(Z)-5-(4-fluorophenyl)pent-4-enoic acid: A precursor for convenient and efficient synthesis of the antihypercholesterolemia agent ezetimibe

Article abstract of DOI:10.1055/s-0030-1258193

A convenient and efficient total synthesis of ezetimibe, an intestinal cholesterol absorption inhibitor and useful anticholesteremic agent, is described. Based on (Z)-5-(4-fluorophenyl)pent-4-enoic acid as a starting compound, and taking the synthesis through further Z-configured intermediates, the total yield is remarkably increased, compared with the use of the corresponding E-configured starting substances or intermediates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258193

PAPER
3433
(Z)-5-(4-Fluorophenyl)pent-4-enoic Acid: A Precursor for Convenient and
Efficient Synthesis of the Antihypercholesterolemia Agent Ezetimibe
Synthesisof
E
zetimibeatej Sova,a Janez Mravljak,a Andreja Kovač,a Slavko Pečar,a,c Zdenko Časar,b Stanislav Gobec*a
a
Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
Lek Pharmaceuticals, d.d., Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Kolodvorska 27,
1234 Mengeš, Slovenia
Institut Jožef Stefan, Jamova 39, 1000 Ljubljana, Slovenia
Fax +386(61)4258031; E-mail: stanislav.gobec@ffa.uni-lj.si
b
c
Received 25 May 2010
and the document itself proposed new processes for the
synthesis of ezetimibe.
Abstract: A convenient and efficient total synthesis of ezetimibe,
an intestinal cholesterol absorption inhibitor and useful anticholes-
teremic agent, is described. Based on (Z)-5-(4-fluorophenyl)pent-4-
enoic acid as a starting compound, and taking the synthesis through
further Z-configured intermediates, the total yield is remarkably in-
creased, compared with the use of the corresponding E-configured
starting substances or intermediates.
OH
OH
Key words: cholesterol absorption inhibitor, (Z)-5-(4-fluorophe-
nyl)pent-4-enoic acid, Wittig reaction, azetidinone, asymmetric
synthesis
N
F
O
F
ezetimibe (1)
Figure 1 Chemical structure of ezetimibe (1)
Elevated plasma cholesterol levels (hypercholester-
olemia) are a major risk factor for the development of car-
diovascular disease. Ezetimibe (1, Figure 1) has recently
been introduced as the first of a new class of LDL-C low-
ering agents that act by direct inhibition of the uptake of
free cholesterol from the small intestine.1–3 Ezetimibe is
absorbed by the intestinal epithelial cells and remains
mainly associated with the epithelial cell membrane,
where it is believed to interfere with the putative sterol
transporter system.1,2 This appears to prevent both free
cholesterol and plant sterols (phytosterols) from being
transported into the cell from the intestinal lumen. In ad-
dition to its mechanistic novelty, ezetimibe has a long du-
ration of action, low systemic exposure, and an excellent
safety profile. Ezetimibe contains three para-substituted
phenyl rings, a chiral benzylic hydroxyl group, and two
additional stereogenic centers on a rigid 2-azetidinone
scaffold. The three chiral centers give rise to eight stereo-
isomers that have been individually characterized and
shown to have significantly different profiles for the inhi-
bition of cholesterol absorbtion.3 In 2009, annual world-
wide sales for ZETIA (ezetimibe) were $2.2 billion, and
for VYTORIN (ezetimibe/simvastatin combination), $2.1
billion, which puts ezetimibe high on the list of valuable
drugs and interesting synthetic targets. To date, several
synthetic routes for the preparation of ezetimibe have
been described, especially over the last few years.3–10 In
the background section of his patent, Shankar4 discussed
various conventional processes for preparing ezetimibe,
One synthetic route starts from (E)-5-(4-fluorophe-
nyl)pent-4-enoic acid and proceeds further via the E-con-
figured intermediates. Similar synthetic approaches have
been described by Rosenblum et al.10 The starting com-
pound, (E)-5-(4-fluorophenyl)pent-4-enoic acid, has been
synthesized by several methods.10–13 Interestingly, the
synthesis of (Z)-5-(4-fluorophenyl)pent-4-enoic acid and
its use has not been reported yet. Although the synthesis
of ezetimibe (1) via (E)-5-(4-fluorophenyl)pent-4-enoic
acid4,10 appears to be appealing, an overall yield of below
10% and the tedious unselective preparation of the E-con-
figured acid precursor makes this approach unsuitable for
practical use.
