7-fluoro-3,4-dihydro-2H-naphthalen-1-one

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound was prepared in an analogous manner to Example 12f with the replacement of 5-fluoro1-tetralone and diethyl (cyclopropylcarbamoyl)methyl phosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclo propylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene) acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz,1H), 7.32 (dd, J=11.2 Hz,1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of aluminum chloride (66 g, 0.50 mol) in carbon disulfide (600 mL) was added dropwise a solution of 4-(4-fluorophenyl)butyryl chloride (75.3 g, 0.37 mole) in carbon disulfide (260 mL) keeping the internal temperature below 10° C. After refluxing for 0.5 h, the reaction mixture was poured into a mixture of concentrated HCl (50 mL) and ice water (800 mL). The mixture was filtered and extracted with diethyl ether. The diethyl ether extracts were dried and concentrated it7 vacuo to give crude 7-fluoro-1-tetralone. Vacuum distillation gave pure 7-fluoro-1-tetralone b.p., 83° C. at 0.3 mm Hg which solidified to a white solid (94%). m.p., 62°-64° C. (lit, J. Am. Chem. Soc., 89, 386, 1967, m.p., 63.5°-65.0° C.); the internal temperature below 10° C After refluxing for 0.5 h The mixture was filtered extracted with diethyl ether The diethyl ether extracts were dried concentrated it7 vacuo to give crude 7-fluoro-1-tetralone Vacuum distillation

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of 4-(p-fluorophenyl) butanoic acid (23g; 0.126 mole) and 85% polyphosphoric acid (200g) was heated at 100° C for 4 hrs., cooled, and poured onto ice-water (800g). After through stirring the precipitated tetralone was filtered off, washed well with water, and recrystallised from ethanol to give 13.07g (63%) of material of m.p. 56°-57° C. (Found; C, 73.31; H, 5.72; C10H9FO requires; C, 73.13; H, 5,53%). , cooled was filtered off washed well with water recrystallised from ethanol

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a specially designed Kel-F reactor (cylindrical shape 1.25"od×3"h equipped with a screw cap and N2 inlet-outlet) was placed hydrogen fluoride-pyridine 6:4 solution (10 mL, prepared by diluting commercially available hydrogen fluoride-pyridine 7:3 solution with dry pyridine). 7-amino-tetralone (644 mg, 4.0 mmol), (Example 35, Step A) was added under N2 and the solution was cooled to 0°. Sodium nitrite (304 mg, 4.4 mol, 1.1 eq) was added in portions and the mixture was stirred for 30 minutes. The mixture was then heated at 90° C. for 1 hour with stirring. The reaction mixture was quenched with approx. 60 mL of ice/water and the solid that separated extracted with methylene chloride (3×30 mL). The combined extracts were washed with water and brine, dried over magnesium sulfate, filtered and evaporated to dryness under vacuum at room temperature. Purification by flash chromatography on silica, eluting with ethyl acetate/hexane (5:95), afforded pure 7-fluoro- 1-tetralone (367 mg, 2.2 mmol, 56%). 1H NMR (300MHz, CDCl3): 2.13 (m,2H), 2.65 (t,7Hz,2H), 2.94 (t,7Hz,2H), 7.1-7.3 (m,2H), 7.69 (dd;2,8Hz;1H). FAB-MS: calculated for C10H9FO 164; found 164 (M+,71%). ×3"h equipped with a screw cap N2 inlet-outlet) was placed the solution was cooled to 0° with stirring The reaction mixture was quenched with approx. 60 mL of ice/water the solid that separated extracted with methylene chloride (3×30 mL) The combined extracts were washed with water and brine dried over magnesium sulfate filtered evaporated to dryness under vacuum at room temperature Purification by flash chromatography on silica eluting with ethyl acetate/hexane (5:95)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1.6 eq. of Nal are suspended in 130 ml of anhydrous THF under a nitrogen atmosphere in a 250 ml three-necked flask. The mixture is cooled in a bath of ice/salt and 1.6 eq. of diethyl cyanomethylenephosphonate in 40 ml of THF are added dropwise. The reaction mixture is stirred for 45 minutes and then, whilst still cold, 1 eq. of the compound obtained in Step E, in 70 ml of THF, is added dropwise. The mixture is stirred for 4 hours and is then poured onto a mixture of ice/water, acidified with 3M HCl solution and extracted 3 times with ethyl ether. The organic phase is dried over MgSO4 and evaporated under reduced pressure; the residue obtained is recrystallised. are added dropwise The mixture is stirred for 4 hours extracted 3 times with ethyl ether The organic phase is dried over MgSO4 evaporated under reduced pressure the residue obtained is recrystallised

