163222-32-0

Basic information

• Product Name: 2-AZETIDINONE, 1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-[4-(PHENYLMETHOXY)PHENYL]-, (3R,4S)-
• Synonyms: 2-AZETIDINONE, 1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-[4-(PHENYLMETHOXY)PHENYL]-, (3R,4S)-;1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-[4-(PHENYLMETHOXY)PHENYL]-, (3R,4S)-2-AZETIDINONE;1-(4-Fluorophenyl)-3-[(3s)-3-(4-Fluorophenyl)-3-Hydroxypropyl]-4-[4-(Phenylmethoxy)Phenyl-(3r,4s)-2-Azetidinone;1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-phenylmethoxy]phenyl]-(3R,4S)-2-azetidinone (intermediate of ezetimibe);(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-[4-(phenylmethoxy)phenyl]-2-azetidinone;E7:synthesis of trans-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl-(4-benzyloxyphenyl)]-2-azetidinone;4’-O-Benzyloxy Ezetimibe;(3R,4S)-4-[(4-Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-2-azetidinone
• CAS NO: 163222-32-0
• Molecular Formula: C₃₁H₂₇F₂NO₃
• Molecular Weight: 499.55
• Product Categories: (intermediate of ezetimibe);Ezetimibe intermediates;Aromatics;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 163222-32-0.mol
• Article Data: 40

Chemical Properties

• Boiling Point: 706.462 °C at 760 mmHg
• Flash Point: 381.055 °C
• Appearance: Off-white solid
• Density: 1.270
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.617
• Storage Temp.: Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated)
• PKA: 14.15±0.20(Predicted)
• CAS DataBase Reference: 2-AZETIDINONE, 1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-[4-(PHENYLMETHOXY)PHENYL]-, (3R,4S)-(CAS DataBase Reference)
• NIST Chemistry Reference: 2-AZETIDINONE, 1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-[4-(PHENYLMETHOXY)PHENYL]-, (3R,4S)-(163222-32-0)
• EPA Substance Registry System: 2-AZETIDINONE, 1-(4-FLUOROPHENYL)-3-[(3S)-3-(4-FLUOROPHENYL)-3-HYDROXYPROPYL]-4-[4-(PHENYLMETHOXY)PHENYL]-, (3R,4S)-(163222-32-0)

Safety Data

• Hazardous Substances Data: 163222-32-0(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

(3R,4S)-4-(4-(Benzyloxy)Phenyl)-1-(4-Fluorophenyl)-3-((S)-3-(4-Fluorophenyl)-3-Hydroxypropyl)Azetidin-2-One is protected Ezetimibe, used for the synthesis of related derivatives.

InChI:InChI=1/C31H27F2NO3/c32-24-10-6-22(7-11-24)29(35)19-18-28-30(34(31(28)36)26-14-12-25(33)13-15-26)23-8-16-27(17-9-23)37-20-21-4-2-1-3-5-21/h1-17,28-30,35H,18-20H2/t28-,29+,30-/m1/s1

Synthetic route

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
With formic acid; [(S,S)-teth-TsDpen RuCl]; triethylamine In ethylbenzene at 35 - 40℃; for 24h; Inert atmosphere;	99.8%
With methanesulfonic acid; dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; methyl tertiarybutylether; toluene at -25 - -20℃; for 2.5 - 3.5h; Product distribution / selectivity;	98.04%
With methanesulfonic acid; dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran; toluene at -25 - -20℃; for 2.5 - 3.5h; Product distribution / selectivity;	98.6%

benzyl bromide (100-39-0) + ezetemibe (163222-33-1) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;	99%

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0) + (3R,4S,3'R)-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-[3'-(4-fluorophenyl)-3'-hydroxy-propyl]-azetidin-2-one (163380-15-2)

