timely manner. Analytical testing of pyrrolidine 17 showed
no Pd or Ru residue (LOQ < 1 ppm), with a GC purity of
99.5% well within specifications. As the manufacturing
requirements increase, efforts are underway to further
improve the process for future campaigns. Interestingly, the
development of this process has set the stage for the
discovery of a tandem methanolysis/hydrogenolysis of a
borane-benzylamine adduct.
filter cake was unloaded and dried under vacuum (35 mmHg)
at 40-45 °C for 12 h, providing the title compound 11 (59.1
kg, 73.3%) as an off-white crystalline solid, mp 129-131
°C; IR (neat, cm-1) 3318, 3010, 1780, 1605, 1585, 1203,
1
1002, 795; H NMR (400 MHz, DMSO-d6) δ 7.32-7.21
(m, 6H), 6.01 (br s, 2H), 4.52 (s, 2H), 4.39 (s, 2H); 13C NMR
(100 MHz, DMSO-d6) δ 177.0, 136.6, 129.1, 128.1, 68.7,
41.5.
Anal. Calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33.
Found: C, 59.38; H, 4.85; N, 6.25.
Experimental Section
General Procedures. Unless otherwise noted, all of the
operations were performed in Clean-By-Test nitrogen-purged
vessels. All charges and transfers are performed using
isolated vacuum whenever possible. The hydrogenation
equipment was prepared as directed by standard operating
procedures.
(meso)-N-Benzyl-3,4-isopropylidenedioxy-2,5-pyrro-
lidinedione (13). To a stirred suspension of (meso)-N-benzyl-
3,4-dihydroxy-2,5-pyrrolidinedione (11) (79.9 kg, 361 mol)
in 2,2-dimethoxypropane (160 L) was added methanesulfonic
acid (2.35 L, 36.1 mol). The resulting slurry was stirred at
20 °C for 9 h, and upon reaction completion, diisopropyl
ether (240 L) was added. The slurry was granulated for 2 h
at 20 °C, cooled to -15 °C, and further stirred an addition
2 h. The product was isolated by filtering the mixture through
a closed system. The reaction vessel and the filter cake were
successively rinsed with diisopropyl ether (200 L). The filter
cake was unloaded and dried under vacuum (35 mmHg) at
40-45 °C for 12 h, providing the title compound 13 (82.8
kg, 87.6%) as an off-white crystalline solid, mp 95-96 °C;
IR (neat, cm-1) 3112, 3090, 1722, 1586, 1001, 799; 1H NMR
(400 MHz, CDCl3) δ 7.40-7.28 (m, 5H), 4.85 (s, 2H), 4.68
(m, 2H), 1.41 (s, 3H), 1.29 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 172.5, 134.8, 129.2, 128.9, 128.5, 75.2, 42.7, 26.8,
25.8.
(meso)-N-Benzyl-3,4-dihydroxy-2,5-pyrrolidinedione
(11). To a stirred solution of ruthenium(III) chloride hydrate
(499 g, 2.20 mol) in water (250 L) was added a solution of
N-benzylmaleimide (10) (50.0 kg, 267 mol) in ethyl acetate
(64 L) and acetonitrile (125 L). The vessel containing the
latter solution was rinsed with ethyl acetate (61 L) and
combined to the reaction mixture. The reaction vessel was
configured to vent through a scrubber solution of sodium
thiosulfate (45 kg, 285 mol) in water (38 L) and then cooled
to 5 °C. Under vigorous agitation, 12 equal portions of
sodium periodate (12 × 6.2 kg, 12 × 29 mol) were added,
allowing the exothermic reaction to cool back to 5 °C
between each charge. Upon completion, the reaction mixture
was quenched with the aqueous sodium thiosulfate scrubber
solution. The vessel containing the latter was rinsed with
water (19 L) and combined with the reaction mixture. The
slurry was then filtered to remove any solid material,
transferring the filtrate to a nitrogen-purged isolation vessel.
The reaction vessel was then rinsed with ethyl acetate (285
L) which was then transferred through the filter cake and
combined with the filtrate. After the contents of the isolation
vessel were allowed to separate (30 min), the aqueous layer
was transferred to the reaction vessel, to which ethyl acetate
(125 L) was added. The contents of the reaction vessel were
stirred (15 min) and then allowed to settle and separate (15
min). The aqueous layer was removed and drummed for
disposal, and the organic layers were combined in the
isolation vessel. A solution of sodium chloride (8.0 kg) in
water (72 L) was added to the isolation vessel, and the
resulting biphasic mixture was stirred (15 min) and then
allowed to settle (15 min). The aqueous layer was removed
and drummed for disposal. The product rich organic layer
was concentrated (final volume of 300 L) by atmospheric
distillation and then cooled to 60 °C. Ethyl acetate (303 L)
was then charged to the isolation vessel, and the solution
was further concentrated (final volume of 250 L) by
atmospheric distillation. The solution was then cooled to 15
°C, and the resulting slurry was stirred for 4 h. Upon addition
of hexanes (360 L), the slurry was further cooled to 5 °C,
and stirred for an additional hour. The crystalline product
was isolated by filtration, and then the isolation vessel and
the filter cake were successively rinsed with a cooled mixture
of ethyl acetate (22 L) and hexanes (91 L) at 10 °C. The
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36.
Found: C, 64.29; H, 5.86; N, 5.30.
(meso)-N-Benzyl-3,4-isopropylidenedioxy-2,5-pyrroli-
dine (12). A stirred solution of (meso)-N-benzyl-3,4-isopro-
pylidenedioxy-2,5-pyrrolidinedione (13) (47.5 kg, 182 mol)
in tetrahydrofuran (378 L) was concentrated to 75% of its
original volume by atmospheric distillation. The solution was
cooled to 10 °C, and a sample was removed for KF
determination. A solution of borane-tetrahydrofuran com-
plex (300 L, 2 M in THF, 600 mol) was slowly charged
portion-wise, maintaining the temperature between 10 and
20 °C throughout the addition. The reaction mixture was then
stirred an additional 4 h at 25 °C. Upon reaction completion
determination, the reaction mixture was cooled to 10 °C and
carefully quenched by slowly adding methanol (239 L)
cooled to 10 °C. The reaction mixture was stirred at the same
temperature for 1 h, warmed to 40 °C, and stirred an
additional 2 h. At this stage, the reaction mixture was further
warmed to reflux and stirred for an addition 2 h. The resulting
solution was then concentrated by atmospheric distillation
(final volume of 145 L). The solution was then cooled to 40
°C, diluted with methanol (473 L), and further concentrated
atmospherically (final volume of 145 L). Upon cooling to
room temperature, water (1.0 L) was added, and the resulting
solution was stirred 2 h. The concentrated title compound
12 (HPLC assay: 93.6%) was drummed and used as such
for the next transformation; IR (neat, cm-1) 3085, 2743,
1
1603, 1347, 1071, 1028, 665; H NMR (400 MHz, CDCl3)
δ 7.35-7.23 (m, 5H), 4.64 (m, 2H), 3.61 (s, 3H), 3.03 (d, J
Vol. 6, No. 1, 2002 / Organic Process Research & Development
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