Efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe

Article abstract of DOI:10.1080/00397911.2016.1221969

An efficient and scalable process for the synthesis of antihypercholesterolemic drug ezetimibe through chiral Evans auxiliary (S)-4-phenyl-2-oxazolidinone is described. The key steps in this process are the condensation of (S)-3-(5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one and N-(4-((tert-butyldimethylsilyl)oxy)benzylidene)-4-fluoroaniline, and the stereoselective reduction of ezetimibe-ketone with NaBH₄/I₂, which is first applied in the synthesis of ezetimibe. The process is concise, mild, easy to operate, and highly stereoselective (99.6% of de value of ezetimibe). In addition, three diastereomers of ezetimibe are synthesized and served as the references in quality control of the product.

Full text of DOI:10.1080/00397911.2016.1221969

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Efficient and Scalable Process for the Synthesis
of Antihypercholesterolemic Drug Ezetimibe
Yijun Zhu, Jing Pan, Shunli Zhang, Zhenren Liu, Deyong Ye & Weicheng Zhou
To cite this article: Yijun Zhu, Jing Pan, Shunli Zhang, Zhenren Liu, Deyong Ye & Weicheng Zhou
(2016): An Efficient and Scalable Process for the Synthesis of Antihypercholesterolemic Drug
Ezetimibe, Synthetic Communications, DOI: 10.1080/00397911.2016.1221969
To link to this article: http://dx.doi.org/10.1080/00397911.2016.1221969
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Date: 20 August 2016, At: 01:23

An efficient and scalable process for the synthesis of antihypercholesterolemic drug
Ezetimibe
Yijun Zhu1,2, Jing Pan1, Shunli Zhang1, Zhenren Liu1, Deyong Ye2, Weicheng Zhou1
1State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of
Anti-Infectives, State Institute of Pharmaceutical Industry, Shanghai, China, 2School of
Pharmacy, Fudan University, Shanghai, China
ABSTRACT
An efficient and scalable process for the synthesis of antihypercholesterolemic drug
Ezetimibe through chiral Evans auxiliary (S)-4-phenyl-2-oxazolidinone is described. The
key
steps
in
this
process
are
the
condensation
of
(S)-3-(5-(4-fluorophenyl)-5,5-dimethoxypentanoyl)-4-phenyloxazolidin-2-one
and
N-(4-((tert-butyldimethylsilyl)oxy)benzylidene)-4-fluoroaniline, and the stereoselective
reduction of Ezetimibe-ketone with NaBH4/I2 which is first applied in the synthesis of
Ezetimibe. The process is concise, mild, easy to operate and highly stereoselective
(99.6% of de value of Ezetimibe). In addition, Three diastereomers of Ezetimibe are
synthesized and served as the referrences in quality control of the product.
GRAPHICALABSTRACT
1

KEYWORDS: Ezetimibe, (S)-4-phenyl-2-oxazolidinone, process, stereoselective,
NaBH4/I2
INTRODUCTION
Antihypercholesterolemic drug Ezetimibe (1,
(1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(S)-(4-hydroxyphen
yl)-2-azetidinone), is a cholesterol absorption inhibitor which was discovered by
Schering-Plough [1-2]. It was approved by FDA in 2002 for the treatment of
hypercholesterolemia[3-4]. Combinations of 1 with all available statins (HMG CoA
reductase inhibitors) have been completed and demonstrated LDLc reductions by the
proof of Improved Reduction of Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT) to any statin dose alone[5].
For its potent therapeutic efficiency and great market prospects, the synthesis of 1 has
attracted many attentions which led to the development of several conventional
processes[6-11]. Most of these were based on the chiral Evans-type auxiliary
(S)-4-phenyl-2-oxazolidinone condensation[12] to establish the correct stereochemistry on
the azetidinone ring, in addition, these methods also applied the Corey-Bakshi-Shibata
oxazaborolidine reduction[13] to set the (S)-form of the hydroxyl group. However many of
these routes involved flash chromatography or chiral HPLC purification and in some
processes, precious metal palladium and unfriendly borane reductant were utilized. To
2

avoid the above issues, an improved, efficient and scalable process for preparation of 1
was developed and described herein.
RESULTS AND DISCUSSION
The synthesis of 1 (Scheme 1) was started from the commercially available material
5-(4-fluorophenyl)-5-oxopentanoic acid(2).
The key intermediate 4 was synthesized via keto-protection of 3 which was obtained by
amidation of 2 and (S)-4-phenyl-2-oxazolidinone(Scheme 1). Different from the
preparation of reported similar compound[10], our synthetic strategy was amidation first
instead of keto-protection of 2, so the extra hydrolysis of the ester (resulted from the
keto-protection of 2) in the literature[10] was avoided. When the keto-protective group was
methyl, compound 4 could directly precipitated out from the reaction mixture after
cooling while in the reported procedures (in which, the protecting group was ethylene)
column chromatography was needed in order to get the solid product.
Tert-butyldimethylsilyl was chosen as the protecting group in
(E)-N-(4-((tert-butyldimethylsilyl)oxy)benzylidene)-4-fluoroaniline(8) so that it could be
deprived in acidic condition along with the ketal protective group in the following
procedures.
3

