An efficient new synthesis of racemic cetiedil and a novel route to α-ketocarboxylic acids utilising mild conditions

Article abstract of DOI:10.1055/s-2007-977414

We describe a new efficient synthesis of the prescribed racemic drug cetiedil [(±)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethylester], Additionally, we report herein a high yielding large scale, route to its acid precursor 7, subsequently enabling large-scale synthesis of the chiral forms of cetiedil, and detailed pharmacological investigations. Additionally, we describe a novel route to α-ketocarboxylic acids, starting from readily available or easily obtainable aldehydes: The mild conditions utilised opens up its applicability for use on molecules of biological interest. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-977414

LETTER
1211
An Efficient New Synthesis of Racemic Cetiedil and a Novel Route to
a-Ketocarboxylic Acids Utilising Mild Conditions
S
ynthesis of Race
r
mic Cet
a
iedil ig J. Roxburgh,*1 C. Robin Ganellin, Andrew J. Thorpe
Department of Chemistry, Christopher Ingold Laboratories, University College London, London, WC1H OAJ, UK
E-mail: sic@inm.mod.uk
Received 25 November 2006
S
Abstract: We describe a new efficient synthesis of the prescribed
racemic drug cetiedil [( )-2-cyclohexyl-2-(3-thienyl)ethanoic acid
H
2-(hexahydro-1H-azepin-1-yl)ethylester]. Additionally, we report
herein a high yielding large scale, route to its acid precursor 7, sub-
sequently enabling large-scale synthesis of the chiral forms of
cetiedil, and detailed pharmacological investigations.
O
*
N
O
cetiedil
Additionally, we describe a novel route to a-ketocarboxylic acids,
starting from readily available or easily obtainable aldehydes: The
mild conditions utilised opens up its applicability for use on mole-
cules of biological interest.
Figure 1
regulatory requirement, where applicable, to produce sin-
gle enantiomer substances warrants a full investigation of
the actions of the enantiomeric forms. There is only one
report in the literature pertaining to the synthesis of its
enantiomers, the route being relatively long and low-
yielding (0.4–0.6% depending on the enantiomer) thus
essentially precluding extensive pharmacological studies.
To this end a higher yielding synthesis is needed; this has
been devised and is herein described.
Key words: cetiedil, enantiomers, synthesis, a-ketocarboxylic
acids, Swern oxidation
Racemic cetiedil possesses analgesic, local anaesthetic
and antispasmodic activities.2 It is currently used in
therapeutics for the treatment of vascular disease where it
is prescribed in Europe for the condition of ischemic leg
pain.3 More recently it has received much attention for its
treatment of vaso-occlusive crises that occur in sickle
cell disease.4 Additionally, it has been demonstrated5
that cetiedil blocks the Ca2+-activated K+ permeability
[Pk(ca)] of erythrocytes which led to the suggestion6 that
this action could underline the beneficial effect of cetiedil
in this condition. It is postulated that the opening of Ca2+-
activated K+ channels in the membrane of sickle cells
causes a net loss of K+ and water, the resulting cell shrink-
age and dehydration leading to polymerisation of HbS, the
haemoglobin variant that is the primary cause of the
disease, with the resulting outcome that the cells become
more rigid and therefore less able to pass through capillar-
ies – this has been reviewed.7 Cetiedil, by blocking the
Ca2+-activated K+-channel permeability, would prevent
the initiation of this sequence of events: although this is
one plausible explanation it is likely that a very complex
series of actions and events are occurring and the fact that
cetiedil has other actions should be borne in mind.
Whilst undertaking the syntheses of various potential
pharmacophores, whose properties encompass some of
those described above, we needed to synthesise various
a-ketocarboxylic acid intermediates. These important
structures8 are utilised as precursors in the synthesis of
many drug structures;9 however, they are in some cases
known to be unstable, decomposing with the expulsion of
carbon dioxide.10 Consequently, during the course of this
work we produced a new route to these molecules which
has the potential for general use since it is applicable to
readily available, and/or easily accessible aldehydes:
Further, the mild conditions utilised additionally opens up
the method for use on biological molecules.
