Organic Process Research & Development
Article
remaining charges were based on 48 as the limiting reagent. To
the toluene solution of 15B in reactor 2 was sequentially
charged 48 (370 kg, 784 mol), titanium tetra-n-butoxide (93.4
kg, 244 mol, 0.35 equiv), and toluene (50 kg, 0.14 kg/kg). The
reaction mixture was then warmed to 85 °C and after 12 h was
judged complete by HPLC (<2 area % 48). The mixture was
then cooled to 50 °C over 4 h, seeded with 48 (0.40 kg, 0.10 wt
%), and aged for 8 h. The resulting slurry was then cooled to 20
°C over 6 h, agitated for an additional 10 h, and filtered. The
isolated cake was then washed sequentially with toluene (962
kg, 2.6 kg/kg) and ethanol (878 kg, 2.4 kg/kg) and dried at 50
°C to afford 405 kg (99.5 LCAP, 82% yield) of 43 as a white
solid with spectra identical to that previously reported in the
literature.26
AUTHOR INFORMATION
Corresponding Author
ORCID
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Chemical and Synthetic Development senior
management for support and Dr. Michael Schmidt for helpful
conversations during the preparation of the manuscript.
Telescoped Preparation of 37 from 43 (Third
Generation Route). Reactor 1. DCM (1337 kg, 5.3 kg/kg)
was charged to the reactor, and the solvent was analyzed for
water concentration. If the measured water content was >150
ppm, the DCM was discarded, and fresh DCM was added. If
the water content was <150 ppm, 43 (252 kg, 400 mol) was
added, and after stirring for 15 min at 20−25 °C, the solution
was cooled to −2 °C. Gaseous chlorine (26.9 kg, 380 mol, 0.95
equiv) was then added subsurface over 1 h, maintaining the
internal temperature <0 °C. The reaction was aged an
additional 1 h after completion of the chlorine addition, and
the reaction conversion was checked by HPLC. On the basis of
the HPLC results, a kicker charge of chlorine (0.8 kg, 11.3 mol,
0.03 equiv) was added, and after an additional 1 h at −2 °C, the
reaction was judged complete by HPLC (<2 area % 43). IPA
(24.1 kg, 400 mol, 1.0 equiv) was then charged, and the
reaction mixture was warmed to 20−25 °C. After an additional
16 h, the resulting slurry was cooled to 5 °C, charged with
water (1261 kg, 5.0 kg/kg), maintaining the internal temper-
ature <10 °C, and aged for 0.5 h. The layers were then
separated, and the lower organic layer was washed with a
solution of sodium bicarbonate (12.6 kg, 0.05 kg/kg) in water
(1247 kg, 4.95 kg/kg). The organic layer was then azeotropi-
cally dried at atmospheric pressure under constant-volume
conditions using DCM (2005 kg, 8.0 kg/kg). The final volume
was adjusted as needed to equal 1184 L (4.7 L/kg based on 43)
and KF < 200 ppm. At 35 °C, the DCM solution was charged
Et4NBr (42.1 kg, 200 mol, 0.5 equiv), followed by di-t-butyl
potassium phosphate (119.3 kg, 480 mol, 1.2 equiv) in four
portions (29.8 kg each) over 1 h. The resulting slurry was
warmed to 40 °C and after 3 h was judged complete by HPLC
(<0.5 area % 44B). The batch was then cooled to 20 °C and
charged with water (1261 kg, 5.0 kg/kg). The layers were
separated, and the lower DCM phase was transferred to a new
reactor via a polish filter. A 20:1 v/v solution of MTBE:IPA
(936 kg, 3.7 kg/kg) was charged at 20−25 °C, followed by 37
(0.60 kg, 0.0025 kg/kg) seeds, and the mixture was aged for 0.5
h. To the resulting thin slurry was charged a 20:1 v/v solution
of MTBE:IPA (2433 kg, 9.7 kg/kg) over 2.5 h, and the
resulting slurry was cooled to 5 °C over 1.5 h and aged for 10 h.
The slurry was then filtered and the wet cake washed with 4.5:1
v/v [(20:1 v/v solution of MTBE:IPA):DCM] (1069 kg, 4.2
kg/kg) MTBE (933 kg, 3.7 kg/kg) and dried at 50 °C under
high vacuum to afford 204 kg (97.1 LCAP, 95.5 wt %, 73%
yield) of 37 as a white solid with spectra identical to that
previously reported in the literature.26
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(14) The choice of personal protective equipment when handling 26
was also critical. Tychem BR and neoprene gloves, with a silver shield
primary glove, provided the highest level of protection.
N
Org. Process Res. Dev. XXXX, XXX, XXX−XXX