In this study, we report on a significant advance in the ef-
ficiency of this process and on new means for the synthe-
sis of ezetimibe. It has been shown that when starting with
compounds based on (Z)-5-(4-fluorophenyl)pent-4-enoic
acid, and proceeding further with the synthesis through
the Z-configured intermediates, the total yield for the syn-
thesis of the final ezetimibe is remarkably increased, to
over 20%.14 There is a surprisingly higher overall yield
when the synthesis route is started and taken through the
Z-configured precursors and Z-configured intermediates14
than through the respective E-configured analogues.4 In
addition, (Z)-5-(4-fluorophenyl)pent-4-enoic acid can be
prepared in significantly higher yields than (E)-5-(4-fluo-
rophenyl)pent-4-enoic acid by the methods reported in the
literature.
5-(4-Fluorophenyl)pent-4-enoic acid and its derivatives
are important intermediates for the total synthesis of
ezetimibe, and here they are provided using a very effec-
SYNTHESIS 2010, No. 20, pp 3433–3438
Advanced online publication: 05.08.2010
DOI: 10.1055/s-0030-1258193; Art ID: P07810SS
x
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x
x
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© Georg Thieme Verlag Stuttgart · New York

3434
M. Sova et al.
PAPER
tive synthetic approach via a Wittig reaction, generating Wittig reaction in this process not only significantly con-
high yields. In this process step, 4-fluorobenzaldehyde is tributes to achieve high total yields, but more importantly,
taken through a Wittig reaction together with (4-ethoxy-4- it generates predominantly the desired Z-isomer, and thus
oxobutyl)triphenylphosphonium bromide (Scheme 1).
allows the selective isolation to obtain the representative
key Z-configured intermediate for the synthesis of
ezetimibe. Remarkably, yields of over 90% and a Z/E ra-
tio of 88:12 can be realized using the Wittig reaction. Pure
Z-configured acid 3 can be obtained by recrystallization
from hexane.
OR
O
H
O
a
The Wittig reaction proceeds more efficiently if the phos-
phorylide is an ester, rather than the parent acid, although
this includes an additional reaction step – ester hydrolysis
is necessary to obtain the corresponding (Z)-5-(4-fluo-
rophenyl)pent-4-enoic acid (3). The saponification was
performed as a one-pot process after the Wittig reaction,
without isolation of the ester derivative. (Z)-5-(4-Fluo-
rophenyl)pent-4-enoic acid (3) was further coupled with
(S)-4-phenyl-2-oxazolidinone using oxalyl chloride and
N,N-diisopropylethylamine (DIPEA) without intermedi-
ate isolation of the unstable acyl chloride. The resulting
oxazolidinone product 4 was enolized in the presence of
TiCl4 and condensed with (E)-N-[4-(benzyloxy)benzyl-
idene]-4-fluoroaniline to give 5 in 59% yield. Due to the
efficient stereodirecting influence of oxazolidinone chiral
auxiliary, compound 5 was obtained in high stereoselec-
tivity (dr = 97:3) as confirmed by NMR analysis.
c
F
F
2 R = Et
b
3 R = H
F
OBn
O
O
N
F
Ph
O
d
N
H
O
F
O
N
4
O
Ph
5
e
OBn
F
OBn
The cyclization of (S)-3-((R,Z)-2-{(S)-[4-(benzyl-
oxy)phenyl](4-fluorophenylamino)methyl}-5-(4-fluorophe-
nyl)pent-4-enoyl)-4-phenyloxazolidin-2-one (5) was
achieved by treatment with a silylating agent, and subse-
quent treatment with a fluoride ion catalyst. The silylation
was performed with N,O-bistrimethylsilylacetamide
(BSA) in anhydrous toluene. This was followed by treat-
ment with tetrabutylammonium fluoride trihydrate
(TBAF·3H2O). Different catalytic amounts of
TBAF·3H2O were examined, whereby 5 mol% was
shown to be optimal for this type of reaction, to obtain the
compound 6 at a 71% yield. The key intermediate,
(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-
[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (7), was
then prepared by Wacker-Tsuji oxidation of alkene 6.15,16
Miller and Wayner16 used different acids and palladium
(II) salts as catalysts for this type of reaction. However,
perchloric acid and palladium acetate were the reagents of
choice for our reaction. Different amounts of HClO4 (up
to 0.45 M) and Pd(OAc)2 (1.0–3.0 mol%) were investigat-
ed. However, optimum conversion of compound 6 to 7
(with 86% yield) was attained with an acid concentration
of 0.15 M and 3.0 mol% Pd(OAc)2. Benzoquinone was
also used as a reoxidant, and for solubility reasons a mix-
ture of acetonitrile and water (10:1) was used as a solvent.
