ETHYL (2-AZIDOETHOXY)ACETOACETATE

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil, which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature, and treated with methyl 2-(2-chlorobenzylidene)acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried, and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°. The mixture was stirred at room temperature for 16 hours to dissolve the solid present the layers were separated The organic layer was evaporated the residue diluted with water (600 ml) evaporated The residue was partitioned between ethyl acetate and water the aqueous layer extracted twice with ethyl acetate The combined ethyl acetate extracts were dried (MgSO4) evaporated

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

实验步骤: A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil, which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature, and treated with methyl 2-(2-chlorobenzylidene)acetocetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried, and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°. The mixture was stirred at room temperature for 16 hours to dissolve the solid present the layers were separated The organic layer was evaporated the residue diluted with water (600 ml) evaporated The residue was partitioned between ethyl acetate and water the aqueous layer extracted twice with ethyl acetate The combined ethyl acetate extracts were dried (MgSO4) evaporated

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

实验步骤: A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was then partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature and treated with methyl 2-(2-chlorobenzylidene)acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°. The mixture was stirred at room temperature for 16 hours to dissolve the solid present the layers were separated The organic layer was evaporated the residue diluted with water (600 ml) evaporated The residue was then partitioned between ethyl acetate and water the aqueous layer extracted twice with ethyl acetate The combined ethyl acetate extracts were dried (MgSO4) evaporated

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was then partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature and treated with methyl 2-(2-chlorobenzylidene)acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°. The mixture was stirred at room temperature for 16 hours to dissolve the solid present the layers were separated The organic layer was evaporated the residue diluted with water (600 ml) evaporated The residue was then partitioned between ethyl acetate and water the aqueous layer extracted twice with ethyl acetate The combined ethyl acetate extracts were dried (MgSO4) evaporated

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

实验步骤: A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour and the ice-cooled solution treated with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil, which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature, and treated with methyl 2-(2-chlorobenzylidene) acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried, and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°. The mixture was stirred at room temperature for 16 hours to dissolve the solid present the layers were separated The organic layer was evaporated the residue diluted with water (600 ml) evaporated The residue was partitioned between ethyl acetate and water the aqueous layer extracted twice with ethyl acetate The combined ethyl acetate extracts were dried (MgSO4) evaporated

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

实验步骤: Ethyl 4-(2-azidoethoxy)acetoacetate (46.4 g), prepared from 2-azidoethanol similarly to the method described in Preparation 3, was reacted with methyl 3-aminocrotonate (24.8 g) and 2-chlorobenzaldehyde (30.3 g) in methanol (150 ml) at reflux for 18 hours. After cooling to room temperature, the resulting solid was collected, washed twice with methanol and dried to give the title compound (28 g). The product could be crystallised from methanol, acetone or ethyl acetate. It was used directly. described in Preparation 3 at reflux for 18 hours the resulting solid was collected washed twice with methanol dried

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

实验步骤: A solution of 2-azidoethanol (160 g) in tetrahydrofuran (300 ml) was added over 40 minutes to a suspension of sodium hydride (114 g; 80% dispersion in oil) in tetrahydrofuran (500 ml). The mixture was stirred at room temperature for 1 hour, then cooled in ice water and treated dropwise with a solution of ethyl 4-chloroacetoacetate (276 g) in tetrahydrofuran (250 ml) over 2 hours. The mixture was stirred at room temperature for 16 hours, diluted with ethanol (150 ml), and the pH adjusted to 6-7 with 4M hydrochloric acid. Sufficient water was added to dissolve the solid present and the layers were separated. The organic layer was evaporated and the residue diluted with water (600 ml) and evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer extracted twice with ethyl acetate. The combined ethyl acetate extracts were dried (MgSO4) and evaporated to give ethyl 4-(2-azidoethoxy)acetoacetate as a brown oil, which was shown by g.l.c. to be 73% pure. A mixture of this crude product and ammonium acetate (92.3 g) in ethanol (600 ml) was heated under reflux for 1 hour, allowed to cool to room temperature, and treated with methyl 2-(2-chlorobenzylidene)-acetoacetate (286.6 g). The mixture was heated under reflux for 5.5 hours and then evaporated. The residue was stirred with methanol (1.5 l) for 16 hours and the resulting solid collected, washed twice with methanol, dried, and recrystallised from methanol to give the title compound (78 g), m.p. 145°-146°. The mixture was stirred at room temperature for 16 hours to dissolve the solid present the layers were separated The organic layer was evaporated the residue diluted with water (600 ml) evaporated The residue was partitioned between ethyl acetate and water the aqueous layer extracted twice with ethyl acetate The combined ethyl acetate extracts were dried (MgSO4) evaporated

