Process for preparing Ezetimibe intermediate by an acid enhanced chemo- and enantioselective CBS catalyzed ketone reduction

Article abstract of DOI:10.1016/S0040-4039(02)02700-4

The S alcohol in the benzylic position of compound 2, a key feature of a novel cholesterol lowering agent Ezetimibe, was introduced by the (R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone 1 using borane tetrahydrofuran complex (BTHF) as the reducing agent. The chemo- and enantioselectivity was dramatically enhanced by using an acid as a scavenger of the stabilizer sodium borohydride present in the commercially supplied pure BTHF. The effect of the critical reaction parameters such as addition mode of reagent, temperature, acids as well as water content on the selectivity has been examined. This reaction has been successfully applied in the commercial process for the preparation of the key intermediate 2 for Ezetimibe.

Full text of DOI:10.1016/S0040-4039(02)02700-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 801–804
Process for preparing Ezetimibe intermediate by an acid
enhanced chemo- and enantioselective CBS catalyzed ketone
reductionꢀ
Xiaoyong Fu,* Timothy L. McAllister, T. K. Thiruvengadam, Chou-Hong Tann† and Dan Su‡
Synthetic Chemistry Department, Schering-Plough Research Institute, 1011 Morris Ave., Union, NJ 07083, USA
Received 30 October 2002; accepted 21 November 2002
Abstract—The S alcohol in the benzylic position of compound 2, a key feature of a novel cholesterol lowering agent Ezetimibe,
was introduced by the (R)-MeCBS catalyzed asymmetric carbonyl reduction of ketone 1 using borane tetrahydrofuran complex
(BTHF) as the reducing agent. The chemo- and enantioselectivity was dramatically enhanced by using an acid as a scavenger of
the stabilizer sodium borohydride present in the commercially supplied pure BTHF. The effect of the critical reaction parameters
such as addition mode of reagent, temperature, acids as well as water content on the selectivity has been examined. This reaction
has been successfully applied in the commercial process for the preparation of the key intermediate 2 for Ezetimibe. © 2003
Elsevier Science Ltd. All rights reserved.
Ezetimibe (SCH 58235, 1-(4-fluorophenyl)-3(R)-[3-(4-
fluorophenyl) - 3(S) - hydroxypropyl] - 4(S) - (4 - hydroxy-
phenyl)-2-azetidinone) is a novel and potent agent that
selectively inhibits cholesterol absorption across the
intestinal wall. It was reported from clinical studies that
Ezetimibe significantly decreased plasma LDL choles-
terol levels and increased plasma HDL levels with an
excellent tolerability profile.2 More interestingly, it has
been demonstrated that Ezetimibe has additive effects
with the statins such as simvastatin. This combination
has been shown to improve LDL reduction to 52% as
compared to 35% with simvastatin alone.3 The
metabolism-based discovery4 of this compound with a
novel mechanism for lowering cholesterol has stimu-
lated much interest in synthetic approaches to
efficiently assemble the molecule.5 The reported synthe-
ses focused on the construction of the azetidinone ring
first followed by introduction of the benzylic chiral
hydroxyl group. A more convergent approach has been
developed to synthesize Ezetimibe by preparing the (S)
hydroxy side chain before the ring construction.6 We
wish to report an acid enhanced CBS catalyzed chemo-
and enantioselective synthesis of a key (S) hydroxy
Ezetimibe intermediate 2.
Reduction of carbonyl compounds with chiral oxaz-
aborolidine catalysts has been demonstrated as a pow-
erful method for the synthesis of chiral alcohols from
prochiral ketones.7 A variety of borane reagents have
been employed for this reaction including borane tetra-
hydrofuran complex (BTHF), borane dimethylsulfide
complex (BMS), borane 1,4-thioxane, borane diethyl-
aniline,8 borane N-ethyl-N-isopropylaniline,9 N-borane
phenylamine,10 catecholborane, and in situ generated
borane.11 BMS is generally considered to be a more
stable and less reactive reagent than BTHF, and it has
been widely used in CBS catalyzed ketone reductions.
However, the use of BMS complex leads to environ-
mental concerns due to release of methylsulfide. There-
fore, BTHF has an advantage over BMS for industrial
applications.
Keywords: Ezetimibe; R-MeCBS; asymmetric ketone reduction.
ꢀ This chemistry was disclosed in our patent application which was
filed on March 28, 2001. See Ref. 1.
* Corresponding author. Tel.: 908-820-6165; fax: 908-820-6620;
e-mail: xiaoyong.fu@spcorp.com
† Present address: Rhodia Chirex, Inc., 56 Roland Street,
Charlestown, MA 02129, USA.
‡ Present address: Steris Laboratories, 620 N 51st Ave., Phoenix, AZ
85043, USA.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02700-4

