2-fluoroethanamine;hydrochloride

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

実験手順: On a water separator, 550 mg (4.97 mmol) of 2-fluoroethylamine hydrochloride, 547 mg (5.47 mmol) of tetronic acid, 408 mg (4.97 mmol) of sodium acetate and 9 mg (0.05 mmol) of 4-toluene-sulphonic acid in 50 ml of toluene are heated under reflux for 5 hours. The reaction mixture is concentrated under reduced pressure and then taken up in ethyl acetate and washed with 1 N aqueous sodium hydroxide solution. The aqueous phase is extracted repeatedly with ethyl acetate and the combined organic phase is dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate/cyclohexane gives 300 mg (42% of theory) of 4-[(2-fluoroethyl)amino]furan-2(5H)-one. under reflux for 5 hours The reaction mixture is concentrated under reduced pressure washed with 1 N aqueous sodium hydroxide solution The aqueous phase is extracted repeatedly with ethyl acetate the combined organic phase is dried over sodium sulphate Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate/cyclohexane

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

実験手順: N,N-Dibenzyl-N′-(2-fluoro-ethyl)ethane-1,2-diamine (160 mg) was prepared by following General Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (520 mg), 2-fluoro-ethylamine hydrochloride (250 mg), DIEA (900 uL) and tetrabutylammonium bromide (60 mg) in DMF (2 mL).

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

実験手順: 1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-fluoro-ethyl)-amide (31 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), 2-fluoroethylamine hydrochloride (24 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 454.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.37 (bs, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.49 (d, 1H), 7.34 (d, 1H), 4.61 (t, 1H), 4.49 (t, 1H), 3.62 (bs, 3H), 3.58-3.48 (m, 2H).

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

実験手順: Pivaloyl chloride (3.66 g, 30 mM) was added dropwise at -5° C. to compound 655 (8.62 g, 28.7 mM) and triethylamine (4.2 ml, 30 mM) dissolved in tetrahydrofuran (50 ml), then the mixture was stirred for 30 minutes. Chloroform (30 ml) in solution with 2-fluoroethylamine hydrochloride (3.48 g) and triethylamine (4.2 ml) was added dropwise thereto with cooling at 0° to -5° C. then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate (5:1) to obtain the product. (9.21 g, yield: 88.8%) with cooling at 0° to -5° C. the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature the mixture was extracted three times with chloroform The extract was dried with anhydrous magnesium sulfate concentrated in vacuo The residue was charged on a column of silica gel (C-200, 175 g) eluted successively with benzene and benzene-ethyl acetate (5:1) to obtain the product

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

実験手順: 3-Ethoxycarbonyl-1-(2-fluoroethyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under conditions similar to Example 3, but starting with ethyl 2-(2-chloro-6,7,8-trifluoro-3-quinolinecarbonyl)(dimethylamino)acrylate (3.9 g), 2-fluoroethylamine hydrochloride (3 g) and triethylamine (4.2 cc) in ethanol (100 cc). After the addition of DBU (1.8 cc), the solution is heated for 2 hours to 80° C. After the same treatment of the reaction mixture as in Example 24, 3-ethoxycarbonyl-7,8,9-trifluoro-1-(2-fluoroethyl)-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.8 g) is obtained in the form of a yellow solid, m.p. 302°-304° C. 3-Ethoxycarbonyl-1-(2-fluoroethyl)-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under conditions similar to Example 3 the solution is heated for 2 hours to 80° C

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

実験手順: As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-fluoroethylamine hydrochloride instead of methylamine, to the title compound (109 mg, 95%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.

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

実験手順: As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using 2-fluoroethylamine hydrochloride instead of methylamine, to the title compound (109 mg, 95%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.

