Organic Process Research & Development
Article
Scheme 7. Final Manufacturing Process of 1.
Table 11. Manufacturing Campaign Results
AUTHOR INFORMATION
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Corresponding Author
racemate synthesis and resolution
recrystallization
yield
yield diastereomer 2 yield
yield
diastereomer 2
batch (kg) (% th)
(% a/a GC)
(kg) (% th)
(% a/a GC)
Notes
a
1
2
3
4
26.8
26.7
27.4
27.1
33.9
33.7
34.7
34.2
0.79
0.85
0.94
0.83
22.9
24.6
26.0
25.2
85.4
92.3
94.9
93.0
not detected
The authors declare no competing financial interest.
b
<0.05
b
<0.05
ACKNOWLEDGMENTS
b
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<0.05
We thank Prof. Ger
́
ard Coquerel for useful discussions of our
a
b
Reduced yield due to losses to filter dryer “heel”. Above limit of
detection but measured at <0.01%. The formal validated limit of
quantification is 0.05%.
results. We would like to thank the entire project team, in
particular Caroline Tudge and Martin Collier-Smith (Analysis),
Lesley Senior (PAT), and Andrew Payne (Process Safety) for
their support of this work.
(Add 6 × 0.5 kg at 15 min intervals and 2 × 3 kg at 30 min
intervals.) Each 3 kg portion was rinsed in with methanol (3 L).
The mixture was heated to 25 °C and was stirred for 30 min.
HPLC confirmed the reaction as complete. 5 M sulfuric acid
(101 L) was added over 2 h with cooling to control
temperature up to 40 °C and the rate of hydrogen evolution.
Final pH ∼ 3. The solution was heated to reflux (ca. 71 °C),
and after 15 min hydrogen evolution ceased. The solution was
cooled to 40 °C and was diluted with water (60 kg). Solvent
was removed by distillation at atmospheric pressure to a total
volume of 300 L. Water (140 L) was added, and the solution
was again distilled to 300 L total volume. The solution was
cooled to 40 °C, and 26% w/w ammonia solution (90 L) was
added with cooling to maintain temperature. The solution was
extracted with ethyl acetate (200 L), and the organic extract
was distilled to a total volume of 150 L. The solution was
azeotroped dry with further distillations of ethyl acetate (3 × 25
L) to water content <0.2% (w/w) (Karl Fisher). Ethyl acetate
(400 L) and L-(−)-malic acid (25 kg, 0.96 equiv) were added,
and the mixture was heated to 60 °C to give a clear solution.
The solution was cooled to 50 °C, and a seed of pure 1 (0.25
kg) as a slurry in ethyl acetate (1 L) was added. The mixture
was stirred for 1 h, cooled to 20 °C over 90 min, and then
stirred for 1 h. The resulting slurry was filtered and was washed
with fresh ethyl acetate (3 × 100 L). The product was dried
under reduced pressure at 50 °C to yield 1 as a white crystalline
solid (27.05 kg, 34.2% th yield). Chiral GC shows 0.79−0.94%
enantiomer.
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Recrystallization. Crude 1 (27.05 kg) was dissolved in
ethyl acetate (271 L) at reflux. The clear solution was cooled to
67 °C and was stirred for 30 min to initiate crystallization. The
suspension was cooled to 15 °C over 150 min and was stirred
for 60 min. The resulting slurry was filtered, washed with ethyl
acetate (108 L), and dried under reduced pressure at 50 °C to
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DMSO) δ 1.45 (d, J = 6.6 Hz, 3H), 2.34 (s, 3H), 2.34−2.39
(m, 1H), 2,56 (dd, J = 7.8 Hz, 1H), 4.05 (dd, J = 7.8, 5.6, 1H),
4.26 (q, J = 6.6, 1H), 8.08 (s, 1H), 8.17 (s, 2H). Chiral GC
shows < 0.05% enantiomer.
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