3-O-benzyl 1-O-methyl propanedioate

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: The title compound was prepared stepwise. In the first step, benzyl methyl malonate was reacted with an equimolar amount of ethyl 2-(bromomethyl)propenoate and sodium hydride in acetonitrile to give the product, benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate, in 43% yield [1H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 2.92 (d, 2H); 3.60 (s, 3H); 3.83 (t, 1H); 4.20 (q, 2H); 5.17 (s, 2H); 5.58 (s,1H); 6.18 (s, 1H) and 7.32 (m, 5H)]. In the second step, to a cooled suspension of sodium hydride (0.30 g, 0.01 mol, 80% dispersion in oil) in acetonitrile (20 mL), was added benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate (2.68 g, 0.0084 mol). The resulting mixture was allowed to stir for 10 minutes before a solution of t-butyl 2-(bromomethyl)propenoate (1.85 g) in acetonitrile (5 mL) was added and stirring continued at room temperature overnight under nitrogen. After work-up, the title product (21) was obtained in 72% yield as a colourless liquid. 1H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 1.46 (s, 9H); 2.94 (s, 2H); 2.96 (s, 2H); 3.58 (s, 3H); 4.16 (q, 2H); 5.10 (s, 2H); 5.60 (s, 1H); 5.67 (s, 1H); 6.17 (s, 1H) and 7.32 (m, 5H).

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

実験手順: Bromine (17.6 g, 0.11 mol) was added to a stirred solution of benzyl methyl malonate (20.8 g, 0.10 mol) in carbon tetrachloride. After 30 minutes the solvent was removed under reduced pressure to give 28 g of product (85% pure by gc, containing 7% benzyl methyl malonate) which was used without further purification. After 30 minutes the solvent was removed under reduced pressure

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

実験手順: Sodium hydride (1.29 g of 60% dispersion in oil) was added portionwise to a stirred solution of malonic acid, methyl benzyl ester (5.84 ml) in dry N,N-dimethylformamide (40 ml). After 2.5 h 2-fluoro-5-nitro-toluene (5.0 g) was added, and the mixture was warmed to 100° for 18 h. The mixture was cooled then partioned between ethyl acetate and water. The aqueous phase was separated and extracted further with ethyl acetate. The combined organic extracts were dried, concentrated, and purified by chromatography eluting with cyclohexane:ethyl acetate (6:1) to give 2-(2-methyl-4-nitro-phenyl)-malonic acid benzyl ester methyl ester, admixed with the starting malonate ester, as a yellow oil (4.60 g). the mixture was warmed to 100° for 18 h The mixture was cooled The aqueous phase was separated extracted further with ethyl acetate The combined organic extracts were dried concentrated purified by chromatography eluting with cyclohexane:ethyl acetate (6:1)

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of benzyl methyl malonate (0.88 g, 4.22 mmol) in 3 mL of anhydrous DMA was added to a suspension of sodium hydride (0.11 g, 4.45 mmol) in 2 mL of anhydrous DMA at 5° C., and the reaction mixture was stirred for 40 min at 5° C. Then 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene [prepared as described in U.S. Pat. No. 5,424,320] (1.21 g, 4.24 mmol) was dissolved in 6 mL of anhydrous DMA and added to this solution. The reaction mixture was stirred for 2 h at 5° C., and for 18 h at room temperature. The reaction mixture was quenched with water (100 mL). The aqueous solution was extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 0.93 g (53%) of benzyl methyl 2-[3-[(4-methoxy)tetrahydropyran-4-yl]phenylmethyl]malonate as a clear oil: HRMS: calcd for C24H28O6 413.1964, found 413.1952. added to this solution The reaction mixture was stirred for 2 h at 5° C. for 18 h at room temperature The reaction mixture was quenched with water (100 mL) The aqueous solution was extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried over magnesium sulfate filtered concentrated The concentrated residue was purified by flash column chromatography on silica gel eluting with 20% ethyl acetate in hexane

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

実験手順: To a solution of benzyl methyl malonate (0.2 g) in DMF (8 mL), was added sequentially NaH (0.08 g, 60% in mineral oil), di(tert-butyl) [[4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (0.83 g), and n-Bu4NI (0.08 g). The reaction mixture was stirred at room temperature for 2.5 h, then quenched with 20 mL of saturated aqueous NH4Cl solution and extracted with 50 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 2:1 hexane/EtOAc. First eluted was 1-benzyl 3-methyl 2-{4-[(di-tert-butoxyphosphoryl)(difluoro)methyl]benzyl}malonate (0.2 g), followed by the title compound (0.3 g) as an oil. quenched with 20 mL of saturated aqueous NH4Cl solution extracted with 50 mL of 1:1 hexane/EtOAc The extract was dried over Na2SO4 concentrated The residue was purified by silica gel chromatography eluted with 2:1 hexane/EtOAc First eluted

