Ethyl 4-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethoxy]-3-oxobutanoate

a, 2400 ml of tetrahydrofuran was charged into the reaction flask A, and the mixture was cooled to -10 °C or less, 750 g of N-hydroxyethyl phthalimide and 345 g of NaH were added successively (while stirring at a low speed, N-hydroxyethyl phthalimide, NaH added to the beginning of the dropwise addition of ethyl 4-chloroacetoacetate time interval within 30min); the reaction flask temperature down to -10 ° C below, 732 g of ethyl 4-chloroacetoacetate was added slowly dropwise, and the temperature was controlled below 0 °C and the addition was completed in 1.5 to 2 hours. The temperature was raised to 28 to 32 °C. After 5 to 6 hours of reaction, 1500 ml of toluene was added, The temperature dropped below 5 °C to give a toluene dilution of the reaction solution; b, add 1700 ml of toluene, 2800 ml of water and 1178 g of acetic acid to the reaction flask B at a temperature below 5 °C; add the toluene dilution of the above reaction solution with 1 to 1.5 h at a temperature below 10 °C; After stirring for 10 min, the mixture was allowed to stand for 15 min, and the aqueous layer was removed. The toluene layer was washed 5 times with a mass fraction of 4percent brine (2500 ml each). After the washed toluene solution was added anhydrous magnesium sulfate, And the toluene solution was concentrated under reduced pressure to remove toluene (the amount of toluene removed was 2700 ml or more and the toluene content was not more than a predetermined value) to give ethyl-4- (2-phthalimidoethoxy) acetoacetate in a yield of 93percentPreparation of Ethyl 4-[2-(PHTHALIMIDO) ETHOXY] ACEFOACETATE (X1 A 250 mL two-necked flask, equipped with a magnetic stirring bar, thermometer and a pressure equalized addition funnel was charged with 75 mL of tetrahydrofuran under nitrogen atmosphere. 7.53 g Sodium hydride (60percent dispersed in oil) was added and the resulting suspension was cooled to-10 °C and 20 g of N- (2-HYDROXYETHYL) PHTHALIMIDE was added slowly over 5 minutes. The resulting slurry was stirred at-10 °C for 30 minutes. To this mixture a solution of 16.35 g ethyl 4-chloroacetoacetate in 30 ML of TETRAHYDRAFURAN was added at-10 °C in 40 minutes. The reaction mixture was warmed to room temperature and then stirred at room temperature for 18 hours. The reaction mixture was placed in an ice bath and quenched by dropwise addition of 10 mL ethanol. The mixture was then poured into 150 mL of IN hydrochloric acid solution in crushed ice and 200 ML of ethyl acetate was added. The resulting mixture was transferred into a separatory funnel and the aqueous phase was separated. The organic phase was first washed with 70 mL of ethyl acetate was added. The resulting mixture was transferred into a separatory funnel and the aqueous phase was separated. The organic phase was first washed with 70 mL of 5 wt. percent OF NAHC03 solution, then with 150 ML of water, dried over 5 G of MgS04. MgS04 was filtered off and the filtrate was concentrated in vacuo to give a light brown oily product. The oil was washed with 15 mL of hexane to remove the mineral oil to give 17.2 g of ethyl 4- [2- (phthalimido) ethoxy] acetoacetate light brown product. (yield 51percent, rel. compound purity > 80percent). IR (KBR, CM~L) : 2995 and 1716. 1H-NMR (CDC13) 6 7.76 (dd, 2H), 7.65 (dd, 2H), 4.11 (S, 2H), 4.02 (q, 2H), 3.80 (t, 2H), 3.70 (t, 2H), 3.37 (s, 2H), 1. 16 (t, 3H). 13C-NMR (CDC13) 8 201.7, 168.4, 167.2, 134.3, 132.2, 123.5, 75.6, 68.7, 61.6, 46.0, 37.4, 14.3.Example 7 : 2-({2-[2-(4-{(2S)-2-Hydroxy-3-[(methylethyl)amino]propoxy}phenoxy) acetylamino] ETHOXY} METHYL)-4-(2-CHLOROPHENYL)-5-CYANO-6-METLLYL-1, 4- dihydropyridine-3-carboxylate is synthesized according to Scheme VI. SCHEME VI 0 Ho- p OEt HO out C1 Ni C1 Me NC Me N N CHO CHO ci NC Me H 0 1. acetone, II. -- . HO /O 2. II wEthyl 4- [2-FL, 3-DIOXOISOMDOLM-2-YDETHOXY1-3-OXOBUTANOATE. A solution of 2- (2- hydroxyethyl) isoindoline-1, 3-dione (10 g; 52.31 mmol) in DMF (150 ml) is cooled to 0°C and treated with 1. 