法匹拉韦杂质17

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-BOC-piperidin-3-one (4.0 g, 20 mmol) was added to a mixture of 5-bromo-2-hydroxybenzamide (2.0 g, 9.2 mmol) and pyrrolidine (0.76 ml, 9.2 mmol) in MeOH (7.5 ml), and the reaction mixture was heated to 70° C. by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3) to give (±)-6-bromo-3,4-dihydro-4-oxo-spiro-[2H-(1,3)-benzoxazine-2,3′-piperidine]-1′-carboxylic acid tert-butyl ester (2.50 g) as a yellow solid. The solution was then concentrated under vacuum the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 5-bromo salicylamide (2.5 g, 11.6 mmol), N—BOC-4-piperidone (2.30 g, 11.6 mmol) and pyrrolidine (0.96 ml, 11.6 mmol) in toluene (40 ml) was heated to reflux under N2 atmosphere. After 3 h, the mixture was cooled down to RT, poured into water and extracted with AcOEt. The organic phase was washed with a 2 M solution of NaOH (150 ml) and then with 2 M HCl (150 ml), dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH 90/10 as eluent, to give 1.82 g of 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester as a white solid (40%). Reaction with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, gave (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.3 g, 71%) as a yellow solid. was heated to reflux under N2 atmosphere extracted with AcOEt The organic phase was washed with a 2 M solution of NaOH (150 ml) with 2 M HCl (150 ml), dried over Na2SO4 filtered the solvent was evaporated under vacuum The crude mixture was purified by column chromatography

反应条件: temp:72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Three batches of 5-bromo salicylamide (5.00 g each, 23.1 mmol), N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) and pyrrolidine (1.64 g, 23.1 mmol) were heated in different flasks at 72° C. under MW irradiation for 1 h. Further N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) was added and the mixtures were heated for 1 h at 72° C. The resulting precipitates were collected by filtration and washed with MeOH to give 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester (17.2 g) as a white solid. The resulting precipitates were collected by filtration washed with MeOH

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 5-bromo salicylamide (2.5 g, 11.6 mmol), N—BOC-4-piperidone (2.30 g, 11.6 mmol) and pyrrolidine (0.96 ml, 11.6 mmol) in toluene (40 ml) was heated to reflux under N2 atmosphere. After 3 h, the mixture was cooled down to RT, poured into water and extracted with AcOEt. The organic phase was washed with a 2 M solution of NaOH (150 ml) and then with 2 M HCl (150 ml), dried over Na2SO4, filtered and the solvent was evaporated under vacuum. The crude mixture was purified by column chromatography using DCM/MeOH 90/10 as eluent, to give 1.82 g of 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester as a white solid (40%). Reaction with methyl acrylate according to the procedure for preparation of Intermediate 1, Step B, gave (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (1.3 g, 71%) as a yellow solid. was heated to reflux under N2 atmosphere extracted with AcOEt The organic phase was washed with a 2 M solution of NaOH (150 ml) with 2 M HCl (150 ml), dried over Na2SO4 filtered the solvent was evaporated under vacuum The crude mixture was purified by column chromatography

反应条件: temp:72.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Three batches of 5-bromo salicylamide (5.00 g each, 23.1 mmol), N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) and pyrrolidine (1.64 g, 23.1 mmol) were heated in different flasks at 72° C. under MW irradiation for 1 h. Further N-Boc-piperidin-4-one (3.45 g, 17.3 mmol) was added and the mixtures were heated for 1 h at 72° C. The resulting precipitates were collected by filtration and washed with MeOH to give 6-bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester (17.2 g) as a white solid. The resulting precipitates were collected by filtration washed with MeOH

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1H), 7.54 (m, 2H), 6.97 (d, J=12 Hz, 1H), 6.00 (broad, 2H). trap/reflux condenser that After heated to reflux for 2 days concentrated to give a pale yellow oil After the reaction complete it was concentrated to give a white solid The crude solid was washed with small amount of EtOAc and hexane

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1 H), 7.54 (m, 2 H), 6.97 (d, J=12 Hz, 1 H), 6.00 (broad, 2 H). trap/reflux condenser that After heated to reflux for 2 days concentrated to give a pale yellow oil After the reaction complete it was concentrated to give a white solid The crude solid was washed with small amount of EtOAc and hexane

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 5-bromo-2-hydroxybenzamide (2.16 g, 10 mol) and NaBH4 (1.52 g, 40 mol) are dissolved in dry THF (150 ml) in a two-neck septum capped round-bottom flask. Iodine (5.06 g, 20 mol)) in dry THF is added under nitrogen atmosphere at 0° C. over 2.5 hours. The reaction mixture is refluxed for 3 hours and then cooled to 0° C. The excess hydride is destroyed by careful addition of 1N HCl. After removing most organic solvent by vacuum, the acidic aqueous solution is diluted in 1N HCl (150 ml) and washed three times with ether (30 ml each time). The pH of the aqueous solution is adjusted to pH=6-7 by careful addition of sodium bicarbonate solid. The product is collected by filtration and then washed with water. The product is further dried in vacuum oven overnight giving 2-(aminomethyl)-4-bromophenol which is used directly in the next step without further purification. capped round-bottom flask The reaction mixture is refluxed for 3 hours The excess hydride is destroyed by careful addition of 1N HCl After removing most organic solvent by vacuum the acidic aqueous solution is diluted in 1N HCl (150 ml) washed three times with ether (30 ml each time) The pH of the aqueous solution is adjusted to pH=6-7 by careful addition of sodium bicarbonate solid The product is collected by filtration washed with water The product is further dried in vacuum oven overnight

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1H), 7.54 (m, 2H), 6.97 (d, J=12 Hz, 1H), 6.00 (broad, 2H). trap/reflux condenser that After heated to reflux for 2 days concentrated to give a pale yellow oil After the reaction complete it was concentrated to give a white solid The crude solid was washed with small amount of EtOAc and hexane

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-BOC-piperidin-3-one (4.0 g, 20 mmol) was added to a mixture of 5-bromo-2-hydroxybenzamide (2.0 g, 9.2 mmol) and pyrrolidine (0.76 ml, 9.2 mmol) in MeOH (7.5 ml), and the reaction mixture was heated to 70° C. by MW (closed vessel) for 5 h. The solution was then concentrated under vacuum and the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3) to give (±)-6-bromo-3,4-dihydro-4-oxo-spiro-[2H-(1,3)-benzoxazine-2,3′-piperidine]-1′-carboxylic acid tert-butyl ester (2.50 g) as a yellow solid. The solution was then concentrated under vacuum the crude mixture was purified by column chromatography on silica gel (eluent: DCM/EtOAc 7:3)