THF (23 L) was added over 1.75 h, while maintaining the
reaction solution at -35 to -55 °C. The tank containing
the 4b solution was rinsed with THF (2 L), and the rinse
was added to the reaction solution. The reaction solution was
stirred at -45 °C for 15 h at which point HPLC assay
showed 1.1% of epoxide 4b remained. The reaction solution
was then transferred over 1.5 h to a 100-gal, glass-lined
stainless steel tank containing a 4 N H2SO4 solution (45 L)
that was maintained at a temperature below 20 °C. The
mixture was stirred for 20 min, and the layers were separated.
The aqueous layer was extracted with MTBE (15 L), and
the layers were separated. The combined organic layers were
washed with water (20 L) and a 20% NaCl solution (25 L).
The organic layer was concentrated by distillation at 34-41
°C at 350-550 mmHg to a volume of 15 L. The organic
layer was then heated at atmospheric pressure to 45-55 °C,
and heptane (35 L) was added slowly over 1 h, while
maintaining a temperature of 44-55 °C. The solution was
cooled to 0-5 °C over 3 h and stirred at 2 °C for 3 h. The
solid was filtered, and the tank was rinsed with a cold (5 °C)
3:1 heptane/MTBE solution (20 L). The rinse was filtered
over the product cake, and the cake was dried dry under N2
for 4 h. The cake was transferred to a vacuum dryer and
dried for 19 h at 50 °C to give 3.61 kg (76.7% yield) of
578242 as white crystals (97.7% potency). Corrected yield
) 74.9%. HPLC assay showed this lot contained 0.59%
alcohol 3c and 0.42% epoxide 4b. Chiral HPLC assay:
99.6% ee. (tR ) 10.07 and 7.10 min for desired and undesired
enantiomer, respectively.) An analytically pure sample of
phoresis assay showed this material to contain 98.5% of the
(R,R)-isomer and 1.5% of the meso-isomer. The (S,S)-isomer
was not detected.
(1S)-1-[[(1,1-Dimethylethoxy)carbonyl]amino]-4-oxo-
2-cyclopentene-1-carboxylic Acid, 1,1-Dimethylethyl Ester
(2b). Compound 3b (3.10 kg, 10.36 mol) was added to
MTBE (31 L) in a 50-gal, glass-lined carbon steel tank. A
solution of KBr (100 g, 0.84 mol, 0.08 equiv) in deionized
H2O (0.15 L) was added to the reaction solution followed
by the addition of TEMPO (0.13 kg, 0.83 mol, 0.08 equiv).
The solution was cooled to 0 °C, and a premixed solution
of NaOCl (41.8 kg, 3 wt % solution, 561.5 mol, 1.6 equiv)
and NaHCO3 (1.6 kg, 19.04 mol, 1.84 equiv) was added over
50 min, while maintaining the reaction mixture solution at
-5 to 5 °C. The reaction was stirred for 2 h at 0 °C, at
which time HPLC assay showed no alcohol 3b remained.
The reaction mixture was warmed to 20-25 °C over 20 min,
and the layers were separated. The aqueous layer was
extracted with MTBE (2 × 15 L), and the MTBE layers
were combined with the original organic layer. A solution
of 1 N HCl (30 L) containing KI (0.35 kg, 2.11 mol) was
added to the organic layer and stirred. The layers were
separated, and the organic layer was washed with Na2S2O3
(3.2 kg dissolved in 30 L of H2O) and deionized H2O (2 ×
32 L). The organic layer tested negative for hypochlorite
with the use of starch/KI paper. The organic layer was
concentrated by vacuum distillation at 50 °C at 550-650
mmHg to a volume of 14 L. Heptane (20 L) was added, and
the solution was again concentrated to 14 L. The solution
was cooled to 40-50 °C, and heptane (30 L) was added
over 60 min, while maintaining the temperature at 45-
55 °C. The solution was cooled to 0 °C over 3 h and stirred
for 2.5 h. The precipitate was filtered, the tank was rinsed
with a cold 3.3:1 heptane/MTBE (13 L) solution, and the
rinse was filtered over the product cake. The cake was blown
dry under N2 for 2.75 h and then dried under vacuum for
15.5 h at 50 °C to give 2.502 kg (81.2% yield) of ketone 2b
compound 3b had a melting point of 111-112 °C. [R]25
)
D
1
+114 (c 1, MeOH). H NMR (500 MHz, CDCl3): δ 6.1
(bs, 1H), 5.9 (bs, 1H), 5.55 (d, J ) 5.0 Hz, 1H), 4.8 (m,
1H), 4.44 (d, J ) 10.5 Hz, 1H), 2.87 (dd, J ) 14.5, 7.5 Hz,
1H), 2.00 (d, J ) 14.5 Hz, 1H), 1.45 (s, 9H), 1.42 (s, 9H).
