potassium;3-methoxy-3-oxopropanoate

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

Procedure: 0.8 g (2.46 mmol) of (E)-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]-acrylic acid in 4 ml of THF are introduced into a 50 ml three-necked round-bottomed flask equipped with a magnetic stirrer, thermometer, reflux condenser and nitrogen delivery line. 0.5 g (2.96 mmol) of 1,1-carbonyldiimidazole is then added in portions in the course of 5 min. and stirring is carried out at room temperature for 1 hour. 0.24 g (2.46 mmol) of magnesium chloride and 0.39 g (2.46 mmol) of monomethyl malonate potassium salt are then added and the suspension is stirred for 24 hours at 35° C. The reaction mixture is cooled and filtered and the residue is washed twice with 25 ml of THF. The filtrate is concentrated by evaporation, taken up in 30 ml of ethyl acetate, washed with 15 ml of 1N hydrochloric acid, three times with 20 ml of saturated sodium hydrogen carbonate solution and three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated by evaporation. The residue is purified by means of flash chromatography (hexane/ethyl acetate=8:1). An orange resin is obtained which, according to NMR, is the product in a keto-enol equilibrium of approximately 3:1. equipped with a magnetic stirrer thermometer, reflux condenser the suspension is stirred for 24 hours at 35° C The reaction mixture is cooled filtered the residue is washed twice with 25 ml of THF The filtrate is concentrated by evaporation washed with 15 ml of 1N hydrochloric acid, three times with 20 ml of saturated sodium hydrogen carbonate solution and three times with saturated sodium chloride solution dried over magnesium sulfate filtered concentrated by evaporation The residue is purified by means of flash chromatography (hexane/ethyl acetate=8:1) An orange resin is obtained which

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1-L 3-neck round-bottomed flask, connected to a mechanical stirrer, was added N-Boc-D-alanine (20.00 g, 106 mmol) followed by THF (529 mL). Then 1,1′-carbonyldiimidazole (25.7 g, 159 mmol) was slowly added into the reaction mixture (note: gas evolution was observed). The mixture was stirred under inert atmosphere for 3 h. Then magnesium chloride (20.13 g, 211 mmol), followed by potassium methyl malonate (33.0 g, 211 mmol) were added into the reaction mixture. The reaction mixture was heated at 50° C. in an oil bath for 16 h. It was cooled to RT, diluted with EtOAc (1 L) and filtered through a pad of celite. The filtrate was concentrated in-vacuo. The organic residue was diluted with CHCl3 (400 mL) and washed with sat. aq. NaHCO3 (300 mL). The aq. layer was extracted with CHCl3 (2×300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude material was purified by chromatography through two Interchim puriFlash UP (25 micron) pre-packed silica-gel column (300 gram), eluting with a gradient of 0-18% EtOAc in hexane. The mixed fractions were combined and purified by chromatography through an Interchim puriFlash UP (15 micron) pre-packed silica-gel column (120 grams), eluting with a gradient of 0-18% EtOAc in hexane. The fractions with desired material were combined and concentrated in-vacuo, to provide a mixture of (R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate and (R,Z)-methyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypent-2-enoate (21.03 g, 86 mmol, 81% yield) as white solid. ee % was not determined. m/z (ESI, +ve) 268.0 (M+23)′. To a 1-L 3-neck round-bottomed flask, connected to a mechanical stirrer were added into the reaction mixture It was cooled to RT filtered through a pad of celite The filtrate was concentrated in-vacuo The organic residue was diluted with CHCl3 (400 mL) washed with sat. aq. NaHCO3 (300 mL) The aq. layer was extracted with CHCl3 (2×300 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated in-vacuo The crude material was purified by chromatography through two Interchim puriFlash UP (25 micron) pre-packed silica-gel column (300 gram) eluting with a gradient of 0-18% EtOAc in hexane purified by chromatography through an Interchim puriFlash UP (15 micron) pre-packed silica-gel column (120 grams) eluting with a gradient of 0-18% EtOAc in hexane concentrated in-vacuo to provide

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 1-L 3-neck round-bottomed flask, connected to a mechanical stirrer, was added N-Boc-D-alanine (20.00 g, 106 mmol) followed by THF (529 mL). Then 1,1′-carbonyldiimidazole (25.7 g, 159 mmol) was slowly added into the reaction mixture (note: gas evolution was observed). The mixture was stirred under inert atmosphere for 3 h. Then magnesium chloride (20.13 g, 211 mmol), followed by potassium methyl malonate (33.0 g, 211 mmol) were added into the reaction mixture. The reaction mixture was heated at 50° C. in an oil bath for 16 h. It was cooled to RT, diluted with EtOAc (1 L) and filtered through a pad of celite. The filtrate was concentrated in-vacuo. The organic residue was diluted with CHCl3 (400 mL) and washed with sat. aq. NaHCO3 (300 mL). The aq. layer was extracted with CHCl3 (2×300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated in-vacuo. The crude material was purified by chromatography through two Interchim puriFlash UP (25 micron) pre-packed silica-gel column (300 gram), eluting with a gradient of 0-18% EtOAc in hexane. The mixed fractions were combined and purified by chromatography through an Interchim puriFlash UP (15 micron) pre-packed silica-gel column (120 grams), eluting with a gradient of 0-18% EtOAc in hexane. The fractions with desired material were combined and concentrated in-vacuo, to provide a mixture of (R)-methyl 4-((tert-butoxycarbonyl)amino)-3-oxopentanoate and (R,Z)-methyl 4-((tert-butoxycarbonyl)amino)-3-hydroxypent-2-enoate (21.03 g, 86 mmol, 81% yield) as white solid. ee % was not determined. m/z (ESI, +ve) 268.0 (M+23)′. To a 1-L 3-neck round-bottomed flask, connected to a mechanical stirrer were added into the reaction mixture It was cooled to RT filtered through a pad of celite The filtrate was concentrated in-vacuo The organic residue was diluted with CHCl3 (400 mL) washed with sat. aq. NaHCO3 (300 mL) The aq. layer was extracted with CHCl3 (2×300 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated in-vacuo The crude material was purified by chromatography through two Interchim puriFlash UP (25 micron) pre-packed silica-gel column (300 gram) eluting with a gradient of 0-18% EtOAc in hexane purified by chromatography through an Interchim puriFlash UP (15 micron) pre-packed silica-gel column (120 grams) eluting with a gradient of 0-18% EtOAc in hexane concentrated in-vacuo to provide