Conditions	Yield
With dimethylsulfide borane complex In tetrahydrofuran at 22℃; for 3h;	A 0.141 g B n/a
With dimethylsulfide borane complex In tetrahydrofuran at 22℃; for 3h;
Stage #1: (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one With sodium tetrahydroborate; chloro-trimethyl-silane; (R)-α,α-diphenylprolinol In tetrahydrofuran at 19 - 22℃; for 2.78333h; Heating / reflux; Stage #2: With hydrogenchloride; water In tetrahydrofuran; toluene at 2℃; for 0.5h; Product distribution / selectivity;	A n/a B n/a
With 1,1,1,3',3',3'-hexafluoro-propanol; C32H39BrMnN2O2P; potassium tert-butylate; hydrogen In methanol at 20℃; under 22502.3 Torr; for 16h; Glovebox; Autoclave; Overall yield = 99 %; enantioselective reaction;	A n/a B n/a
With C32H39BrMnN2O2P; potassium tert-butylate; hydrogen In methanol at 20℃; under 22502.3 Torr; for 16h; Glovebox; Autoclave; Optical yield = 85 percent ee; enantioselective reaction;

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 6 steps 1: 64 percent / LDA; DMPU; LiCl / dimethylformamide; tetrahydrofuran / 18 h / -30 - -25 °C 2: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 3: BF3 etherate / toluene / 0.08 h / -30 °C 4: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 5: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 6: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme
Multi-step reaction with 4 steps 1: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 3 h / -5 °C 2: N,O-Bis(trimethylsilyl)acetamide; tetrabutyl ammonium fluoride / toluene / 48 h / Reflux 3: formic acid / dichloromethane / 12 h / Reflux 4: dimethyl sulfide borane / dichloromethane; toluene; tetrahydrofuran / 12 h / 15 °C View Scheme
Multi-step reaction with 2 steps 1: N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride / toluene / 60 °C 2: dimethylsulfide borane complex / dichloromethane; toluene / 3 h / -5 - 0 °C / Inert atmosphere View Scheme

(2S,3S)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxazetidine-3-carbaldehyde (221349-58-2) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: BF3 etherate / toluene / 0.08 h / -30 °C 2: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 3: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 4: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme

(3S,4S)-4-(4-Benzyloxy-phenyl)-3-((S)-1,2-dihydroxy-ethyl)-1-(4-fluoro-phenyl)-azetidin-2-one (221349-56-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 90 percent / NaIO4 / acetonitrile; H2O / 2 h / 20 °C 2: BF3 etherate / toluene / 0.08 h / -30 °C 3: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 4: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 5: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme

lithium; 1-(4-fluoro-phenyl)-ethenolate → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: BF3 etherate / toluene / 0.08 h / -30 °C 2: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 3: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 4: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme

(3R,4S)-4-(4-Benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[(E)-3-(4-fluoro-phenyl)-3-oxo-propenyl]-azetidin-2-one (221349-60-6) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 2: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme

(3S,4S)-4-(4-Benzyloxy-phenyl)-1-(4-fluoro-phenyl)-3-[3-(4-fluoro-phenyl)-1-hydroxy-3-oxo-propyl]-azetidin-2-one (231301-00-1) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 99 g / p-toluenesulfonic acid monohydrate; molecular sieves / toluene / 4 h / 40 - 50 °C 2: 71 percent / (PPh3)3RhCl; hydrogen / CH2Cl2 / 18 h / 3102.89 Torr 3: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C View Scheme

(Z)-1-(4-(benzyloxy)phenyl)-N-(4-fluorophenyl)methaneimine (219653-96-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: (nBu)3N / heptane; toluene / 80 - 90 °C 2: LiOH*H2O / methanol / 2 h 3: oxalyl chloride / CH2Cl2 / 16 h / 22 °C 4: (Ph3P)4Pd / tetrahydrofuran / 1 h / 10 °C 5: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C View Scheme

