875446-37-0

Basic information

• Product Name: Anacetrapib
• Synonyms: Anacetrapib;Mk0859;Mk-0859;Unii-p7T269pr6s;(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-[[4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl]-4-methyl-1,3-oxazolidin-2-one;(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl}methyl)-4-methyl-1,3-oxazolidin-2-one;Anacetrapib(MK0859);2-Oxazolidinone, 5-[3,5-bis(trifluoroMethyl)phenyl]-3-[[4'-fluoro-2'-Methoxy-5'-(1-Methylethyl)-4-(trifluoroMethyl)[1,1'-biphenyl]-2-yl]Methyl]-4-Methyl-, (4S,5R)-
• CAS NO: 875446-37-0
• Molecular Formula: C₃₀H₂₅F₁₀NO₃
• Molecular Weight: 637.508432
• EINECS: 1312995-182-4
• Product Categories: Aromatics;Chiral Reagents;Heterocycles;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Anacetrapib;Inhibitor;CETP inhibitor
• Mol File: 875446-37-0.mol
• Article Data: 17

Chemical Properties

• Boiling Point: 555.309 °C at 760 mmHg
• Flash Point: 289.641 °C
• Appearance: /
• Density: 1.345
• Solubility: ≥31.9 mg/mL in DMSO; insoluble in H2O; ≥86.6 mg/mL in EtOH
• PKA: -2.30±0.60(Predicted)
• CAS DataBase Reference: Anacetrapib(CAS DataBase Reference)
• NIST Chemistry Reference: Anacetrapib(875446-37-0)
• EPA Substance Registry System: Anacetrapib(875446-37-0)

Safety Data

• Hazardous Substances Data: 875446-37-0(Hazardous Substances Data)

Usage

Uses

An orally active and potent cholesterol ester transfer protein (CETP) inhibitor for the treatment of atherosclerosis, in particular dyslipidemia.

Biological Activity

anacetrapib, also known as mk-0859, is a potent and selective inhibitor of cholesteryl ester transfer protein (cetp) that exhibits strong inhibition against cetp-mediated transfer of cholesteryl esters and triglycerides with values of inhibition constant ic50 of 16 nm and 29 nm respectively. anacetrapib is mainly metabolized by cyp3a4 through o-demethylation, hydroxylation on the biphenyl moiety and hydroxylation on the isopropyl side chain resulting in three oxidative metabolites m1, m2 and m3 respectively. anacetrapib is being investigated for the treatment of primary hypercholesterolemia and mixed hyperlipidemia due to its impressive effects to lower low-density lipoprotein (ldl) cholesterol levels and increase high-density lipoprotein (hdl) cholesterol levels without any associated major adverse events.tan ey, hartmann g, chen q, pereira a, bradley s, doss g, zhang as, ho jz, braun mp, dean dc, tang w, kumar s. pharmacokinetics, metabolism, and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in rats and rhesus monkeys. drug metab dispos. 2010;38(3):459-473.kumar s, tan ey, hartmann g, biddle z, bergman aj, dru j, ho jz, jones an, staskiewicz sj, braun mp, karanam b, dean dc, gendrano in, graves mw, wagner ja, krishna r. metabolism and excretion of anacetrapib, a novel inhibitor of the cholesteryl ester transfer protein, in humans. drug metab dispos. 2010;38(3):474-483

Enzyme inhibitor

This cholesteryl ester transfer protein (or CETP) inhibitor (FW = 637.51 g/mol; CAS 875446-37-0), also known by the code name MK-0859, reduces plasma cholesterol concentrations, thereby increasing serum highdensity lipoprotein levels and preventing cardiovascular disease associated with hypercholesteremia. X-ray crystal studies suggest that CETP is a crescent-shaped protein with a 6-nm hydrophobic tunnel traversing its core Both of the tunnel’s two entrances face the protein’s concave surface, which most likely is the interaction platform for binding HDL particles and engaging its lipoprotein constituents. CETP mediates the reciprocal transfer of neutral lipids (e.g., cholesteryl esters and triglycerides) and phospholipids between different lipoprotein fractions in blood plasma. Anacetrapib is unlike many CETP inhibitors, which increase systolic blood pressure. Anacetrapib also exhibits a low-to-moderate degree of absorption after oral dosing and majority of the absorbed dose is eliminated via oxidation to a series of hydroxylated metabolites that undergo conjugation with glucuronate before excretion into bile. Unlike torcetrapib, another CETP inhibitor, anacetrapib does not elevate blood pressure, alter electrolytes, or cause any significant side effects.