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X. Fu et al. / Tetrahedron Letters 44 (2003) 801–804
Reduction of ketone 1 with BMS in the presence of
(R)-MeCBS provided (S)-chiral alcohol 2 with excellent
enantioselectivity (>98% de, vs 3) in greater than 95%
yield. The addition sequence of reagents was to add 1
slowly into a premixed solution of BMS and catalyst.
Due to the increased reactivity of BTHF over BMS,
simple replacement of BMS with BTHF in the reduc-
tion generated a substantial amount (>30%) of over-
reduction of the amide bond to give the diol 4,
identified by HPLC/MS analysis. Attempts to separate
the diol 4 from the major product 2 were unsuccessful
due to its instability. Instead, (S)-(+)-4-phenyl-2-oxazo-
lidinone was isolated as a by-product of the decomposi-
tion. The enantioselectivity was comparable with the
BMS reaction (>95% de). Attempts to overcome the
chemoselectivity problem by introduction of additives12
such as isopropanol and triethylamine, pyridine, and
2,6-lutidine were unsuccessful. When triethylamine
(0.25 equiv.) was used as an additive, the reaction
proceeded with good de (93%) and the overreduced
by-product was less than 5%. However, the reaction
was not complete when all of 1 was charged slowly, and
additional BTHF was required to push the reduction to
completion. These results implied that the complex of
triethylamine with borane formed in situ was not reac-
tive enough for the reduction. This was confirmed by
carrying out the reaction with commercially available
borane triethylamine complex. The results also hinted
that change of the addition mode might offer an advan-
tage to resolve the chemoselectivity issue since limiting
the BTHF reagent should allow the reaction with the
more reactive ketone function in the presence of the
amide bond. When the reaction was executed by adding
about 0.6 equiv. of BTHF to a solution of 1 in the
presence of 3% (R)-MeCBS catalyst in THF, the
chemoselectivity was indeed controlled to less than 1%
diol and the reaction gave a near quantitative yield with
ꢀ95% de (Scheme 1). It is critical to divide the BTHF
addition into two portions. The reaction progress was
monitored by HPLC analysis when about 85% of the
calculated amount of reagent was charged. The rest of
the BTHF was added based on the reaction completion
to minimize overreduction to diol 4.
range such as −10 to 35°C to produce the chiral alcohol
with acceptable selectivity since the corresponding
products from the minor diastereomer 3 are largely
removed during the subsequent purification steps.
Due to the sensitivity of the R-MeCBS catalyst to
moisture, it is critical to keep the reaction mixture free
of water. For example, when the water content was
0.3% by KF analysis, the reaction only yielded the
chiral alcohol 2 in 70% de compared to 95% de under
the dry conditions (ꢀ0.02% by KF). Decomposition of
the catalyst with water would produce diphenylproli-
nol. Although R-diphenylprolinol itself was reported to
catalyze ketone reduction to give high enantioselectiv-
ity, it only provided moderate de (ꢀ70%) under our
reaction conditions for the reduction of 1 to 2. To
ensure dry conditions, the solution of 1 in THF was
concentrated to the water content of below 0.02% by
KF analysis.
The results described above were all from the reactions
using BTHF from Aldrich. Since Aldrich was not the
primary commercial supplier for BTHF, it was desir-
able to look for alternative sources for both the price
and availability of this reagent. Callery Chemical is the
primary supplier for borane tetrahydrofuran complex.
To our surprise the reduction of 1 gave a much inferior
selectivity when the BTHF from Callery Chemical was
used. To understand the reasons for the lower selectiv-
ity with borane tetrahydrofuran complex purchased
from Callery, NMR studies on the BH3·THF were
initiated. Analysis of the proton NMR spectrum clearly
indicated that about 3–5% of borane 1-butanol complex
was present in the Aldrich samples which was absent in
the other samples. Boron NMR suggested that the
complex was a mixture of di-butoxyborane (major) and
mono-butoxyborane. Clearly the formation of those
compounds was from the complexation of borane with
1-butanol which was generated by the reduction of
tetrahydrofuran with BH3·THF. The di-butoxyborane
prepared by reaction of 1-butanol and borane was
mixed with the Callery BTHF complex and used for the
reduction. However the results indicated that the
butoxyborane had no effect on the selectivity.
The temperature effects on the enantioselectivity of the
reduction were studied and the results are summarized
in Table 1. As reported in the literature,13 the enan-
tioselectivity decreases with decreasing temperature.
The reduction of 1 gave the best enantioselectivity at a
temperature of about 25°C. It should be noted that the
reaction can be conducted over a wide temperature
Careful analysis of the boron NMR also indicated that
some other minor boron species were present in the
Aldrich borane. One possibility could be BF3 etherate
since it might be used in the generation of diborane gas.
With this in mind, we conducted a systematic study on
the effect of acid additives on the selectivity of the
reduction.
Table 1. Temperature effects on the enantioselectivity
When the reduction was conducted with Callery borane
mixing with 1 mol% of BF3·OEt2 the selectivity sig-
Entry
Temperature
Enantioselectivity (% de)
14
nificantly enhanced from about 87% de to about 94%
de. This result supported the hypothesis of a trace
amount of BF3·OEt2 present in the Aldrich borane
which actually assisted the chiral reduction to achieve
higher selectivity. The butoxyborane species present in
the Aldrich borane, but absent in the Callery borane,
could now be easily understood for the acid destroyed
1
2
3
4
5
6
−11
0
10
18
25
35
92.5
93.3
93.9
95.2
96.2
94.5