1 equivalents of a 60percent dispersion of sodium hydride in mineral oil. After gas evolution has ceased, ethyl 4-chloro-3-oxobutanoate (7.75 g; 47.08 mmol) in 20 ml of DMF is added drop-wise, and the resulting solution is stirred overnight at room temperature. The pH of the mixture is then adjusted to 6-7 by the addition of 1 N HC1, and the product is partitioned between H2O and EtOAc. The aqueous phase is extracted again with EtOAc, and the combined organic phases are washed with water and brine, dried over magnesium sulfate, and concentrated to a crude residue, which is purified on a silica gel column, eluting with 25percent EtOAc in hexane to obtain 7.52 g (23.54 mmol ; 50percent) of the product as an oil.To a mechanically stirred suspension of NaH (15g, 0. 375 mol, 60percent dispersion in mineral oil) in THF (250 mL) and DMF (25 mL) was added N- (2-hydroxyethyl)-phtalimide (43g, 0. 225 mol). The mixture was stirred at room temperature for about 4 h and then cooled to about 0°C in an ice bath. Ethyl-4- chloroacetate (21. 4 mL, 0. 15 mol) in THF (4 mL) was then added via an addition funnel over a period of about 0. 5 h and the resulting mixture allowed to stir overnight. The mixture was then poured into a 2 L sepratory funnel containing 500 mL ice water and 700 mL EtOAc and separated. The organic layer was washed 2x with 500 mL of water and dried over MGS04. The solution was then filtered through a 4-inch plug of silica and then CONCENTRATED IN VACUO. The resulting yellow oil was then dissolved in 250 mL CH3CN and washed 2x with 30 mL hexane. The CH3CN layer was the concentrated in vacuo to yield 19. 4g (40. 5percent) OF 4- [2- (1, 3-DIOXO-1, 3-DIHYDRO-ISOINDOL-2-YL)-ETHOXY]-3-OXO-BUTYRIC acid ethyl ester as a yellow oil. This crude compound was used for the next stepTo a mechanically stirred suspension of NaH (15g, 0. 375 mol, 60percent dispersion in mineral oil) in THF (250 mL) and DMF (25 mL) was added N- (2-hydroxyethyl)-phtalimide (43g, 0. 225 mol). The mixture was stirred at room temperature for about 4 h and then cooled to about 0°C in an ice bath. Ethyl-4- chloroacetate (21. 4 mL, 0. 15 mol) in THF (4 mL) was then added via an addition funnel over a period of about 0. 5 h and the resulting mixture allowed to stir overnight. The mixture was then poured into a 2 L sepratory funnel containing 500 mL ice water and 700 mL EtOAc and separated. The organic layer was washed 2x with 500 mL of water and dried over MGS04. The solution was then filtered through a 4-inch plug of silica and then CONCENTRATED IN VACUO. The resulting yellow oil was then dissolved in 250 mL CH3CN and washed 2x with 30 mL hexane. The CH3CN layer was the concentrated in vacuo to yield 19. 4g (40. 5percent) OF 4- [2- (1, 3-DIOXO-1, 3-DIHYDRO-ISOINDOL-2-YL)-ETHOXY]-3-OXO-BUTYRIC acid ethyl ester as a yellow oil. This crude compound was used for the next stepInto the reaction tank, put 4-[(2-phthalimido) ethyoxyl] ethyl acetoacetate toluene solution, distillation under reduced pressure at 70 C or less, so that the water separator is filled, and then continue to reflux under reduced pressure, until the water content in the reflux liquid is add 27kg of 2-chlorobenzaldehyde and maintain the internal temperature at 25 C, add 1.5 kg of piperidine and stir for 30 minutes, water is refluxed under reduced pressure at 65 C for more than 12 hours, the pressure under reflux under reduced pressure is -0.07Mpa, the temperature is lowered at 25 C, and added 120 kg of water, stir, stand, layer, and recover the lower layer of water, the upper layer is 2-(2-chlorobenzyl)-4-[(2-phthalimido) ethyoxyl] ethyl acetoacetate toluene solution;