甲基2-(二亚甲基氨基)醋酸盐

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dry tetrahydrofuran (250 ml) was cooled to -78° C. Potassium tert-butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino)acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was stirred 30 min at -78° C. Benzoyl chloride (6.59 g; 56.72 mmol) was added dropwise and the reaction mixture was stirred 30 min at -78° C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. The reaction mixture was heated to room temperature and 2/3 of the solvent was removed in vacuo. Water (700 ml) was added and the reaction mixture was washed with diethyl ether (400 ml). The aqueous phase was evaporated in vacuo and the residue was dissolved in methanol and evaporated (2×150 ml). Methanol (80 ml) was added. The mixture was filtrated and the filtrate was evaporated in vacuo. The residue was recrystallised from tetrahydrofuran/diethyl ether to afford 8.86 g of 2-amino-3-oxo-3-phenylpropionic acid methylester as a hydrochloride. added the reaction mixture was stirred 30 min at -78° C The reaction mixture was heated to room temperature 2/3 of the solvent was removed in vacuo Water (700 ml) was added the reaction mixture was washed with diethyl ether (400 ml) The aqueous phase was evaporated in vacuo the residue was dissolved in methanol evaporated (2×150 ml) Methanol (80 ml) was added The mixture was filtrated the filtrate was evaporated in vacuo The residue was recrystallised from tetrahydrofuran/diethyl ether

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

实验步骤: A 500 mL, 1-necked rbf equipped with a magnetic stirrer, and a Dean-Stark apparatus with a nitrogen inlet was charged with benzophenone (58.0 g, 0.318 mol), glycine methyl ester hydrochloride (20 g, 0.159 mol) and toluene (100 mL). The resulting white suspension was heated to reflux and DIEA (56 mL, 0.318 mol) was added over three hours using a syringe pump. The resulting pale yellow solution was stirred at reflux for an additional 1 h. Upon reaction completion, the reaction mixture was cooled to rt. The reaction mixture was then washed with water (50 mL). The layers were separated and the organic solution was washed with water (50 mL) and concentrated in vacuo at 35-40° C. to give (Benzhydrylideneamino)-acetic acid methyl ester (82.59 g). In a similar fashion, (benzhydrylideneamino)-acetic acid ethyl ester was prepared. A 500 mL, 1-necked rbf equipped with a magnetic stirrer The resulting white suspension was heated to reflux at reflux for an additional 1 h Upon reaction completion The reaction mixture was then washed with water (50 mL) The layers were separated the organic solution was washed with water (50 mL) concentrated in vacuo at 35-40° C.

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

实验步骤: Under argon, 15 g (59.2 mmol) of methyl N-(diphenylmethylene)glycinate [described in: WO2010/123792 A1, 2010; pp. 11-13] were initially charged in 127 ml of 1,4-dioxane, the mixture was cooled to 0° C. and 68.1 ml (68.1 mmol) of a 1 N potassium tert-butoxide solution in THF were added. The reaction solution was stirred at 0° C. for 1 h, 21.2 g (78.7 mmol) of 4,4,5,5,5-pentafluoropentyl methanesulphonate [commercially available; additionally described in: H. Kimura et al. Chemistry and Biology 2010, 17, 18-27] were added and the mixture was stirred at 50° C. overnight. The mixture was cooled to RT, 59.2 ml (118.4 mmol) of 2 N hydrochloric acid in diethyl ether and 2.1 ml (118.4 mmol) of water were added and the mixture was stirred vigorously at RT overnight. The reaction mixture was concentrated and the residue was dried under high vacuum. This gave about 17 g of the target compound as a crude mixture which was used without further purification for the next step. Kimura et al. Chemistry and Biology 2010, 17, 18-27] were added the mixture was stirred at 50° C. overnight The mixture was cooled to RT the mixture was stirred vigorously at RT overnight The reaction mixture was concentrated the residue was dried under high vacuum This gave about 17 g of the target compound as a crude mixture which was used without further purification for the next step