(3R,4S)-1-(4-fluorophenyl)-3-(3-hydroxy-3-oxopropyl)-4-(4-benzyloxyphenyl)-2-azetidinone (204589-82-2) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: oxalyl chloride / CH2Cl2 / 16 h / 22 °C 2: (Ph3P)4Pd / tetrahydrofuran / 1 h / 10 °C 3: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C View Scheme

3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride (204589-84-4) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: (Ph3P)4Pd / tetrahydrofuran / 1 h / 10 °C 2: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C View Scheme

methyl 3-((2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl)propanoate (204589-80-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: LiOH*H2O / methanol / 2 h 2: oxalyl chloride / CH2Cl2 / 16 h / 22 °C 3: (Ph3P)4Pd / tetrahydrofuran / 1 h / 10 °C 4: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C View Scheme
Multi-step reaction with 3 steps 1.1: diethyl aluminiumcholoride / toluene / -12 - 20 °C / Inert atmosphere 2.1: magnesium / tetrahydrofuran / 1 h / 40 - 50 °C / Inert atmosphere 2.2: 1 h / -5 - 0 °C 3.1: [(S,S)-teth-TsDpen RuCl]; triethylamine; formic acid / ethylbenzene / 24 h / 35 - 40 °C / Inert atmosphere View Scheme

[14C]-Sch 57871 (191330-56-0) + (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (112022-83-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Stage #1: [14C]-Sch 57871; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at -20℃; for 0.0833333h; Stage #2: With dimethylsulfide borane complex In tetrahydrofuran at -20℃; for 1.5h;

1-(4-fluorophenyl)-4(S)-(4-hydroxyphenyl)-3(R)-(3-oxo-3-phenylpropyl)-2-azetidinone (163222-31-9) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at -20℃; for 1.5h;

methanol (67-56-1) + (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) + (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole (112022-83-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran

1-Bromo-4-fluorobenzene (460-00-4) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: magnesium; Bis<2-(N,N-dimethylamino)aethyl>aether / 0.5 h / 0 °C 2.1: (R)-1,1'-Bi-2-naphthol / titanium(IV) isopropylate / diethyl ether; tetrahydrofuran / 1.5 h / 0 - 25 °C 2.2: -20 - 25 °C 2.3: 0 °C View Scheme
Multi-step reaction with 2 steps 1.1: magnesium / tetrahydrofuran / 1 h / 40 - 50 °C / Inert atmosphere 1.2: 1 h / -5 - 0 °C 2.1: [(S,S)-teth-TsDpen RuCl]; triethylamine; formic acid / ethylbenzene / 24 h / 35 - 40 °C / Inert atmosphere View Scheme

3-[(2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]propanal (1412967-16-8) + 4-flourophenylmagnesium bromide (352-13-6) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Stage #1: 4-flourophenylmagnesium bromide With (R)-1,1'-Bi-2-naphthol; titanium(IV) isopropylate In tetrahydrofuran; diethyl ether at 0 - 25℃; for 1.5h; Stage #2: 3-[(2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]propanal In tetrahydrofuran; diethyl ether at -20 - 25℃; Stage #3: With hydrogenchloride; water In tetrahydrofuran; diethyl ether at 0℃;

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-hydroxypropyl)azetidin-2-one (1412967-14-6) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate; sodium hypochlorite; potassium bromide; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical / Difluoromethane / 25 °C / Cooling with ice 2.1: (R)-1,1'-Bi-2-naphthol / titanium(IV) isopropylate / diethyl ether; tetrahydrofuran / 1.5 h / 0 - 25 °C 2.2: -20 - 25 °C 2.3: 0 °C View Scheme

(1'R,6R)-3-[(4-benzyloxyphenyl)-(4-fluorophenylamino)-methyl]-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one (1416263-33-6) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: lithium hydroxide / tetrahydrofuran; water / 18 h 2: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 3: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

