An improved synthesis of Lu AA20465

Tetrahedron Letters

Volumn 47, Issue 30, 2006, Pages 5355-5357

  Krafft, Eva A ^a   Pinard, Emmanuel ^a   Thomas, Andrew W ^a  

^a F HOFFMANN LA ROCHE LTD   (Switzerland)

Author keywords

[No Author keywords available]

Indexed keywords

COPPER; GLYCINE TRANSPORTER 1; GLYCINE TRANSPORTER 1 INHIBITOR; LU AA 20465; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; PROTEIN INHIBITOR; UNCLASSIFIED DRUG;

AMINATION; AQUEOUS SOLUTION; ARTICLE; ARYLATION; CATALYSIS; CATALYST; CHEMICAL REACTION; DIAZOTIZATION; DRUG SYNTHESIS; IODINATION; REDUCTION; STEREOCHEMISTRY;

EID: 33745224538     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2006.05.117     Document Type: Article

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16. 5 Selected Experimental Details for Key reaction steps. Step (a): To a solution of 4-chloro-2-fluoro-nitrobenzene 4 (5.0 g, 28.5 mmol) in DMF (56 mL) and triethylamine (7.9 mL, 57.0 mmol) was added (R)-2-methylpiperazine (2.85 g, 28.5 mmol) and the resulting mixture was heated at 80 °C for 3 h. After cooling to rt, the mixture was poured into water and extracted with ethyl acetate. Drying the combined organic layers over sodium sulfate, followed by filtration, evaporation and purification on silica gel (eluting with DCM-MeOH) afforded 5 (7.13 g, 98%) as a light red solid. Step (c): To a mixture of 6 (9.28 g, 24.0 mmol) in acetic acid (270 mL) was added iron powder (8.1 g, 145 mmol) and the resulting mixture was heated at 60 °C overnight. After cooling to rt, the mixture was evaporated and slurried in ethyl acetate. It was then filtered and the filtrate poured into water and extracted with ethyl acetate. Drying the combined organic layers over sodium sulfate, followed by filtration, evaporation and purification on silica gel (eluting with EtOAc-heptane) afforded 7 (6.56 g, 77%) as a light yellow gum. Step (d): To a solution of 7 (5.4 g, 15 mmol) in 1,2-dimethoxyethane (63 mL) was successively added cesium iodide (3.93 g, 15.0 mmol), iodine (1.92 g, 8.0 mmol), cuprous iodide (893 mg, 5.0 mmol) and isoamylnitrite (9.53 mL, 91 mmol) and the resulting mixture was heated at 60 °C for 1.5 h. After cooling to rt, the mixture was partitioned between ammonium chloride (saturated solution) and ethyl acetate and then the whole mixture filtered through celite. The organic layer was then separated, washed with sodium sulfite (5% solution), dried over sodium sulfate, filtered, evaporated and purified on silica gel (eluting with EtOAc-heptane) to afford 8 (4.93 g, 69%) as a light yellow gum. Step (e): A solution of 8 (4.87 g, 10 mmol) in dioxane (21 mL) was added to a mixture of copper iodide (99 mg, 1 mmol), 4-methoxythiophenol (1.77 g, 12 mmol), N-methylglycine (184 mg, 2 mmol) and potassium hydroxide pellets (1.69 g, 26 mmol). The resulting light brown suspension was then heated under reflux overnight. After cooling to rt, the mixture was extracted with ethyl acetate. Drying the combined organic layers over sodium sulfate, followed by filtration, evaporation and purification on silica gel (eluting with EtOAc-heptane) afforded 10 (3.13 g, 63%) as a colourless gum.