3-oxopentanoic acid

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

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Oxopentanoic acid (II in Scheme 1; Example 1.1; 2 g; 17.2 mmol) was dissolved in 30 ml THF and cooled to 0° C. To the solution, was added dicarbodiimidazole (3.6 g; 22.2 mmol; Aldrich). The reaction mixture was stirred for 18 h at 25° C., neutralized with 2% HCl, extracted with 3×30 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to a white solid. The product was purified via silica chromatography (20% EtOAc in hexanes). To the solution, was added dicarbodiimidazole (3.6 g; 22.2 mmol; Aldrich) extracted with 3×30 ml EtOAc dried with anhydrous Na2SO4 evaporated to a white solid The product was purified via silica chromatography (20% EtOAc in hexanes)

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

Procedure: A stirred suspension of magnesium turnings (1.83 g, 75.0 mmol) in methanol (85 ml) was heated under reflux for 90 minutes. The suspension was cooled to room temperature and a solution of 3-ketopentanoic acid (17.4 g, 150.0 mmol) in methanol (15 ml) was added. The white suspension dissolved to give a pale yellow solution. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a pale yellow solid which was dissolved in N,N-dimethylformamide (50 ml). In a separate flask carbonyldiimidazole (13.4 g, 83.0 mmol) was added portionwise to a stirred solution of cyclopropanecarboxylic acid (6.46 g, 75.0 mmol) in N,N-dimethylformamide (150 ml) at room temperature under nitrogen. The reaction was stirred for 90 minutes and then the magnesium salt previously prepared was added dropwise. The reaction was stirred for 3 days and then poured into 1.0M hydrochloric acid (150 ml). The aqueous phase was extracted with ether (3×200 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (90:10, by volume) to provide the title compound (9.33 g) as a yellow oil. was heated under reflux for 90 minutes The white suspension dissolved to give a pale yellow solution concentrated under reduced pressure to give a pale yellow solid which The reaction was stirred for 90 minutes was added dropwise The reaction was stirred for 3 days The aqueous phase was extracted with ether (3×200 ml) the combined organic phases were dried over magnesium sulphate filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (90:10, by volume)

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

Procedure: A stirred suspension of magnesium turnings (1.83 g, 75.0 mmol) in methanol (85 ml) was heated under reflux for 90 minutes. The suspension was cooled to room temperature and a solution of 3-ketopentanoic acid (17.4 g, 150.0 mmol) in methanol (15 ml) was added. The white suspension dissolved to give a pale yellow solution. The reaction was stirred at room temperature for 1 hour and then concentrated under reduced pressure to give a pale yellow solid which was dissolved in N,N-dimethylformamide (50 ml). In a separate flask carbonyldiimidazole (13.4 g, 83.0 mmol) was added portionwise to a stirred solution of cyclopropanecarboxylic acid (6.46 g, 75.0 mmol) in N,N-dimethylformamide (150 ml) at room temperature under nitrogen. The reaction was stirred for 90 minutes and then the magnesium salt previously prepared was added dropwise. The reaction was stirred for 3 days and then poured into 1.0M hydrochloric acid (150 ml). The aqueous phase was extracted with ether (3×200 ml) and the combined organic phases were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (90:10, by volume) to provide the title compound (9.33 g) as a yellow oil. was heated under reflux for 90 minutes The white suspension dissolved to give a pale yellow solution concentrated under reduced pressure to give a pale yellow solid which The reaction was stirred for 90 minutes was added dropwise The reaction was stirred for 3 days The aqueous phase was extracted with ether (3×200 ml) the combined organic phases were dried over magnesium sulphate filtered concentrated under reduced pressure The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (90:10, by volume)

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

Procedure: Intermediates of formula 3 are prepared using methods known in the art. See for example U.S. Pat. No. 3,974,275 to Bossert et al., incorporated fully herein by reference. Additionally, certain intermediates of formula 3 are commercially available, e.g., methyl β-aminocrotonate. Under Claisen reaction conditions, acetone is reacted with methyl propionate in the presence of sodium ethoxide, followed by protonation with dilute HCl, to yield 2,4-hexadione (13). The resulting diketone is then oxidized to 3-oxopentanoic acid (14) by treatment with I2 or Cl2 in aqueous NaOH. The resulting acid is esterified with methanol to yield methyl 3-oxopentanoate (15). The ester is then heated with ammonia, removing water during the reaction to yield methyl 3-aminopent-2-eneoate (3).

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

Procedure: The β-keto acid (14) is then esterified with an alkanol of formula R3 -OH to yield a β-keto ester (15). For example, 3-oxopentanoic acid is heated at reflux with methanol to yield methyl 3-oxopentanoate (15) (Scheme V, Step 3).

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

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

Procedure: Intermediates of formula 3 are prepared using methods known in the art. See for example U.S. Pat. No. 3,974,275 to Bossert et al., incorporated fully herein by reference. Additionally, certain intermediates of formula 3 are commercially available, e.g., methyl β-aminocrotonate. Under Claisen reaction conditions, acetone is reacted with methyl propionate in the presence of sodium ethoxide, followed by protonation with dilute HCl, to yield 2,4-hexadione (13). The resulting diketone is then oxidized to 3-oxopentanoic acid (14) by treatment with I2 or Cl2 in aqueous NaOH. The resulting acid is esterified with methanol to yield methyl 3-oxopentanoate (15). The ester is then heated with ammonia, removing water during the reaction to yield methyl 3-aminopent-2-eneoate (3).

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

Procedure: The β-keto acid (14) is then esterified with an alkanol of formula R3 -OH to yield a β-keto ester (15). For example, 3-oxopentanoic acid is heated at reflux with methanol to yield methyl 3-oxopentanoate (15) (Scheme V, Step 3).

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

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-Oxopentanoic acid (II; 2 g; 17.2 mmol) was dissolved in 30 ml THF and cooled to 0° C. To the solution, was added dicarbodiimidazole (3.6 g; 22.2 mmol; Aldrich). The reaction mixture was stirred for 18 h at 25° C., neutralized with 2% HCl, extracted with 3×30 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to a white solid. The product was purified via silica chromatography (20% EtOAc in hexanes). To the solution, was added dicarbodiimidazole (3.6 g; 22.2 mmol; Aldrich) extracted with 3×30 ml EtOAc dried with anhydrous Na2SO4 evaporated to a white solid The product was purified via silica chromatography (20% EtOAc in hexanes)