190595-65-4

Basic information

• Product Name: (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one
• Synonyms: (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one;E6:synthesis of trans-1-(4-fluorophenyl)-3-[3-oxo-3-(4-fluorophenyl)propyl;2-Azetidinone, 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]-4-[4-(phenylMethoxy)phenyl]-, (3R,4S)-;3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopr;EzetiMibe interdiate;(3R,4S)-4-(4-(Benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-o;ZTB-7;1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-oxopropyl)azetidin-2-one
• CAS NO: 190595-65-4
• Molecular Formula: C₃₁H₂₅F₂NO₃
• Molecular Weight: 497.53
• EINECS: 1308068-626-2
• Product Categories: Ezetimibe intermediates
• Mol File: 190595-65-4.mol
• Article Data: 28

Chemical Properties

• Boiling Point: 706.794 °C at 760 mmHg
• Flash Point: 381.255 °C
• Appearance: WHITE
• Density: 1.264
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.61
• Storage Temp.: 2-8°C
• PKA: -0.48±0.60(Predicted)
• CAS DataBase Reference: (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one(CAS DataBase Reference)
• NIST Chemistry Reference: (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one(190595-65-4)
• EPA Substance Registry System: (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one(190595-65-4)

Safety Data

• Hazardous Substances Data: 190595-65-4(Hazardous Substances Data)

Usage

Description

(3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one is a complex organic compound with a unique molecular structure. It is characterized by its azetidinone core, which is a four-membered nitrogen-containing ring, and is further substituted with various aromatic and fluorophenyl groups. (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one is significant due to its role as an intermediate in the synthesis of pharmaceuticals, specifically in the preparation of ezetimibe and its derivatives.

Uses

Used in Pharmaceutical Industry:
(3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one is used as an intermediate in the synthesis of ezetimibe and its derivatives for the following reasons:
1. As an intermediate in the synthesis of Ezetimibe-d4: Ezetimibe-d4 is a labeled analogue of Ezetimibe (E975000), which is an antihyperlipoproteinemic agent. (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one serves as a crucial intermediate in the production of Ezetimibe-d4, aiding in the development of pharmaceuticals for the treatment of hyperlipidemia.
2. In the preparation of Ezetimibe: Ezetimibe is a cholesterol absorption inhibitor, which helps in the regulation of cholesterol levels in the body. The compound (3R,4S)-4-[4-(Benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one plays a vital role in the synthesis process, contributing to the development of this important medication.

InChI:InChI=1/C31H25F2NO3/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/h1-17,28,30H,18-20H2/t28-,30-/m1/s1

Synthetic route

(3R,4S)-4-(4-benzyloxyphenyl)-1-(4-fluoro phenyl)-3-{2-[2-(4-fluorophenyl)-[1,3]-dioxolan-2-yl]ethyl}azetidin-2-one (954109-22-9) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With water; toluene-4-sulfonic acid In acetone at 20℃; for 6h; Product distribution / selectivity; Reflux;	99%

(S)-ethyl 2-((4-(benzyloxy)phenyl)(4-fluorophenylamino)methyl)-5-(4-fluorophenyl)-5-oxopentanoate → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
at 20℃; for 0.166667h; Temperature;	91.6%

(3R,4S)-4-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-3-{2-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]dioxan-2-yl]-ethyl}azetidin-2-one (953805-24-8) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With formic acid In dichloromethane for 12h; Reflux;	90%
With sulfuric acid In water; isopropyl alcohol at 20 - 25℃; for 1h; Product distribution / selectivity;	87.9%
With acetic acid at 20 - 25℃; for 1h; Product distribution / selectivity;	85.3%

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-((E)-3-(4-fluorophenyl)allyl)azetidin-2-one (190595-64-3) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With perchloric acid; palladium diacetate; p-benzoquinone In water; acetonitrile for 16h;	90%

(S)-3-{4-[2-(4-fluorophenyl)dioxolan-2-yl]butanoyl}-4-phenyl-oxazolidin-2-one (942485-56-5) + 4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride In toluene at 60℃;	88.94%

