tert-butyl (2S)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate

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

実験手順: To a solution of (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (279 mg, 1.00 mmol) and 4-bromo-2-methoxyphenol (325 mg, 1.57 mmol) in N,N-dimethylformamide (5.55 mL) was added cesium carbonate (651 mg, 2.00 mmol). The mixture was heated to 100° C. After 22 h, the mixture was allowed to cool to 23° C. and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane) afforded the title compound as an amber oil. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, CDCl3): δ 7.07-6.79 (m, 3H), 4.25-4.10 (m, 2H), 4.01-3.73 (m, 1H), 3.84 (s, 3H), 3.48-3.26 (m, 2H), 2.16-1.80 (m, 4H), 1.48 (s, 9H). to cool to 23° C. The mixture was extracted with ethyl acetate (3×30 mL) The combined organics were dried over sodium sulfate filtered The filtrate was concentrated in vacuo Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane)

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

実験手順: To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.00 mmol) and triethylamine (0.21 mL, 1.5 mmol) in tert-butyl methyl ether (4 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). After 90 min., the mixture was filtered, washing the white solid with tert-butyl methyl ether (3×2 mL). The filtrate was concentrated in vacuo to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3,): δ 4.40-3.95 (m, 3H), 3.49-3.32 (m, 2H), 3.02 (s, 3H), 2.11-1.80 (m, 4H), 1.48 (s, 9H). the mixture was filtered washing the white solid with tert-butyl methyl ether (3×2 mL) The filtrate was concentrated in vacuo

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

実験手順: The product from Example 164A (7 g) in 100 mL of THF and tetrabutylammonium fluoride (42 mL of a 1M solution in THF) was heated at reflux for 17 hours, cooled, concentrated to dryness, diluted with 125 mL of ethyl acetate, washed with 5% aqueous NaHCO3, brine, dried over MgSO4, filtered, and the filtrate was concentrated under reduced pressure to provide an oil. The oil was distilled in vacuo (50° C., 1.2 torr) to give 4.9 g of the title compound as a colorless oil. at reflux for 17 hours cooled concentrated to dryness diluted with 125 mL of ethyl acetate washed with 5% aqueous NaHCO3, brine dried over MgSO4 filtered the filtrate was concentrated under reduced pressure to provide an oil The oil was distilled in vacuo (50° C., 1.2 torr)

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

実験手順: N-Boc-(2S)-prolinol (6.04 g) in 100 mL of dichloromethane was treated with 4.04 g of triethylamine, cooled to 0° C., and treated with methanesulfonyl chloride (4.0 g) slowly. After stirring at 0° C. for 30 minutes, the reaction was allowed to warm to room temperature, washed with 5% aqueous NaHCO3 solution, dried over sodium sulfate, and concentrated to dryness to give the title compound as an off-white oil (8.47 g). to warm to room temperature washed with 5% aqueous NaHCO3 solution dried over sodium sulfate concentrated to dryness

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

実験手順: N-Boc-(2S)-prolinol (6.04 g) in 100 mL of dichloromethane was treated with 4.04 g of triethylamine, cooled to 0° C., and treated with methanesulfonyl chloride (4.0 g) slowly. After stirring at 0° C. for 30 minutes, the reaction was allowed to warm to room temperature, washed with 5% aqueous NaHCO3 solution, dried over sodium sulfate, and concentrated to dryness to give the title compound as an off-white oil (8.47 g). to warm to room temperature washed with 5% aqueous NaHCO3 solution dried over sodium sulfate concentrated to dryness

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

実験手順: To a solution of (S)-tert-butyl 2-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (279 mg, 1.00 mmol) and 4-bromo-2-methoxyphenol (325 mg, 1.57 mmol) in N,N-dimethylformamide (5.55 mL) was added cesium carbonate (651 mg, 2.00 mmol). The mixture was heated to 100° C. After 22 h, the mixture was allowed to cool to 23° C. and diluted with water (30 mL). The mixture was extracted with ethyl acetate (3×30 mL). The combined organics were dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo. Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane) afforded the title compound as an amber oil. MS (ES+) 408.2 (M+Na)+. 1H NMR (400 MHz, CDCl3): δ 7.07-6.79 (m, 3H), 4.25-4.10 (m, 2H), 4.01-3.73 (m, 1H), 3.84 (s, 3H), 3.48-3.26 (m, 2H), 2.16-1.80 (m, 4H), 1.48 (s, 9H). to cool to 23° C. The mixture was extracted with ethyl acetate (3×30 mL) The combined organics were dried over sodium sulfate filtered The filtrate was concentrated in vacuo Purification by column chromatography (silica gel, 0-50% ethyl acetate in dichloromethane)