Synthetic route

2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl + (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (875444-08-9) → anacetrapib (875446-37-0)

Conditions	Yield
With tetra-(n-butyl)ammonium iodide; potassium carbonate In N,N-dimethyl-formamide at 60℃; for 17h;	92%
Stage #1: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one With sodium hexamethyldisilazane In N,N-dimethyl-formamide at -15℃; for 1h; Stage #2: 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl In N,N-dimethyl-formamide at -15 - 12℃;	88%
Stage #1: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one With sodium hexamethyldisilazane In N,N-dimethyl-formamide at -15℃; for 1h; Stage #2: 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl In N,N-dimethyl-formamide at -10 - 12℃;	88%

C37H33F10NO4 → anacetrapib (875446-37-0)

Conditions	Yield
With potassium hydroxide In tetrahydrofuran; methanol at 20℃; Inert atmosphere;	89%

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one + 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl → anacetrapib (875446-37-0)

Conditions	Yield
Stage #1: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one With sodium hexamethyldisilazane In N,N-dimethyl-formamide at -15℃; for 1.5h; Stage #2: 2'-(chloromethyl)-4-fluoro-5-isopropyl-2-methoxy-4'-(trifluoromethyl)biphenyl In N,N-dimethyl-formamide at -15 - 12℃;	88%

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (875444-08-9) + (4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methanol (875548-97-3) → anacetrapib (875446-37-0)

Conditions	Yield
Stage #1: [4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-1,1'-biphenyl-2-yl]methanol With thionyl chloride In dichloromethane at 5 - 20℃; Stage #2: (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one With tetra-(n-butyl)ammonium iodide; potassium carbonate In dichloromethane at 60℃;	72%

(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (875446-35-8) + [4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]boronic acid (875446-29-0) → anacetrapib (875446-37-0)

Conditions	Yield
With sodium carbonate; tetrakis(triphenylphosphine) palladium(0) In ethanol; water; benzene at 100℃; for 14h; Heating / reflux;
With potassium carbonate; palladium diacetate In water; acetone for 1h; Heating / reflux;

C34H29F10NO8(2-)*2Na(1+) → anacetrapib (875446-37-0)

Conditions	Yield
In water-d2 at 37℃; for 3.75h; pH=7.52; Sodium phosphate buffer;

1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene (886496-63-5) + (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (875444-08-9) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / tetrahydrofuran / 0 °C 1.2: 0 - 20 °C 2.1: tetrakis(triphenylphosphine) palladium(0); potassium carbonate / ethanol; water; toluene / Reflux View Scheme

[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]boronic acid (875446-29-0) + (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-oxazolidin-2-one (1185737-50-1) → anacetrapib (875446-37-0)

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In ethanol; water; toluene Suzuki coupling; Reflux;

1-(2-fluoro-4-methoxyphenyl)-1-ethanone (74457-86-6) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -15 - 12 °C View Scheme
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 3.1: N-Bromosuccinimide / acetonitrile / 35 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: Inert atmosphere 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -15 - 12 °C View Scheme
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: N-Bromosuccinimide / acetonitrile / 60 °C 3.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C View Scheme

2-(2-fluoro-4-methoxyphenyl)-2-isopropanol (96826-25-4) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -15 - 12 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: Inert atmosphere 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -15 - 12 °C View Scheme
Multi-step reaction with 6 steps 1.1: hydrogenchloride; hydrogen / palladium 10% on activated carbon / ethanol; water / 1 h / 40 °C / 775.74 Torr 2.1: N-Bromosuccinimide / acetonitrile / 35 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C View Scheme

[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]boronic acid (875446-29-0) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 2.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 3.2: -15 - 12 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 2.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 3.2: -15 - 12 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 3.2: -10 - 12 °C View Scheme