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

実験手順: To a solution of benzyl methyl malonate (0.2 g) in DMF (8 mL), was added sequentially NaH (0.08 g, 60% in mineral oil), di(tert-butyl) [[4-(bromomethyl)phenyl](difluoro)methyl]phosphonate (0.83 g), and n-Bu4NI (0.08 g). The reaction mixture was stirred at room temperature for 2.5 h, then quenched with 20 mL of saturated aqueous NH4Cl solution and extracted with 50 mL of 1:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 2:1 hexane/EtOAc. First eluted was 1-benzyl 3-methyl 2-{4-[(di-tert-butoxyphosphoryl)(difluoro)methyl]benzyl}malonate (0.2 g), followed by the title compound (0.3 g) as an oil. quenched with 20 mL of saturated aqueous NH4Cl solution extracted with 50 mL of 1:1 hexane/EtOAc The extract was dried over Na2SO4 concentrated The residue was purified by silica gel chromatography eluted with 2:1 hexane/EtOAc First eluted

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

実験手順: The title compound was prepared stepwise. In the first step, benzyl methyl malonate was reacted with an equimolar amount of ethyl 2-(bromomethyl)propenoate and sodium hydride in acetonitrile to give the product, benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate, in 43% yield [1H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 2.92 (d, 2H); 3.60 (s, 3H); 3.83 (t, 1H); 4.20 (q, 2H); 5.17 (s, 2H); 5.58 (s,1H); 6.18 (s, 1H) and 7.32 (m, 5H)]. In the second step, to a cooled suspension of sodium hydride (0.30 g, 0.01 mol, 80% dispersion in oil) in acetonitrile (20 mL), was added benzyl 2-methoxycarbonyl-4-ethoxycarbonyl-pent-4-enoate (2.68 g, 0.0084 mol). The resulting mixture was allowed to stir for 10 minutes before a solution of t-butyl 2-(bromomethyl)propenoate (1.85 g) in acetonitrile (5 mL) was added and stirring continued at room temperature overnight under nitrogen. After work-up, the title product (21) was obtained in 72% yield as a colourless liquid. 1H-NMR (CDCl3) δ(ppm): 1.28 (t, 3H); 1.46 (s, 9H); 2.94 (s, 2H); 2.96 (s, 2H); 3.58 (s, 3H); 4.16 (q, 2H); 5.10 (s, 2H); 5.60 (s, 1H); 5.67 (s, 1H); 6.17 (s, 1H) and 7.32 (m, 5H).

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

実験手順: Bromine (17.6 g, 0.11 mol) was added to a stirred solution of benzyl methyl malonate (20.8 g, 0.10 mol) in carbon tetrachloride. After 30 minutes the solvent was removed under reduced pressure to give 28 g of product (85% pure by gc, containing 7% benzyl methyl malonate) which was used without further purification. After 30 minutes the solvent was removed under reduced pressure

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

実験手順: Bromine (17.6 g, 0.11 mol) was added to a stirred solution of benzyl methyl malonate (20.8 g, 0.10 mol) in carbon tetrachloride. After 30 minutes the solvent was removed under reduced pressure to give 28 g of product (85% pure by gc, containing 7% benzyl methyl malonate) which was used without further purification. After 30 minutes the solvent was removed under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of benzyl methyl malonate (0.88 g, 4.22 mmol) in 3 mL of anhydrous DMA was added to a suspension of sodium hydride (0.11 g, 4.45 mmol) in 2 mL of anhydrous DMA at 5° C., and the reaction mixture was stirred for 40 min at 5° C. Then 3-[(4-methoxy)tetrahydropyran-4-yl]-α-bromotoluene [prepared as described in U.S. Pat. No. 5,424,320] (1.21 g, 4.24 mmol) was dissolved in 6 mL of anhydrous DMA and added to this solution. The reaction mixture was stirred for 2 h at 5° C., and for 18 h at room temperature. The reaction mixture was quenched with water (100 mL). The aqueous solution was extracted with ethyl acetate (3×70 mL). The combined organic extracts were washed with brine (1×100 mL), dried over magnesium sulfate, filtered and concentrated. The concentrated residue was purified by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, to give 0.93 g (53%) of benzyl methyl 2-[3-[(4-methoxy) tetrahydropyran-4-yl]phenylmethyl]malonate as a clear oil: HRMS: calcd for C24H28O6 413.1964, found 413.1952. added to this solution The reaction mixture was stirred for 2 h at 5° C. for 18 h at room temperature The reaction mixture was quenched with water (100 mL) The aqueous solution was extracted with ethyl acetate (3×70 mL) The combined organic extracts were washed with brine (1×100 mL) dried over magnesium sulfate filtered concentrated The concentrated residue was purified by flash column chromatography on silica gel eluting with 20% ethyl acetate in hexane