琥珀酸单甲酯

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:

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

实验步骤: To 48.3 g of methyl hydrogen succinate dissolved in 840 ml of dichloroethane were added 46.4 g of oxalyl chloride and 2 drops of dimethylformamide. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. The organic layer was collected by separation, washed with water and dried, and the solvent was removed to obtain 51.8 g of 2-(acetylamino) methyl-5-(3methoxycarbonylpropionyl) indane. After the mixture was stirred for 1 hour The organic layer was collected by separation washed with water dried the solvent was removed

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

实验步骤: To 48.3 g of methyl hydrogen succinate dissolved in 840 ml of dichloroethane were added 46.4 g of oxalyl chloride and 2 drops of dimethylformamide. The mixture was stirred at room temperature for 5 hours. Then, under ice cooling, 34.6 g of 2-(acetylaminomethyl)indane dissolved in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride were added to the reaction mixture. After the mixture was stirred for 1 hour, the reaction mixture was poured into ice water. The organic layer was collected by separation, washed with water and dried, and the solvent was removed to obtain 51.8 g of 2-(acetylamino) methyl-5-(3methoxycarbonylpropionyl) indane. After the mixture was stirred for 1 hour The organic layer was collected by separation washed with water dried the solvent was removed

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

实验步骤: Monomethyl hydrogen succinate (4.7 g, 0.035 mol) was refluxed in thionyl chloride (20 ml) for 2 hrs. After consumption of starting material, excess of thionyl chloride was distilled off. The reaction mixture dissolved in dioxane (10 ml) and was added drop wise to 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide 1 (7 g, 0.035 moles) in dioxane (10 ml) at 0° C. and stirred at room temperature (R.T) for 2 hrs. The reaction mixture was diluted with water to give crude product which was filtered and washed with water. The crude was purified by chromatography on silica gel using 1:1 Ethyl acetate:Hexane to give 5 g (46%) of N-(3-carbonyl-4,5,6,7-tetrahydro-benzo[b]thiophen-2-yl)-succinamic acid methyl ester. 1H NMR (400 MHz, DMSO) δ ppm=1.72 (m, 4H), 2.6 (m, 4H), 2.68 (m, 4H), 3.59 (s, 3H), 6.99 (s, 1H), 7.55 (s, 1H), 11.48 (s, 1H). LC-MS: [M−H]=308.9. After consumption of starting material excess of thionyl chloride was distilled off The reaction mixture dissolved in dioxane (10 ml) to give crude product which was filtered washed with water The crude was purified by chromatography on silica gel using 1:1 Ethyl acetate

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

实验步骤: PyBop (0.47 g) was added to a mixture of the product from example 1 step (viii) (0.25 g), Et3N (0.7 ml) and succinic acid monomethyl ester (0.16 g) in DMF (8 ml) and stirred at rt for 4 days. MeOH (10 ml) was added, the solvent evaporated under reduced pressure and the residue purified by RPHPLC, yield 46 mg. the solvent evaporated under reduced pressure the residue purified by RPHPLC, yield 46 mg

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

实验步骤: PyBop (0.47 g) was added to a mixture of the product from example 1 step (viii) (0.25 g), Et3N (0.7 ml) and succinic acid monomethyl ester (0.16 g) in DMF (8 ml) and stirred at rt for 4 days. MeOH (10 ml) was added, the solvent evaporated under reduced pressure and the residue purified by RPHPLC, yield 46 mg. the solvent evaporated under reduced pressure the residue purified by RPHPLC, yield 46 mg

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a single-necked, 100 mL round-bottom flask equipped with a teflon stirbar, is added 20 g succinic anhydride dissolved in 50 mL methanol. The flask is equipped with a reflux condenser topped with a septa and argon balloon, and the reaction mixture is heated to reflux (70° C.) in an oil bath (Dow Corning Fluid) for a 16 hr time period. The reaction flask is then allowed to cool to room temperature, the stirbar removed, and the excess methanol removed via rotary evaporator to give 26.4 g of succinic acid monomethyl ester. In the same 100 mL flask containing succinic acid monomethyl ester is added a teflon stirbar, 35 mg palladium dichloride, 1.31 g triphenylphosphine, and 38 mL acetic anhydride, respectively. The flask is equipped with a short-path distillation apparatus with a thermometer, argon balloon, and an attached 100 mL collecting flask in an ice-bath. The reaction flask is heated to a temperature of 230° C. in an oil bath over a 30-40 minute time period, distilling out the excess acetic anhydride, acetic acid byproduct, and methyl acrylate. The reaction is complete after approximately 30 min heating at 230° C. when no more product distills and the solution darkens to a black color due to inactivation of the catalyst. The distillate is then analyzed by NMR to verify the presence of methyl acrylate. The reaction flask is cooled and weighed to determine how much starting material was removed due to reaction (17.9 g, 68% conversion to methyl acrylate). The flask is equipped with a reflux condenser the reaction mixture is heated to cool to room temperature the stirbar removed the excess methanol removed via rotary evaporator

