known in the literature using Pd(PPh3)4, and the main disad-
vantage of using Pd(PPh3)4 is to purify the product by using
column chromatography, which is not preferable on large scale.
We have replaced the Pd(PPh3)4 with Pd(OAc)2 to get the
ketone 9 with good quality and without doing any column
chromatography. By this modification there is no need to purify
the product by column chromatography. R-Methyloxazaboro-
lidine-mediated reduction of ketone 9 with borane dimethyl-
sulfide delivered the compound 10 with the required stereo-
chemistry.20 The final deprotection of the benzyl group by using
5% Pd/C in methanol-water (20:1) gave the ezetimibe 1 as a
white solid.
pylethylamine (66.5 g, 0.514 mol), and this mixture stirred for
1 h at the same temperature. 4-Benzyloxybenzylidene(4-
fluoro)aniline (157.4 g, 0.514 mol) was added to the above
reaction mixture and stirred for 6 h at -10 °C. The reaction
mixture was quenched with a mixture of acetic acid (100 mL)
and dichloromethane (200 mL) and 2 N H2SO4 solution (300
mL), and stirred at 30 °C for 1 h. The organic layer was
separated, and the aqueous layer was extracted with dichlo-
romethane (200 mL). The combined organic layer was washed
with water (600 mL), dried, and concentrated to get the crude
4. Methanol was added to the above crude product, stirred for
1 h, and then filtered to get 98.3 g (48%) of compound 5. 1H
NMR (200 MHz, CDCl3, δ) 1.4-2.6 (m, 6H), 3.7 (s, 3H),
3.92-4.78 (m, 3H), 5.1 (s, 2H), 5.47 (m, 1H), 6.4-7.4 (m,
18H, Ar); IR (KBr pellet): 3383.97, 1767.4, 1736.98 cm-1,
1699.9; MS: m/z 596.2 (M+).
Conclusion
In conclusion we have developed an improved and practical
synthesis of ezetimibe 1, the first example of a cholesterol-
lowering drug that inhibits cholesterol absorption in the small
intestine. The present synthesis is free of column chromatog-
raphy in all stages.
Preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3-(methoxy)-
3-oxopropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 6. To a solu-
tion of compound 5 (200 g, 0.336 mol) in toluene (1400 mL)
was added N,O-bis(trimethylsilyl)acetamide (119.46 g, 0.587
mol) at 60 °C and was maintained at the same temperature for
30 min. TBAF (3.7 g, 0.012 mol) was added to the reaction
mixture, and the reaction mixture was stirred at 60 °C until the
completion of reaction. The reaction mixture was cooled to 40
°C and neutralized with acetic acid (20 mL), and the solvent
was distilled to get the crude compound. Toluene (200 mL)
was added to the above crude compound and stirred at 0 °C
for 30 min and filtered. The combined filtrates were distilled,
and the crude compound was crystallized from methanol to get
Experimental Section
The 1H NMR spectra were measured using Varian Gemini
FT NMR spectrometer; the chemical shifts are reported in δ
ppm relative to TMS. The FT-IR spectra were recorded in the
solid state as KBr dispersion using a Perkin-Elmer 1650 FT-
IR spectrophotometer. The mass spectrum (70 ev) was recorded
on HP- 5989A LC/MS spectrometer. The CHN analysis was
carried out on a Perkin-Elmer model 2400S analyzer. The
solvents and reagents were used without further purification.