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

实验步骤: 2-Azidoethanol (3 g) was converted to ethyl 4-(2-azidoethoxy)acetoacetate similarly to the method described in Preparation 3 hereinafter using ethyl 4-chloroacetoacetate, and the crude ketoester (not characterised) was used in the Hantzsch reaction using the method described in Preparation 9, i.e. by reacting it with methyl 3-aminocrotonate and 2-chlorobenzaldehyde. The crude Hantzsch product (not characterised) dissolved in methanol (250 ml) and 3N hydrochloric acid (200 ml) was stirred on a water bath at room temperature while zinc dust (15 g) was added portionwise over 10 minutes. After stirring a further 10 minutes the solution was decanted from excess zinc, the methanol evaporated and the aqueous acid residue washed with toluene (100 ml), basified with concentrated ammonia and extracted with methylene chloride (2×100 ml). The extracts were dried (Na2CO3), filtered and evaporated to dryness. The residue in toluene was chromatographed on a medium pressure column of silica (T.L.C. grade, Merck "Kieselgel" [Trade Mark] 60H, 7 g) eluting initially with toluene, changing gradually to methylene chloride and then to methylene chloride plus 3% methanol. Appropriate fractions were combined and converted to the maleate salt in ethyl acetate. Recrystallisation from acetone and ethyl acetate (1:1) gave the title compound (maleate salt) (190 mg, 1% yield from 2-azido ethanol) as a white solid, m.p. 169°, identical by t.l.c. with the product obtained in Example 9. described in Preparation 3 was used in the Hantzsch reaction described in Preparation 9, i.e. was added portionwise over 10 minutes was decanted from excess zinc the methanol evaporated the aqueous acid residue washed with toluene (100 ml) extracted with methylene chloride (2×100 ml) The extracts were dried (Na2CO3) filtered evaporated to dryness The residue in toluene was chromatographed on a medium pressure column of silica (T.L.C. grade, Merck "Kieselgel" [Trade Mark] 60H, 7 g) eluting initially with toluene Recrystallisation from acetone and ethyl acetate (1:1)

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

实验步骤: A mixture of 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester (3 g, 13.94 mmol), 2-chlorobenzaldehyde (3 g, 21.34 mmol) and pyridine (1.5 mL, 1.47 g, 18.55 mmol) in EtOH (14 mL) was heated to 60° C. and maintained at this temperature for 3 h. The mixture was concentrated in vacuo. The concentrate was taken up in EtOAc (100 mL), washed successively with 1N HCl (25 mL) and brine (25 mL), dried (Na2SO4), filtered, concentrated in vacuo. The crude product was purified by chromatography using the ISCO Combiflash SQ16× (120 gram Redisep silica gel column, 0 to 60% EtOAc in hexanes for 30 min at 40 mL/min) to afford 2.00 g of 2-[2-(2-azido-ethoxy)-acetyl]-3-(2-chloro-phenyl)-acrylic acid ethyl ester (mixture of E/Z isomers) and 1.01 g of recovered starting material. maintained at this temperature for 3 h The mixture was concentrated in vacuo washed successively with 1N HCl (25 mL) and brine (25 mL) dried (Na2SO4) filtered concentrated in vacuo The crude product was purified by chromatography