ChemicalBook CAS DataBase List Ezetimibe

Ezetimibe synthesis

5synthesis methods

Product Name:Ezetimibe
CAS Number:163222-33-1
Molecular formula:C24H21F2NO3
Molecular Weight:409.43

Ezetimibe is a well-known drug that lowers blood cholesterol levels by reducing its absorption in the small intestine when joining to Niemann-Pick C1-like protein (NPC1L1).A new method for preparing ezetimibe comprising a step of cyclizing the compound (4S)-phenyl-3-[(5S)-(4-fluorophenyl)-(2R)-[(1S)-(4-fluorophenylamino)-1-(4-nitrophenyl)methyl]-5-hydroxypentanoyl]oxazolidin-2-one or the derivatives thereof in which the hydroxyl group is protected.

(3R,4S)-4-(4-(Benzyloxy)Phenyl)-1-(4-Fluorophenyl)-3-((S)-3-(4- Fluorophenyl)-3-Hydroxypropyl)Azetidin-2-One

163222-32-0
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163222-33-1
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Yield:163222-33-1 99%

Reaction Conditions:

with 10 wt% Pd(OH)2 on carbon;hydrogen in methanol;cyclohexane at 70; under 760.051 Torr; for 3 h;

Steps:

7 Step (7): Synthesis of (3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one (Compound 11)
(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)azetidin-2-one (10, 258 mg, 0.5 mmol), 20% Pd(OH)₂/C (10.53 mg, 15 mol %) and cyclohexane (55.71 μL, 0.55 mmol) were added to a MeOH solvent (6.25 mL) under H₂(1 atm) and then reacted at 70° C. for 3 hr [deprotection]. After completion of the reaction, the reaction product was cooled to room temperature and then filtered through celite using ethyl acetate (25 mL). The filtered solution was concentrated and then recrystallized two times with MeOH and H₂O (1/3, 3 mL/9 mL). The obtained solid was filtered using H₂O (20 mL), thereby yielding a desired compound (3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one (11, 203 mg, 99%).(3R,4S)-1-(4-fluorophenyl)-3-((S)-3-(4-fluorophenyl)-3-hydroxypropyl)-4-(4-hydroxyphenyl)azetidin-2-one (11) 203 mg, 99%, White solid; Rf=0.2 (ethyl acetate:hexane=1:1); 99% ee; [α]²⁰_D-28.05 (c 0.15, MeOH) [lit.¹-28.1 (c 0.15, MeOH); ¹H NMR (400 MHz, CD₃OD) δ 7.34-7.27 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 7.06-6.96 (m, 4H), 6.81 (d, J=8.5 Hz, 2H), 4.87 (s, 2H), 4.74 (d, J=2.0 Hz, 1H), 4.63-4.60 (m, 1H), 3.10-3.07 (m, 1H), 1.97-1.84 (m, 4H); ¹³C{¹H} NMR (100 MHz, CD₃OD) δ 169.9, 163.5 (J=243.6 Hz), 160.5 (J=242.0 Hz), 159.0, 142.2 (J=3.0 Hz), 135.3 (J=2.7 Hz), 129.5, 128.8 (J=8.0 Hz), 128.6, 119.9 (J=7.9 Hz), 117.0, 116.6 (J=22.9 Hz), 115.9 (J=21.6 Hz), 73.8, 62.3, 61.2, 37.5, 26.1; ¹⁹F NMR (376 MHz, CD₃OD) δ -117.77, -120.15; IR (KBr) 2947, 2924, 1722, 1604, 1509, 1391, 1223 cm^-1; HRMS (EI) m/z: [M]⁺ Calcd for C₂₄H₂₁F₂NO₃409.1489; Found 409.1488.

References:

Kangwon National University, University Industry Cooperation Foundation;Lee, Phil Ho;Lee, Koo Yeon;Baek, Yonghyeon;Um, Kyusik;Kim, Byeong Su US2019/256479, 2019, A1 Location in patent:Paragraph 0080-0082

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191330-56-0 Synthesis