IR (KBr): 3413, 2983, 1703, 1491, 1370, 1309, 1255, 1155,
1055 cm-1. MS (ES) m/e (% relative intensity): 300.3 (M+
+ 1, 15), 226.2 (29), 170.1 (100), 126.1 (89), 108.3 (20).
Anal. Calcd for C15H25NO5: C, 60.18; H, 8.41; N, 4.68.
Found: C, 60.59; H, 8.58; N, 4.78.
as white crystals, mp 116-118 °C. HPLC potency ) 99.7%.
1
Corrected yield ) 80.9%. [R]25 ) +123 (c 1, MeOH). H
D
The filtrate was concentrated to approximately 10 L under
vacuum to yield a slurry. The solids were filtered, washed
with 1 L of hexanes, and vacuum dried at 45 °C to obtain
431 g (12% yield) of 3b, 86.2% ee by chiral HPLC assay.
Recovery of Diamine 17-Dihydrochloride. To a 100-
gal glass reactor was charged 150 L of an aqueous sulfuric
acid solution containing a maximum of 68.6 mol diamine 17.
The pH was adjusted to 13 with 50% NaOH solution. The
mixture was extracted with 2 × 115 L of MTBE. The com-
bined organic layers were washed with 60 L of deionized
water. The organic layer was distilled under atmospheric pres-
sure to a volume of 35 L and subsequently diluted with 250 L
of ethanol (denatured with toluene). Hydrochloric acid (32
wt %, 15.5 kg, 136 mol) was then added over 50 min at
15-30 °C. The resulting slurry was cooled to -8 °C, stirred
1 h, and filtered. The filter cake was rinsed with 45 L of
ethanol, dried with nitrogen flow for 3 h, and then vacuum-
dried at 70 °C for 4 days to yield 19.55 kg (55.0 mol, 80%
overall recovery) of 17-dihydrochloride. Capillary electro-
NMR (500 MHz, CDCl3): δ 7.4 (bs, 1H), 6.32 (d, J ) 5.5
Hz, 1H), 5.6 (bs, 1H), 2.87 (d, J ) 18.2 Hz, 1H), 2.70 (d, J
) 18.2 Hz, 1H), 1.43 (s, 18H). 13C NMR (CDCl3): δ 206.1,
170.2, 160.8, 154.9, 136.1, 84.5, 66.1, 46.6, 28.9, 28.4. IR
(KBr): 3419, 2983, 1722, 1487, 1730, 1300, 1259, 1151,
1012 cm-1. MS (ES) m/e (% relative intensity): 254.2 (M+
+ 1, 11), 242.3 (18), 228.2 (13), 186.1 (76), 143.2 (11), 242.3
(100). Anal. Calcd for C15H23NO5: C, 60.59; H, 7.79; N,
4.71. Found: C, 60.57; H, 7.85; N, 4.81.
N,N′-Bis-[(R)-1-phenethyl]-(S,S)-1,2-diamino-1,2-diphen-
ylethane (13). This compound was prepared via modification
of the literature method.7 Sodium sulfate (500 g, 3.5 mol)
was stirred in heptane (1.8 L) in a 5-L three-neck flask
equipped with mechanical stirrer, nitrogen inlet, and ther-
mocouple. Glyoxal (40 wt/wt % in water, 115 mL, 0.96 mol)
was added followed by formic acid (6.0 mL, 0.15 mol).
R-(+)-R-Methylbenzylamine (274 mL, 2.15 mol) was then
added, resulting in a temperature rise to 33 °C. Sodium
sulfate (625 g, 4.4 mol) was added, and the reaction mixture
558
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Vol. 11, No. 3, 2007 / Organic Process Research & Development