匹维溴铵杂质2

反应条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 5-bromo-2-hydroxypyrimidine (1.00 g, 5.75 mmol) in DMF (19 mL) was added sodium iodide (1.29 g, 8.6 mmol), cesium carbonate (4.68 g, 14.4 mmol), 4-(2-chloroethyl)morpholine hydrochloride (1.18 g, 6.32 mmol) and the reaction mixture was stirred at 60° C. for 2.5 h. The solution was filtered, and the filtrate was concentrated. The residue was purified by flash chromatography, eluting with gradient of methanol (5-15%) in dichloromethane to give title compound 413 (1.29 g, 78% yield). MS (m/z): 288.1 (50%) (M+H), 290.0 (50%) (M+H). 1H NMR (DMSO-d6) δ (ppm): 8.61 (d, J=3.3 Hz, 1H), 8.46 (d, J=3.3 Hz, 1H), 3.93 (t, J=5.9 Hz, 2H), 3.51 (t, J=4.5 Hz, 4H), 2.57 (t, J=6.1 Hz, 2H), 2.45-2.39 (m, 4H). The solution was filtered the filtrate was concentrated The residue was purified by flash chromatography eluting with gradient of methanol (5-15%) in dichloromethane

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

实验步骤: To a solution of 18 (1.8 g, 8.71 mmol) in acetone (80 mL) were added 4-(2-chloroethyl)morpholine hydrochloride (1.95 g, 10.5 mmol), potassium iodide (360 mg, 2.2 mmol) and potassium carbonate (6.0 g, 44.0 mmol), respectively. The reaction mixture was refluxed for 16 h and concentrated. The residue was diluted with water and the aqueous phase was extracted twice with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated to form a residue was purified by flash chromatography on silica gel (EtOAc/CH2Cl2, 50/50 to MeOH/CH2Cl2: 2/98) to afford the title compound 19 (2.7 g, 8.4 mmol, 96% yield). The reaction mixture was refluxed for 16 h concentrated The residue was diluted with water the aqueous phase was extracted twice with EtOAc The combined organic extracts were dried over anhydrous Na2SO4 filtered concentrated to form a residue was purified by flash chromatography on silica gel (EtOAc/CH2Cl2, 50/50 to MeOH/CH2Cl2: 2/98)

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

实验步骤: N-(2-Phenoxyethyl) morpholine was prepared by a modified method of Grail. et al (Journal of American Chemical Society, 1952, 74, 1313-1315). For example, 9.2 g of phenol and 18.6 g of N-(2-chloroethyl)morpholine HCl salt were dissolved in 120 ml of isopropanol and 12 g of potassium hydroxide was added with cooling. The reaction mixture was refluxed for 12 hours. Solid (KCl) was filtered off. The filtrate was distilled off. The residual material was treated with 150 ml of 1N NaOH, then, extracted with dichloromethane (200 ml). Dichloromethane layer was again washed with a solution of 0.1N sodium carbonate in 10% NaCl solution. Dichloromethane layer was dried over anhydrous magnesium chloride, and evaporated under reduced pressure. Residual syrup was dissolved in 100 ml of 1.5N HCl solution, and washed with 100 ml of chloroform. Aqueous layer was treated with 100 ml of toluene and water was removed by Dean-Stark apparatus by distillation. Residual toluene layer was cooled to give crystalline solid, which was collected by filtration. 12 g of N-[(2-phenoxy)ethyl]morpholine HCl salt (50% yield )was obtained. with cooling The reaction mixture was refluxed for 12 hours Solid (KCl) was filtered off The filtrate was distilled off The residual material was treated with 150 ml of 1N NaOH extracted with dichloromethane (200 ml) Dichloromethane layer was again washed with a solution of 0.1N sodium carbonate in 10% NaCl solution Dichloromethane layer was dried over anhydrous magnesium chloride evaporated under reduced pressure Residual syrup was dissolved in 100 ml of 1.5N HCl solution washed with 100 ml of chloroform Aqueous layer was treated with 100 ml of toluene and water was removed by Dean-Stark apparatus by distillation Residual toluene layer was cooled to give crystalline solid, which was collected by filtration

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

实验步骤: 4-(2-Chloro-ethyl)-morpholine hydrochloride (4.2 g, 22 mmol, 1.2 equiv) is added in one portion to a mixture of 4-aminophenol (2 g, 18.3 mmol) and finely powdered sodium hydroxide (1.87 g, 45.8 mmol, 2.5 equiv) in DMF (32 mL), under an argon atmosphere. The reaction mixture is stirred for 23.5 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×60 mL). The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/EtOH, 95:5→7:3) provides the title compound as a yellow-brown solid: API-MS: 223.2 [MH]+; TLC: Rf=0.31 (DCM/EtOH, 9:1). The resulting dark suspension is filtered The filtrate is diluted with DCM (200 ml) washed with brine (2×60 mL) The organic phase is dried (sodium sulfate) filtered concentrated Purification of the residue by silica gel column chromatography (DCM/EtOH, 95:5→7:3)