2-(2-fluoro-4-methoxyphenyl)isopropane → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -15 - 12 °C View Scheme
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: Inert atmosphere 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -15 - 12 °C View Scheme
Multi-step reaction with 5 steps 1.1: N-Bromosuccinimide / acetonitrile / 35 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C View Scheme

1-bromo-4-fluoro-2-methoxy-5-(propan-2-yl)-benzene (944317-92-4) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 24 h / 35 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -15 - 12 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 30 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -15 - 12 °C View Scheme
Multi-step reaction with 4 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: 1 h / 15 - 20 °C / pH 2 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C View Scheme

(4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methanol (875548-97-3) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 0 - 20 °C 2.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 2.2: -15 - 12 °C View Scheme
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 2.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 2.2: -10 - 12 °C View Scheme
Multi-step reaction with 2 steps 1.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 2.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 2.2: -10 °C View Scheme
Multi-step reaction with 4 steps 1: Dess-Martin periodane / dichloromethane / 2 h / 20 °C 2: isopropyl alcohol / 2 h / 35 - 40 °C 3: sodium tetrahydroborate / methanol / 2 h / 20 °C 4: tetrahydrofuran; N,N-dimethyl-formamide / 2 h / 70 - 75 °C View Scheme
Multi-step reaction with 2 steps 1: thionyl chloride; N,N-dimethyl-formamide / 10 - 15 °C 2: potassium carbonate; tetra-(n-butyl)ammonium iodide / N,N-dimethyl-formamide / 17 h / 60 °C View Scheme

2,4-difluorobromobenzene (348-57-2) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C View Scheme
Multi-step reaction with 8 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C View Scheme
Multi-step reaction with 9 steps 1.1: tetrahydrofuran / 5 h / 65 - 68 °C 2.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 3.1: tetrahydrofuran / 1 h / -15 - 0 °C 4.1: sulfuric acid / 12 h / Reflux 5.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 6.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 6.2: 1 h / 15 - 20 °C / pH 2 7.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 8.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 9.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 9.2: -10 - 12 °C View Scheme

1-bromo-4-fluoro-2-methoxybenzene (450-88-4) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 2.1: tetrahydrofuran / 1 h / -15 - 0 °C 3.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C View Scheme
Multi-step reaction with 7 steps 1.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 2.1: tetrahydrofuran / 1 h / -15 - 0 °C 3.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C View Scheme
Multi-step reaction with 8 steps 1.1: aluminum (III) chloride / 1,2-dichloro-ethane / 1 h / -10 - 5 °C 2.1: tetrahydrofuran / 1 h / -15 - 0 °C 3.1: sulfuric acid / 12 h / Reflux 4.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 5.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 5.2: 1 h / 15 - 20 °C / pH 2 6.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 7.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 8.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 8.2: -10 - 12 °C View Scheme

1-(5-bromo-2-fluoro-4-methoxyphenyl)ethan-1-one (914221-54-8) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C View Scheme
Multi-step reaction with 6 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C View Scheme
Multi-step reaction with 7 steps 1.1: tetrahydrofuran / 1 h / -15 - 0 °C 2.1: sulfuric acid / 12 h / Reflux 3.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 4.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 4.2: 1 h / 15 - 20 °C / pH 2 5.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 6.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 7.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 7.2: -10 - 12 °C View Scheme

(4'-fluoro-2'-methoxy-5'-(prop-1-en-2-yl)-4-(trifluoromethyl)biphenyl-2-yl)methanol (1383814-85-4) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 2.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 3.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 3.2: -10 - 12 °C View Scheme
Multi-step reaction with 3 steps 1: hydrogen; 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr 2: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 3: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C View Scheme

2-(5-bromo-2-fluoro-4-methoxyphenyl)propan-2-ol (958029-46-4) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C View Scheme
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; 1,1,3,3-Tetramethyldisiloxane / 1,2-dichloro-ethane / 0.25 h / -20 - -10 °C 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C View Scheme
Multi-step reaction with 6 steps 1.1: sulfuric acid / 12 h / Reflux 2.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 3.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 3.2: 1 h / 15 - 20 °C / pH 2 4.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 5.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 6.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 6.2: -10 - 12 °C View Scheme