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.055 mol of the compound obtained in Step D is introduced into a 500 ml round-bottomed flask together with 100 g of polyphosphoric acid. The reaction mixture is heated at 60° C. for 4 hours. The mixture is then cooled and poured into water; the precipitate formed is then dried and recrystallised. The mixture is then cooled the precipitate formed is then dried recrystallised

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 0.055 mol of the compound obtained in Step D is introduced into a 500 ml round-bottomed flask together with 100 g of polyphosphoric acid. The reaction mixture is heated at 60° C. for 4 hours. The mixture is then cooled and poured into water; the precipitate formed is then dried and recrystallised. The mixture is then cooled the precipitate formed is then dried recrystallised

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolved 7-fluorotetralone, 51 (10.0 g, 60.9 mmol) in 1,2-ethanedithiol (10 mL) and cooled reaction to 0° C. Boron trifluoride diethyl etherate (7.5 mL) was added dropwise. The white suspension became yellow and homogenous. The wet ice bath was removed and the reaction was warmed to ambient temperature. The reaction was then diluted with heptanes (25 mL) and poured into an ice cold solution of saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and concentrated to give colorless oil (14.69 g, 60.9 mmol, 100% yield). 1H NMR (400 MHz, CDCl3) δ: 7.60 (d, J=12 Hz, 1H), 6.94 (t, J=4 Hz, 1H), 6.84 (t, J=8 Hz, 1H), 3.56 (m, 2H), 3.46 (m, 2H), 2.75 (m, 2H), 2.37 (m, 2H), 1.99 (m, 2H). cooled reaction to 0° C The wet ice bath was removed The reaction was then diluted with heptanes (25 mL) poured into an ice cold solution of saturated sodium bicarbonate The organic layer was separated dried over sodium sulfate concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: This compound was prepared in an analogous manner to Example 27d with the replacement of 6-chloro-1-indanone and diethyl carbamoylmethylphosphonate with 7-fluoro-1-tetralone (7.76 g, 0.05 mol) and diethyl(cyclopropylcarbamoyl)methylphosphonate (11.1 g, 0.05 mol). Chromatography on Silica gel using ethyl acetate:hexanes (1:2) as eluent gave 4.38 g (37%) of (E)-N-Cyclopropyl-2-(7-fluoro-1,2,3,4-tetrahydro-1-naphthylidene)acetamide, m.p., 122.8°-123.3° C.; NMR (DMSO-d6): d 8.00 (d, J=4.0 Hz, 1H), 7.32 (dd, J=11.2 Hz, 1H), 7.04-7.23 (m, 2H), 6.33 (s, 1H), 3.06 (m,2H), 2.69 (m, 3H), 1.70 (m, 2H), 0.66 (m, 2H), 0.40 (m, 2H); steady-state nOe: irradiation at 6.39 d, observed significant nOe at 7.32 d.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a mixture of aluminum chloride (66 g, 0.50 mol) in carbon disulfide (600 mL) was added dropwise a solution of 4-(4-fluorophenyl)butyryl chloride (75.3 g, 0.37 mole) in carbon disulfide (260 mL) keeping the internal temperature below 10° C. After refluxing for 0.5 h, the reaction mixture was poured into a mixture of concentrated HCl (50 mL) and ice water (800 mL). The mixture was filtered and extracted with diethyl ether. The diethyl ether extracts were dried and concentrated in vacuo to give crude 7-fluoro-1-tetralone. Vacuum distillation gave pure 7-fluoro-1-tetralone b.p., 83° C. at 0.3 mm Hg which solidified to a white solid (94%). m.p., 62°-64° C. (lit, J. Am. Chem. Soc., 89, 386, 1967; m.p., 63.5°-65.0° C.) the internal temperature below 10° C After refluxing for 0.5 h The mixture was filtered extracted with diethyl ether The diethyl ether extracts were dried concentrated in vacuo to give crude 7-fluoro-1-tetralone Vacuum distillation