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5.5. Resolution of 1-phenylethylamine 4 with 3-carboxy-
e.e. of (R)-2 92.0% (64.8%, before recrystallisation)
[determined on the corresponding methyl ester, pre-
pared by treatment of a liberated sample of (R)-2 with
diazomethane, by HPLC on a Chiralcel OD column,
using a mixture of n-hexane and propan-2-ol (96:4) as a
2-naphthoate of (R)-isopropylidene glycerol (S)-2
Compound 4 (10.48 g, 86.5 mmol) was added to a
stirred solution of (S)-213 (28.57 g, 86.5 mmol) in
methanol (80 mL). A white precipitate formed in a few
minutes. The mixture was boiled for 5 min and then
allowed to cool to 20°C. After 90 min, the precipitate
was collected by filtration, rinsed with cold methanol
and dried yielding (S)-2·(S)-4 salt as a white crystalline
solid (17.52 g, 90% of the theoretical amount): mp
1
mobile phase (flow-rate 1.5 mL/min)]; H NMR identi-
cal to (S)-2·(S)-4. The salt was suspended in ethyl
acetate and 2N H2SO4. The organic phase was sepa-
rated, washed with water, dried over Na2SO4, and
concentrated to give (R)-2 (15.05 g, 60.2% of the theo-
retical amount) as a white solid: e.e. 92.0% (by chiral
HPLC of the methyl ester under the above conditions);
1H NMR identical to 2.
1
154.4–155.6°C; H NMR (DMSO-d6) l 1.25 (s, 3H),
1.31 (s, 3H), 1.49 (d, 3H, J=7.1 Hz), 3.82 (dd, 1H,
J=8.4, 6.2 Hz), 4.03 (pseudo t, 1H, J=8.4 Hz), 4.20 (d,
2H, J=5.5 Hz), 4.32–4.37 (m, 2H), 7.29–7.39 (m, 3H),
7.49–7.58 (m, 4H), 7.95–7.99 (m, 3H), 8.25 (s, 1H), 8.81
(br s, 3H). The salt was decomposed by treatment with
2N H2SO4 and ethyl acetate. The aqueous phase was
separated, made alkaline by addition of sodium
hydroxide and extracted with ethyl acetate. Removal of
the solvent from the extract, previously dried over
Na2SO4, gave an oily residue, which was distilled under
vacuum yielding (S)-4 (3.9 g, 74.4% of the theoretical
amount): [h]2D0=−39.7 (neat); e.e. 98.3% (by HPLC on a
Crownpack CR (+) column; pH 1.5 HClO4 aq., 0.8
mL/min at 200 nm); 1H NMR identical to that reported
in the literature.14
(R)-2 was saponified by treatment with 2.5N NaOH (60
mL) at 90°C for 1 h. After cooling to room tempera-
ture, the reaction mixture was extracted with ethyl
acetate. Removal of the solvent from the extract, previ-
ously dried over Na2SO4, gave an oily residue, which
was distilled under vacuum yielding (S)-isopropylidene
glycerol (5.44 g, 54.5% of the theoretical amount):
1
h2D0=+13.47 (neat); H NMR identical to that reported
in the literature.14 Addition of 2N H2SO4 to the
aqueous phase resulted in the immediate precipitation
of a white solid, which was isolated and dried to give
pure naphthalene 2,3-dicarboxylic acid (8.91 g, 89.6%
on the basis of the amount of (R)-2·(R)-4 salt submit-
ted to decomposition).
The methanolic filtrate resulting from the isolation of
(S)-2·(S)-4 was concentrated to give (S)-2·(R)-4 salt
(21.24 g, 108.8% of the theoretical amount). Decompo-
sition of the latter by the procedure described for the
(S)(S)-salt and successive distillation of the recovered
crude amine afforded 4.3 g (82.0% of the theoretical
amount) of (R)-4: [h]2D0=+33.4 (neat); e.e. 80.0% (by
HPLC under the conditions reported for the (S)-
isomer).
Method B: by crystallisations from methanol and from
ethanol. (R)-4 (17.36 g, 143.3 mmol) was added to a
stirred solution of 2 (47.34 g, 143.3 mmol) in methanol
(380 mL). Precipitation occurred after about 30 min.
The mixture was stirred at room temperature overnight
and then cooled to 5°C. The precipitate was collected
by filtration, rinsed with cold methanol, and dried
yielding a white solid (24.76 g), which was suspended in
ethanol (200 mL). The suspension was boiled with
stirring for 90 min, cooled to 20°C, and filtered. The
isolated solid (18 g) was submitted to the same treat-
ment again, but using 140 mL of ethanol. Filtration
allowed isolation of (R)-2·(R)-4 salt (15.81 g, 48.9% of
the theoretical amount) as a white crystalline solid:
154.7–155.4°C; e.e. of (R)-2 96.1% (70.7%, after the
crystallisation from methanol, and 90.4% after the first
treatment in refluxing ethanol) (determined as described
The two organic phases remaining after extraction of
(S)-4 and (R)-4 with 2N H2SO4 were combined, washed
with water several times, dried over Na2SO4 and con-
centrated recovering 26.68 g (93.4% of the starting
amount) of (S)-2 as a viscous oil, which solidified upon
standing. NMR spectrum of such a solid confirmed the
identity with the starting acid revealing only traces of
the deketalised derivative, which could be easily
removed by recrystallisation from toluene.
1
in method A); H NMR identical to (S)-2·(S)-4.
5.6. Resolution of isopropylidene glycerol 3-carboxy-2-
The methanolic mother liquors were concentrated to
give 38.86 g of a solid, whence 28.43 g of (S)-2 (45.6%
e.e.) were liberated upon ethyl acetate/2N H2SO4
extraction. Treatments with equimolar (S)-4 in
methanol (230 mL) and then with boiling ethanol twice
(150 and 135 mL) under the same conditions as above
led to the ultimate isolation of (S)-2·(S)-4 salt (16.0 g,
49.5% of the theoretical amount) as a white crystalline
solid: mp 153.5–154.6°C; e.e. of (S)-2 98.8% (93.4%,
after the crystallisation from methanol, and 97.2% after
the first treatment in refluxing ethanol) (determined as
described in method A).
naphthoate 2 with (R)-1-phenylethylamine (R)-4
Method A: by crystallisations from methanol. (R)-4
(18.3 g, 151 mmol) was added to a stirred solution of 2
(50 g, 151 mmol) in methanol (220 mL). A white
precipitate was formed in a few minutes. The mixture
was boiled for 10 min and then allowed to cool to
20°C. After 90 min, the precipitate was collected by
filtration, rinsed with cold methanol, and dried yielding
a white solid (30.37 g), which was suspended in
methanol (200 mL). The mixture was stirred under
reflux for 30 min, cooled to 20°C, and filtered to give
(R)-2·(R)-4 salt (20.75 g, 60.8% of the theoretical
amount) as a white crystalline solid: mp 149.6–150.2°C;
From the two resolved diastereomeric salts, (R)-2 and
(S)-2 were liberated in 48.0 and 48.4% yield, respec-