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

实验步骤: 0.022 g (0.61 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.189 g (1.37 mmol) of potassium carbonate are added, under an inert atmosphere, to 0.3 g (0.55 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid in 8 ml of DMF. After stirring for 18 h at ambient temperature and then for 8 hours at 50° C., the reaction medium is hydrolysed with water, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.61 ml of a 1N aqueous solution of hydrochloric acid is added to 0.334 g of the yellow solid obtained, in 5 ml of methanol. The reaction medium is stirred for 1 hour at ambient temperature. Dyethyl ether is added and then the reaction medium is filtered. The precipitate obtained is rinsed with dyethyl ether and then dried under reduced pressure at 50° C. overnight. 0.298 g of a yellow solid is obtained. for 8 hours at 50° C. extracted with ethyl acetate The organic phase is washed with water dried over sodium sulphate filtered concentrated under reduced pressure The yellow solid obtained is purified by silica gel column chromatography, elution 0.61 ml of a 1N aqueous solution of hydrochloric acid is added to 0.334 g of the yellow solid obtained, in 5 ml of methanol The reaction medium is stirred for 1 hour at ambient temperature the reaction medium is filtered The precipitate obtained is rinsed with dyethyl ether dried under reduced pressure at 50° C. overnight

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

实验步骤: Combine N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide (0.70 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (0.84 mmol), and potassium carbonate (3.36 mmol) in acetone (10 mL), water (4 mL), and dichloromethane (5 mL). Heat to reflux. After 20 hours, cool to ambient temperature and concentrate the reaction mixture invacuo and dilute with ethyl acetate. Extract with saturated aqueous ammonium chloride solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution. Dry the organic layer over MgSO., filter, and concentrate invacuo to give the title compound. Heat to reflux concentrate the reaction mixture invacuo dilute with ethyl acetate Extract with saturated aqueous ammonium chloride solution, water, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution Dry the organic layer over MgSO , filter concentrate invacuo

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

实验步骤: 4-Amino-1-naphthol hydrochloride (40) can be neutralized with a base, such as n-butyl lithium, in a non-protic solvent, such as THF, and reacted with di-tert-butyl dicarbonate ((BOC)2O) at temperatures between −78 −25° C. The product, 4-tert-butyloxycarbonylamino-1-naphthol (41) can be alkylated with 4-(2-chloroethyl)morpholine hydrochloride in a non-protic solvent, such as acetonitrile, with a base, such as powdered potassium carbonate, at temperatures between 60-80° C. Purification of the product 4-tert-butyloxycarbonylamino-1-(2-(morpholin-4-yl)ethoxy)naphthalene (42) can be accomplished by silica gel chromatography. Removal of the BOC-protecting group can be accomplished with HCl in a non-protic solvent, such as dioxane, to furnish 1-amino-4-(2-(morpholin-4-yl)ethoxy)naphthalene (39) as the hydrochloride salt. Purification of the product 4-tert-butyloxycarbonylamino-1-(2-(morpholin-4-yl)ethoxy)naphthalene (42) Removal of the BOC-

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

实验步骤: A mixture of DMSO (6 mL), chloroethylmorpholine hydrochloride (1.23 g, 6.6 mmol), 1-ethyl-6-hydroxy-N- (cyclohexylmethyl) -1H-pyrazolo[3,4-b]quinolin-4-amine (2 g, 6.6 mmol) and KOH (1 g) was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and water and the CH2Cl2 layer was separated and evaporated. The residue was purified by column chromatography on silica gel eluting with 10% ethanol/ethyl acetate to afford the product as the free base. The free base was recrystallized from hot ethyl acetate/hexane to afford 0.425 g of 1-ethyl-6-[2-(4-morpholinyl)ethoxy]-N-(cyclohexylmethyl)-1H-pyrazolo[ 3,4-b]quinolin-4-amine, as a yellow powder, m.p. 176°-178° C. The reaction mixture was partitioned between CH2Cl2 and water the CH2Cl2 layer was separated evaporated The residue was purified by column chromatography on silica gel eluting with 10% ethanol/ethyl acetate to afford the product as the free base The free base was recrystallized from hot ethyl acetate/hexane

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

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131-132° C. was heated at reflux for 24 hours filtered The solvent was concentrated to an oil (~7.1 g) Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131-132° C.

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

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C. was heated at reflux for hours filtered The solvent was concentrated to an oil (~7.1 g) Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C.

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

实验步骤: A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.0 g, 13.6 mmol), 2-chloroethyl morpholine hydrochloride (4.46 g, 29.7 mmol) and K2CO3 (7.3 g, 2.2 eq) in acetonitrile (60 ml) was heated at reflux for 24 hours. The crude mixture was diluted with DCM and filtered. The solvent was concentrated to an oil (~7.1 g). Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product weighing 4 g. Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C. was heated at reflux for 24 hours filtered The solvent was concentrated to an oil (~7.1 g) Purification on a silica gel column (55 g, SiO2, eluted with MeOH:DCM) yielded a solid product Recrystallization from hot ethanol yielded 2.1 g (48%), m.p.=131°-132° C.

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

实验步骤: The title compound was prepared as in Example 30 starting with 0.224 g (1.2 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid with the exception that a total of 0.730 g of cesium carbonate was added to neutralize the hydrochloride. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.40 (t, 2H), 4.10 (t, 2H), 3.70 (app t, 4H), 2.70 (t, 2H), 2.55 (app t, 4H), 1.80 (p, 2H), 1.18-1.55 (m, 22H), 0.89 (t, 3H). was added