1-bromo-4-fluoro-2-methoxy-5-(1-methylvinyl)benzene (1383814-82-1) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrogen; hydrogen bromide / 5%-palladium/activated carbon / water; methanol / 0.25 h / 20 °C / 3102.97 Torr / Inert atmosphere 2.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 2.2: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C View Scheme
Multi-step reaction with 5 steps 1.1: n-butyllithium / toluene; hexane; tetrahydrofuran / -80 - -35 °C / Inert atmosphere 1.2: -35 °C 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 4.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 - 12 °C View Scheme

4-fluoro-2-methoxy-5-(2-propenyl)phenylboronic acid (1383814-83-2) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 2.1: hydrogen / 5%-palladium/activated carbon / methanol / 20 °C / 1551.49 Torr / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C View Scheme
Multi-step reaction with 4 steps 1.1: hydrogen / 5%-palladium/activated carbon / methanol / 0.5 h / 20 °C / 1292.9 Torr / Inert atmosphere 2.1: potassium carbonate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / water; tetrahydrofuran / 32 h / 20 - 45 °C / Inert atmosphere 3.1: N,N-dimethyl-formamide; thionyl chloride / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 - 12 °C View Scheme

2-fluoro-4-methoxy-1-(prop-1-en-2-yl)benzene (875446-55-2) → anacetrapib (875446-37-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: hydrogen / palladium on activated carbon / methanol / 50 °C / 2250.23 Torr / Inert atmosphere 1.2: 40 °C 2.1: n-butyllithium / toluene; hexane / -80 - -55 °C / Inert atmosphere 2.3: 1 h / 15 - 20 °C / pH 2 3.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 4.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 5.2: -10 °C View Scheme

C10H12BrFMgO (1383676-72-9) → anacetrapib (875446-37-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: toluene; tetrahydrofuran / 5 - 10 °C 1.3: 15 - 20 °C / pH 2 2.1: potassium carbonate / dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II) / water; tetrahydrofuran / 32 h / 35 - 45 °C / Inert atmosphere 3.1: thionyl chloride / N,N-dimethyl-formamide / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / 1 h / -15 °C 4.2: -10 °C View Scheme

C9H11I2NO → anacetrapib (875446-37-0)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 2.1: copper(l) chloride; potassium tert-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 2.2: 18 h / 50 °C / Inert atmosphere 3.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 3.2: 18 h / 20 °C View Scheme

(4S,5R)-5-(3,5-diiodophenyl)-4-methyloxazolidin-2-one → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: copper(l) chloride; potassium tert-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 1.2: 18 h / 50 °C / Inert atmosphere 2.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 2.2: 18 h / 20 °C View Scheme

(1R,2S)-1-(3,5-diiodophenyl)-2-nitropropan-1-ol → anacetrapib (875446-37-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: hydrogenchloride; zinc / 1 h / 0 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 3.1: copper(l) chloride; potassium tert-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 3.2: 18 h / 50 °C / Inert atmosphere 4.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 4.2: 18 h / 20 °C View Scheme

3,5-diiodobenzaldehyde (17352-25-9) → anacetrapib (875446-37-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: / tetrahydrofuran / 20 h / -60 - 20 °C / Inert atmosphere 2.1: hydrogenchloride; zinc / 1 h / 0 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 4.1: copper(l) chloride; potassium tert-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 4.2: 18 h / 50 °C / Inert atmosphere 5.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 5.2: 18 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: / tetrahydrofuran / 64 h / -60 °C 2.1: hydrogenchloride; zinc / 1 h / 0 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 12 h / 0 - 20 °C / Inert atmosphere 4.1: copper(l) chloride; potassium tert-butylate; 1,10-Phenanthroline / N,N-dimethyl-formamide / 1 h / 20 °C / Inert atmosphere 4.2: 18 h / 50 °C / Inert atmosphere 5.1: sodium hexamethyldisilazane / tetrahydrofuran; N,N-dimethyl-formamide / 1 h / -20 °C / Inert atmosphere 5.2: 18 h / 20 °C View Scheme

2-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxazole (851513-74-1) → anacetrapib (875446-37-0)

Conditions

Yield

Multi-step reaction with 4 steps 1.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 2.2: 13 h / 0 - 20 °C 3.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 4.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C View Scheme