X. Fu et al. / Tetrahedron Letters 44 (2003) 801–804
803
Scheme 1. R-MeCBS catalyzed reduction of 1.
Table 2. Acid additive effects on the enantioselectivity
ferent (52% de with NaBH4 vs 87% de by the control).
In a separate experiment with 3% pTSA added to the
reaction mixture, the % de was enhanced to greater
than 95% while the overreduction of product was held
under 0.5%. The results demonstrated clearly that the
reaction with pTSA was much cleaner than without
pTSA. The process with the addition of NaBH4 scav-
enger (an acid) is robust and the reaction parameters
are easily controlled. When a Lewis acid such as
BF3·OEt2 is used, the Lewis acid reacts directly with
NaBH4 to form BH3. However, when a protic acid such
as pTSA is employed, the structures of the active
species which destroys NaBH4 is not very clear and
might be an adduct of the acid and BH3. Further
studies are needed to understand the reaction pathway
in detail.
Entry
BH3·THF
source
Acid (mol% to Selectivity
BH3)
SS 2/SR 3
% de
1
2
3
4
Callery
Aldrich
Callery
Callery
None
None
93.7/6.3
96.3/3.7
87.4
92.6
93.8
93.4
BF3·OEt2 (1%) 96.9/3.1
BF3·OEt2
96.7/3.3
(2.5%)
5
6
Callery
Callery
BF3·OEt2 (5%) 97.5/2.5
95.0
93.5
BF3·OEt2
(10%)
96.7/3.3
7
8
9
10
11
Callery
Callery
Callery
Callery
Callery
BCl3 (5%)
pTSA (5%)
TFA (5%)
MSA (5%)
CSA (5%)
95.3/4.7
96.5/3.5
95.9/4.1
96.0/4.0
96.6/3.4
90.6
93.0
91.8
92.0
93.2
The effect of the R-MeCBS catalyst loading on the
enantioselectivity was also tested in order to develop a
most cost effective commercial process. The results are
tabulated in Table 3. The results indicated that the
catalyst loading has a less profound effect on the
selectivity than the other parameters described above.
The product selectivity was calculated from chiral HPLC analysis
(Chiralcel OD column, 30% EtOH in hexane as mobile phase with a
flow rate of about 0.7 mL/min, an UV detector at 215 nm).
Table 3. Effects of R-MeCBS loading on product % de
In summary, an efficient R-MeCBS catalyzed ketone
reduction protocol has been successfully applied in the
process for preparation of Ezetimibe intermediate 2. An
acid additive such as pTSA has dramatic effects on
both the chemo- and enantioselectivities. The robust
process has been scaled up to multikilogram levels.
R-MeCBS (%)
KF (ppm)
de (%)
Diol (4) (%)
1
2
3
54
50
67
93.1
95.1
95.3
0.97
0.25
0.89
All experiments were carried out with addition of 3% pTSA to
compound 1 in THF. The solution was subsequently dried via
distillation before the addition of R-MeCBS.
Acknowledgements
the stabilizer (NaBH4). It was obvious that the stabi-
lizer, NaBH4, participated in the reduction of 1, which
resulted in the racemic 2. The overall result would
reduce the selectivity (% de). Different acids were
screened for this reduction. The results are summarized
in Table 2.
The authors thank Drs. Michael B. Mitchell and Doris
P. Schumacher for helpful discussions, Dr. Tze-Ming
Chan for NMR studies, Dr. Larry Heimark for HPLC/
MS analysis and Mr. Danny Angeles for experimental
assistance.
It is clear from the above results that the various acid
additives can significantly enhance the enantioselectivity
for the reduction of 1 to 2. It is interesting to note that
the NaBH4 present in the BTHF has not only detrimen-
tal effects on the enantioselectivity but also on the
chemoselectivity. Experiments were carried out with
addition of an extra 2.7% NaBH4 into the reaction to
test the effect on the overreduction. There was greater
than 9% of diol 4 observed with extra NaBH4 while less
than 3% was detected in the control experiment. It was
no surprise that the selectivities were dramatically dif-
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