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

実験手順: Pivaloyl chloride (3.66 g, 30 mM) was added dropwise at -5° C. to compound 655 (8.62 g, 28.7 mM) and triethylamine (4.2 ml, 30 mM) dissolved in tetrahydrofuran (50 ml), then the mixture was stirred for 30 minutes. Chloroform (30 ml) in solution with 2-fluoroethylamine hydrochloride (3.48 g) and triethylamine (4.2 ml) was added dropwise thereto with cooling at 0° to -5° C. then the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature. Dilute aqueous potassium carbonate was added to the reaction mixture and the mixture was extracted three times with chloroform. The extract was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 175 g) and eluted successively with benzene and benzene-ethyl acetate (5:1) to obtain the product. (9.21 g, yield: 88.8%). with cooling at 0° to -5° C. the mixture was stirred for 1 hour with ice cooling and 4 hours at room temperature the mixture was extracted three times with chloroform The extract was dried with anhydrous magnesium sulfate concentrated in vacuo The residue was charged on a column of silica gel (C-200, 175 g) eluted successively with benzene and benzene-ethyl acetate (5:1) to obtain the product

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Fluoroethylamine hydrochloride salt (282.4 mg, 2.83 mmol) was suspended in 1:1 THF:DCM (6 mL) followed by addition of DIPEA (2.5 mL, 14.35 mmol). The mixture was cooled to 0° C. followed by slow addition of thiophosgene (217 uL, 2.8 mmol) by syringe over five minutes then allowed to slowly warm to room temperature over 30 minutes. 4-Bromobenzene-1,2-diamine (530 mg, 2.8 mmol) was then added and the reaction mixture was allowed to stir at room temperature over an additional 12 h. The mixture was concentrated and the residue partitioned with ethyl acetate and 10% aqueous citric acid. The organic phase was washed twice with additional 10% aqueous citric acid then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture of thiourea thus obtained was taken into THF (15 mL) followed by addition of mercury (II) oxide (640 mg, 2.95 mmol). The mixture was brought to reflux for 6 h then stirred an additional 60 h at room temperature. The crude mixture was filtered through a bed of celite with ethyl acetate washing and the filtrate concentrated then taken back into ethyl acetate. The organic solution was washed once with 1 M aqueous hydrochloric acid and the organic phase discarded. The aqueous phase was filtered to remove trace insoluble residue and the filtrate basified to pH 9-10 by dropwise addition of 50% aqueous sodium hydroxide. The aqueous phase was then extracted once with ethyl acetate and the organic solution was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford crude 5-bromo-N-(2-fluoroethyl)-1H-benzo[d]imidazol-2-amine (390 mg, 53% yield) which was carried forward without further purification. MS (EI) for C9H9BrFN3: 258, 260 (MH+). to slowly warm to room temperature over 30 minutes The mixture was concentrated the residue partitioned with ethyl acetate and 10% aqueous citric acid The organic phase was washed twice with additional 10% aqueous citric acid brine, dried over anhydrous sodium sulfate filtered concentrated The crude mixture of thiourea thus obtained to reflux for 6 h then stirred an additional 60 h at room temperature The crude mixture was filtered through a bed of celite with ethyl acetate washing the filtrate concentrated The organic solution was washed once with 1 M aqueous hydrochloric acid The aqueous phase was filtered to remove trace insoluble residue the filtrate basified to pH 9-10 by dropwise addition of 50% aqueous sodium hydroxide The aqueous phase was then extracted once with ethyl acetate the organic solution was washed with brine then dried over anhydrous sodium sulfate filtered concentrated

