| 57% |
With ytterbium(III) trifluoromethanesulfonate hydrate; In acetonitrile; at 90℃; for 12h;sealed reaction bottle; |
A mixture of <strong>[319-24-4]2-amino-5-fluoro-benzoic acid methyl ester</strong> (12.1 g, 71.4 mmol), 3-bromo-benzaldehyde (13.2 g, 71.4 mmol) and ytterbium(III) triflate hydrate (4.4 g, 71.4 mmol) in acetonitrile (200 mL) was cooled to 0 C. in a sealed reaction bottle. Then a cooled solution of isobutene (28 g, 500 mmol) was added into. The reaction mixture was heated to 90 C. and stirred for 12 h. The solvent was removed in vacuo and the residue was purified on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (20% ethyl acetate/hexanes) to afford 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (16 g, 57%) as a white solid: MS (ESI) M+1=392.1. |
| 51% |
ytterbium(III) triflate; In acetonitrile; at 85℃; for 16h;Sealed tube;Product distribution / selectivity; |
Example 56N-[6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline- 8-carbonyl]-methanesulfonamideTo a stirred solution of <strong>[319-24-4]2-amino-5-fluoro-benzoic acid methyl ester</strong> (8.46 g, 50 mmol) and 3-bromobenzaldehyde (6.4 mL, 55 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 200 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85C for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl- l,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (10 g, 51%) as a light yellow solid: MS(ESI) M+l = 392.0 & 394.0.A mixture solution of 2-(3-bromo-phenyl)-6-fluoro-4,4-dimethyl-l,2,3,4-tetrahydro- quinoline-8-carboxylic acid methyl ester (5 g, 12.7 mmol), morpholine (11.1 mL, 125 mmol), copper(I) iodide (1.43 g, 7.5 mmol), N,N-dimethylglycine hydrochloride (1.4 g, 10 mmol), and potassium carbonate (5.2 g, 75 mmol) in dimethyl sulfoxide (20 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (150 mL x 2), washed with saturated aqueous ammonium chloride solution (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 50% ethyl acetate in petroleum ether) to afford 6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro- quinoline-8-carboxylic acid (3 g, 61%) as a white solid: MS(ESI) M+l = 385.1.To a suspension of 60% sodium hydride (360 mg, 9 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (865 mg, 9.1 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A56. A solution of 6- fluoro-4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-8- carboxylic acid (500 mg, 1.3 mmol) and Iota,Gamma-carbonyldiimidazole (422 mg, 2.6 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70C for 1 h and cooled to roomtemperature to afford Solution B56. Solution B56 was added to Solution A56 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-fluoro-4,4-dimethyl-2-(3-morpholin-4-yl- phenyl)-l,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (270 mg, 45%) as a white solid: MS(ESI) M+l = 462.1. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