The compound 5 with two chiral centres was synthesized by the condensation of 4 with
the protected imine 8 in the presence of TiCl4 and Ti(O-iPr)4(Scheme 2), the investigation
of key reaction parameters such as reactant feed ratio and reaction temperature was not
found in the literature. In this paper, they were screened and the experimental results
were presented in Table 1. At the beginning, the ratio of reactants 4 and 8 was set as 1:1.2
other than 1:2 as reported in the patent[10], and it was carried out under the presence of
TiCl4/Ti(O-i-Pr)4 in DCM at -30~35oC for 1.5h (Table 1, entry 1), both the de and yield
were moderate. Excellent de and good yield were obtained when the reaction temperature
decreased to -70oC (Table 1, entry 2~3). Additional ratios of 4 and 8 was investigated, but
no better result was obtained (Table 1, entry 4).
The key intermediate 5 was cyclized in the presence of
N,O-bistrimethylsilylacetamide(BSA) and tetrabutylammonium fluoride trihydrate
(TBAF·3H2O). The crude oilly 6 was refluxed in acidic condition to remove both ketone
and phenol protecting groups at the same time. In this process, the Ezetimibe-ketone 7
was produced in one step and first isolated by recrystallization from isopropanol in the
chiral purity of over 99.9% ee as well as the chemical purity of 99.7%.
In the last step, Ezetimibe was obtained by the reduction of 7 with boron reduction
reagents in the catalysis of (R)-Me-CBS(Scheme 3). The reduction was initially carried
out with different borane reductants and the results were given in Table 2 (entry 1~3).
4

Although the de and yield were moderate, BH3/Me2S was unfriendly to the enviroment
due to the disgusting smell of the sulfide, BH3/THF was high inflammable and
BH3/DEAN added an organic impurity(DEAN) to the system which may complicate the
purification of product. So other borohydride reagents were tested (Table 2, entry 4~7).
Fortunately, NaBH4/I2 gave quite good result[14-15] (entry 8). Although the yield was a
slightly lower than BH3/DEAN, NaBH4/I2 could be served as an alternative reagent. The
obtained crude product was crystallized from isopropanol/H2O to afford product 1 with
99.80% optical purity and 99.77% of chemical purity.
In addition, three diastereomers of Ezetimibe,
1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(R)-hydroxypropyl]-4(S)-(4-hydroxyphen
yl)-2-azetidinone (1’) (Scheme 4),
1-(4-fluorophenyl)-3-(S)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(R)-(4-hydroxypheny
l)-2-azetidinone (1’’) and
1-(4-fluorophenyl)-3-(R)-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4(R)-(4-hydroxyphen
yl)-2-azetidinone (1’’’) (Scheme 5) were synthesized referred to the above improved
process just by changing the configuration of chiral auxiliary or Me-CBS reductant. And
these isomers were well separated from Ezetimibe by HPLC and the HPLC results were
showed in Table 3.
5

CONCLUSION
In summary, an efficient and improved synthetic process of Ezetimibe 1 via
(S)-4-phenyl-2-oxazolidinone was developed. Three improvements were presented in this
process. The ketal 4 could precipitated directly in methanol instead of
extraction,concentration and column chromatography in the reported patent[10]; second,
the ketone and phenol protecting groups of compound 6 were removed simultaneously in
acidic condition and easily recrystallized from isopropyl alcohol to yield
Ezetimibe-ketone 7, while most routes needed to remove benzyl group with
hydrogenation in the catalysis of palladium carbon; third, inexpensive NaBH4/I2
reductant which was first reported in preparation of Ezetimibe could be a green method
for ketone reduction instead of the boron reduction reagents. This improved process was
consice, efficient, easy to perform and both the stereoselectivity and total yield of the
product were excellent.
EXPERIMENTAL
Solvents and reagents were obtained from commercial sources and used without further
purification. 1H-NMR and 13C-NMR spectra were recorded in CDCl3 or DMSO-d6 on
Bruker Avance III-400 MHz using TMS as an internal standard. Mass spectra were
recorded with a Q-TOF mass spectrometer using electrospray positive ionization (ESI+).
Chiral HPLC analyses were recorded with Agilent 1100 Series chromatography. Melting
6