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a single-necked, 100 mL round-bottom flask equipped with a teflon stirbar, is added 20 g succinic anhydride dissolved in 50 mL methanol. The flask is equipped with a reflux condenser topped with a septa and argon balloon, and the reaction mixture is heated to reflux (70° C.) in an oil bath (Dow Corning Fluid) for a 16 hr time period. The reaction flask is then allowed to cool to room temperature, the stirbar removed, and the excess methanol removed via rotary evaporator to give 26.4 g of succinic acid monomethyl ester. In the same 100 mL flask containing succinic acid monomethyl ester is added a teflon stirbar, 35 mg palladium dichloride, 1.31 g triphenylphosphine, and 38 mL acetic anhydride, respectively. The flask is equipped with a short-path distillation apparatus with a thermometer, argon balloon, and an attached 100 mL collecting flask in an ice-bath. The reaction flask is heated to a temperature of 230° C. in an oil bath over a 30-40 minute time period, distilling out the excess acetic anhydride, acetic acid byproduct, and methyl acrylate. The reaction is complete after approximately 30 min heating at 230° C. when no more product distills and the solution darkens to a black color due to inactivation of the catalyst. The distillate is then analyzed by NMR to verify the presence of methyl acrylate. The reaction flask is cooled and weighed to determine how much starting material was removed due to reaction (17.9 g, 68% conversion to methyl acrylate). The flask is equipped with a reflux condenser the reaction mixture is heated to cool to room temperature the stirbar removed the excess methanol removed via rotary evaporator

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

实验步骤: To a solution of 4-methoxy-4-oxobutanoic acid (14.6 g, 110.6 mmol) in toluene (530 mL) was added diphenylphosphoryl azide (30.4 g, 110.5 mmol) followed by triethylamine (18.3 g, 181.2 mmol). The reaction was stirred at RT for 30 min then 2-amino-5-bromonicotinic acid (15.9 g, 73.61 mmol) was added. The reaction was refluxed for 6 h, cooled to RT then diluted with EA (530 mL) and washed with brine (2×300 mL). The combined aqueous layers were acidified to PH 5 by adding aq. 2N HCl and a solid formed which was filtered off. The solid was dried to give 5-bromo-2-(3-(3-methoxy-3-oxopropyl)ureido)nicotinic acid (15 g, 39.3% yield) as pale yellow solid. LCMS: MH+ 347 and TR=1.047 min. Used without further purification. The reaction was refluxed for 6 h cooled to RT washed with brine (2×300 mL) by adding aq. 2N HCl a solid formed which was filtered off The solid was dried

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

实验步骤: To a solution of 4-methoxy-4-oxobutanoic acid (9.7 g, 73.5 mmol) in toluene (368 mL) was added diphenylphosphoryl azide (20.2 g, 73.5 mmol) followed by TEA (12.4 g, 122.7 mmol). The reaction was stirred at RT for 30 min then 5-amino-2-chloroisonicotinic acid (8.47 g, 49 mmol) was added. The reaction was heated at reflux for 6 h, cooled to RT then diluted with EA (300 mL). The mixture was washed with brine (300 mL) and out of the organic layer precipitated a solid which was filtered. The separated aqueous layer was acidified to PH 5 by adding aq. 2N HCl and a precipitate formed. The solid was filtered and combined with the organic layer solid. The combined solids were dried to give 2-chloro-5-(3-(3-methoxy-3-oxopropyl)ureido) isonicotinic acid (26 g, >100% yield) as brown semi-solid. LCMS: MH+ 302 MH+ and TR=2.752 min. Used without further purification. The reaction was heated at reflux for 6 h cooled to RT The mixture was washed with brine (300 mL) and out of the organic layer precipitated a solid which was filtered by adding aq. 2N HCl a precipitate formed The solid was filtered The combined solids were dried