In our hands, oxidation of Z-alkene gives an 86% yield of
ketone 7, while E-alkene oxidation gives the ketone in 70–
80% yield, as described in the patent literature.4
O
f
N
F
N
O
O
F
F
6
7
g
OR
OH
N
F
O
F
8 R = Bn
h
1 R = H
Scheme 1 Reagents and conditions: (a) Ph3P+(CH2)3CO2Et Br–,
NaHMDS, THF, r.t., 97%; (b) i. NaOH, H2O, THF, r.t., ii. aq 40%
HCl, 94%; (c) i. oxalyl chloride, CH2Cl2, r.t., ii. (S)-4-phenyloxazoli-
din-2-one, DIPEA, DMAP, CH2Cl2, r.t., 93%; (d) (E)-N-[4-(benzyl-
oxy)benzylidene]-4-fluoroaniline, TiCl4, DIPEA, CH2Cl2, r.t., 59%;
(e) i. BSA, ii. TBAF·3H2O, toluene, r.t., 71%; (f) benzoquinone,
Pd(OAc)2, 70% aq HClO4, MeCN, H2O, 86%; (g) Me2S·BH3, (R)-te-
trahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxaza-
borole, THF, –20 °C, 96%; (h) 5% Pd/C, H2, 60 psi, EtOH, r.t., 80%.
Compound 7 was then reduced to an alcohol by reaction
with a chiral borane, to obtain and isolate the desired S-
OH-isomeric product (3R,4S)-4-[4-(benzyloxy)phenyl]-
1-(4-fluorophenyl)-3-{[(S)-3-(4-fluorophenyl]-3-hydroxy-
The mixture of E- and Z-isomers of 5-(4-fluorophe-
nyl)pent-4-enoic acid or its esters that is obtained can then
be isolated as the E-isomer and the Z-isomer. Use of the
Synthesis 2010, No. 20, 3433–3438 © Thieme Stuttgart · New York

PAPER
Synthesis of Ezetimibe
3435
fluorobenzaldehyde (2.61 g, 21.0 mmol) was added at 18 °C, rapid-
ly decolorising the red-orange mixture. After stirring at r.t. for 4 h,
a sample of 100 mg was taken from the reaction mixture and puri-
fied by flash chromatography (hexane–EtOAc, 10:1), to get the pure
ethyl ester 2 as a colorless oil. The reaction mixture was cooled
down in an ice bath, and NaOH (1.6 g, 40 mmol) in H2O (10 mL)
was added. The resulting solution was stirred at r.t. for an additional
12 h, followed by the addition of H2O (100 mL) and Et2O (200 mL).
The phases were separated and the aqueous phase was rinsed with
Et2O (2 × 50 mL), acidified with 4 M aq HCl, and extracted with
EtOAc (4 × 50 mL). The combined EtOAc extracts were dried
(Na2SO4), and concentrated. Kugelrohr distillation (124 °C/0.11
Torr) gave 3.52 g (91%) of pure 3 as white crystals, containing 88%
of the Z-isomer, which was obtained in pure form after recrystalli-
zation from hexane.
