3,3-diethoxypropanoic acid

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (9.01 g, 32.9 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), 4-methylmorpholine (4.34 mL, 39.4 mmol), and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in pyridine (200 mL) was chilled in an ice-water under a nitrogen atmosphere. The mixture was treated drop-wise with a solution of 3,3-diethoxypropionic acid (6.40 g, 39.4 mmol) in pyridine (50 mL). The reaction was allowed to slowly come to ambient temperature and stirred overnight. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a dark red solid. The solid was dissolved in chloroform (150 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 13.75 g of crude tert-butyl N′-[3-(3,3-diethoxypropionylamino)quinolin-4-yl]hydrazinecarboxylate as a dark red solid. to slowly come to ambient temperature After 15 h the reaction mixture was concentrated under reduced pressure to yield a dark red solid transferred to a separatory funnel The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL) dried over Na2SO4 filtered concentrated under reduced pressure

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Small pellets of solid NaOH (5.00 g, 125 mmol) were slowly added to a mixture of ethyl 3,3-diethoxypropionate (19.02 g, 100 mmol) and water (35 mL). As the NaOH dissolved the mixture became a homogeneous solution. The solution was heated to 110° C. for 30 min. The reaction was allowed to cool to ambient temperature and then chilled with an ice-water bath. The solution was acidified with drop-wise addition of concentrated aqueous HCl (9.37 mL, 113 mmol). The solution was allowed to warm to ambient temperature and then extracted with dichloromethane (4×15 mL). The combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to yield 15.11 g of 3,3-diethoxypropionic acid as a yellow oil. to cool to ambient temperature chilled with an ice-water bath to warm to ambient temperature extracted with dichloromethane (4×15 mL) The combined organic extracts were washed with brine (15 mL) dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: To a 250 mL round-bottomed flask with magnetic stirring that contained ethyl 3,3-diethoxypropanoate (20.0 g, 102.0 mmol, colourless oil, 97%), a previously prepared solution of NaOH (5.23 g, 131.0 mmol) in H2O (30 mL) was added. The resulting mixture was stirred to reflux (100° C.) during 1 h. After allowing it to temper, the mixture was acidified using HCl 37% and it was extracted with AcOEt, 8×20 mL. The resulting organic phase was washed with 1×20 mL NaCl sat., dried with Na2SO4, filtered and concentrated to dryness. The obtained oil was confirmed to correspond to the title compound (15.9 g, 98.0 mmol, 96%). The resulting mixture was stirred was extracted with AcOEt, 8×20 mL The resulting organic phase was washed with 1×20 mL NaCl sat. dried with Na2SO4 filtered concentrated to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified. The mixture obtained After returning to ambient temperature After concentration the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution The mixture is stirred vigorously until no more gas After separation of the phases the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine After drying over MgSO4 concentrating to dryness

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 16 mL of 3-ethoxy-3-oxomalonic acid (135 mmol) in 40 mL of tetrahydrofuran there are added, under argon, 21.9 g of powdered magnesium (90.4 mmol). The mixture obtained is then heated at 80° C. for 7 hours. After returning to ambient temperature, this mixture is transferred by cannula to a solution of 10 g of the compound obtained in Step A (61.7 mmol) in 64 mL of tetrahydrofuran to which there has previously been added, in portions, 11 g of carbonyldiimidazole (66 mmol). The reaction mixture is stirred for 3 days at ambient temperature. After concentration, the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution. The mixture is stirred vigorously until no more gas is evolved. After separation of the phases, the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified. The mixture obtained After returning to ambient temperature After concentration the residue is taken up in a mixture of ethyl acetate and aqueous sodium hydrogen sulphate (NaHSO4) solution The mixture is stirred vigorously until no more gas After separation of the phases the organic phase is washed successively with water, saturated aqueous NaHCO3 solution and finally brine After drying over MgSO4 concentrating to dryness