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

Procedure: 18.74 g (0.12 mol) of potassium monomethyl malonate were suspended in 18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine were added at room temperature with stirring and the mixture was boiled under reflux until the evolution of carbon dioxide had ceased (about 2 h). A further 60 ml of pyridine were added and the mixture was stirred under reflux for a further 1 h. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was stirred for a further 20 min, and the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 12.85 g (62%). (about 2 h) the mixture was stirred under reflux for a further 1 h The reaction mixture was treated After the addition the mixture was stirred for a further 20 min the product was filtered off with suction washed with water recrystallized from isopropanol

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

Procedure: 18.74 g (0.12 mol) of potassium monomethyl malonate were suspended in 18 ml of pyridine. 15.01 g (0.1 mol) of 4-carboxybenzaldehyde and 0.85 g (0.01 mol) of piperidine were added at room temperature with stirring and the mixture was boiled under reflux until the evolution of carbon dioxide had ceased (about 2 h). A further 60 ml of pyridine were added and the mixture was stirred under reflux for a further 1 h. The reaction mixture was treated with stirring with 500 ml of ice and 110 ml of concentrated hydrochloric acid. After the addition was complete, the mixture was stirred for a further 20 min, and the product was filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 12.85 g (62%). (about 2 h) the mixture was stirred under reflux for a further 1 h The reaction mixture was treated After the addition the mixture was stirred for a further 20 min the product was filtered off with suction washed with water recrystallized from isopropanol

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

Procedure: 272 mg of monomethyl malonate potassium salt and 0.41 ml of trimethylsilyl chloride are stirred at room temperature in 5 ml of acetonitrile for 4 hrs. Subsequently, the mixture is cooled to 0° and 0.75 ml of diaza-bicycloundecane is added. The mixture is stirred at room temperature for 30 min. Thereafter, 0.5 g of 3-iodo-4,5-dimethoxy-benzoyl chloride is added portionwise thereto and the mixture is stirred at room temperature for 19 hrs. The mixture is brought to about pH4 with 10 percent citric acid and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 1:1 gives 126 mg of ethyl 3-(3-iodo-4,5-dimethoxy-phenyl)-3-oxo-propionate as a yellowish oil (Keto/Enol mixture). Yield: 26%. Mass spectrum: peaks inter alia at m/e: 378 (M+, 40%); 291 (100%). Subsequently, the mixture is cooled to 0° the mixture is stirred at room temperature for 19 hrs extracted three times with ethyl acetate

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

Procedure: 272 mg of monomethyl malonate potassium salt and 0.41 ml of trimethylsilyl chloride are stirred at room temperature in 5 ml of acetonitrile for 4 hrs. Subsequently, the mixture is cooled to 0° and 0.75 ml of diaza-bicycloundecane is added. The mixture is stirred at room temperature for 30 min. Thereafter, 0.5 g of 3-iodo-4,5-dimethoxy-benzoyl chloride is added portionwise thereto and the mixture is stirred at room temperature for 19 hrs. The mixture is brought to about pH4 with 10 percent citric acid and extracted three times with ethyl acetate. Chromatography on silica gel with ethyl acetate/hexane 1:1 gives 126 mg of ethyl 3-(3-iodo-4,5-dimethoxy-phenyl)-3-oxo-propionate as a yellowish oil (Keto/Enol mixture). Yield: 26%. Mass spectrum: peaks inter alia at m/e: 378 (M+, 40%); 291 (100%). Subsequently, the mixture is cooled to 0° the mixture is stirred at room temperature for 19 hrs extracted three times with ethyl acetate

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

Procedure: The title compound was prepared from 2-(2,4-difluorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 3.54 (2H, s), 3.76 (3H, s), 3.86 (2H, s), 6.83-6.90 (2H, m), 7.13-7.19 (1H, m).

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

Procedure: The title compound was prepared from 2-(2,4-difluorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 3.54 (2H, s), 3.76 (3H, s), 3.86 (2H, s), 6.83-6.90 (2H, m), 7.13-7.19 (1H, m).

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

Procedure: The title compound was prepared from 2-(2-fluoro-4-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 2.35 (3H, s), 3.52 (2H, s), 3.74 (3H, s), 3.83 (2H, s), 6.89-6.95 (2H, m), 7.05-7.08 (1H, m).

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

Procedure: The title compound was prepared in 78% yield from 2-(4-fluoro-2-methylphenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A. 1H NMR (300 MHz, CDCl3): δ 2.24 (3H, s), 3.47 (2H, s), 3.74 (3H, s), 3.83 (2H, s), 6.88-6.94 (2H, m), 7.07-7.12 (1H, m).

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

Procedure: The title compound was prepared in 78% yield from 2-(3,5-dichlorophenyl)acetic acid and 3-methoxy-3-oxopropanoic acid potassium salt according to the procedure for the preparation of Example 170, part A.