point was measured by Buchi Melting Point M-565. The optical rotations were measured
by Autopol®IV Automatic Polarimeter.
(S)-3-((R)-2-((S)-(4-((TERT-BUTYLDIMETHYLSILYL)OXY)PHENYL)((4-FLUO
ROPHENYL)AMINO)METHYL)-5-(4-FLUOROPHENYL)-5,5-DIMETHOXYPE
NTANOYL)-4-PHENYLOXAZOLIDIN-2-ONE (5)
1) Preparation of Titanium-trichloride-isopropoxyde reagent:
To the solution of TiCl4 (135 mL, 1.22 mol, 0.9 eq) in DCM (2 L) was added Ti(O-iPr)4
(128.3 mL, 0.41 mol, 0.3 eq) dropwise at 0oC under N2 atmosphere. The mixture was
stirred for 15 min at 0 oC and was used in the following coupling step.
2) Coupling of compound 4 and 8
To a solution of compound 4 (540 g, 1.35 mol, 1 eq) and 8 (533.8 g, 1.62 mol, 1.2 eq)
dissolved in DCM (3 L) equipped with mechanical stirrer was added DIPEA (360 g, 2.78
mol, 2.07 eq) at -70oC under N2 atmosphere. Then the titanium reagent prepared in
advance was added dropwise at this temperature. After addition, the reaction mixture was
stirred for 1.5 h. HPLC showed compound 4 was reacted up and the orange mixture was
quenched with isopropanol (675 mL) at the temperature of no more than -30 oC. Stirred
for about 30 min, the mixture was slowly poured into tartarate buffer (1.4 Kg/8 L) and
stirred for 15 min (color changed to white), then separated, the aqueous phase was
extracted with DCM (2L ×2), the combined organic phase was washed with water (2L
×2), dried over Na2SO4, then concentrated to get about 1.3 Kg crude oil. The residue was
7

recrystallized from methanol to afford 5 as an off-white solid (689.7 g, 70.1% yield,
99.4% de). And 141.5 g solid 5 was recovered from the mother liquid in 98.9% de. The
total yield was 84.5%. mp: 133~136oC, HPLC purity:97.90%, [α]D25 =7.7o(c 1,CDCl3).
1H-NMR(CDCl3, 400MHz): δ7.27-7.14 (m, 4H), 7.12-7.04 (m, 3H), 6.96-6.89 (m, 4H),
6.72-6.62 (m, 4H), 6.31-6.11 (m, 2H), 5.38 (t, 1H, J=8), 4.74 (d, 1H, NH), 4.66-4.62 (m,
1H), 4.31-4.23 (m, 1H), 4.21-4.15 (m, 2H), 3.04 (s, 6H), 1.89-1.76 (m, 2H), 1.41-1.38 (m,
2H), 1.0 (s, 9H), 0.17 (s, 6H). 13C-NMR(CDCl3, 100MHz): δ175.1, 163.5, 161.0, 157.1,
154.9, 154.8, 154.3, 142.8, 138.2, 135.8, 133.2, 128.9, 128.6, 128.5, 127.8, 125.2, 120.1,
115.5, 115.3, 115.1, 115.0, 114.9, 114.6, 102.9, 70.0, 61.0, 58.1, 48.6, 48.4, 48.1, 34.6,
25.6, 24.4, 18.1, 4.5. MS (ESI) m/z calcd. for C41H48F2N2O4Si: 730.32, calcd. for
C41H48F2N2O4SiNa (M+Na) =753.32, found 753.24 (M+Na).
(3R,4S)-1-(4-FLUOROPHENYL)-3-((S)-3-(4-FLUOROPHENYL)-3-HYDROXYPR
OPYL)-4-(4-HYDROXYPHENYL)AZETIDIN-2-ONE (1, EZETIMIBE)
To the suspension of NaBH4 (8.3 g, 0.22 mol, 2.2 eq) in THF (80 mL) was added the
solution of I2 (27.8 g, 0.11 mol, 1.1 eq) in THF (135 mL) at -5 oC under N2 atmosphere.
After addition, the mixture was stirred to clear. Followingly, the (R)-Me-CBS (14.4 mL,
14.4 mmol, 0.1 eq) toluene solution was added at 0 oC, then the solution of 7 (40.7 g, 0.1
mol, 1 eq) dissolved in DCM (100 mL) was added dropwise at -15oC. After addition, the
mixture was stirred at -8~0 oC for 4 h and TLC showed the ketone 7 was consumed up.
The mixture was quenched with methanol (60 mL) and HCl aq(2 N), the mixture was
8