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

Procedure: To a solution of 25 g of ethyl 3,3-diethoxypropionate (131 mmol) in 79 mL of methanol there are added 13.1 mL of aqueous 35% sodium hydroxide solution (452 mmol). The reaction mixture is stirred at ambient temperature for 3 hours. The reaction mixture is then concentrated to remove the methanol. After dissolving the undissolved material by adding water, aqueous 5N HCl solution is added to obtain a pH of 5. Dichloromethane is added and then the organic phase is washed with brine. After drying over MgSO4 and concentrating to dryness, the title product is obtained in the form of an oil which is used in the next Step without being otherwise purified. The reaction mixture is then concentrated to remove the methanol After dissolving the undissolved material by adding water, aqueous 5N HCl solution is added to obtain a pH of 5 the organic phase is washed with brine After drying over MgSO4 concentrating to dryness

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 3,3-diethoxypropanoate (4.2 g, 22.0 mmol, 1 eq) and NaOH (1.1 g, 28 mmol, 1.3 eq) in water (8 mL) was heated in a 110° C. oil bath for 1.25 h. The reaction was then cooled to 0° C. and was stirred with concentrated HCl (2.3 mL) and EtOAc (20 mL). The organic layer was saved, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and evaporated to afford 3,3-diethoxypropanoic acid (3.41 g, 96% yield) as an orange oil, which was used in the next step without any further purification. the aqueous layer was extracted with CH2Cl2 The combined organic layers were dried over MgSO4 filtered evaporated

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of ethyl 3,3-diethoxypropanoate (4.2 g, 22.0 mmol, 1 eq) and NaOH (1.1 g, 28 mmol, 1.3 eq) in water (8 mL) was heated in a 110° C. oil bath for 1.25 h. The reaction was then cooled to 0° C. and was stirred with concentrated HCl (2.3 mL) and EtOAc (20 mL). The organic layer was saved, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and evaporated to afford 3,3-diethoxypropanoic acid (3.41 g, 96% yield) as an orange oil, which was used in the next step without any further purification. the aqueous layer was extracted with CH2Cl2 The combined organic layers were dried over MgSO4 filtered evaporated

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

Procedure: A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (9.01 g, 32.9 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), 4-methylmorpholine (4.34 mL, 39.4 mmol), and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in pyridine (200 mL) was chilled in an ice-water under a nitrogen atmosphere. The mixture was treated drop-wise with a solution of 3,3-diethoxypropionic acid (6.40 g, 39.4 mmol) in pyridine (50 mL). The reaction was allowed to slowly come to ambient temperature and stirred overnight. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a dark red solid. The solid was dissolved in chloroform (150 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 13.75 g of crude tert-butyl N′-[3-(3,3-diethoxypropionylamino)quinolin-4-yl]hydrazinecarboxylate as a dark red solid. to slowly come to ambient temperature After 15 h the reaction mixture was concentrated under reduced pressure to yield a dark red solid transferred to a separatory funnel The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL) dried over Na2SO4 filtered concentrated under reduced pressure

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

Procedure: A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (9.01 g, 32.9 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.56 g, 39.4 mmol), 4-methylmorpholine (4.34 mL, 39.4 mmol), and 4-dimethylaminopyridine (0.200 g, 1.64 mmol) in pyridine (200 mL) was chilled in an ice-water under a nitrogen atmosphere. The mixture was treated drop-wise with a solution of 3,3-diethoxypropionic acid (6.40 g, 39.4 mmol) in pyridine (50 mL). The reaction was allowed to slowly come to ambient temperature and stirred overnight. After 15 h, the reaction mixture was concentrated under reduced pressure to yield a dark red solid. The solid was dissolved in chloroform (150 mL) and transferred to a separatory funnel. The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 13.75 g of crude tert-butyl N′-[3-(3,3-diethoxypropionylamino)quinolin-4-yl]hydrazinecarboxylate as a dark red solid. to slowly come to ambient temperature After 15 h the reaction mixture was concentrated under reduced pressure to yield a dark red solid transferred to a separatory funnel The organic solution was washed with 10% Na2CO3 aqueous solution (35 mL), water (2×35 mL), and brine (35 mL) dried over Na2SO4 filtered concentrated under reduced pressure