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

実験手順: To a solution of (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate (201 mg, 1.00 mmol) and triethylamine (0.21 mL, 1.5 mmol) in tert-butyl methyl ether (4 mL) was added methanesulfonyl chloride (0.095 mL, 1.2 mmol). After 90 min., the mixture was filtered, washing the white solid with tert-butyl methyl ether (3×2 mL). The filtrate was concentrated in vacuo to provide the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3,): δ 4.40-3.95 (m, 3H), 3.49-3.32 (m, 2H), 3.02 (s, 3H), 2.11-1.80 (m, 4H), 1.48 (s, 9H). the mixture was filtered washing the white solid with tert-butyl methyl ether (3×2 mL) The filtrate was concentrated in vacuo

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

実験手順: The procedure described in preparation 5-(2) was repeated, but using 12.16 g of (2S)-1-t-butoxycarbonyl-2-methanesulfonyloxymethylpyrroldine [prepared by the methanesulfonylation of (2S)-1-t-butoxycarbonyl-2-hydroxymethylpyrrolidine], 7.3 ml of 4-methoxybenzyl mercaptan and 2.3 g of sodium hydride (as a 55% w/w suspension in mineral oil) in 100 ml of dry dimethylformamide, to afford 13.93 g of the title compound as an oil. The procedure described in preparation 5-(2)

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

実験手順: The procedure described in preparation 5-(2) was repeated, but using 12.16 g of (2S)-1-t-butoxycarbonyl-2-methanesulfonyloxymethylpyrroldine [prepared by the methanesulfonylation of (2S)-1-t-butoxycarbonyl-2-hydroxymethylpyrrolidine], 7.3 ml of 4-methoxybenzyl mercaptan and 2.3 g of sodium hydride (as a 55% w/w suspension in mineral oil) in 100 ml of dry dimethylformamide, to afford 13.93 g of the title compound as an oil. The procedure described in preparation 5-(2)

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

実験手順: A solution of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.590 g, 0.97 mmol), cesium carbonate (1.95 g, 5.98 mmol) and tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 1.16 mmol) in dimethylacetamide (10 ml) was heated at 80° C. for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography. Elution with 5 to 7% methanol in dichloromethane gave tert-butyl (2S)-2-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.332 g, 61% yield) as a light brown solid. extracted with ethyl acetate The organic layer was separated dried over magnesium sulphate evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography Elution with 5 to 7% methanol in dichloromethane

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

実験手順: A solution of N-(3-fluorophenyl)-2-{4-[(7-hydroxyquinazolin-4-yl)amino]-1H-pyrazol-1-yl}acetamide (0.590 g, 0.97 mmol), cesium carbonate (1.95 g, 5.98 mmol) and tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 1.16 mmol) in dimethylacetamide (10 ml) was heated at 80° C. for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulphate and evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography. Elution with 5 to 7% methanol in dichloromethane gave tert-butyl (2S)-2-[({4-[(1-{2-[(3-fluorophenyl)amino]-2-oxoethyl}-1H-pyrazol-4-yl)amino]quinazolin-7-yl}oxy)methyl]pyrrolidine-1-carboxylate (0.332 g, 61% yield) as a light brown solid. extracted with ethyl acetate The organic layer was separated dried over magnesium sulphate evaporated in vacuo to leave a brown oil which was purified by silica gel chromatography Elution with 5 to 7% methanol in dichloromethane

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

実験手順: Methane sulphonyl chloride (0.11 ml, 1.4 mmol) was added to a solution of tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (0.25 g, 1.24 mmol) and 4-(dimethylamino)pyridine (0.167 g, 1.4 mmol) in dichloromethane (5 ml). The mixture was stirred at room temperature for 1 hour and then 4-(dimethylamino)pyridine (0.051 g, 0.42 mmol) and methane sulphonyl chloride (0.033 ml, 0.42 mmol) were added and the mixture stirred at room temperature for a further 1 hour. The mixture was purified directly by silica gel chromatography, eluting with a 3:1 to 1:1 mixture of iso-hexane:ethyl acetate to yield tert-butyl (2S)-2-{[(methylsulphonyl)oxy]methyl}pyrrolidine-1-carboxylate (0.325 g, 94% yield): the mixture stirred at room temperature for a further 1 hour The mixture was purified directly by silica gel chromatography eluting with a 3:1 to 1:1 mixture of iso-hexane