stirred for 15 min. And it was extracted with DCM, combined the organic phase, washed
with water (100 mL X2)、brine(100 mL) ,accordingly, dried over Na2SO4, filtered,
concentrated to get the crude oil (61.1 g). The residue was crystallized from isopropanol:
deionized water (120 mL: 90 mL) to afford qualified Ezetimibe as white solid with
99.60% de. (22.5 g, 55.4% yield). mp: 163~165oC [lit.11 164~166 oC], [α]D25 =-29.8o(c 3,
methanol) [lit.11 [α]2D0 =-28.1o(c 3, methanol)]. HPLC purity: 99.77%. Optical purity:
99.80%. 1H-NMR(DMSO-d6, 400MHz): δ9.5 (s, 1H), 7.31 (d, 2H, J=8), 7.24-7.21 (m,
4H), 7.15-7.10 (m, 4H), 6.76 (d, 2H, J=8), 5.26 (d, 1H, J=4), 4.81 (d, 1H, J=4), 4.52-4.48
(m, 1H), 3.10-3.07 (m, 1H), 1.85-1.69 (m, 4H). 13C-NMR(DMSO-d6, 100MHz): δ167.8,
162.7, 159.7, 157.9, 157.3, 142.6, 134.5, 134.4, 128.4, 128.1, 128.0, 127.9, 118.8, 118.7,
116.4, 116.3, 116.2, 115.2, 115.0, 71.7, 60.1, 59.9, 36.9, 25.0. MS (ESI) m/z calcd. for
C24H21F2NO3: 409.15, calcd. for C24H21F2NO3Na (M+Na)=432.15, found 432.05
(M+Na).
SUPPLEMENTARY MATERIAL:
Full experimental details, 1H-NMR and 13C-NMR, ESI-MS spectra, HPLC of
compounds 1, 3, 4, 5, 5’, 7 and 8. Chiral HPLC of compound 1 and 7. This material can
be found via the “Supplementary Material” section of this article’s webpage.
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11

Table 1: Conditions for preparation of intermediate 5.
entry ratio of T (oC)
3:8a
Time
(h)
de of crude
product(5:5’b) via
recrystallization
de of product 5
yield(%)c
1
2
3
4
1:1.2
1:1.2
1:1.2
1:1.5
-30~-35 1.5
-40~-55
-70~-80 2~3
-70~-80
81.8%
87.2%
93.3%
84.1%
90.5%
97.5%
99.4%
91.7%
61.1%
64.8%
70.1%
63.2%
2
2
aAll reactions were carried out under the catalysis of TiCl4/Ti(O-i-Pr)4/DIPEA (0.9:0.3:2);
bstructure confirmation of 5’ was given in the supporting information; c yield after
recrystallization
12

Table 2: Reductants Screening for preparation of 1.
entry Reductanta
de of crude 1:1’
90.3%:9.70%=80.6%
88.6%:11.2%=77.6%
90.0%:9.10%=81.6%
NAd
de of 1b
99.7%
99.7%
99.6%
Yield(%)b
61.1
1
2
3
4
5
6
7
BH3/Me2S(2eq)
BH3/THF(2eq)
BH3/DEANc(2eq)
NaBH(OAc)3(2.5eq)
NaBH3CN(2eq)
NaBH4(2eq)
NaBH4/BF3-Et2O
(2:2.67)
56.4
60.8
NAd
50.4%:49.2%=1.2%
86.4%:13.6%=72.8%
96.7%
99.6%
98.9%
49.7
55.4
50.5
8
9
NaBH4/I2
91.2%:8.8%=82.4%
87.8%:12%=76.0%
(2.2:1.1)
NaBH4/I2
(1.1:0.55 )
aAll reactions were carried out under the catalysis of (R)-Me-CBS (0.1eq) bafter
recrystallization; cDEAN=N,N-diethyl aniline; dNA= no reaction.
13

Table 3: HPLC results of Ezetimibe and three isomers.
Chiral HPLC
Chemical HPLC
purity(%) time(min) RRT
purity(%) time(min) RRT
99.80
99.08
96.43
99.09
28.788
27.224
23.119
24.018
1
99.77
99.85
99.98
99.62
9.910
9.800
9.783
9.910
1
1
0.946
0.803
0.834
0.989
0.987
1
1’
1”
1”’
14

Figure 1: Ezetimibe (1).
15

Scheme 1: Synthetic process for Ezetimibe 1.
16

Scheme 2: Preparation of key intermediate 5.
17

Scheme 3: Reduction of Ezetimibe-ketone 7.
18

Scheme 4: Synthesis of RRS-Ezetimibe 1’.
19

Scheme 5: Synthesis of SSR-Ezetimibe 1” and RSR-Ezetimibe 1”’.
20