3-trifluoromethylbenzonitrile (368-77-4) → anacetrapib (875446-37-0)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: calcium chloride / 5,5-dimethyl-1,3-cyclohexadiene / 24 h / 125 °C / Inert atmosphere 2.1: potassium phosphate; potassium acetate; triphenylphosphine; dichloro(benzene)ruthenium(II) dimer / 1-methyl-pyrrolidin-2-one / 42 h / 110 - 130 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine; methyl chloroformate / tetrahydrofuran / 0.75 h / 62 °C 3.2: 13 h / 0 - 20 °C 4.1: thionyl chloride / N,N-dimethyl-formamide / 5 h / 10 - 20 °C 5.1: sodium hexamethyldisilazane / N,N-dimethyl-formamide / -15 - 12 °C View Scheme

anacetrapib (875446-37-0) → (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-hydroxy-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyl-1,3-oxazolidin-2-one (875550-05-3)

Conditions	Yield
Stage #1: anacetrapib With boron tribromide In dichloromethane at 15 - 16℃; for 1h; Stage #2: With water In dichloromethane	60%

anacetrapib (875446-37-0) → (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-[({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl}methyl)amino]propan-1-ol (1220703-07-0)

Conditions	Yield
With water; potassium hydroxide In isopropyl alcohol at 75℃; Sealed tube;

Upstream product

• 886496-63-5 1-bromo-2-(bromomethyl)-4-(trifluoromethyl)benzene 
• 875444-08-9 (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one 
• 875446-29-0 [4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]boronic acid 
• 1185737-50-1 (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-3-(2-bromo-5-trifluoromethyl-benzyl)-4-methyl-oxazolidin-2-one 
• 875446-55-2 2-fluoro-4-methoxy-1-(prop-1-en-2-yl)benzene 
• 1383676-72-9 C₁₀H₁₂BrFMgO 
• 17352-25-9 3,5-diiodobenzaldehyde 
• 851513-74-1 2-(3-(trifluoromethyl)phenyl)-4,5-dihydrooxazole 
• 368-77-4 3-trifluoromethylbenzonitrile 
• 958029-47-5 2-[4'-fluoro-2'-methoxy-5'-(propan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]-4,5-dihydro-1,3-oxazole 
• 702641-06-3 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene 
• 1383814-88-7 (4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)methanamine 
• 1383676-71-8 4'-fluoro-5'-isopropyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-carbonitrile 
• 121-50-6 3-amino-4-chlorobenzotrifluoride 

Downstream Products

• 1220703-07-0 (1R,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-[({2-[4-fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl}methyl)amino]propan-1-ol 
• 875550-05-3 (4S,5R)-5-(3,5-bis(trifluoromethyl)phenyl)-3-((4'-fluoro-5'-isopropyl-2'-hydroxy-4-(trifluoromethyl)biphenyl-2-yl)methyl)-4-methyl-1,3-oxazolidin-2-one 

Relevant articles and documents

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties ()

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Preparation method of Anacetrapib

The invention relates to a preparation method of a compound represented by the formula (I). The preparation method comprises the following steps: (1) reacting 2-chloro-5-trifluoromethyl-aniline (II) with (4-fluoro-5-isopropyl-2-methoxyphenyl)boric acid (III) to obtain 2-(4-fluoro-5-isopropyl-20methoxyphenyl)-5-trifluoromethyl-aniline (formula IV); (2) reacting the compound (formula IV) with tert-butyl nitrite, acetaldehyde, and alkalis to obtain 2-(4-fluoro-5-isopropyl-2-methoxyphenyl)-5-trifluoromethyl-benzyl alcohol (formula V); (3) reacting the compound (formula V) with a halogenation reagent, and then adding (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidine-2-one (VI) into the reaction mixture to carry out reactions so as to obtain (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4'-fluoro-5'-isoproypyl-2'-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidine-2-one represented by the formula (I), namely Anacetrapib.

PROCESS FOR PREPARATION OF ANACETRAPIB AND INTERMEDIATES THEREOF

The present invention relates to a novel process for the preparation of anacetrapib. The present invention also relates to novel intermediate or its salt and its use in the preparation of anacetrapib.