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[(Z)-3-(4-fluorophenyl)allyl]azetidin-2-one (1206694-77-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With perchloric acid; p-benzoquinone; palladium diacetate In water; acetonitrile for 48h; Inert atmosphere;	86%
With perchloric acid; water; palladium diacetate; p-benzoquinone In acetonitrile Wacker-Tsuji oxidation; Inert atmosphere;	86%

C33H31F2NO4 → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With lithium hexamethyldisilazane In tetrahydrofuran at -20℃; for 0.666667h;	77%
With lithium hexamethyldisilazane In tetrahydrofuran at -20℃; for 0.666667h;	77%

3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide (934245-14-4) + 4-flourophenylmagnesium bromide (352-13-6) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
In tetrahydrofuran; toluene at 30 - 32℃; for 2.5h; Solvent; Temperature;	75.7%

(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)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With Wilkinson's catalyst; hydrogen In dichloromethane under 3102.89 Torr; for 18h; Hydrogenation;	71%

4-flourophenylmagnesium bromide (352-13-6) + 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride (204589-84-4) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Stage #1: 4-flourophenylmagnesium bromide With zinc(II) chloride In tetrahydrofuran at 4℃; Stage #2: 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride; tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0℃; for 4.5h;	37%
With zinc(II) chloride; palladium diacetate In toluene at 0 - 20℃; for 2h;

4-fluorophenylzinc bromide (181705-93-1) + 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride (204589-84-4) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 10℃; for 1h; Yield given;
palladium diacetate In toluene at 20℃; for 0.75h;
Stage #1: 4-fluorophenylzinc bromide; 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride; palladium diacetate In toluene at 10 - 11℃; for 0.333333h; Stage #2: With hydrogenchloride; water In toluene

4-benzyloxybenzylidene-N-(4-fluoro)phenylanisidine (70627-52-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 5 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 View Scheme
Multi-step reaction with 3 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 View Scheme

(2S,3S)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxazetidine-3-carbaldehyde (221349-58-2) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 3 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 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)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

lithium; 1-(4-fluoro-phenyl)-ethenolate → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 3 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 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)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme

(Z)-1-(4-(benzyloxy)phenyl)-N-(4-fluorophenyl)methaneimine (219653-96-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 4 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 View Scheme

(3R,4S)-1-(4-fluorophenyl)-3-(3-hydroxy-3-oxopropyl)-4-(4-benzyloxyphenyl)-2-azetidinone (204589-82-2) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

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

methyl 3-((2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl)propanoate (204589-80-0) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: LiOH*H2O / methanol / 2 h 2: oxalyl chloride / CH2Cl2 / 16 h / 22 °C 3: (Ph3P)4Pd / tetrahydrofuran / 1 h / 10 °C View Scheme
Multi-step reaction with 2 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 View Scheme

1-Bromo-4-fluorobenzene (460-00-4) + 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride (204589-84-4) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With magnesium; Iron acetylacetonate In tetrahydrofuran at -85 - -78℃; for 1.08333h; Purification / work up;
With iodine; magnesium; Iron acetylacetonate In tetrahydrofuran at -90 - -78℃; for 0.0333333h; Purification / work up;

4-fluorophenylzinc chloride (133472-27-2) + 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride (204589-84-4) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
tetrakis(triphenylphosphine) palladium(0) In tetrahydrofuran at 0 - 22℃; for 1.5h;

4-fluorophenylzinc chloride (133472-27-2) + (3R,4S)-1-(4-fluorophenyl)-3-(3-hydroxy-3-oxopropyl)-4-(4-benzyloxyphenyl)-2-azetidinone (204589-82-2) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Stage #1: (3R,4S)-1-(4-fluorophenyl)-3-(3-hydroxy-3-oxopropyl)-4-(4-benzyloxyphenyl)-2-azetidinone With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Negishi coupling reaction; Stage #2: 4-fluorophenylzinc chloride With palladium diacetate In tetrahydrofuran; toluene at 10 - 11℃; for 0.333333h; Negishi coupling reaction;	127.5 g