propyl}azetidin-2-one (8). The yield of this asymmetric
reduction was significantly increased, since compound 8
was obtained in 95% yield, while the reduction step of the
ketone derived from the E-configured intermediates gives
only a 42% yield, as described previously.4 Subjecting
compound 8 to an OH-deprotection reaction finally yield-
ed the target ezetimibe (1) in 80% yield. A suitable OH-
deprotection reaction included catalytic hydrogenation
using palladium on carbon.17
In conclusion, we have developed an efficient and practi-
cal synthesis route for the antihypercholesterolemia drug
ezetimibe. The main feature of our synthetic approach is
the use of the Z-configured starting and intermediate com-
pounds, which provides the unexpectedly high 20% over-
all yield for the total synthesis.14 This compares to the
reported use of the corresponding E-configured starting
substances or intermediates, where ca. an 8% overall yield
has been obtained.4,10,17 This was mainly due to the appli-
cation of the ‘clean’ Wittig reaction, which gave the pure
Z-configured acid 3 starting precursor, while in the previ-
ously published reactions,10–13 a complex mixture of E-
configured acid and derivatives was obtained. Further-
more, our synthetic design has revealed a conspicuous ex-
ample that demonstrates that the efficiency of a total
synthetic approach can markedly depend on the nature
(geometry) of the selected starting precursors, which can
themselves be prepared in high yield in a cleaner manner.
This ascertains that the subsequent reactions take place
with minimum side reactions, which results in a high-
yield process and facilitates the isolation of the intermedi-
ates. Moreover, the physical properties of the Z-config-
ured intermediates allowed more efficient purification,
which contributed further to the overall efficiency of the
total synthesis of ezetimibe (1).
(Z)-Ethyl 5-(4-Fluorophenyl)pent-4-enoate (2)
Rf = 0.42 (hexane–EtOAc, 10:1).
IR (NaCl): 2982, 1735, 1602, 1508, 1373, 1224, 1158, 1096, 1055,
843 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.1 Hz, 3 H, CH3),
2.42–2.47 (m, 2 H, CH2), 2.60–2.68 (m, 2 H, CH2CO), 4.15 (q,
J = 7.1 Hz, 2 H, COOCH2), 5.63 (td, J = 7.2, 11.6 Hz, 1 H, =CH),
6.44 (d, J = 11.6 Hz, 1 H, ArCH=), 7.00–7.08 (m, 2 H, ArH), 7.22–
7.28 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 14.1, 23.8, 34.2, 60.2, 114.9 (d,
3
2JC,F = 21.3 Hz), 128.9, 130.1 (d, JC,F = 7.8 Hz), 130.2, 133.1 (d,
4JC,F = 3.4 Hz), 161.5 (d, 1JC,F = 246.2 Hz, C-3), 172.7 (C=O).
HRMS-ESI: m/z [M + Na]+ calcd for C13H15FO2 + Na: 245.0954;
found: 245.0958.
(Z)-5-(4-Fluorophenyl)pent-4-enoic Acid (3)
Mp 43–45 °C; Rf = 0.49 (Et2O–PE–AcOH, 3:1:3‰).
IR (KBr): 2904, 1894, 1730, 1636, 1604, 1509, 1401, 1322, 1278,
1244, 1175, 1161, 1101, 1051, 1030, 1012, 966, 842 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.46–2.51 (m, 2 H, CH2), 2.59–
2.66 (m, 2 H, CH2CO), 5.64 (td, J = 7.0, 11.6 Hz, 1 H, =CH), 6.44
(d, J = 11.6 Hz, 1 H, ArCH=), 7.00–7.08 (m, 2 H, ArH), 7.22–7.27
(m, 2 H, ArH), 9.99 (br s, 1 H, CO2H).
All of the chemicals used were obtained from commercial sources
(Acros, Aldrich, Fluka, and Merck) and used without further purifi-
cation. Solvents used as reaction media were purchased as absolute
grades and used as received. Petroleum ether (PE) used refers to the
fraction boiling in the range 40–60 °C. Reactions were monitored
using analytical TLC plates (Merck, silica gel 60 F254, 0.25 mm),
and compounds were visualized with ultraviolet light and 2,4-dini-
trophenylhydrazine or bromocresol green. Circular chromatogra-
phy was carried out on a Chromatotron® centrifugal thin-layer
chromatograph (Harrison Research), using silica gel 60 GP254-
containing gypsum. Silica gel grade 60 (70–230 mesh, Merck) was
used for column chromatography. 1H and 13C NMR spectra were re-
corded on a Bruker Avance DPX 300 instrument operating at
300.13 MHz (1H), and 75 MHz (13C). Chemical shifts (d) are report-
ed in ppm using TMS as a reference. Mass spectra were obtained
with a VG-Analytical Autospec Q mass spectrometer (Centre for
Mass Spectrometry, Institute Jožef Stefan, Ljubljana). IR spectra
were recorded on a PerkinElmer FTIR 1600 spectrometer. Melting
points were determined using a Reichert hot-stage microscope and
are uncorrected.