The synthesis of racemic cetiedil was originally reported
by Robba in 1967;2 with yields of its precursor 2-cyclo-
hexyl-2-(3-thienyl)-acetic acid (7) of under 7%, and the
final product a mere 4.6% (Scheme 1). There is only one
reported synthesis to the enantiomers of cetiedil11
(claimed in a patent,12 however, no chemical, physical or
biological data is reported): Their synthesis stems directly
from esterification of the chiral acids of 7 since direct
resolution of the enantiomers of cetiedil was not possi-
ble.11 Thus, clearly, the only present route to the chiral
forms of cetiedil lies through esterification of its enantio-
meric acids 7. As the chiral acids are presently obtained
by a process of fractional crystallisation with a chiral base
[(–)-quinine],11 a procedure which results in high mechan-
ical losses, a simple, high-yielding, large-scale synthesis
of the racemic acid 7 is needed before a full pharmacolog-
ical study of the enantiomers can be undertaken.
All the above pharmacological and biological activity has
been demonstrated on the racemic compound: Cetiedil
(Figure 1) has a chiral centre and the synthesis of its enan-
tiomers could have significance relevance for its thera-
peutic applications as the individual enantiomers often
possess both advantageous and undesirable effects. For
this reason, and the fact that there is an ever-increasing
SYNLETT 2007, No. 8, pp 1211–1214
1
6.
0
5.
2
0
0
7
Advanced online publication: 03.04.2007
DOI: 10.1055/s-2007-977414; Art ID: D36006ST
© Georg Thieme Verlag Stuttgart · New York

1212
C. J. Roxburgh et al.
LETTER
OH
S
O
OH
H
S
ii
i
i
O
NH
t-Bu
O
H
CN
O
1
2
3
10
9
OH
ii
OEt
iii
S
S
O
O
iv
H
O
H
O
iii
OH
NH
t-Bu
OEt
OH
O
O
5
4
iv
7
11
S
iv
S
H
O
OH
O
v
cetiedil (8)
OH
OH
Scheme 2 High-yielding route to 2-cyclohexyl-2-(3-thienyl)etha-
noic acid. Reagents and conditions: (i) EtOH, HCl, warm 1 h; (ii) a)
LDA (1.1 equiv), DMF; b) cyclohexylbromide, warm 6 h; (iii) a)
MeOH, KOH, 24 h, r.t.; b) dil. HCl; (iv) 2-hydroxyethylazepine, sl.
molar excess, PTSA, toluene, heat.
7
6
vi
S
H
O
N
11 with 2-hydroxyethyl azepine: This was effectively
achieved by heating the mixture, for eight hours, in dry
toluene with a slight molar excess of p-toluene sulfonic
acid. Thus, we have realised the synthesis of this increas-
ingly important therapeutic drug structure in very high
yield, further facilitating ongoing pharmacological inves-
tigations.
O
cetiedil (8)
Scheme 1 Synthesis of racemic cetiedil. Reagents and conditions:
(i) H2O, EtOAc, NaHSO3, 24 h, 0 °C then 25 °C, KCN, 5 h; (ii) t-
BuOH, 0 °C, then concd H2SO4 (<50 °C) followed by 75 °C, 1 h; (iii)
CrO3, AcOH, 6 h, 75 °C; (iv) a) 3-bromothiophene, n-BuLi, Et2O, N2,
–78 °C, 10 min; b) 2-cyclohexyl pyruvic acid (5), –78 °C, 5 h, then
–78 °C to –10 °C, H2O, H+; (v) AcOH, HCl, SnCl2·2H2O, reflux 5.5
h; (vi) 2-(N-chloroethyl)azepine, reflux 24 h.
