m, 1H), 7.30−7.25 (m, 1H), 4.40
(
dd, J = 2.6, 10.5 Hz, 1H), 4.24−4.18 (m, 1H), 4.18 (s, 1H),
4
2
1
1
.05−4.01 (m, 1H), 4.01−3.94 (m, 2H), 3.26−3.21 (m, 1H),
13
.15 (s, 3H). C NMR (D O) 175.75, 160.79, 159.17, 136.38,
2
36.36, 128.07, 128.01, 125.19, 125.10, 124.41, 124.39, 120.19,
20.03, 77.92, 77.87, 71.10, 67.32, 67.30, 61.00, 49.27, 25.30.
+
+
HRMS (ESI ): calcd. for C H FN O [M + H ] 262.1296;
mixture was cooled to rt, and 143 kg of H O and 290 kg of
1
3
18
2
3
2
found 262.1290.
toluene were added. The mixture was agitated, and the layers
N-((4aS,7aS)-7a-(5-Acetamido-2-fluorophenyl)-4a,5,7,7a-
tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide 4-
methylbenzenesulfonate (17·TsOH). To amino alcohol 8
were separated. Diamine 21 seed crystals (2.4 kg) were slurried
in H O (190 kg) in a separate reactor fitted with a pump, a
2
recirculation loop, and mixing elbows (see the API step for a
detailed description of the mixing elbow coaddition equipment
set). The seed slurry bed was heated at 55 °C and recirculated
through the mixing elbows and recirculation loop. A solution of
approximately 175 kg of 35% aqueous NaOH and the acidic
diamine solution from above were added simultaneously into
the mixing elbow recirculation loop at a rate that maintained
the pH range of 10−13. The amine solution vessel was rinsed
(
40 kg, 131 mol) was added THF (333 kg), Et N (14.6 kg, 144
3
mol, 1.1 equiv), and a THF (25 kg) rinse of the charge vessel.
The mixture was heated at 50 °C as a solution of BzNCS (21.4
kg, 131 mol, 1.0 equiv) in THF (66 kg) was added over 1.5 h,
followed by a THF (5 kg) rinse of the charge vessel. After 1 h,
the IPC showed <2.0% remaining 8, or an additional charge of
BzNCS (0.66 kg, 4.0 mol, 0.03 equiv) was added (required on
only one batch). To this solution at 50 °C was added CDI
with 10 kg of H O. The product slurry was cooled to rt, and the
2
(21.3 kg, 131 mol, 1.0 equiv) as a solid through the reactor inlet
product was collected via centrifuge and washed with H O (2 ×
2
connected to a glovebag. After 60 min, the IPC showed <2.0%
remaining alcohol intermediate 11 or an additional charge of
CDI (charge adjusted based on the area % remaining 11, i.e., if
190 kg). After drying, the average isolated yield of diamine 21
over five approximately 95 kg batches was 89%. Purity = 99.9−
100 HPLC area %. Assay = 99.9−100%. mp 129 °C. HPLC
1
3
3
% 11, then add 3% of the original CDI charge) was added. For
of 8 batches, an additional charge of CDI was required. After
Method A t = 4.67 min. H NMR (DMSO-d ) 6.77 (dd, J =
R
6
8.9, 12.2 Hz, 1H), 6.63 (dd, J = 2.7, 7.0 Hz, 1H), 6.41 (td, J =
3.4, 8.5 Hz, 1H), 5.92 (s, 2H), 4.89 (s, 2H), 4.15 (d, J = 7.9 Hz,
1H), 3.97−3.82 (m, 2H), 3.62 (dd, J = 2.4, 7.9 Hz, 1H), 2.96−
the IPC was met, the mixture was heated at reflux for 8 h. The
mixture was transferred to another reactor with a THF (40 kg)
rinse, and the solvent was exchanged under vacuum using
EtOAc (890 kg) added in two portions, until GC showed <2%
THF remaining. 10% aqueous citric acid (200 kg) was added,
and the layers were agitated and separated at 20 °C. An
additional wash with 10% aqueous citric acid (200 kg) was
completed. The organic layer was heated at 60 °C as an 8%
solution of p-TsOH·H O (130 kg, 54.7 mol p-TsOH·H O, 0.42
1
3
2.83 (m, 2H), 2.85−2.79 (m, 1H). C NMR (DMSO-d )
6
152.52, 150.67, 148.24, 144.62, 144.61, 130.59, 130.50, 116.19,
115.99, 114.82, 114.80, 112.92, 78.00, 77.96, 69.67, 65.45,
65.41, 36.04, 24.01. HRMS (ESI): calcd. for C H FN OS [M
12
15
3
+
+ H ]: 268.0914; found 268.0906.