C31H23F2NO3 (231301-01-2) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With hydrogen; Wilkinson's catalyst In dichloromethane under 3375.34 Torr; for 18h;

3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide (934245-14-4) + 1-Bromo-4-fluorobenzene (460-00-4) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Stage #1: 1-Bromo-4-fluorobenzene With magnesium In tetrahydrofuran at 40 - 45℃; for 1h; Heating / reflux; Stage #2: 3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide In tetrahydrofuran at 0 - 10℃; for 0.75 - 0.833333h; Stage #3: With hydrogenchloride In tetrahydrofuran; water at 10 - 15℃;
Stage #1: 1-Bromo-4-fluorobenzene With magnesium In tetrahydrofuran at 40 - 50℃; for 1h; Inert atmosphere; Stage #2: 3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide In tetrahydrofuran at -5 - 0℃; for 1h;	34.5 g

C32H28F2N2O3 → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
With hydrogenchloride; water In 1,4-dioxane; acetone at 90 - 95℃; for 6h;

(S)-1-(4-fluorophenyl)-5-(2-oxo-4-phenyloxazolidin-3-yl)pentane-1,5-dione (189028-93-1) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride / pyridine / 0 - 20 °C 2.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 0 °C 2.2: -15 °C 3.1: N,O-bis-(trimethylsilyl)-acetamide / toluene / 0.5 h / 60 °C 3.2: 8 h / 60 °C 3.3: 20 h / 20 °C 4.1: hydrogenchloride; formaldehyd / water; tetrahydrofuran / 6 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydroxylamine hydrochloride / pyridine / 0 - 20 °C 2.1: dmap; 1H-imidazole / dichloromethane / 0.17 h / 20 °C 2.2: 5 h 3.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 0 °C 3.2: 3 h / -15 °C 4.1: N,O-bis-(trimethylsilyl)-acetamide / toluene / 0.5 h / 60 °C 4.2: 8 h / 60 °C 5.1: hydrogenchloride; formaldehyd / water; tetrahydrofuran / 4 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: phosphorus pentoxide; sulfuric acid / dichloromethane / 5 h / Reflux 2: N-ethyl-N,N-diisopropylamine; titanium(IV) isopropylate; titanium tetrachloride / dichloromethane / 3 h / -5 °C 3: N,O-Bis(trimethylsilyl)acetamide; tetrabutyl ammonium fluoride / toluene / 48 h / Reflux 4: formic acid / dichloromethane / 12 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: toluene-4-sulfonic acid / hexane / 6 h / 25 °C 2: N,O-bis-(trimethylsilyl)-acetamide; tetrabutyl ammonium fluoride / toluene / 60 °C View Scheme

(S)-3-(5-(4-fluorophenyl)-5-(hydroxyimino)pentanoyl)-4-phenyloxazolidin-2-one → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 0 °C 1.2: -15 °C 2.1: N,O-bis-(trimethylsilyl)-acetamide / toluene / 0.5 h / 60 °C 2.2: 8 h / 60 °C 2.3: 20 h / 20 °C 3.1: hydrogenchloride; formaldehyd / water; tetrahydrofuran / 6 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: dmap; 1H-imidazole / dichloromethane / 0.17 h / 20 °C 1.2: 5 h 2.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 0 °C 2.2: 3 h / -15 °C 3.1: N,O-bis-(trimethylsilyl)-acetamide / toluene / 0.5 h / 60 °C 3.2: 8 h / 60 °C 4.1: hydrogenchloride; formaldehyd / water; tetrahydrofuran / 4 h / 20 °C View Scheme

(3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-(hydroxyimino)propyl)azetidin-2-one (1380431-24-2) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Stage #1: (3R,4S)-4-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-3-(3-(4-fluorophenyl)-3-(hydroxyimino)propyl)azetidin-2-one With hydrogenchloride; formaldehyd In tetrahydrofuran; water at 20℃; for 6h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate

(3R,4S)-4-(4-(benzyloxy)phenyl)-3-(3-(tert-butyldimethylsilyloxyimino)-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)azetidin-2-one (1380431-27-5) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Stage #1: (3R,4S)-4-(4-(benzyloxy)phenyl)-3-(3-(tert-butyldimethylsilyloxyimino)-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)azetidin-2-one With hydrogenchloride; formaldehyd In tetrahydrofuran; water at 20℃; for 4h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate Product distribution / selectivity;

(S)-3-(5-(tert-butyldimethylsilyloximino)-5-(4-fluorophenyl)pentanoyl)-4-phenyloxazolidin-2-one (1380431-20-8) → (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: titanium(IV) isopropylate; N-ethyl-N,N-diisopropylamine; titanium tetrachloride / dichloromethane / 0 °C 1.2: 3 h / -15 °C 2.1: N,O-bis-(trimethylsilyl)-acetamide / toluene / 0.5 h / 60 °C 2.2: 8 h / 60 °C 3.1: hydrogenchloride; formaldehyd / water; tetrahydrofuran / 4 h / 20 °C View Scheme

(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%

(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(S)-hydroxy-3-(4-fluorophenyl)propyl]-[4-(phenylmethoxy)phenyl]-2-azetidinone

Conditions	Yield
Stage #1: (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one With di-methylsulfide borane; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In tetrahydrofuran at -10 - 20℃; for 2.5h; Inert atmosphere; Stage #2: With methanol In tetrahydrofuran for 0.5h; Inert atmosphere;	98.7%
With dimethylsulfide borane complex In dichloromethane

2,2-Dimethyl-1,3-propanediol (126-30-7) + (3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → (3R,4S)-4-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-3-{2-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]dioxan-2-yl]-ethyl}azetidin-2-one (953805-24-8)

Conditions	Yield
With Pyridine hydrobromide In toluene at 20 - 115℃; for 8h; Product distribution / selectivity;	77.1%
With pyridinium p-toluenesulfonate In toluene at 20 - 115℃; for 8h; Product distribution / selectivity;	72%
With toluene-4-sulfonic acid In toluene at 20 - 115℃; for 8h; Product distribution / selectivity;	70.4%

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → [14C]-Sch 57871 (191330-56-0)

Conditions	Yield
With hydrogen; palladium on activated charcoal In ethanol under 3102.9 Torr; for 12h;
With hydrogen; palladium on activated charcoal In methanol under 2942.29 - 3310.08 Torr;

(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;

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → ezetemibe (163222-33-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / CBS; BH3-Me2S / toluene; CH2Cl2 / 2 h / -20 °C 2: 79 percent / ammonium formate; HOAc / Pd-C / methanol / 3 h / 45 - 55 °C / pH 3 - 5 View Scheme
Multi-step reaction with 2 steps 1: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C 2: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr View Scheme
Multi-step reaction with 2 steps 1: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / dichloromethane; tetrahydrofuran / 5 h / 0 °C 2: palladium on activated charcoal; hydrogen / methanol / 6 h / 20 °C / 3800.26 Torr View Scheme
Multi-step reaction with 2 steps 1: dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole / tetrahydrofuran; dichloromethane / 5 h / 0 °C 2: palladium on activated charcoal; hydrogen / methanol / 6 h / 20 °C / 3800.26 Torr View Scheme
Multi-step reaction with 2 steps 1: dimethylsulfide borane complex / tetrahydrofuran / 4 h / -10 °C / Inert atmosphere 2: palladium on activated charcoal; formic acid; ammonium formate / isopropyl alcohol / 3 h / 40 °C View Scheme

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → 1-(4-fluorophenyl)-(3R)-[(4-fluorophenyl)-(2E)-propenyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone

Conditions	Yield
Multi-step reaction with 3 steps 1: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C 2: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr 3: p-TsOH*H2O / toluene / 6 h / 80 °C View Scheme

(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-[(3R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one (163380-16-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C 2: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr View Scheme