2
13C NMR (75 MHz, CDCl3): d = 23.6, 34.1, 115.1 (d, JC,F = 21.4
Hz), 129.3, 129.7 (d, 5JC,F = 1.3 Hz), 130.2 (d, 3JC,F = 7.9 Hz), 133.1
(d, 4JC,F = 3.4 Hz), 161.6 (d, 1JC,F = 246.3 Hz, C-3), 179.4 (C=O).
HRMS-ESI: m/z [M – H]– calcd for C11H10FO2: 193.0665; found:
193.0672.
(S,Z)-3-[5-(4-Fluorophenyl)pent-4-enoyl]-4-phenyloxazolidin-
2-one (4)
To a solution of 3 (2.3 g) in CH2Cl2 (40 mL) were added slowly ox-
alyl chloride (1.81 g) and DMF (2 drops) at 0 °C. The solution was
warmed to r.t. and refluxed for 1 h. The solvent was evaporated un-
der reduced pressure and the excess of oxalyl chloride was removed
azeotropically with CH2Cl2 (2 × 50 mL). The resultant acid chloride
was redissolved in CH2Cl2 (40 mL) and the solution was added
dropwise to a cooled solution of (S)-(+)-4-phenyl-2-oxazolidone
(1.99 g), DIPEA (3.07 g), and DMAP (0.05 g) in CH2Cl2 (20 mL).
The resulting mixture was stirred at r.t. for 2 h. Then, CH2Cl2 (100
mL) was added, and the organic layer was washed with aq 0.5 M
HCl (2 × 40 mL), H2O (40 mL) and brine (40 mL), dried (Na2SO4),
and concentrated. The product 4 was recrystallized from EtOAc–
hexane and collected by filtration.
(Z)-Ethyl 5-(4-Fluorophenyl)pent-4-enoate (2) and
(Z)-5-(4-Fluorophenyl)pent-4-enoic Acid (3)
Powdered (4-ethoxy-4-oxobuthyl)triphenylphosphonium bromide
(10.5 g, 23.7 mmol) in anhyd THF (30 mL) was treated with sodium
hexamethyldisilazide (12.5 mL, 25 mmol; 2 M solution in THF) at
18 °C with stirring under an argon atmosphere. After 20 min, 4-
Yield: 3.7 g (93%); mp 65–67 °C; Rf = 0.42 (EtOAc–hexane, 1:2);
[a]D25 +0.088 (c 5.0, MeOH).
IR (KBr): 3390, 3039, 2965, 1790 (C=O), 1704 (C=O), 1601, 1506,
1457, 1430, 1388, 1331, 1222 cm–1.
Synthesis 2010, No. 20, 3433–3438 © Thieme Stuttgart · New York

3436
M. Sova et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 2.55–2.70 (m, 2 H, CH2), 3.05–
3.15 (m, 2 H, CH2CO), 4.29 (dd, J = 8.9, 3.7 Hz, 1 H, CHaO), 4.69
(t, J = 8.8 Hz, 1 H, NCH), 5,43 (dd, J = 8.7, 3.6 Hz, 1 H, CHbO),
5.57–5.66 (m, 1 H, =CH), 6.40 (d, J = 11.6 Hz, 1 H, ArCH=), 6.95–
7.04 (m, 2 H, ArH), 7.20–7.43 (m, 7 H, ArH).
Yield: 0.256 g (71%); mp 45–49 °C; Rf = 0.5 (hexane–EtOAc, 2:1);
[a]D25 +32.8 (c 0.5, MeOH).