(1'S,3R,6S)-3-[(4-benzyloxyphenyl)-(4-fluorophenylamino)-methyl]-6-(4-fluorophenyl)-tetrahydro-2H-pyran-2-one (1416263-36-9) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
With tert-butylmagnesium chloride In diethyl ether at 0℃; for 2h;

(3S,3aS,6S,7aS)-3-(4-(benzyloxy)phenyl)-2,6-bis(4-fluorophenyl)tetrahydro-2H-pyrano[3,4-d]isoxazol-4(6H)-one (1416263-37-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 2: Burgess Reagent / toluene / 18 h / 90 °C 3: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 4: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

(R)-2,3-dihydro-2-(4-fluorophenyl)-4H-pyran-4-one → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 10 steps 1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 2: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 3: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 4: toluene / 72 h / Reflux 5: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 6: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 7: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 8: Burgess Reagent / toluene / 18 h / 90 °C 9: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 10: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 10 steps 1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 2: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 3: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 4: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 5: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 6: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 7: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 8: Burgess Reagent / toluene / 18 h / 90 °C 9: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 10: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1.1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 2.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 3.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 4.1: toluene / 72 h / Reflux 5.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 6.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 6.2: 0.25 h / 20 °C 7.1: lithium hydroxide / tetrahydrofuran; water / 18 h 8.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 9.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1.1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 2.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 3.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 4.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 5.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 6.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 6.2: 0.25 h / 20 °C 7.1: lithium hydroxide / tetrahydrofuran; water / 18 h 8.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 9.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

(3S,4S,6S)-3-((S)-(4-(benzyloxy)phenyl)(4-fluorophenylamino)methyl)-6-(4-fluorophenyl)-4-hydroxytetrahydro-2H-pyran-2-one → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: Burgess Reagent / toluene / 18 h / 90 °C 2: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 3: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

(6S)-3-((R)-(4-(benzyloxy)phenyl)(4-fluorophenylamino)-methyl)-6-(4-fluorophenyl)-5,6-dihydro-2H-pyran-2-one (1416263-38-1) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 2: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

4-fluorobenzaldehyde (459-57-4) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 10 steps 1.1: [(R,R)-salen-Cr]BF4 / tert-butyl methyl ether / 24 h / -30 °C / Molecular sieve 1.2: 5 h / 20 °C 2.1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 3.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 4.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 5.1: toluene / 72 h / Reflux 6.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 7.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 7.2: 0.25 h / 20 °C 8.1: lithium hydroxide / tetrahydrofuran; water / 18 h 9.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 10.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 10 steps 1.1: [(R,R)-salen-Cr]BF4 / tert-butyl methyl ether / 24 h / -30 °C / Molecular sieve 1.2: 5 h / 20 °C 2.1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 3.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 4.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 5.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 6.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 7.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 7.2: 0.25 h / 20 °C 8.1: lithium hydroxide / tetrahydrofuran; water / 18 h 9.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 10.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 11 steps 1.1: [(R,R)-salen-Cr]BF4 / tert-butyl methyl ether / 24 h / -30 °C / Molecular sieve 1.2: 5 h / 20 °C 2.1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 3.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 4.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 5.1: toluene / 72 h / Reflux 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 8.1: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 9.1: Burgess Reagent / toluene / 18 h / 90 °C 10.1: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 11.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 11 steps 1.1: [(R,R)-salen-Cr]BF4 / tert-butyl methyl ether / 24 h / -30 °C / Molecular sieve 1.2: 5 h / 20 °C 2.1: cerium(III) chloride heptahydrate; sodium tetrahydroborate / dichloromethane; methanol / 0.5 h / -20 °C 3.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 4.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 5.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 6.1: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 8.1: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 9.1: Burgess Reagent / toluene / 18 h / 90 °C 10.1: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 11.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