Preparation of 1-[(5-Methoxy-1,5-dioxopenta)yl]-4(S)-
phenyloxazolidi-2-one 4. To a solution of monomethyl glut-
arate (300 g, 2.05 mol) in dichloromethane (1500 mL) was
added triethyl amine (496 g, 4.92 mol) and pivaloyl chloride
(299.8 g, 2.48 mol) at room temperature and stirred for 3 h at
the same temperature. To the above reaction mixture S-4-
phenyloxazolidinone (267 g, 1.74 mol) and DMAP (17 g, 0.137
mol) were added and heated to 45 °C. The reaction mixture
was maintained for 7 h at 45 °C. After cooling to room
temperature water was added, and the organic layer was
separated. The aqueous layer was washed with dichloromethane,
and the combined organic extracts were dried over anhydrous
Na2SO4 and concentrated under reduced pressure to give the
crude compound. Hexane was added to the oily compound, and
the mixture stirred for 60 min and was filtered to give 448.5 g
1
110.3 g (76%) of pure compound 6 as a crystalline solid. H
NMR (200 MHz, CDCl3, δ) 1.72-1.94 (m, 2H), 2.4-2.7 (m,
2H), 3.65 (m, 2H), 3.7 (s, 3H), 4.68 (m, 1H), 5.0 (s, 2H),
6.4-7.4 (m, 13H, Ar); IR: 1736.13 cm-1; MS: m/z 433 (M+).
Preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3-(hydroxy)-
3-oxopropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 7. To a
solution of ester 6 (250 g, 0.576 mol) in acetone was added 4
N NaOH (625 mL) and stirred at room temperature for 4 h.
Water was added to the above reaction mixture, and the pH
was adjusted to 6.6 with 1 N hydrochloric acid. The reaction
mixture was extracted with ethyl acetate, dried over sodium
sulphate, and concentrated to afford the 217.7 g (90%) of crude
acid 7, which was used as such for the next reaction. 1H NMR
(CDCl3, δ) 1.6-1.8 (m, 2H), 2.4-2.8 (m, 2H), 3.65 (m, 1H),
4.64 (m, 1H), 5.1 (s, 2H), 6.8-7.6 (m, 13H, Ar); IR (KBr pellet)
3518.23, 1740.274 cm-1; MS: m/z 419.1 (M+).
1
(75%) of compound 4 as a crystalline solid. H NMR (200
Preparation of (3R,4S)-1-(4-Fluorophenyl)-3-[3-(4-fluoro-
phenyl)-3-oxopropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 9.
To a clean and dry round-bottom flask were added magnesium
turnings (14.5 g, 0.60 mol) and a catalytic amount (1.2 g) of
iodine and tetrahydrofuran (187.5 mL), and this mixture was
heated to 48 °C. 1-Bromo-4-fluorobenzene (105.7 g, 0.60 mol)
was added to the above solution. After 5 min of stirring extra
1-bromo-4-fluorobenzene (85 mL) was added slowly and stirred
at 48 °C. The reaction mass was then cooled to 0 °C, and 580 g
of zinc chloride (81.75 g, 0.60 mol) was added to the above
reaction mass.
MHz, CDCl3, δ) 1.8-2.0 (m, 2H), 2.3 (m, 2H), 2.8-3.2 (m,
2H), 3.6 (s, 3H), 4.3-4.4 (m, 1H), 4.6-4.8 (m, 1H), 5.65 (m,
1H), 7.2-7.4 (m, 5H, Ar); IR (KBr pellet) 1781.89, 1736.61,
1701.56 cm-1. MS: m/z 596.2 (M+).
Preparation of 1-{2-[3-(Methoxy)-3-(oxo)-propyl]-3-(4-
fluorophenylamino)-3-(4-benzyloxyphenyl)-1-oxo-propyl}-
4-(S)-phenyloxazolidin-2-one 5. To a solution of oxazolidinone
compound 4 (100 g, 0.34 mol) in dichloromethane (1000 mL)
at -10 °C were added titanium chloride (65.18 g, 0.34 mol),
titanium tetra(isopropoxide) (19.5 g, 0.068 mol), and diisopro-
(20) (a) Quallich, G. J.; Woodall, T. M. Tetrahedron Lett. 1993, 34, 785–
788. (b) Kawanami, Y.; Murao, S.; Ohga, T.; Kobayashi, N. Tetra-
hedron. 2003, 59, 8411–8414.
In a separate round-bottom flask, the intermediate acid 6 (125
g, 0.298 mol) was dissolved in dichloromethane (625 mL), and
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