反应条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Under argon, 132 g (521.0 mmol) of methyl N-(diphenylmethylene)glycinate [described in: WO2010/123792 A1, 2010, 11-13; additionally: commercially available] were initially charged in 1000 ml of THF (anhydrous) and cooled to −40° C. 625.2 ml (625.2 mmol) of bis(trimethylsilyl)lithium amide (1 M in THF) were added dropwise over 30 min. After 10 min, the cooling bath was replaced by a water/ice bath, and the internal temperature was allowed to increase to 0° C. over a period of 35 min. At 0° C., 192.86 g (651.25 mmol) of 3,3,4,4,4-pentafluorobutyl trifluoromethanesulphonate from Example 132A, dissolved in 400 ml of THF, were added dropwise to the reaction solution. After 10 min, the cooling bath was removed and the mixture was stirred at RT for 3 days. The reaction mixture was then cooled to 0° C., and 410 ml (1.33 mol) of 3 N hydrochloric acid were added dropwise. The cooling bath was removed and the reaction solution was stirred at RT for 2 hours. The mixture was then concentrated. This gave 141.5 g of the target compound as a crude mixture which was used without any further purification for the next step. the cooling bath was replaced by a water/ice bath to increase to 0° C. over a period of 35 min were added dropwise to the reaction solution After 10 min the cooling bath was removed The reaction mixture was then cooled to 0° C. The cooling bath was removed the reaction solution was stirred at RT for 2 hours The mixture was then concentrated This gave 141.5 g of the target compound as a crude mixture which was used without any further purification for the next step

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dry tetrahydrofuran (250 ml) was cooled to −78° C. Potassium tert-butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino) acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was stirred 30 min at −78° C. Benzoyl chloride (6.59 g; 56.72 mmol) was added dropwise and the reaction mixture was stirred 30 min at −78° C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. The reaction mixture was heated to room temperature and 2/3 of the solvent was removed in vacuo. Water (700 ml) was added and the reaction mixture was washed with diethyl ether (400 ml). The aqueous phase was evaporated in vacuo and the residue was dissolved in methanol and evaporated (2×150 ml). Methanol (80 ml) was added. The mixture was filtrated and the filtrate was evaporated in vacuo. The residue was recrystallised from tetrahydrofuran/diethyl ether to afford 8.86 g of 2-amino-3-oxo-3-phenylpropionic acid methylester as a hydrochloride. added the reaction mixture was stirred 30 min at −78° C The reaction mixture was heated to room temperature 2/3 of the solvent was removed in vacuo Water (700 ml) was added the reaction mixture was washed with diethyl ether (400 ml) The aqueous phase was evaporated in vacuo the residue was dissolved in methanol evaporated (2×150 ml) Methanol (80 ml) was added The mixture was filtrated the filtrate was evaporated in vacuo The residue was recrystallised from tetrahydrofuran/diethyl ether

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

实验步骤: A mixture of Zn(OTf)2 (0.064 g, 0.17 mmol) and 6-methoxy-[1,5]naphthyridine-4-carbaldehyde (0.5 g, 2.6 mmol) and molecular sieves (4 Å, 0.66 g) in toluene (13 mL) at 0° C. was treated with (benzhydrylidene-amino)-acetic acid methyl ester (0.44 g, 1.7 mmol) and diallylamine (0.25 g, 1.7 mmol). The mixture was left at 4° C. over the weekend. The reaction was quenched by careful addition of Na2CO3 and filtered. The filtrate was diluted with EA and water and the 2 phases separated. The org. phase was dried over MgSO4 and concentrated. The residue was dissolved in MeOH (10 mL) and AcOH (0.175 g, 3 mmol) and NaCNBH3 (0.166 g, 2.6 mmol) was added. The mixture was stirred at rt overnight and partitioned between a NaHCO3 solution and EA. The org. phase was dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 1:1) gave the title intermediate as a yellow oil (0.5 g, 64% yield). The mixture was left at 4° C. over the weekend The reaction was quenched by careful addition of Na2CO3 filtered The filtrate was diluted with EA and water the 2 phases separated phase was dried over MgSO4 concentrated The residue was dissolved in MeOH (10 mL) partitioned between a NaHCO3 solution and EA phase was dried over MgSO4 concentrated

