3-O-tert-butyl 1-O-ethyl propanedioate

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

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

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

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

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

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

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Potassium carbonate (28.0 g.) was added to a stirred solution of t-butyl ethyl malonate (37.6 g.) in dry N,N-dimethylformamide (DMF) (100 ml.). After 1 hour allyl bromide (34 ml.) was added. The mixture was heated at 70° C. for 66 hours, cooled to room temperature and diluted with water (900 ml.). The mixture obtained was extracted with ethyl acetate (3×200 ml.). The extracts were dried (MgSO4) and evaporated. The oil obtained was purified by flash column chromatography eluting with 1:15 v/v ethyl acetate/petroleum ether (b.p. 60°-80° C.) to give t-butyl ethyl 2-allylmalonate as a colourless oil (15.6 g.), b.p. 70°-72° C. at 0.2 mmHg; NMR: 1.21 (3H,t), 1.42 (9H,s), 2.66 (2H,m), 3.28 (1H,m), 4.16 (2H,q), 5.06 (2H,m) and 5.76 (1H,m) ppm. cooled to room temperature The mixture obtained was extracted with ethyl acetate (3×200 ml.) The extracts were dried (MgSO4) evaporated The oil obtained was purified by flash column chromatography eluting with 1:15 v/v ethyl acetate/petroleum ether (b.p. 60°-80° C.)

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

Procedure: To a solution of 15.35 g of monoethyl tert.butyl malonate in 200 ml of anhydrous CH2Cl2 are stirred, at ambient temperature, 15.88 g of N,N'-carbonyldiimidazole in small batches. After 30 minutes, 14.8 g of 2-(3,4-dimethoxyphenyl)ethylamine are added. After a further 15 hours the solvent is distilled off in vacuo. The residue is mixed with 200 ml of water, acidified with 2N HCl and extracted with ethyl acetate. The organic phase is washed with water and concentrated by evaporation after drying over Na2SO4. The residue is triturated with petroleum ether (40° to 60° C.) and brought to crystallisation. After a further 15 hours the solvent is distilled off in vacuo The residue is mixed with 200 ml of water extracted with ethyl acetate The organic phase is washed with water concentrated by evaporation after drying over Na2SO4 The residue is triturated with petroleum ether (40° to 60° C.) brought to crystallisation

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

Procedure: To a stirred solution of tert-butyl ethyl malonate (5.35 ml, 28.2 mmol) in DMF (150 ml) was added NaH (60% in oil, 3.38 g, 84.7 mmol) at rt. After 20 min, 2,3-difluoronitrobenzene (5 g, 28.2 mmol) in DMF (50 mL) was added dropwise via dropping funnel. Following the addition, the mixture was stirred for 3 hours at rt. The mixture was poured into ice-water and sat. NH4Cl (100 mL). The mixture was extracted with EtOAc and the combined organic layer was washed with 1M HCl and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved to dichloromethane (20 mL), and added TFA (20 mL) at rt. The mixture was refluxed for 18 h. The mixture was evaporated in vacuo, coevaporated with toluene (20 mL×2). The residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, φ50 mm×300 mm, 15 mL/min) to give ethyl 2,3-difluoro-4-nitrophenylacetic acid (5.85 g, 85%) as a yellow oil. 1H-NMR (CDCl3) δ1.30 (m, 3H), 3.78 (s, 2H), 4.22 (m, 2H), 7.22 (m, 1H), 7.84 (m, 1H); MS (FAB) m/z 246 (M++1). the addition The mixture was extracted with EtOAc the combined organic layer was washed with 1M HCl and brine dried over MgSO4 filtered concentrated The residue was dissolved to dichloromethane (20 mL) added TFA (20 mL) at rt The mixture was refluxed for 18 h The mixture was evaporated in vacuo The residue was chromatographed on silica gel (middle pressure chromatography system: YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, φ50 mm×300 mm, 15 mL/min)

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

Procedure: To a stirred solution of tert-butyl ethyl malonate (5.35 ml, 28.2 mmol) in DMF (150 ml) was added NaH (60% in oil, 3.38 g, 84.7 mmol) at rt. After 20 min, 2,3-difluoronitrobenzene (5 g, 28.2 mmol) in DMF (50 mL) was added dropwise via dropping funnel. Following the addition, the mixture was stirred for 3 hours at rt. The mixture was poured into ice-water and sat. NH4Cl (100 mL). The mixture was extracted with EtOAc and the combined organic layer was washed with 1M HCl and brine, dried over MgSO4, filtered and concentrated. The residue was dissolved to dichloromethane (20 mL), and added TFA (20 mL) at rt. The mixture was refluxed for 18 h. The mixture was evaporated in vacuo, coevaporated with toluene (20 mL×2). The residue was chromatographed on silica gel (middle pressure chromatography system:YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, φ50 mg×300 mg, 15 mL/min) to give ethyl 2,3-difluoro-4-nitrophenylacetic acid (5.85 g, 85%) as a yellow oil. 1H-NMR (CDCl3) δ 1.30 (m, 3 H), 3.78 (s, 2 H), 4.22 (m, 2 H), 7.22 (m, 1 H), 7.84 (m, 1 H); MS (FAB) m/z 246 (M++1). the addition The mixture was extracted with EtOAc the combined organic layer was washed with 1M HCl and brine dried over MgSO4 filtered concentrated The residue was dissolved to dichloromethane (20 mL) added TFA (20 mL) at rt The mixture was refluxed for 18 h The mixture was evaporated in vacuo The residue was chromatographed on silica gel (middle pressure chromatography system:YAMAZEN YFLC-5404-FC, linear gradient hexane-EtOAc 10:0 to 1:1, φ50 mg×300 mg, 15 mL/min)

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

Procedure: A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 3-(1-pentadeca-4,14-dienylamino)benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 4-(1-pentadeca-4,14-dienylamino)benzoylmalonate. The reaction mixture is refluxed for 5 hours cooled poured on ice extracted with ether The ether solution is washed with water and saturated sodium chloride solution dried over anhydrous sodium sulfate concentrated to dryness The residue is then recrystallized from ether