1
Scheme 1
°C); H NMR (CDCl
) δ 1.41 (m, 2 H, CH
CH OH), 2.36 (t, J ) 7.4 Hz, 2 H,
H), 3.65 (t, J ) 6.5 Hz, 2 H, CH OH), 6. 99 (br s,
) δ 24.4, 25.1, 31.9, 33.9,
2
), 1.63 (m, 4 H,
3
CH
CH
1
6
2
CH
CO
2
CO
2
H, CH
2
2
2
2
2
1
3
H, CO
2.3, 178.8.
-Hydroxyheptanoic Acid Potassium Salt. The product
2 3
H); C NMR (CDCl
7
cenoate.10 Lactone C11 was prepared from 11-bromounde-
1
was prepared from heptanolactone: mp 210-214 °C; H
NMR (D O) δ 1.33 (m, 4 H, (CH ), 1.55 (m, 4 H,
CO K, CH CH OH), 2.17 (t, J ) 7.4 Hz, 2 H,
K), 3.60 (t, J ) 6.6 Hz, 2 H, CH OH).
1
1
canoic acid. Lactones were purified by distillation (>99.5%
purity by GC). ICP-MS analysis of the HCAs showed a
sulfur content <0.03%. Melting points were determined on
a Kofler apparatus and are uncorrected. H (299.94 MHz,
internal Me
2
2 2
)
CH
2
CH
CO
2
2
2
2
CH
2
2
2
1
7
-Hydroxyheptanoic Acid. The product was prepared
13
4
Si) and C NMR (75.43 MHz, internal CDCl
3
)
from its potassium salt: mp 43-44 °C (ref 12 appeared to
spectra were recorded for solutions in CDCl
3
or D O.
2
1
be a syrup); H NMR (CDCl
.53-1.71 (m, 4 H, CH CH CO
J ) 7.4 Hz, 2 H, CH CO H), 3.65 (t, J ) 6.6 Hz, 2 H,
CH OH), 5.60 (br s, 1 H); C NMR (CDCl
8.7, 32.3, 33.9, 62.8, 179.2.
-Hydroxyoctanoic Acid Potassium Salt. The product
3
) δ 1.39 (m, 4 H, (CH
2 2
) ),
1
To determine the purity, H NMR analysis was far more
reliable than other used methods such as GC, HPLC, or
titration. The use of 0.2 wt % of p-xylene as internal standard
1
2
2
2
H, CH CH OH), 2.36 (t,
2
2
2
2
13
2
3
) δ 24.6, 25.3,
1
in H NMR measurement has unequivocally proven the
2
presence of HCA dimer to be well below this value. The
signal of the aromatic protons of p-xylene in H NMR is at
δ 7.07 (s, 4 H) and is very well separated from the signals
of HCAs and their dimers. H NMR measurement with a
8
1
1
was prepared from octanolactone: mp 227-230 °C; H
NMR (D O) δ 1.32 (m, 6 H, (CH ), 1.55 (m, 4 H,
CO K, CH CH OH), 2.17 (t, J ) 7.4 Hz, 2 H,
K), 3.60 (t, J ) 6.6 Hz, 2 H, CH OH).
2
2 3
)
1
CH
2
CH
CO
2
2
2
2
relaxation delay d ) 60 s allows the quantitative determi-
1
CH
2
2
2
nation of all compounds in the solution. It is noteworthy that
the signal at δ 4.1 (t, 2 H) corresponding to the presence of
HCA dimers was not detected in the pure samples; however,
heating the pure samples at 60 °C for 30 min resulted in its
appearance.
8
-Hydroxyoctanoic Acid. The product was prepared from
1
its potassium salt: mp 60-61.5 °C (ref 13 57-58 °C); H
NMR (CDCl ) δ 1.36 (m, 6 H, (CH ), 1.51-1.71 (m, 4 H,
H, CH CH OH), 2.35 (t, J ) 7.3 Hz, 2 H,
H), 3.65 (t, J ) 6.6 Hz, 2 H, CH OH), 5.88 (br s, 1
3
2 3
)
CH
CH
2
CH
CO
2
CO
2
2
2
2
1
2
2
3
Preparation of 6-Hydroxycaproic Acid Potassium
Salt: To a solution of KOH (224 g, min. 85%) in methanol
H); C NMR (CDCl ) δ 24.6, 25.5, 28.9, 32.5, 34.0, 62.8,
3
179.3.
