2-[2-(二甲基氨基)乙氧基]乙醇

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). MS: 236 (M+1). Calc'd. for C12H17N3O2—235.29. After the addition the reaction mixture was heated to 70° C. for 2 h DMF was removed in vacuo The residue was partitioned between CH2Cl2/H2O The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo

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

实验步骤: The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 2-(2-(dimethylamino)ethoxy)ethanol as starting materials to give the aimed compound.

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

实验步骤: A magnesium methoxide solution was prepared by dissolving magnesium metal (4 g) in anhydrous methanol (100 ml) in the presence of a small amount of iodine (approximately 0.1 g). A portion of the resulting solution (18 ml) was placed in a 250 ml reaction vessel and then 2-(2-dimethylaminoethoxy)ethanol (23.6 g) was added, followed by the addition of phenothiazine (0.1 g) and methyl methacrylate (117 g). The mixture was stirred and heated until the methanol started to distill. When all of the methanol was collected, the mixture was cooled to room temperature and the solids were filtered off. The filtrate was subjected to fractionation under reduced pressure. The excess of methyl methacrylate was separated and then pure 2-(2-dimethylaminoethoxy)ethyl methacrylate was collected at 97-102° C./4 mmHg. Yield 22.1 g. to distill When all of the methanol was collected the solids were filtered off The excess of methyl methacrylate was separated pure 2-(2-dimethylaminoethoxy)ethyl methacrylate was collected at 97-102° C./4 mmHg

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

实验步骤: A magnesium methoxide solution was prepared by dissolving magnesium metal (4 g) in anhydrous methanol (100 ml) in the presence of a small amount of iodine (approximately 0.1 g). A portion of the resulting solution (18 ml) was placed in a 250 ml reaction vessel and then 2-(2-dimethylaminoethoxy)ethanol (23.6 g) was added, followed by the addition of phenothiazine (0.1 g) and methyl methacrylate (117 g). The mixture was stirred and heated until the methanol started to distill. When all of the methanol was collected, the mixture was cooled to room temperature and the solids were filtered off. The filtrate was subjected to fractionation under reduced pressure. The excess of methyl methacrylate was separated and then pure 2-(2-dimethylaminoethoxy)ethyl methacrylate was collected at 97-102° C./4 mmHg. Yield 22.1 g. to distill When all of the methanol was collected the solids were filtered off The excess of methyl methacrylate was separated pure 2-(2-dimethylaminoethoxy)ethyl methacrylate was collected at 97-102° C./4 mmHg

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). MS: 236 (M+1). Calc'd. for C12H17N3O2−235.29. After the addition the reaction mixture was heated to 70° C. for 2 h DMF was removed in vacuo The residue was partitioned between CH2Cl2/H2O The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). MS: 236 (M+1). Calc'd. for C12H17N3O2—235.29. After the addition the reaction mixture was heated to 70° C. for 2 h DMF was removed in vacuo The residue was partitioned between CH2Cl2/H2O The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). After the addition the reaction mixture was heated to 70° C. for 2 h DMF was removed in vacuo The residue was partitioned between CH2Cl2/H2O The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). After the addition the reaction mixture was heated to 70° C. for 2 h DMF was removed in vacuo The residue was partitioned between CH2Cl2/H2O The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo

反应条件: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a DMF (30 mL) solution of 2-[2-(dimethylamino)ethoxy]ethan-1-ol (3.33 g, 25 mmol) was added NaH (60% in mineral oil, 900 mg, 22.5 mmol, hexane washed) and heated at 50° C. for 2 h. The warm sodium alkoxide solution was added to 2-chloro-4-cyanopyridine (3.12 g, 22.5 mmol) in DMF (10 mL). After the addition, the reaction mixture was heated to 70° C. for 2 h, then DMF was removed in vacuo. The residue was partitioned between CH2Cl2/H2O. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give a light yellow oil (5.6 g). After the addition the reaction mixture was heated to 70° C. for 2 h DMF was removed in vacuo The residue was partitioned between CH2Cl2/H2O The organic layer was washed with brine dried over Na2SO4 concentrated in vacuo

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

实验步骤: In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(2-(dimethylamino)ethoxy)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-dimethylamino-ethoxy)-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C37H42Cl2F2N4O5: (M+): 731. found: 731.

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

实验步骤: In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with 2-(2-(dimethylamino)ethoxy)ethanol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-dimethylamino-ethoxy)-ethyl ester, hydrochloride. MS (ES+) m/z calcd. for C37H42Cl2F2N4O5: (M+): 731. found: 731.

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

实验步骤: The solution of 2-[2-(dimethylamino)-ethoxy]ethanol (6.65 g, 50 mmol, 2.5 equiv.) and 4-dimethylaminopyridine (11 mg) in toluene (20 ml) is cooled to −20° C. Separate solutions of fumaryl chloride (2.3 ml, 20 mmol, 1.0 equiv.) and 1,1,3,3-tetramethylguanidine (5.0 ml, 40 mmol, 2.0 equiv.) in toluene (each 25 ml) are added dropwise simultaneously via syringe pump over 80 min. A dark suspension is formed. After complete addition, the cooling bath is removed and stirring continued at 23° C. for 40 min. Active charcoal (1.0 g) is added and the mixture is filtered over a short pad of basic Al2O3, which is further rinsed with toluene/EtOAc (360 ml). The solution is concentrated and dried in vacuo (0.05 mbar) to yield the product as a yellow oil (2.79 g, 40%). A dark suspension is formed After complete addition the cooling bath is removed Active charcoal (1.0 g) is added the mixture is filtered over a short pad of basic Al2O3, which is further rinsed with toluene/EtOAc (360 ml) The solution is concentrated dried in vacuo (0.05 mbar)