Finally, during the course of our studies it became
necessary to synthesise some a-ketocarboxylic acids, in
particular b-cyclohexylpyruvic acid (b-cyclohexyl-a-ke-
tocarboxylic acid) a useful and key intermediate in the
synthesis of several drug structures. Since many of these
acids are unstable, including the above, we were interest-
ed in investigating a new general route, utilising mild con-
ditions, which would be particularly suitable to more
sensitive and biological molecules (a-hydroxy carboxylic
acids can, either spontaneously, or when attempting to
oxidise the a-hydroxyl group, decarboxylate). To this end
we envisaged protection of the acid grouping by forma-
tion of its benzyl ester: This is a labile grouping which can
readily be removed under very mild conditions using cat-
alytic hydrogenolysis; however, is stable enough to with-
stand the conditions used for oxidation of the a-hydroxyl
group (providing the appropriate conditions are chosen).
It is additionally important to recognise that even a-hy-
droxyesters can readily be decarboxylated by initial in situ
hydrolysis of the ester grouping to the carboxylic acid;13
thus careful selection of the reaction/oxidation conditions
are required.
Whilst out reported,11 (Scheme 1) and slightly different
route to a-keto-b-cyclohexylcarboxylic acid (b-cyclohex-
yl-pyruvic acid, 5), is much higher yielding than the route
reported by Robba2 (60% vs. 16%) it is still insufficient to
be considered for a large-scale synthesis of the enantio-
meric forms of cetiedil, since a further two steps to the
intermediate acid precursor 7 are required. This route en-
abled us to synthesise cetiedil in an overall yield of 18%,
almost four times that of the method originally reported.
In the light of the above we required and thus devised the
simple, effective, and very high-yielding synthesis of 2-
cyclohexyl-2-(3-thienyl)acetic acid (7) in an excellent
74% overall yield (Scheme 2).
Commercially available 3-thiophene acetic acid (9) was
esterified with ethanol using a trace of acid, yielding the
ester 10 (98%); this was reacted with cyclohexyl bromide
in DMF, containing 1.1 equivalents of lithium diisoprop-
ylamide (LDA) as the base, to furnish 11 (76%). Hydrol-
ysis of the ester proceeded almost quantitatively to give
the required acid 7 in an overall 74% yield, as opposed to
the previously reported method (7%) – an order of magni-
tude higher. This is of sufficiently high yield to proceed
with a large-scale resolution of the racemic acid 7, and
consequently the synthesis of the enantiomers of cetiedil.
The route is exemplified for b-cyclohexyl pyruvic acid 5
(Scheme 3). The cyanohydrin 2 was synthesised from
readily available cyclohexane carboxaldehyde in almost
quantitative yield, subsequent hydrolysis yielding the a-
hydroxy-b-cyclohexyl carboxylic acid 12 (84%). Protec-
tion of the carboxylic acid from decarboxylation,14 whilst
undertaking oxidation of the a-hydroxyl group, was
achieved by benzylating with benzyl bromide under
phase-transfer conditions (Aliquat®) to yield 13 (75%).
Further to the above we have been able to synthesise race-
mic cetiedil in an overall 73% yield (almost 16 times that
previously reported) by transesterification the ethyl ester
Synlett 2007, No. 8, 1211–1214 © Thieme Stuttgart · New York

LETTER
Synthesis of Racemic Cetiedil
1213
Elemental analyses were performed by A. A. T. Stones, UCL
microanalytical services, and were within 0.4% of the calculated
values. Chemical intermediates were from Aldrich Chemical
Company unless otherwise stated.
Subsequent oxidation of the a-hydroxyl group was
achieved utilising the mild Swern oxidation15 to furnish
14 (26% – no yield optimisation was undertaken at this
stage), before finally removing the benzyl protecting
group (78%) to afford a-keto-b-cyclohexylpyruvic acid
(5).