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → 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 3 steps 1: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C 2: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr 3: 0.260 g / pyridine / CH2Cl2 / 1 h / 22 °C View Scheme

(3R,4S)-4-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-oxopropyl]azetidin-2-one (190595-65-4) → 3(R)-[3(R)-(acetyloxy)-3-(4-fluorophenyl)propyl]-4(S)-[4-(acetyloxy)phenyl]-1-(4-fluorophenyl)-2-azetidinone

Conditions	Yield
Multi-step reaction with 3 steps 1: BH3*Me2S / tetrahydrofuran / 3 h / 22 °C 2: H2 / 10percent Pd/C / ethanol / 16 h / 3102.9 Torr 3: pyridine / CH2Cl2 / 1 h / 22 °C View Scheme

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

Upstream product

• 133472-27-2 4-fluorophenylzinc chloride 
• 204589-84-4 3-((3R,4S)-1-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy)phenyl)azetidin-3-yl)propionic acid chloride 
• 954109-22-9 (3R,4S)-4-(4-benzyloxyphenyl)-1-(4-fluoro phenyl)-3-{2-[2-(4-fluorophenyl)-[1,3]-dioxolan-2-yl]ethyl}azetidin-2-one 
• 231301-01-2 C₃₁H₂₃F₂NO₃ 
• 934245-14-4 3-[(2S,3R)-2-(4-benzyloxyphenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl]-N-methoxy-N-methylpropaneamide 
• 460-00-4 1-Bromo-4-fluorobenzene 
• 403-43-0 4-fluorobenzoyl chloride 
• 204589-80-0 methyl 3-((2S,3R)-2-(4-(benzyloxy)phenyl)-1-(4-fluorophenyl)-4-oxoazetidin-3-yl)propanoate 
• 149437-76-3 5-(4-fluorophenyl)-5-oxopentanoic acid 
• 953805-20-4 3-{4-[2-(4-fluorophenyl)-5,5-dimethyl-[1,3]dioxin-2-yl]butyryl}(4S)-phenyl-1,3-oxazolidin-2-one 
• 123-08-0 4-hydroxy-benzaldehyde 
• 100-39-0 benzyl bromide 
• 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 
• 462-06-6 fluorobenzene 

Downstream Products

• 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 
• 163222-33-1 ezetemibe 
• 163380-16-3 (3R,4S)-1-(4-fluorophenyl)-3-[(3R)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-azetidin-2-one 
• 163380-15-2 (3R,4S,3'R)-1-(4-fluorophenyl)-4-(4-hydroxyphenyl)-3-[3'-(4-fluorophenyl)-3'-hydroxy-propyl]-azetidin-2-one 
• 163222-32-0 (3R,4S)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3(S)-hydroxypropyl]-4-(4-benzyloxyphenyl)-2-azetidinone 
• 163380-20-9 4(S)-(4-acetyloxyphenyl)-3(R)-(3(S)-acetyloxy-3-(4-fluorophenyl)propyl)-1-(4-fluorophenyl)-2-azetidinone 
• 204589-68-4 1-(4-fluorophenyl)-(3R)-[(4-fluorophenyl)-(2E)-propenyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone 
• 191330-56-0 [14C]-Sch 57871 

Relevant articles and documents

METHOD OF PREPARING EZETIMIBE AND INTERMEDIATE THEREOF

Disclosed is a method of preparing ezetimibe, including cross-metathesis using a Grubbs 2nd catalyst and deprotection using a Pearlman's catalyst, and an intermediate thereof. The method of preparing ezetimibe is useful as an efficient ezetimibe synthesis technique in pharmaceutical fields using ezetimibe as a raw material.

METHOD FOR PRODUCING DIPHENYL AZETIDINE DERIVATIVE

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MANUFACTURING METHOD OF (3R,4S)-1-(4-FLUOROPHENYL)-[3(S)-HYDROXY-3-(4-FLUOROPHENYL)PROPYL]-[4-(PHENYLMETHOXY)PHENYL]-2-AZETIDINONE

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