methyl 4,4-dimethoxybutanoate

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1 g of benzil, 1.01 g of methyl 4,4-dimethoxybutyrate and 2.87 g of ammonium acetate in 23 mL of acetic acid was refluxed for 5 h. The mixture was poured into water, basified with a 25% aq. ammonium hydroxide solution and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 85/15 to 0/100 as eluant to yield 633 mg of 3-(4,5-diphenyl-1H-imidazol-2-yl)-propionic acid methyl ester as a yellowish solid. extracted with DCM The organic phase was dried over anh. Na2SO4 concentrated in vacuo The resulting crude material was purified by CC

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4,4-dimethoxy-butyrate(4.99 g, 30.8 mmol) and N,O-dimethylhydroxylamine HCl(4.65 g, 47.68 mmol) in 60 mL of THF at −20° C., is added isopropylmagnesiumchloride(46 mL, 92.28 mmol, 2.0M in THF) maintaining the temperature below −20° C. After stirring at −10° C. for 30 min, the reaction mixture is quenched with 50 mL of water and extracted with 3×80 mL of EtOAc. The combined organic layers is dried over Na2SO4 and filtered through a short silica gel pluge. The solution is concentrated to give 4,4,N-Trimethoxy-N-methyl-butyramide(5.9 g, 99%) as pale liquid. M/Z=191.0 maintaining the temperature below −20° C the reaction mixture is quenched with 50 mL of water extracted with 3×80 mL of EtOAc The combined organic layers is dried over Na2SO4 filtered through a short silica gel pluge The solution is concentrated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of 1 g of benzil, 1.01 g of methyl 4,4-dimethoxybutyrate and 2.87 g of ammonium acetate in 23 mL of acetic acid was refluxed for 5 h. The mixture was poured into water, basified with a 25% aq. ammonium hydroxide solution and extracted with DCM. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using heptane/EtOAc from 85/15 to 0/100 as eluant to yield 633 mg of 3-(4,5-diphenyl-1H-imidazol-2-yl)-propionic acid methyl ester as a yellowish solid. extracted with DCM The organic phase was dried over anh. Na2SO4 concentrated in vacuo The resulting crude material was purified by CC

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4,4-dimethoxy-butyrate(4.99 g, 30.8 mmol) and N,O-dimethylhydroxylamine HCl(4.65 g, 47.68 mmol) in 60 mL of THF at −20° C., is added isopropylmagnesiumchloride(46 mL, 92.28 mmol, 2.0M in THF) maintaining the temperature below −20° C. After stirring at −10° C. for 30 min, the reaction mixture is quenched with 50 mL of water and extracted with 3×80 mL of EtOAc. The combined organic layers is dried over Na2SO4 and filtered through a short silica gel pluge. The solution is concentrated to give 4,4,N-Trimethoxy-N-methyl-butyramide(5.9 g, 99%) as pale liquid. M/Z=191.0 maintaining the temperature below −20° C the reaction mixture is quenched with 50 mL of water extracted with 3×80 mL of EtOAc The combined organic layers is dried over Na2SO4 filtered through a short silica gel pluge The solution is concentrated

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of methyl 4,4-dimethoxy-butyrate (4.99 g, 30.8 mmol) and N,O-dimethylhydroxylamine HCl (4.65 g, 47.68 mmol) in 60 mL of THF at −20° C., is added isopropylmagnesiumchloride (46 mL, 92.28 mmol, 2.0M in THF) maintaining the temperature below −20° C. After stirring at −10° C. for 30 min, the reaction mixture is quenched with 50 mL of water and extracted with 3×80 mL of EtOAc. The combined organic layers is dried over Na2SO4 and filtered through a short silica gel pluge. The solution is concentrated to give 4,4,N-Trimethoxy-N-methyl-butyramide (5.9 g, 99%) as pale liquid. M/Z=191.0 maintaining the temperature below −20° C the reaction mixture is quenched with 50 mL of water extracted with 3×80 mL of EtOAc The combined organic layers is dried over Na2SO4 filtered through a short silica gel pluge The solution is concentrated

反応条件: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-trifluoromethylphenylhydrazine (5 g), 4,4-dimethoxybutyric acid methyl ester (6 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 90° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. A 2 N sodium hydroxide aqueous solution (10 ml) and methanol (10 ml) were added to the obtained residue, and the mixture was heated to reflux for one hour. Water was added to the reaction mixture which was then rendered acidic with concentrated aqueous hydrochloric acid, extracted with ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of dichloromethane, methanol, and acetic acid to obtain 0.11 g of the title compound as a colorless powder (1.5% yield). to cool extraction The organic layer was dried over sodium sulfate concentrated under reduced pressure A 2 N sodium hydroxide aqueous solution (10 ml) and methanol (10 ml) were added to the obtained residue the mixture was heated to reflux for one hour Water was added to the reaction mixture which rendered acidic with concentrated aqueous hydrochloric acid, extracted with ethyl acetate dried over sodium sulfate concentrated under reduced pressure The obtained residue was purified by silica gel column chromatography

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound, white solid (114 mg, 99%), MS (ISP) m/z=461.5 [(M+H)+], mp 205.5° C., was prepared in accordance with the general method of example 2 from trans-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and methyl 4,4-dimethoxy-butanoate.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To 0.5 moles of diethylmalonate in 0.5 liters of dry benzene is added 0.5 moles of sodium hydride cautiously and the mixture stirred until hydrogen evolution ceases. Then 0.5 moles of bromoacetaldehydedimethylacetal [(CH3O)2 --CH--CH2 --Br] in 100 ml. of benzene is added and the mixture stirred overnight followed by refluxing for 2 hours. The reaction mixture is cooled, washed with water and purified by vacuum distillation to give β,β-dimethoxyethylmalonic acid diethyl ester. A mixture of 5 g. of this ester in 100 ml. of ethanol containing 5 g. of sodium hydroxide is heated under reflux until evolution of carbon dioxide ceases. The reaction mixture is then saturated with carbon dioxide and evaporated to dryness under vacuum. The residue is suspended in 50 ml. of dry dimethylformamide to which is added a large excess of methyl iodide. The reaction mixture is stirred at room temperature for about 24 hours and then poured into water. The resulting mixture is extracted with ether and the ether extracts combined, washed with water and evaporated to give 4,4-dimethoxybutyric acid methyl ester which is purified by distillation. A mixture of 4 g. of this methyl ester, 50 ml. of dry tetrahydrofuran and 1.1 equivalents of lithium aluminum hydride is refluxed overnight. The reaction mixture is allowed to cool and then filtered with water. This mixture is extracted with ether and the ether extracts are combined, washed, dried and evaporated to dryness to afford 4,4-dimethoxybutanol [(CH3O)2 --CH--CH2 --CH2 --CH2 --OH]. A mixture of 5 g saturated with carbon dioxide and evaporated to dryness under vacuum of dry dimethylformamide to which is added a large excess of methyl iodide poured into water The resulting mixture is extracted with ether washed with water evaporated