4-methylidenemorpholin-4-ium;chloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+. is heated at reflux for 2 hours Upon cooling this solution is partitioned between ethyl acetate (50 mL) and water (50 mL) The organic layer is washed with brine dried over Na2SO4 filtered concentrated to give a pink oil Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of DMF (50 mL) was added (4-aminopyrrolo[2,1-f][1,2,4]triazin-6-yl)methanol (550 mg, 3.35 mmol) and 4-methylenemorpholin-4-ium chloride (Eur. J. Med. Chem. 1989, 24, 379-384) (636 mg, 4.69 mmol). The solution was stirred at rt for 1 h and then the solvent was evaporated. The oil was triturated with CH2Cl2 and a white solid was collected. The free based was obtained by stirring over a Dowex 66 solid support resin in MeOH. The material was filtered and evaporated yielding 794 mg (90%) of the desired product as a white solid. MS [M+H]+=264; LCMS RT=1.07. the solvent was evaporated The oil was triturated with CH2Cl2 a white solid was collected The free based was obtained The material was filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin-4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+. is heated at reflux for 2 hours Upon cooling this solution is partitioned between ethyl acetate (50 mL) and water (50 mL) The organic layer is washed with brine dried over Na2SO4 filtered concentrated to give a pink oil Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.08 g 1-(4-fluorophenyl)-1,4-di -hydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (Example 1 h), 0.45 g N-methylenemorpholinium chloride and 10 ml DMF was heated at 100° C. for 15 min. The reaction mixture was cooled, poured into 100 ml water and the pH adjusted to 8 with saturated sodium bicarbonate solution. The solid precipitate was collected, dried and recrystallized from an acetonitrile -chloroform mixture to give 0.90 g N-(4-morpholinylmethyl)-1-(4-fluorophenyl)1,4 -dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide, m.p. 258-260° C. The reaction mixture was cooled The solid precipitate was collected dried recrystallized from an acetonitrile -chloroform mixture

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.08 g 1-(4-fluorophenyl)-1,4-di -hydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (Example 1 h), 0.45 g N-methylenemorpholinium chloride and 10 ml DMF was heated at 100° C. for 15 min. The reaction mixture was cooled, poured into 100 ml water and the pH adjusted to 8 with saturated sodium bicarbonate solution. The solid precipitate was collected, dried and recrystallized from an acetonitrile -chloroform mixture to give 0.90 g N-(4-morpholinylmethyl)-1-(4-fluorophenyl)1,4 -dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide, m.p. 258-260° C. The reaction mixture was cooled The solid precipitate was collected dried recrystallized from an acetonitrile -chloroform mixture

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+. is heated at reflux for 2 hours Upon cooling this solution is partitioned between ethyl acetate (50 mL) and water (50 mL) The organic layer is washed with brine dried over Na2SO4 filtered concentrated to give a pink oil Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(4-chlorobenzyl)-4-hydroxy-1-benzothiophene-5-carboxamide (Preparation 14, 0.15 g), 4-methylenemorpholin4-ium chloride (0.13 g), and anhydrous acetonitrile (5 mL) is heated at reflux for 2 hours. Upon cooling, a saturated solution of sodium bicarbonate is added until the pH=9 and this solution is partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated to give a pink oil. Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL) affords 140 mg (76%) of the title compound as a white solid. Physical characteristics: Mp 200° C.; MS (ESI+) for C21H21ClN2O3S m/z 417 (M+H)+. is heated at reflux for 2 hours Upon cooling this solution is partitioned between ethyl acetate (50 mL) and water (50 mL) The organic layer is washed with brine dried over Na2SO4 filtered concentrated to give a pink oil Chromatography on a Biotage column eluting with 20% ethyl acetate in heptane (250 mL) and 50% ethyl acetate in heptane (500 mL)