N-[3-[(4aS,7aS)-2-Amino-4a,5-dihydro-4H-furo[3,4-d]-
[1,3]thiazin-7a(7H)-yl]-4-fluorophenyl]-5-fluoro-2-pyridine-
carboxamide (LY2886721, 1). Acid chloride preparation: To a
2
2
equiv) in EtOAc was added. The solution was seeded with 0.2
kg of 17·TsOH in 0.5 L of EtOAc. After 30−45 min a slurry
glass-lined reactor was added CH CN (65 kg) and DMF (9.4
3
resulted, and an 8% solution of p-TsOH·H O (182 kg, 76.6 mol
kg, 129 mol, 1.1 equiv), followed by oxalyl chloride (15.6 kg,
123 mol, 1.05 equiv) over approximately 2 h, as the
temperature was maintained below 30 °C. The feed vessel
2
p-TsOH·H O, 0.58 equiv) in EtOAc was added over 3 h. After
2
an additional 1 h at 60 °C, the mixture was cooled to 20 °C
over 3 h and stirred for 1 h. The solids were collected by
was rinsed with CH CN (1 kg). To this slurry was added five
3
2
filtration on a 1 m (1000 L) agitated filter and washed with
approximately equal portions of solid acid 28 (16.5 kg, 118
mol) using a butterfly valve, with a 10 min stir time between
EtOAc (2 × 72 kg) to afford the wet cake product. A total of 8
wet cake batches were collected and combined for drying in 5
batches to afford 478 kg (75% average yield for four 40 kg
batches and four 42.5 kg batches) of aminothiazine 17·TsOH.
portions. The addition port was rinsed with CH CN (1 kg).
3
The mixture was stirred at 30 °C for approximately 30 min, or
until the solids were dissolved. A sample was quenched using
Purity = 99.8−99.9 HPLC area %. Assay = 98.7−99.6%. mp
MeOH and analyzed using HPLC Method B (acid t = 1.73
R
1
1
1
1
7
7
44 °C. HPLC Method A t = 6.15 min. H NMR (CDCl )
min, methyl ester/acid chloride t = 3.46 min). If >3.0% acid
R
3
R
2.52 (br s, 1H), 11.91 (br s, 1H), 9.33 (s, 1H), 8.19−8.08 (m,
H), 8.05 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 7.8 Hz, 2H), 7.65−
.63 (m, 1H), 7.57 (t, J = 7.3 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H),
.15 (d, J = 8.3 Hz, 2H), 7.09 (dd, J = 9.3, 12.2 Hz, 1H), 4.29
s, 1H), 4.27−4.24 (m, 2H), 4.16 (dd, J = 6.6, 9.0 Hz, 1H),
.83−3.76 (m, 1H), 3.34 (dd, J = 2.9, 13.7 Hz, 1H), 3.00 (dd, J
4.4, 14.2 Hz, 1H), 2.36 (s, 3H), 2.09 (s, 3H). 13C NMR
CDCl ) 171.38, 169.56, 166.71, 155.85, 153.95, 140.89,
remained, an additional oxalyl chloride (0.3 kg, 0.025 equiv)
was added. The solution was degassed to remove CO for safety
reasons (3 cycles of 6−7 psi vacuum alternating with N ). The
2
acid chloride solution (approximately 99 kg) was transferred
into a drum and used within 48 h (longer storage at 0−5 °C is
an option).
(
3
=
Coupling: To a glass-lined reactor was added diamine 21
(
(25.6 kg, 95.7 mol), H O (256 kg), and EtOH (202 kg, 96%,
3
2
1
1
7
36.30, 134.41, 129.72, 128.96, 128.91, 125.81, 123.34,
23.27, 122.12, 122.02, 120.39, 117.55, 117.36, 76.50, 76.47,
not denatured, used throughout). The mixture was heated to 45
°C to afford a solution, and approximately 93 kg of acid
chloride solution prepared above (1.2 equiv based on 98% yield
in acid chloride preparation) was added subsurface at 45 °C
0.12, 68.07, 68.03, 39.34, 39.30, 25.18, 24.09, 21.32. HRMS
+
(ESI): calcd. for C H FN O S [M + H ]: 414.1282; found
2
1
21
3
3
75
414.1267.
over 1 h. The transfer line was rinsed with CH CN (3 kg).
3
N
Org. Process Res. Dev. XXXX, XXX, XXX−XXX