2-(3-Thienyl)ethylethanoate (10)
Dry HCl gas was bubbled through a stirred ethanolic solution (100
mL) of 2-(3-thienyl) ethanoic acid (9, 10 g, 70 mmol) for 10 min.
After this period the solution was evaporated under reduced pres-
sure to yield 10 as a viscous clear oil 11.7 g (98%), bp 217–220 °C.
Lit.16 bp 218 °C (97–98 °C at 8 mmHg).
OH
OH
OH
H
i
ii
O
CO2H
CN
O
CH2Ph
12
13
2
2-Cyclohexyl-2-(3-thienyl)ethylethanoate (11)
iii
To 2-(3-thienyl)ethylethanoate (10, 10 g, 59 mmol) in dry DMF
(100 mL) was added LDA (1.1 equiv) in DMF (50 mL). The result-
ing mixture was stirred for 15 min before cyclohexyl bromide 7.3
mL, dried over 4 Å MS, was added. The resulting mixture was
stirred for 10 min before heating at 80 °C for 1.5 h and the resulting
mixture allowed to cool. After this period EtOH (10 mL) was added.
The remaining dark coloured solution was filtered, reduced in vol-
ume under reduced pressure and subjected to flash chromatography
over silica using Et2O as the eluent. This afforded the title com-
pound, after evaporation of the solvent, as a white crystalline solid
11.3g (76%). 1H NMR (CDCl3): d = 7.0–7.25 (3 H, m, thiophene),
4.1 (2 H, q, OCH2), 3.4 (1 H, d, Jvic = 10 Hz, CHCO), 1.3 (3 H, t,
CH3), 0.7–2.0 (11 H, m, cyclohexyl). IR (CDCl3): nmax = 2930 (sat
CH), 1730 (CO2CH2CH3), 770 (monosubst. thiophene) cm–1. MS:
m/e = 252 (M+). Anal. Calcd for C14H20O2S: C, 66.67, H, 7.9; N,
12.7. Found: C, 66.55; H, 7.8; S, 12.6).
O
O
iv
O
OH
O
CH2Ph
O
14
5
Scheme 3 New route to b-cyclohexyl-a-ketocarboxylic acid.
Reagents and conditions: (i) HCl, dioxane, 24 h, r.t.; (ii) a) NaHCO3,
PhCH2Br; b) Aliquat®, 48 h; (iii) a) (COCl2)2, DMSO, CH2Cl2, 15
min; b) Et3N; (iv) H2, 5% Pd/C, EtOH, r.t., atmospheric pressure.
We have described an effective, short, very high-yielding
route to the important and pharmacologically active drug,
racemic cetiedil.
Additionally, we have described a short high-yielding
synthesis of the intermediate 2-cylcohexyl-2-(3-thien-
yl)ethanoic acid (7), enabling for the first time, large-scale
resolution of its enantiomers to be undertaken. This sub-
sequently permits the synthesis of significant quantities of
2-Cyclohexyl-2-(3-thienyl)ethanoic Acid (7)
2-Cyclohexyl-2-(3-thienyl)ethylethanoate (11, 12 g, 47.6 mmol)
was dissolved in EtOH (100 mL) and an aq soln of KOH, containing
5.34 g of KOH (2 equiv). This resulting solution was stirred over-
night at r.t., acidified with dilute HCl, filtered, and reduced in
the enantiomeric forms of cetiedil, allowing extensive volume. The resulting thick oil was taken up in a minimal amount
of PE (bp 60–80 °C) containing a quantity of EtOAc (7:3), and left
pharmacological studies, previously precluded, to be
realised.
to stand whereupon it yielded the title compound 7 as a white
crystalline solid 10.56g (99%), mp 127 °C. Lit 128 °C.2
Finally, a new route to an important class of intermediates
(a-ketocarboxylic acids) is described. The synthesis has 2-Cyclohexyl-2-hydroxy Benzylethanoate (13)
To a stirred solution of 2-cyclohexyl-2-hydroxyethanoic acid (12,
general applicability since it utilises readily available and/
or easily obtainable aldehydes: Further, the methodology
uses mild conditions which makes it additionally suited to
molecules of biological interest.