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ethyl 4-hydroxy-3-methylthieno[2,3-b]pyridine-5-carboxylate (Preparation 26, 0.92 g) and 4-methylenemorpholin-4-ium chloride (1.57 g) in acetonitrile (40 mL) is heated to 60° C. for 4 h. The resulting suspension is allowed to cool to room temperature, poured into water, and adjusted to neutral pH with saturated aq. sodium bicarbonate. The solution is extracted with CH2Cl2 (3×100 mL). The combined organic layers are washed with brine (25 mL), dried (Na2SO4), and concentrated to afford 1.26 g of the title compound as a yellow solid. Physical characteristics. M.p. 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.64, 4.37, 3.70, 3.38, 2.51, 2.47, 1.35; MS (ESI−) m/z 335 (M-H). Anal. Found. C, 56.93; H, 6.10; N, 8.26; S, 9.34. to cool to room temperature The solution is extracted with CH2Cl2 (3×100 mL) The combined organic layers are washed with brine (25 mL) dried (Na2SO4) concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of ethyl 4-hydroxy-3-methylthieno[2,3-b]pyridine-5-carboxylate (Preparation 26, 0.92 g) and 4-methylenemorpholin-4-ium chloride (1.57 g) in acetonitrile (40 mL) is heated to 60° C. for 4 h. The resulting suspension is allowed to cool to room temperature, poured into water, and adjusted to neutral pH with saturated aq. sodium bicarbonate. The solution is extracted with CH2Cl2 (3×100 mL). The combined organic layers are washed with brine (25 mL), dried (Na2SO4), and concentrated to afford 1.26 g of the title compound as a yellow solid. Physical characteristics. M.p. 182-185° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.64, 4.37, 3.70, 3.38, 2.51, 2.47, 1.35; MS (ESI−) m/z 335 (M-H). Anal. Found. C, 56.93; H, 6.10; N, 8.26; S, 9.34. to cool to room temperature The solution is extracted with CH2Cl2 (3×100 mL) The combined organic layers are washed with brine (25 mL) dried (Na2SO4) concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(3-tert-butoxycarbonyl-thien-2-yl)-methylaminomethylene-malonic acid diethyl ester (19.0 g) from Preparation No. 2 and 4-methylene morpholinium chloride (Dimmock, JR, et al Eur. J. Med. Chem. 1989, 24, 379-383) (13.4 g) in dry acetonitrile (50 ml) is heated at reflux for about 4 hr. The solution is then cooled in an ice bath and saturated aqueous sodium carbonate (98 ml) is slowly added. The solution is extracted three times with ethyl acetate (300 ml total) and the combined organic layers are then washed three times with water (600 ml total). The solvents are removed in vacuo to afford 23.0 g (96%) of the title compound as a brown oil. from Preparation No at reflux for about 4 hr The solution is then cooled in an ice bath The solution is extracted three times with ethyl acetate (300 ml total) the combined organic layers are then washed three times with water (600 ml total) The solvents are removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(3-tert-butoxycarbonyl-thien-2-yl)-methylaminomethylene-malonic acid diethyl ester (19.0 g) from Preparation No. 2 and 4-methylene morpholinium chloride (Dimmock, JR, et al Eur. J. Med. Chem. 1989, 24, 379-383) (13.4 g) in dry acetonitrile (50 ml) is heated at reflux for about 4 hr. The solution is then cooled in an ice bath and saturated aqueous sodium carbonate (98 ml) is slowly added. The solution is extracted three times with ethyl acetate (300 ml total) and the combined organic layers are then washed three times with water (600 ml total). The solvents are removed in vacuo to afford 23.0 g (96%) of the title compound as a brown oil. from Preparation No at reflux for about 4 hr The solution is then cooled in an ice bath The solution is extracted three times with ethyl acetate (300 ml total) the combined organic layers are then washed three times with water (600 ml total) The solvents are removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(3-tert-butoxycarbonyl-thien-2-yl)-methylaminomethylene-malonic acid diethyl ester (19.0 g) from Preparation No. 2 and 4-methylene morpholinium chloride (Dimmock, JR, et al Eur. J. Med. Chem. 1989, 24, 379-383) (13.4 g) in dry acetonitrile (50 ml) is heated at reflux for about 4 hr. The solution is then cooled in an ice bath and saturated aqueous sodium carbonate (98 ml) is slowly added. The solution is extracted three times with ethyl acetate (300 ml total) and the combined organic layers are then washed three times with water (600 ml total). The solvents are removed in vacuo to afford 23.0 g (96%) of the title compound as a brown oil. from Preparation No at reflux for about 4 hr The solution is then cooled in an ice bath The solution is extracted three times with ethyl acetate (300 ml total) the combined organic layers are then washed three times with water (600 ml total) The solvents are removed in vacuo