methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-(2,5-dichloro-phenoxy)-5-fluoro-nicotinoyl chloride (48.1 mg, 0.15 mmol, 1.0 equiv; Example 146, Step 1) in anhydrous DMF (1 mL) was added N-ethyldiisopropylamine (97 mg, 128 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and 1,2,3,4-tetrahydro-quinoline-4-carboxylic acid methyl ester (31.6 mg, 0.165 mmol, 1.1 equiv; [CAS RN 68066-85-3]) and the reaction mixture stirred at rt for 2 h. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 9.1 mg (13%) of the title compound as a light yellow solid. MS (ISP): 475.1 [M+H]+. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of methyl 1,2,3,4-tetrahydroquinoline-4-carboxylate (51.0 g) in tetrahydrofuran (THF, 200 ml) was heated under refluxing and a solution of oxalyl chloride (30 ml) in dry THF was added thereto. The mixture was refluxed for 4 hours, then cooled and concentrated. The residue was dissolved in carbon disulfide (800 ml) and aluminum chloride (66.7 g) was added portionwise. The mixture was refluxed for 4 hours, and then allowed to stand overnight. The solvent was eliminated by decantation and to the residue was added ice-water (1 litter). The mixture was extracted with chloroform. The chloroform layer was washed well with water, dried over anhydrous sodium sulfate and concentrated to give the title compound (55.15 g, 83.3%) which was recrystallized from acetonitrile to dark red crystals, mp 135° C.-136° C. under refluxing The mixture was refluxed for 4 hours cooled concentrated The residue was dissolved in carbon disulfide (800 ml) aluminum chloride (66.7 g) was added portionwise The mixture was refluxed for 4 hours was added ice-water (1 litter) The mixture was extracted with chloroform The chloroform layer was washed well with water dried over anhydrous sodium sulfate concentrated