IR (KBr): 3455, 3014, 2900, 1888, 1733 (C=O), 1611, 1510, 1452,
1428, 1291, 1221, 1158, 1142, 1105, 1044, 1012 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.74–2.95 (m, 1 H, CH2), 3.13–
3.19 (m, 1 H, CHCO), 4.52 (d, J = 2.3 Hz, 1 H, CHN), 5.07 (s, 2 H,
OCH2Ph), 5.63–5.71 (m, 1 H, =CH), 6.52 (d, J = 11.5 Hz, 1 H,
ArCH=), 6.86–7.04 (m, 6 H, ArH), 7.15–7.24 (m, 6 H, ArH), 7.30–
7.41 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): d = 23.0, 35.5, 57.5, 70.0, 115.0 (d,
2JC,F = 21.3 Hz), 125.8, 128.6, 128.9, 129.1, 130.1, 130.2 (d,
4
3JC,F = 7.9 Hz), 133.1 (d, JC,F = 3.3 Hz), 139.0, 153.6, 161.5 (d,
1JC,F = 246.1 Hz, C15), 171.8 (C=O).
HRMS-ESI: m/z [M + Na]+ calcd for C20H18FNO3 + Na: 362.1168;
found: 362.1165.
13C NMR (75 MHz, CDCl3): d = 27.3, 60.1, 60.3, 70.06, 115.3 (d,
2
2JC,F = 21.4 Hz), 115.5, 115.7 (d, JC,F = 22.6 Hz), 118.4 (d,
3JC,F = 7.8 Hz), 127.0, 127.1, 127.4, 128.0, 128.6, 129.5, 130.3 (d,
(S)-3-((R,Z)-2-{(S)-[4-(Benzyloxy)phenyl](4-fluorophenylami-
no)methyl}-5-(4-fluorophenyl)pent-4-enoyl)-4-phenyloxazoli-
din-2-one (5)
3JC,F = 7.9 Hz), 130.6, 132.8 (d, 4JC,F = 3.3 Hz), 133.8 (d, 4JC,F = 2.6
1
Hz), 136.6, 158.7 (d, JC,F = 208.9 Hz), 159.0, 161.9 (d,
1JC,F = 212.3 Hz), 166.6 (C=O).
To a stirred solution of 4 (1.0 g, 3 mmol) in CH2Cl2 (15 mL) at
–20 °C was added slowly a 1 M solution of TiCl4 in CH2Cl2 (3.25
mL). After 15 min, DIPEA (0.97 mL) was added, and the mixture
was stirred for 30 min at –20 °C. A solution of (E)-N-[4-(benzyl-
oxy)benzylidene]-4-fluoroaniline (1.53 g) in CH2Cl2 (30 mL) was
added to the solution keeping the temperature below –20 °C. After
1.5 h, the reaction was quenched with glacial AcOH (1 mL) in
CH2Cl2 (3 mL) at –20 °C and stirred for 30 min. The mixture was
poured into 1 M aq H2SO4 (40 mL) and stirred for another 30 min.
Then, EtOAc (150 mL) was added, and the organic layer was
washed with sat. aq NaHCO3 (3 × 40 mL) and brine (40 mL), dried
(Na2SO4), and concentrated. The product was recrystallized from
EtOAc–hexane and collected by filtration. The crystals were
washed with cold MeOH (5 mL).
HRMS-ESI: m/z [M + H]+ calcd for C31H26F2NO2: 482.1932; found:
482.1930.
(3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-
fluorophenyl)-3-oxopropyl]azetidin-2-one (7)
Pd(OAc)2 (3.0 mol%, 0.042 mmol, 9.43 mg), benzoquinone (2.1
mmol, 227 mg), and 70% aq HClO4 (0.15 M, 0.100 mL) were dis-
solved in MeCN (3.5 mL) and deoxygenated by purging with argon
for at least 20 min. H2O (0.7 mL), which was deoxygenated with ar-
gon, was then added. The reaction mixture was stirred vigorously
for another 5 min under argon, and then a solution of 6 (1.40 mmol)
in MeCN (3.5 mL) (also previously deoxygenated by purging with
argon for 30 min) was added. After 4 h, an additional amount of
70% aq HClO4 (0.100 mL) was added. The resulting solution was
stirred for 48 h and then diluted with EtOAc (50 mL). The aqueous
layer was extracted with EtOAc (30 mL). The combined organic
layers were washed with H2O (2 × 40 mL) and brine (40 mL), dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
crude product was purified by flash chromatography, eluting with
EtOAc–hexane (1:4) to obtain compound 7 as a white stable foam
with physical and spectroscopic properties in agreement with those
reported in the literature.17
Yield: 1.15 g (59%); mp 175–179 °C; Rf = 0.20 (EtOAc–hexane,
1:2); [a]D25 +0.054 (c 5.0, DMF).