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

实验步骤: Potassium tert-butylate (17.8 g, 157.9 mmol) was introduced into THF (120 ml), and a solution of N-diphenylmethylideneglycine methyl ester (40 g, 157.9 mmol) in THF (60 ml) was added at −70° C. After the yellowish solution had been stirred for 30 minutes at this temperature, it was added dropwise at −70° C. to a solution of acetyl chloride (12.4 g, 157.9 mmol) in THF (70 ml). After the mixture had been stirred at this temperature for 1.75 hours, 3N HCl (160 ml) was added, and the yellowish suspension was stirred for a further 10 minutes at room temperature. The THF was removed at room temperature on a rotary evaporator, and the remaining aqueous phase was washed 3× with diethyl ether. The aqueous phase was freeze-dried and the residue was extracted by stirring with methanol. The methanolic solution of the product was concentrated on a rotary evaporator at 35° C. Yield: 26.4 g (157.9 mmol, quant., yellowish solid). After the mixture had been stirred at this temperature for 1.75 hours the yellowish suspension was stirred for a further 10 minutes at room temperature The THF was removed at room temperature on a rotary evaporator the remaining aqueous phase was washed 3× with diethyl ether The aqueous phase was freeze-dried the residue was extracted by stirring with methanol The methanolic solution of the product was concentrated on a rotary evaporator at 35° C

反应条件: temp:-40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 132 g (521.0 mmol) of methyl N-(diphenylmethylene)glycinate [described in: WO2010/123792 A1, 2010; p. 11-13] were initially charged in 1000 ml of THF (anhydrous) under argon and cooled to −40° C. 625.2 ml (625.20 mmol) of bis(trimethylsilyl)lithium amide (1 M in THF) were added dropwise within 30 min. After 10 min at −40° C., the internal temperature was allowed to rise to 0° C. within 35 min 192.86 g (651.25 mmol) of 3,3,4,4,4-pentafluorobutyl trifluoromethanesulphonate from Example 24A, dissolved in 400 ml of THF, were added dropwise to the reaction solution at 0° C. After 10 min, the cooling bath was removed and the mixture was stirred at RT for 3 days. Subsequently, the reaction mixture was cooled to 0° C. and 410 ml (1.33 mol) of 3 N aqueous hydrochloric acid were added dropwise. The cooling bath was removed and the reaction mixture was stirred at RT for two hours. The mixture was subsequently concentrated. This gave 141.5 g of the target compound as a crude mixture (purity unknown), which was used in the subsequent stage without further purification. to rise to 0° C. within 35 min were added dropwise to the reaction solution at 0° C After 10 min the cooling bath was removed Subsequently, the reaction mixture was cooled to 0° C. The cooling bath was removed the reaction mixture was stirred at RT for two hours The mixture was subsequently concentrated This gave 141.5 g of the target compound as a crude mixture (purity unknown), which was used in the subsequent stage without further purification

反应条件: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dry tetrahydrofuran (250 ml) was cooled to -78° C. Potassium tert-butoxide (6.37 g; 56.72 mmol) was dissolved in dry tetrahydrofuran (100 ml) and added. (Benzhydrylideneamino)acetic acid methyl ester (14.35 g; 56.72 mmol) was added and the reaction mixture was stirred 30 min at -78° C. Benzoyl chloride (6.59 g; 56.72 mmol) was added dropwise and the reaction mixture was stirred 30 min at -78° C. Hydrochloric acid (1.0 M; 175 ml) was added dropwise. The reaction mixture was heated to room temperature and 2/3 of the solvent was removed in vacuo. Water (700 ml) was added and the reaction mixture was washed with diethyl ether (400 ml). The aqueous phase was evaporated in vacuo and the residue was dissolved in methanol and evaporated (2×150 ml). Methanol (80 ml) was added. The mixture was filtrated and the filtrate was evaporated in vacuo. The residue was recrystallised from tetrahydrofuran/diethyl ether to afford 8.86 g of 2-amino-3-oxo-3-phenylpropionic acid methylester as a hydrochloride. added the reaction mixture was stirred 30 min at -78° C The reaction mixture was heated to room temperature 2/3 of the solvent was removed in vacuo Water (700 ml) was added the reaction mixture was washed with diethyl ether (400 ml) The aqueous phase was evaporated in vacuo the residue was dissolved in methanol evaporated (2×150 ml) Methanol (80 ml) was added The mixture was filtrated the filtrate was evaporated in vacuo The residue was recrystallised from tetrahydrofuran/diethyl ether