(2R)-2-(4-fluorophenyl)-3,4-dihydro-2H-pyran-4-ol (1416263-27-8) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 2.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 3.1: toluene / 72 h / Reflux 4.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 5.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 5.2: 0.25 h / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 8.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 8 steps 1.1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 2.1: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 3.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 4.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 5.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 5.2: 0.25 h / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 8.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 2: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 3: toluene / 72 h / Reflux 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 6: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 7: Burgess Reagent / toluene / 18 h / 90 °C 8: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 9: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1: dihydrogen peroxide; molybdenum(VI) oxide / acetonitrile / 24 h 2: pyridine; acetic anhydride / dichloromethane / 2 h / 20 °C 3: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 6: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 7: Burgess Reagent / toluene / 18 h / 90 °C 8: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 9: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

4-hydroxy-benzaldehyde (123-08-0) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2.1: methanesulfonic acid / acetone / 2 h / 20 °C 3.1: toluene / 72 h / Reflux 4.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 5.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 5.2: 0.25 h / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 8.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2.1: methanesulfonic acid / acetone / 2 h / 20 °C 3.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 4.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 5.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 5.2: 0.25 h / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 8.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2: methanesulfonic acid / acetone / 2 h / 20 °C 3: toluene / 72 h / Reflux 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 6: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 7: Burgess Reagent / toluene / 18 h / 90 °C 8: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 9: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2: methanesulfonic acid / acetone / 2 h / 20 °C 3: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 6: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 7: Burgess Reagent / toluene / 18 h / 90 °C 8: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 9: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 5 steps 1.1: potassium carbonate / 12 h / 20 °C 1.2: 4 h / Reflux 2.1: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 3 h / -5 °C 3.1: N,O-Bis(trimethylsilyl)acetamide; tetrabutyl ammonium fluoride / toluene / 48 h / Reflux 4.1: formic acid / dichloromethane / 12 h / Reflux 5.1: dimethyl sulfide borane / dichloromethane; toluene; tetrahydrofuran / 12 h / 15 °C View Scheme

benzyl chloride (100-44-7) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2.1: methanesulfonic acid / acetone / 2 h / 20 °C 3.1: toluene / 72 h / Reflux 4.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 5.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 5.2: 0.25 h / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 8.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 8 steps 1.1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2.1: methanesulfonic acid / acetone / 2 h / 20 °C 3.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 4.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 5.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 5.2: 0.25 h / 20 °C 6.1: lithium hydroxide / tetrahydrofuran; water / 18 h 7.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 8.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2: methanesulfonic acid / acetone / 2 h / 20 °C 3: toluene / 72 h / Reflux 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 6: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 7: Burgess Reagent / toluene / 18 h / 90 °C 8: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 9: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 9 steps 1: potassium carbonate; potassium iodide / tetrahydrofuran / 20 h / Reflux 2: methanesulfonic acid / acetone / 2 h / 20 °C 3: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 4: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 5: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 6: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 7: Burgess Reagent / toluene / 18 h / 90 °C 8: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 9: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

p-benzyloxybenzaldehyde (4397-53-9) → (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: methanesulfonic acid / acetone / 2 h / 20 °C 2.1: toluene / 72 h / Reflux 3.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 4.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 4.2: 0.25 h / 20 °C 5.1: lithium hydroxide / tetrahydrofuran; water / 18 h 6.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 7.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 7 steps 1.1: methanesulfonic acid / acetone / 2 h / 20 °C 2.1: scandium tris(trifluoromethanesulfonate) / toluene / 72 h / 30 °C / Molecular sieve 3.1: potassium iodide; chloro-trimethyl-silane / acetonitrile / 0.58 h / 20 °C 4.1: chloro-trimethyl-silane; 1H-imidazole / dichloromethane / 0.5 h / 20 °C 4.2: 0.25 h / 20 °C 5.1: lithium hydroxide / tetrahydrofuran; water / 18 h 6.1: triphenylphosphine; di-isopropyl azodicarboxylate / 3 h / 0 °C 7.1: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme
Multi-step reaction with 8 steps 1: methanesulfonic acid / acetone / 2 h / 20 °C 2: toluene / 72 h / Reflux 3: lithium hydroxide monohydrate / tetrahydrofuran; water / 18 h 4: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 3 h / 0 °C 5: potassium iodide / acetonitrile; water / 0.58 h / 20 °C 6: Burgess Reagent / toluene / 18 h / 90 °C 7: platinum(IV) oxide; hydrogen / toluene / 20 °C / 750.08 Torr 8: tert-butylmagnesium chloride / diethyl ether / 2 h / 0 °C View Scheme