IR (KBr): 3381, 3035, 1754 (C=O), 1698, 1607, 1511, 1456, 1422,
1388, 1317, 1229, 1110, 1012 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.31–2.40 (m, 1 H, CHaH), 2.65–
2.75 (m, 1 H, CHbH), 4.22 (dd, J = 8.8, 3.1 Hz, 1 H, CHaO), 4.39 (t,
J = 9.4 Hz, 1 H, CH) 4.36–4.60 (m, 1 H, CHNH), 4.69 (t, J = 8.7
Hz, 1 H, NCH), 4.95 (d, J = 10.3 Hz, 1 H, NH), 5.03 (s, 2 H,
CH2Ph), 5.43 (dd, J = 8.5, 3.1 Hz, 1 H, CHbO), 5.51–5.60 (m, 1
H, =CH), 6.24–6.42 (m, 1 H, ArCH=), 6.69–6.81 (m, 2 H, ArH),
6.84–6.96 (m, 4 H, ArH), 7.08–7.18 (m, 10 H, ArH), 7.38–7.50 (m,
7 H, ArH).
20
Yield: 0.600 g (86%); Rf = 0.63 (hexane–EtOAc, 1:1); [a]D +4.9
(c 1.0, MeOH).
IR (KBr): 3448, 3066, 2928, 1744, 1685, 1598, 1508, 1453, 1409,
1386, 1367, 1290, 1227, 1175, 1155, 1136, 1104, 1012, 990, 833
cm–1.
1H NMR (300 MHz, CDCl3): d = 2.21–2.47 (m, 2 H, CH2), 3.10–
3.21 (m, 2 H, COCH2), 3.24–3.35 (m, 1 H, CHCO), 4.68 (d, J = 2.3
Hz, 1 H, CHN), 5.05 (s, 2 H, OCH2Ph), 6.90–6.99 (m, 4 H, ArH),
7.09–7.17 (m, 2 H, ArH), 7.22–7.27 (m, 4 H, ArH), 7.33–7.44 (m,
5 H, ArH), 7.96–8.02 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 29.2, 48.7, 58.1, 60.8, 70.0, 114.9,
115.0 (d, 2JC,F = 21.4 Hz), 115.0, 115.4 (d, 2JC,F = 22.3 Hz), 125.2,
3
127.5, 128.0 (d, JC,F = 7.8 Hz), 128.2, 128.6, 128.9, 130.1 (d,
4
3JC,F = 7.8 Hz), 130.4, 132.7 (d, JC,F = 3.5 Hz), 132.8, 133.8 (d,
1
4JC,F = 2.6 Hz), 136.6, 154.3, 155.9 (d, JC,F = 235.3 Hz), 158.2,
161.6 (d, 1JC,F = 246.1 Hz), 174.6 (C=O).
HRMS-ESI: m/z [M + H]+ calcd for C40H35F2N2O4: 645.2565;
found: 645.2575.
13C NMR (75 MHz, CDCl3): d = 23.2, 35.5, 59.8, 61.1, 70.0, 115.5,
2
2
115.6 (d, JC,F = 21.9 Hz), 115.7 (d, JC,F = 22.6 Hz), 118.4 (d,
3JC,F = 7.8 Hz), 127.2, 127.4, 128.0, 128.6, 129.5, 130.6 (d,
(3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(Z)-3-
(4-fluorophenyl)allyl]azetidin-2-one (6)
3JC,F = 9.3 Hz), 133.0 (d, JC,F = 3.0 Hz), 133.9 (d, JC,F = 2.7 Hz),
4
4
1
1
158.9 (d, JC,F = 243.4 Hz), 159.0, 165.8 (d, JC,F = 254.9 Hz),
A suspension of 5 (0.484 g, 0.75 mmol) in anhyd toluene (5.0 mL)
was deoxygenated with argon, and after 15 min, BSA (1.50 mmol,
0.37 mL) was added. After stirring for 30 min at r.t., TBAF·3H2O
(5.0 mol%, 0.0375 mmol, 11.8 mg) was added, and the mixture was
left stirring for 4 h. Then glacial AcOH (0.027 mL) and MeOH (4.0
mL) were added. After 5 min, the reaction mixture was concentrat-
ed under reduced pressure, and then EtOAc (50 mL) was added. The
organic layer was washed with 5% aq NaHCO3 (25 mL), H2O (25
mL), and brine (25 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The crude product was purified by flash
chromatography using EtOAc–hexane (1:4) as the eluent to afford
compound 6.