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Fluoroethylamine hydrochloride salt (282.4 mg, 2.83 mmol) was suspended in 1:1 THF:DCM (6 mL) followed by addition of DIPEA (2.5 mL, 14.35 mmol). The mixture was cooled to 0° C. followed by slow addition of thiophosgene (217 uL, 2.8 mmol) by syringe over five minutes then allowed to slowly warm to room temperature over 30 minutes. 4-Bromobenzene-1,2-diamine (530 mg, 2.8 mmol) was then added and the reaction mixture was allowed to stir at room temperature over an additional 12 h. The mixture was concentrated and the residue partitioned with ethyl acetate and 10% aqueous citric acid. The organic phase was washed twice with additional 10% aqueous citric acid then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude mixture of thiourea thus obtained was taken into THF (15 mL) followed by addition of mercury (II) oxide (640 mg, 2.95 mmol). The mixture was brought to reflux for 6 h then stirred an additional 60 h at room temperature. The crude mixture was filtered through a bed of celite with ethyl acetate washing and the filtrate concentrated then taken back into ethyl acetate. The organic solution was washed once with 1 M aqueous hydrochloric acid and the organic phase discarded. The aqueous phase was filtered to remove trace insoluble residue and the filtrate basified to pH 9-10 by dropwise addition of 50% aqueous sodium hydroxide. The aqueous phase was then extracted once with ethyl acetate and the organic solution was washed with brine then dried over anhydrous sodium sulfate, filtered and concentrated to afford crude 5-bromo-N-(2-fluoroethyl)-1H-benzo[d]imidazol-2-amine (390 mg, 53% yield) which was carried forward without further purification. MS (EI) for C9H9BrFN3: 258, 260 (MH+). to slowly warm to room temperature over 30 minutes The mixture was concentrated the residue partitioned with ethyl acetate and 10% aqueous citric acid The organic phase was washed twice with additional 10% aqueous citric acid brine, dried over anhydrous sodium sulfate filtered concentrated The crude mixture of thiourea thus obtained to reflux for 6 h then stirred an additional 60 h at room temperature The crude mixture was filtered through a bed of celite with ethyl acetate washing the filtrate concentrated The organic solution was washed once with 1 M aqueous hydrochloric acid The aqueous phase was filtered to remove trace insoluble residue the filtrate basified to pH 9-10 by dropwise addition of 50% aqueous sodium hydroxide The aqueous phase was then extracted once with ethyl acetate the organic solution was washed with brine then dried over anhydrous sodium sulfate filtered concentrated

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

実験手順: To a suspension of 2-fluoroethylamine hydrochloride (0.287 g) in dichloro-methane (4 ml) was added triethylamine (0.4 ml) followed by (2,4-dichloro-phenyl)-methanesulfonyl chloride (Example 1.2) (0.25 g). The reaction mixture was stirred at ambient temperature for 3 hours then left to stand at ambient temperature for 16 hours. Dichloromethane (20 ml) was added to the reaction mixture and the mixture was washed with water (20 ml). The phases were separated and the organic layer was dried over magnesium sulfate and concentrated to give C-(2,4-dichloro-phenyl)-N-(2-fluoro-ethyl)-methanesulfonamide (15 mg) (60% pure). 1H-NMR (400 MHz, CDCl3): 7.47-7.51 (m, 2H), 7.29-7.32 (dd, 1H), 4.77 (bs, 1H), 4.49 (s, 2H), 4.51-4.53 (m, 1H), 4.39-4.42 (m, 1H), 3.33-3.36 (m, 1H), 3.27-3.29 (m, 1H) ppm. then left to stand at ambient temperature for 16 hours the mixture was washed with water (20 ml) The phases were separated the organic layer was dried over magnesium sulfate concentrated

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

実験手順: To a suspension of 2-fluoroethylamine hydrochloride (0.287 g) in dichloro-methane (4 ml) was added triethylamine (0.4 ml) followed by (2,4-dichloro-phenyl)-methanesulfonyl chloride (Example 1.2) (0.25 g). The reaction mixture was stirred at ambient temperature for 3 hours then left to stand at ambient temperature for 16 hours. Dichloromethane (20 ml) was added to the reaction mixture and the mixture was washed with water (20 ml). The phases were separated and the organic layer was dried over magnesium sulfate and concentrated to give C-(2,4-dichloro-phenyl)-N-(2-fluoro-ethyl)-methanesulfonamide (15 mg) (60% pure). 1H-NMR (400 MHz, CDCl3): 7.47-7.51 (m, 2H), 7.29-7.32 (dd, 1H), 4.77 (bs, 1H), 4.49 (s, 2H), 4.51-4.53 (m, 1H), 4.39-4.42 (m, 1H), 3.33-3.36 (m, 1H), 3.27-3.29 (m, 1H) ppm. then left to stand at ambient temperature for 16 hours the mixture was washed with water (20 ml) The phases were separated the organic layer was dried over magnesium sulfate concentrated