(3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0) → ezetemibe (163222-33-1)

Conditions	Yield
With 10 wt% Pd(OH)2 on carbon; hydrogen In methanol; cyclohexane at 70℃; under 760.051 Torr; for 3h;	99%
With 5%-palladium/activated carbon; hydrogen In tetrahydrofuran; ethanol at 50 - 55℃; under 37.5038 - 75.0075 Torr;	90.3%
With palladium 10% on activated carbon; ammonium formate; acetic acid for 6h; Reflux;	90%

L-N-Boc-Ala (15761-38-3) + (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0) → (1S)-3-[(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-1-(4-fluorophenyl)propyl (2S)-2-{[(tert-butoxy)carbonyl]amino}propanoate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane Inert atmosphere;	69%

(3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0) → 1-(4-fluorophenyl)-(3R)-[(4-fluorophenyl)-(2E)-propenyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone

Conditions	Yield
Multi-step reaction with 2 steps 1: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr 2: p-TsOH*H2O / toluene / 6 h / 80 °C View Scheme

(3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0) → 4(S)-(4-acetyloxyphenyl)-3(R)-(3(S)-acetyloxy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone (163380-20-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr 2: 0.260 g / pyridine / CH2Cl2 / 1 h / 22 °C View Scheme

(3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone (163222-32-0) → EZT-FAM (1197811-72-5) + ezetemibe (163222-33-1)

Conditions	Yield
With formic acid; ammonium formate; 5%-palladium/activated carbon In methanol at 20℃; Product distribution / selectivity; Inert atmosphere;

Upstream product

• 934245-14-4 3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide 
• 190595-64-3 (3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one 
• 405-99-2 para-fluorostyrene 
• 942485-56-5 (S)-3-{4-[2-(4-fluorophenyl)dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one 
• 108-55-4 glutaric anhydride, 
• 462-06-6 fluorobenzene 
• 953805-24-8 4(S)-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-3(R)-{2-[2-(4-fluorophenyI)-5,5-dimethyl-[1,3]-dioxan-2-yl]-ethyl}azetidine-2-one 
• 953805-22-6 3-{(2R,3S)-3-[(4-fluorophenyl)amino]-2-[2-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxan-2-yl]-3-[4-(benzyloxy)phenyI]propanoyl}-(4S)-4-phenyl-1,3-oxazolidin-2-one 
• 100-39-0 benzyl bromide 
• 953805-20-4 3-{4-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]dioxin-2-yl]butyryl}(4S)-phenyl-1,3-oxazolidin-2-one 
• 189028-93-1 (S)-1-(4-fluorophenyl)-5-(2-oxo-4-phenyloxazolidin-3-yl)pentane-1,5-dione 
• 149437-76-3 5-(4-fluorophenyl)-5-oxopentanoic acid 
• 350-46-9 4-Fluoronitrobenzene 
• 1416263-30-3 C₁₁H₁₁FO₃ 

Downstream Products

• 204589-68-4 1-(4-fluorophenyl)-(3R)-[(4-fluorophenyl)-(2E)-propenyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone 
• 163380-20-9 4(S)-(4-acetyloxyphenyl)-3(R)-(3(S)-acetyloxy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone 
• 1197811-72-5 EZT-FAM 
• 163222-33-1 ezetemibe 

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