PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE
1991
Isolation was performed in four batches with a total of 15.66 kg of crystal-
line solid isolated. The material had an average wt% purity of 91.1%, which
was 14.27 kg of pure product. The overall yield for the step was 92%. 2: m.p.
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1
2
34–236 C; H NMR (D O) d 3.32 (m, cis NH –CH), 3.17 (m, trans NH –
2
2
2
CH), 2.42 (m, cis CO H–CH), 2.14 (m, trans CO H–CH), 2.09 (m, trans
H3,5 eq), 1.90–2.00 (m, H2,6 eq), 1.87 (m, cis H3,5 eq), 1.56–1.70 (m, H2,6
2
2
1
3
ax, cis H3,5 ax), 1.43 (m, trans H3,5 ax); C NMR (D O) d 185.5 (trans
2
CO H), 184.3( cis CO H), 50.7 (trans C4), 49.9 (cis C4), 46.0 (trans C1), 42.2
(cis C1), 30.5 (trans C3,5), 28.5 (trans C2,6), 28.1 (cis C3,5), 25.7 (cis C2,6).
2
2
Anal. Calcd for C H NO Á 0:5 H O: C, 55.24; H, 9.27; N, 9.20. Found: C,
7
13
2
2
55.09; H, 9.21; N, 8.81.
3-Isoquinuclidinone (3). Method A: In a 72-L round bottomed flask
equipped with a mechanical stir, and a distillation apparatus, a mixture of
cis- and trans-4-aminocyclohexanecarboxylic acid 2 (3.83 kg, 92.6 wt%,
Õ
2
4.8 mol) and Dowtherm A (23.5 L) is heated as a slurry to reflux tempera-
ꢀ
ture (250–260 C) under a slight nitrogen sweep using two 220-volt heating
mantles. Heating is continued for 30 min during which time water formed is
Õ
allowed to distill away (ꢁ3–4 L of Dowtherm A and water is collected). A
homogeneous solution is formed by the end of the reaction. The solution is
allowed to cool to 22 C. The mixture is concentrated under reduced pressure
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ꢀ
(
b.p. 165–175 C/25–27 Hg in) to about half volume (ꢁ12 L). The mixture is
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cooled to 20 C and then diluted with heptane (55 L). After aging at À5 to
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0
C for 1–2 h, the mixture is filtered and washed with cold heptane
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(3 Â 6.3L). The wet cake is dried under vacuum/nitrogen sweep at 20 C,
yielding 2.55 kg of 3-isoquinuclidone 3 as a beige solid. The product is
8
Õ
0 wt% pure along with ꢁ19 wt% Dowtherm A based on LC assay. This
corresponds to a yield of 2.05 kg (66%) pure. Product loss to the mother
liquor is ꢁ150 g (5%). About 800 g (26%) of product is lost to the distillate
(
14.4 L), which is recycled the subsequent runs as follows.
The distillate (ꢁ800 g lactam/14.4 L) is combined with 24.8 mol of
a mixture of cis- and trans-4-aminocyclohexanecarboxylic acid 2 and
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ꢀ
Dowtherm A (10 L) and heated to reflux temperature (250–260 C)
under a slight nitrogen sweep as before and processed as described
above to provide 3.38 kg of 3-isoquinuclidone 3 as a light beige solid.
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The product is 76.4 wt% along with ꢁ20 wt% Dowtherm A based on
LC assay. This gives a yield of 2.58 kg (83%) pure. Product loss to the
mother liquor is ꢁ100 g (3%). About 920 g (30%) of product is lost to the
distillate (17.7 L).
The distillate (ꢁ920 g lactam/17.7 L) is again combined with 24.8 mol
of a mixture of cis- and trans-4-aminocyclohexanecarboxylic acid and
Dowtherm A (7 L) and processed as before to provide 3.06 kg of 3-isoqui-
nuclidone 3 as an off-white solid. The product is 87.6 wt% along with
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