167.1, 197.3 (C=O).
HRMS-ESI: m/z [M + H]+ calcd for C31H26F2NO3: 498.1881; found:
498.1883.
(3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(S)-3-
(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (8)
(R)-Tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-
oxazaborole (96 mg, 0.346 mmol) and 7 (760 mg, 1.528 mmol)
were dissolved in anhyd THF (2 mL) under argon. The solution was
cooled to –22 °C, and after stirring for 5 min, Me2S·BH3 complex
(2 M solution in THF, 0.864 mL, 1.728 mmol) was added dropwise
over 2 h. After stirring for a total of 5 h at –22 °C, the reaction was
Synthesis 2010, No. 20, 3433–3438 © Thieme Stuttgart · New York

PAPER
Synthesis of Ezetimibe
3437
quenched by the addition of MeOH (3 mL). EtOAc (30 mL) and 1
M aq HCl (15 mL) were added, and the phases were separated. The
aqueous phase was extracted with EtOAc (2 × 20 mL). The com-
bined EtOAc extracts were dried (Na2SO4), and concentrated to a
stable foam (0.900 g). The resulting crude product was purified by
flash chromatography using EtOAc–hexane (1:3) as the mobile
phase, to obtain the title compound 8 as a white stable foam with
physical and spectroscopic properties in agreement with those re-
ported in the literature.17
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Yield: 0.731 g (96%); Rf = 0.50 (hexane–EtOAc, 1:1); [a]D20 –15.8
(c 1.0, MeOH).
IR (KBr): 3482, 2937, 2406, 2348, 2293, 1742, 1609, 1509, 1387,
1223, 1156, 1013, 834 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.84–2.05 (m, 4 H, CH2CH2),
3.07–3.17 (m, 1 H, CHCO), 4.59 (d, J = 2.4 Hz, 1 H, CHN), 4.71–
4.76 (m, 1 H, ArCH), 5.07 (s, 2 H, OCH2Ph), 6.91–7.06 (m, 6 H,
ArH), 7.22–7.46 (m, 11 H, ArH).
13C NMR (75 MHz, CDCl3): d = 24.9, 36.5, 60.2, 61.0, 70.0, 72.8,
2
115.2 (d, JC,F = 21.3 Hz), 115.5, 115.7 (d, 2JC,F = 22.7 Hz), 118.3
3
(d, JC,F = 7.8 Hz), 127.1, 127.2, 127.4 128.0, 128.5, 129.5, 133.8
4
4
(d, JC,F = 2.7 Hz), 136.6, 140.1 (d, JC,F = 3.1 Hz), 158.9 (d,
1JC,F = 243.4 Hz), 159.0, 162.0 (d, 1JC,F = 245.4 Hz), 167.6.
HRMS-ESI: m/z [M + Na]+ calcd for C31H27F2NO3 + Na: 522.1857;
found: 522.1864.
Ezetimibe (1)
To a solution of 8 (618 mg, 1.24 mmol) in EtOH (3 mL) was added
5% Pd/C (13 mg, 0.5 mol%). The resulting suspension was stirred
under a H2 gas atmosphere at an elevated pressure of 60 psi, until all
of the starting material 7 had been consumed. The catalyst was re-
moved by filtration. The solution obtained was concentrated under
reduced pressure and recrystallized, to provide the title compound 1
(406 mg, 80%), with specific rotation and physical and spectroscop-
ic properties in agreement with those reported in the literature.17
Acknowledgment
The authors gratefully acknowledge Lek Pharmaceuticals, d.d., for
financial support of this work and Dr. Bogdan Kralj and Dr. Dušan
Žigon (Mass Spectrometry Center, Jožef Stefan Institute, Ljubljana,
Slovenia) for mass spectrometry analyses.
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