Organic Process Research & Development
Article
were instituted between production runs as a measure to
ensure adequate light penetration and to avoid clogging of the
lines. A total of 51.8 kg of cyclobutane 2 of 97.9 wt % and
and ethylene gas feeds were initiated at 138.4 g/min and 1800
mL/min (1.5 equiv), respectively. Samples of the reaction
stream were collected at regular intervals for analysis by GC,
and the bulk solution was collected into a 2000 L stainless steel
reactor. The crude mixture was concentrated until the residual
of acetone was 45 wt %, and then the solvent was exchanged
with toluene (197 L, 3.0 L/kg) until the acetone content was
1
00.0 purity by GC area % was delivered from this specific
campaign, exceeding the 5 kg/day production target.
CONCLUSIONS
■
<
1 wt % and the toluene content was around 25−40 wt %. The
The continuous [2 + 2] photocycloaddition of maleic
anhydride and ethylene was performed on multikilogram
scale to provide cyclobutane 2 as a white crystalline solid at
throughputs exceeding 5 kg/day. Key to this effort was focused
reaction optimization, execution of demonstration runs
utilizing equipment representative of the production skid,
comprehensive studies focused on isolation of the crystalline
solid from the crude reaction stream, and an exhaustive
evaluation of process safety prior to production.
solution was warmed to 60 °C, and MTBE (132 L, 2.0 L/kg)
was added. The resultant slurry was agitated for 2 h at 60 °C
and filtered to remove an insoluble impurity. The supernatant
containing cyclobutane 2 was collected in a 500 L stainless
steel reactor and cooled to 0 °C at a rate of 5−10 °C/h. The
slurry was filtered and washed two times with MTBE (66 L,
1
3
.0 L/kg). The filter cake was dried under a nitrogen flow at
0−50 °C to afford 51.8 kg (61% yield) of cyclobutane 2 as a
white crystalline solid with 97.9% potency, 100.0 purity by GC
area %, and spectra matching those previously reported:
6
1
H
EXPERIMENTAL SECTION
NMR (400 MHz, CD COCD ) δ 3.51−3.54 (m, 2H), 2.68−
■
5
3
3
2.69 (m, 2H), 2.24−2.28 (m, 2H); melting point = 72−76 °C.
General Procedure for Reaction Optimization. To a
00 mL volumetric flask were charged maleic anhydride (12.25
g, 125 mmol), benzophenone (2.28 g, 12.5 mmol), and
acetone (ca. 485 mL) to a total volume of 500 mL. The
solution was sparged with nitrogen gas for 20 min and then
continuously with ethylene at ambient pressure. The solution
was recirculated at 80 mL/min through 0.31 L of FEP tubing
ASSOCIATED CONTENT
■
*
sı Supporting Information
(
o.d. = 3 mm, i.d. = 2 mm, irradiation volume = 0.25 L),
Details of analytical methods and experimental results
wrapped around four 40 W 365 nm LED arrays (irradiation
intensity = 10 mW/cm ) and back into the 500 mL flask until
2
<
5−10 GC area % maleic anhydride remained. The crude
reaction mixture was concentrated in vacuo and slurried with
cyclohexane (2 mL/g) at 20 °C for 30 min followed by
filtration. The cake was reslurried with MTBE (1 mL/g) at 20
■
Corresponding Authors
°
C for 30 min, filtered, and washed with MTBE (0.5 mL/g) to
afford cyclobutane 2 as a crystalline solid.
Procedure for the 500 g/day Demonstration. To a 50
L flask were charged maleic anhydride (1.19 kg, 12.1 mol),
benzophenone (0.220 kg, 1.21 mol), and acetone (39.0 L, 32.8
L/kg). The solution was sparged with nitrogen gas for 20 min
prior to use. The solution was pumped at 10.4 g/min, mixed
with ethylene (136 mL/min) via a tee mixer, and then pumped
through a 1.56 L coil of FEP tubing (o.d. = 10 mm, i.d. = 8
mm) wrapped around three 300 W panels of 365 nm LEDs
Authors
Zhi-qing Liu − Asymchem Life Science (Tianjin) Co., Ltd.,
Song-yuan Zheng − Asymchem Life Science (Tianjin) Co., Ltd.,
(
dimensions: 30 cm × 40 cm; irradiation intensity = 60 mW/
2
cm ) at a system pressure of 6−8 bar. Samples of the reaction
stream were collected at regular intervals for analysis by GC,
and the bulk solution was collected into a 50 L flask. The
reaction mixture was concentrated in vacuo to provide crude
cyclobutane 2 in 91% potency-adjusted yield, corresponding to
a productivity of 26.9 g/h. The material from this
demonstration run was segregated and used for the develop-
ment of the isolation strategy; therefore, a cumulative isolated
yield is not available.
Bin Wang − Asymchem Life Science (Tianjin) Co., Ltd., Tianjin
3
Jiang-ping Lu − Asymchem Life Science (Tianjin) Co., Ltd.,
Jian Tao − Asymchem Life Science (Tianjin) Co., Ltd., Tianjin
3
Miguel Gonzalez − Asymchem Life Science (Tianjin) Co., Ltd.,
̂
Sian Jones − Process Development, Amgen, Inc., Thousand Oaks,
California 91320, United States
Jason S. Tedrow − Process Development, Amgen, Inc.,
Representative Production-Scale Procedure. To a
3
3
000 L stainless steel reactor were added acetone (2180 L,
3.0 L/kg), maleic anhydride (66.0 kg, 673 mol), and
benzophenone (12.3 kg, 67.5 mol). Acetone was pumped
through a 29 L FEP coil with an effective irradiation volume of
2
1 L (o.d. = 10 mm, i.d. = 8 mm) until the coil was full, and
then the system was pressurized to 6−8 bar with ethylene gas
flow and equilibrated for 30 min. The 365 nm LEDs were
turned on (six 3 kW surface-mounted panels; irradiation
Notes
2
intensity = 60 mW/cm ), and the maleic anhydride solution
The authors declare no competing financial interest.
G
Org. Process Res. Dev. XXXX, XXX, XXX−XXX