4 g, 25 mmol) in toluene (50 mL) was added NaHCO3 (2.3 g, 27.5
mmol), benzyl bromide (3.11 mL, 25 mmol) and Aliquat® 336 (1
mL; as a phase-transfer catalyst). The resulting mixture was stirred
for 48 h after which time the solution was filtered and the solvent
removed in vacuo. Flash chromatography of the resultant oil over
1
silica gave the title compound as a mobile oil, 4.65 g (75%). H
Melting points were determined in open capillary tubes with an
Electrothermal melting point apparatus and are uncorrected. Optical
NMR (CDCl3): d = 7.2 (5 H, m, ArH), 6.0 (2 H, s, OCH2Ph), 5.3 [1
H, d, CH(OH)], 0.7–2.2 (11 H, m, cyclohexyl). IR (CDCl3): nmax
=
rotation of solutions in absolute EtOH was measured on an Optical
Activity AA-10 polarimeter. IR spectra were recorded with a
2700–3200 (OH, br), 1715 (CO2CH2Ph), 1600 (ArH) cm–1. MS:
m/e = 248 [M+]. Anal. Calcd for C15H20O3·0.5H2O: C, 70.0; H, 8.2.
Found: C, 69.8; H, 8.1.
1
PerkinElmer 983 spectrometer. H NMR spectra were recorded at
60 MHz on a Joel PMXSI spectrometer, at 200 MHz on a Varian
XL200 spectrometer, samples were dissolved in CDCl3 and TMS
was used as internal standard. Multiplicities are reported as (s) sin-
glet, (d) doublet, (t) triplet, (q) quartet, (m) multiplet. Assignments
of hydroxyl and ammonium protons were checked by deuterium ex-
change. Mass spectra were recorded with a VG 7070H mass spec-
trometer interfaced with a Finnegan Incos data system. Circular
dichroism (CD) spectral measurements were recorded with a Jasco
J600 spectropolarimeter using MeOH solutions (1 mg mL–1) in 0.02
cm and 0.05 cm cylindrical cells. Thin-layer chromatography was
performed over glass plates coated with Merck silica gel 60 F254;
flash chromatography was performed using Merck 7734 silica gel
(20–63 mm). Preparative and analytical high-performance liquid
chromatography (HPLC) were performed with a Gilson binary
grading system with an LB diode-array detector set at 240 nm.
2-Cyclohexyl-2-keto Benzylethanoate (14)
To a stirred solution of oxalyl chloride (9 mmol) in CH2Cl2 (20 mL)
at –60 °C was added dropwise, over 5 min, DMSO (18 mmol) in
CH2Cl2 (8 mL). Stirring was continued for 10 min at –60 °C where-
upon 2-cyclohexyl-2-hydroxy benzylethanoate (13, 2g, 8 mmol) in
CH2Cl2 (8 mL) was added dropwise over 5 min. The resulting mix-
ture was stirred and maintained at –60 °C for a further 15 min
whereupon TEA (dried over 4 Å MS, 40 mmol) was added dropwise
over a period of 5 min at –60 °C. After this period the temperature
was allowed to rise to ambient whereupon H2O (25 mL) was added.
Stirring was continued for a further 10 min before the resultant mix-
ture was filtered and the solvents removed, at r.t., under high vacu-
um. The resultant oil was taken up in a little Et2O and subjected to
Synlett 2007, No. 8, 1211–1214 © Thieme Stuttgart · New York

1214
C. J. Roxburgh et al.
LETTER
chromatography over silica, using Et2O as the eluent, to afford the
title compound as a mobile oil, 0.52 g, (26%). H NMR (CDCl3):
7.2 (5 H, m, ArH), 6.1 (2 H, s, OCH2Ph), 3.0 [1 H, m, CH(CO)],
0.7–2.2 (10 H, m, cyclohexyl). IR (CDCl3): nmax = 1755
(CO2CH2Ph), 1745 (CO), 1600 (ArH) cm–1. MS: m/e = 246 [M+].