(
2.5 L) was added ꢀ-caprolactone (456 g, 4 mol) under
10-Hydroxydecanoic Acid Potassium Salt. The product
was prepared from methyl 10-hydroxydecanoate. The salt
was washed with dry tetrahydrofuran: mp 244-248 °C;
stirring. After addition, the mixture was concentrated to
dryness on a rotary evaporator (35-40 °C/12 mbar), and
1
the solid was washed with dry ether (2 × 1 L) to afford a
H NMR (D O) δ 1.29 (m, 10 H, (CH ) ), 1.53 (m, 4 H,
2
2 5
1
white salt (586 g, 86%): mp 203-205 °C; H NMR (D
2
O)
K,
K), 3.60 (t,
CH CH CO K, CH CH OH), 2.16 (t, J ) 7.3 Hz, 2 H,
2
2
2
2
2
δ 1.34 (m, 2H, CH
CH CH OH), 2.18 (t, J ) 7.4 Hz, 2 H, CH
J ) 6.6 Hz, 2 H, CH OH).
2
), 1.56 (m, 4 H, CH
2
CH
2
CO
2
CH CO K), 3.58 (t, J ) 6.6 Hz, 2 H, CH OH).
2
2
2
2
2
2
CO
2
10-Hydroxydecanoic Acid. The acidification of 10-
hydroxydecanoic acid potassium salt was carried out in
2
Preparation of 6-Hydroxycaproic Acid. Method A: To
a cold (0 °C) solution of 6-hydroxycaproic acid potassium
salt (400 g, 2.34 mol) in water (450 mL) was added dropwise
water/tetrahydrofuran (2:1): mp 74-75 °C (ref 14 mp 75
1
°C); H NMR (CDCl
3
) δ 1.31 (m, 10 H, (CH
CO H, CH CH OH), 2.35 (t, J ) 7.3
H), 3.65 (t, J ) 6.6 Hz, 2 H, CH
) δ 24.6, 25.6, 29.0, 29.1, 29.3 (2 s), 32.7, 33.9,
2 5
) ), 1.52-
1.68 (m, 4 H, CH
Hz, 2 H, CH CO
2
CH
2
2
2
2
1
3
a solution of H SO
2 4
(114 g, 1.16 mol) in water (150 mL).
2
2
2
OH); C
The mixture was concentrated by freeze-drying or on a rotary
evaporator (30 °C/8 mbar) and then further dried in vacuo
NMR (CDCl
63.0, 179.3.
3
over P
2
O
5
. The residue was extracted with dry ether. After
11-Hydroxyundecanoic Acid Potassium Salt. The prod-
concentration, a colorless solid (288 g, 93%) was obtained.
Crystallin 6-hydroxycaproic acid could be obtained through
recrystallization from ether/diisopropyl ether.
Method B: To a solution of KOH (276 g, min 85%) (or
NaOH) in water (3.5 L) was added ꢀ-caprolactone (456 g, 4
mol) under stirring. After addition, the solution was acidified
uct was prepared from undecanolactone. The salt was washed
1
with dry tetrahydrofuran: mp 236-243 °C; H NMR (D
2
O)
H,
H), 3.59 (t,
δ 1.30 (m, 12 H, (CH
CH CH OH), 2.17 (t, J ) 7.4 Hz, 2 H, CH
J ) 6.7 Hz, 2 H, CH OH).
2
)
6
), 1.54 (m, 4 H, CH
2 2 2
CH CO
2
2
2
CO
2
2
11-Hydroxyundecanoic Acid. The acidification of 11-
at 0 °C with H
The mixture was concentrated by freeze-drying and then
further dried in vacuo over P . The residue was extracted
with dry ether. After concentration, a colorless solid (422 g,
0%) was obtained: mp 40-41 °C (ref 3a, mp 41.8-43.1
2
SO
4
(114 g, 1.16 mol) in water (400 mL).
hydroxyundecanoic acid potassium salt was carried out in
water/tetrahydrofuran (2:1): mp 65-66 °C (ref 15 mp
1
O
2 5
62-63 °C); H NMR (CDCl
3
2 6
) δ 1.31 (m, 12 H, (CH ) ),
(
(
12) Nesmeyanov, A. N.; Zakharkin, L. I. Bull. Acad. Sci. USSR 1955, 199.
13) Hagiwara, H.; Numata, M.; Shimabara, N. JP 40019323, 1965; Chem. Abstr.
965, 63, 88461.
8
1
(10) (a) Sousa, J. A.; Bluhm, A. L. J. Org. Chem. 1960, 25, 108. (b) Benton, F.
L.; Kiess, A. A. J. Org. Chem. 1960, 25, 470.
(14) Fray, G. I.; Jaeger, R. H.; Morgan, E. D. GB 894244, 1962; Chem. Abstr.
1962, 57, 42557.
(11) Org. Synth., Coll. Vol. 6, 698.
(15) Dulou, R.; Chretien-Bessiere, Y. Bull. Soc. Chim. Fr. 1959, 1362.
482
•
Vol. 10, No. 3, 2006 / Organic Process Research & Development