Anal. Calcd for C15H18O3: C, 73.2; H, 7.3. Found: C, 73.1; H, 7.4.
(4) Benjamin, L.; Berkowitz, L. R.; Orringer, E.; Mankad, V.
N.; Prasad, A. S.; Lewkow, L. M.; Chillar, R. K.; Peterson,
C. M. Blood 1986, 67, 1442.
(5) Berkowitz, L. R.; Orringer, E. P. J. Clin. Invest. 1981, 68,
1215.
(6) Berkowitz, L. R.; Orringer, E. P. Blood Cells 1982, 8, 283.
(7) Joiner, C. H. Am. J. Physiol. 1993, 264, C251.
(8) Cooper, A. J. L.; Ginos, J. Z.; Meister, A. Chem. Rev. 1983,
83, 321.
(9) Luyten, M. A.; Burr, D.; Wynn, H.; Parris, W.; Gold, M.;
Friesen, J. D.; Jones, J. B. J. Am. Chem. Soc. 1989, 111,
6800.
1
2-Cyclohexyl-2-ketoethanoic Acid (5)
2-Cyclohexyl-2-ketobenzylacetate (14, 2 g, 8.1 mmol) was dis-
solved in absolute EtOH (100 mL) containing concd HCl (1 mL).
To this solution was added 100 mg of 5% Pd/C and the resultant
stirred mixture hydrogenated at r.t. and atmospheric pressure until
the theoretically required amount of hydrogen had been taken up
(182 mL): Following, this the mixture was filtered and the solvent
removed under reduced pressure to yield a viscous oil. Kugelrohr
distillation of the oil yielded 5 as a fine white crystalline solid, 0.99g
(78%), mp 50–51 °C, lit. 53 °C.2
(10) Oshry, L.; Rosenfeld, S. M. Org. Prep. Proced. Int. 1982,
14, 249.
(11) (a) Roxburgh, C. J.; Ganellin, C. R.; Shiner, M. A. R.;
Benton, D. C. H.; Dunn, P. M.; Ayalew, M. Y.; Jenkinson,
D. H. J. Pharm. Pharmocol. 1996, 48, 851. (b) Roxburgh,
C. J.; Ganellin, C. R.; Athmani, S.; Bisi, A.; Quaglia, W.;
Benton, D. C. H.; Shiner, M. A. R.; Malik-Hall, M.; Haylett,
D. G.; Jenkinson, D. H. J. Med. Chem. 2001, 44, 3244.
(12) Innothera, FR 1392671, 1973; Chem. Abstr. 1974, 80,
3401u.
Acknowledgment
We are grateful to the Wellcome Trust for financial support.
(13) Larock, R. C. Comprehensive Organic Transforms: A Guide
to Functional Group Preparations; VCH: New York, 1989,
774–775.
(14) Newman, D.; Owen, L. J. Chem. Soc. 1952, 4713.
(15) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(16) Beilstein Handbook of Organic Chemistry, 3/4 Suppl.*;
E III/IV, 17/27, 1930–1959, 4066.
References and Notes
(1) Current address: The Institute of Naval Medicine,
Alverstoke, Gosport, Hants, PO12 2DL, UK.
(2) Robba, M.; Le Guen, Y. Chim. Therap. 1967, 2, 120.
(3) Schmidt, W. F. III; Asakura, T.; Schwartz, E. J. Clin. Invest.
1982, 69, 589.
Synlett 2007, No. 8, 1211–1214 © Thieme Stuttgart · New York

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