4-oxohexanoic acid

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

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

Procedure: To a stirring suspension of 8.15 g (25 mmol) of Cs2CO3 in DMF was added 5.79 g (44 mmol) of 4-oxohexanoic acid. After 5 minutes, 6.81 g (48 mmol) of iodomethane was added. The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction was then added 250 mL of EtOAc and 250 mL of H2O. The layers were separated, and the organic layer was washed with 3×250 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated under vacuum. The yield of methyl 4-oxohexanoate (16) was 4.15 g (65%), which was employed in Example 17 below. The layers were separated the organic layer was washed with 3×250 mL of H2O The organic layer was then dried over Na2SO4 anhydrous filtered concentrated under vacuum

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

Procedure: To a stirring suspension of 8.15 g (25 mmol) of Cs2CO3 in DMF was added 5.79 g (44 mmol) of 4-oxohexanoic acid. After 5 minutes, 6.81 g (48 mmol) of iodomethane was added. The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction was then added 250 mL of EtOAc and 250 mL of H2O. The layers were separated, and the organic layer was washed with 3×250 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated under vacuum. The yield of methyl 4-oxohexanoate (16) was 4.15 g (65%), which was employed in Example 17 below. The layers were separated the organic layer was washed with 3×250 mL of H2O The organic layer was then dried over Na2SO4 anhydrous filtered concentrated under vacuum

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

Procedure: To a solution of 2.6 mL (19 mmol) of triethylamine in 56 mL of anhydrous THF was added 2.47 g (19 mmol) of 4-oxo-hexanoic acid (Sigma Aldrich, Milwaukee Wis.). The reaction was stirred for 15 min at rt under a N2 atmosphere after which 2.4 mL (19 mmol) of isobutyl chloroformate was added drop wise by a syringe. The reaction was stirred for 3.0 h during which time a white precipitate formed. The 4-oxo-hexanoic acid carbonic anhydride was used in the next step without further purification. To a solution of 3.6 g (17 mmol) of mannosamine hydrochloride in 112 mL of 1:1 H2O/THF was added 3.1 mL (22 mmol) of triethylamine. The solution was stirred for 15 min at rt after which the 4-oxo-hexanoic acid carbonic anhydride was added drop wise by an addition funnel. The reaction was stirred for another 36 h under a N2 atmosphere and the solution was concentrated in vacuo. The crude compound was acetylated by treatment with 40 mL of 2:1 Pyr/Ac2O. The reaction was stirred for 12 h at rt and then the solution was concentrated in vacuo. The resulting syrup was washed with 1.0 M HCl (2×30 mL) and saturated NaHCO3 (1×30 mL), then dried over Na2SO4. Purification of the crude compound by silica gel chromatography yielded a white foam. was added drop wise by a syringe formed The 4-oxo-hexanoic acid carbonic anhydride was used in the next step without further purification was added drop wise by an addition funnel The reaction was stirred for another 36 h under a N2 atmosphere the solution was concentrated in vacuo The reaction was stirred for 12 h at rt the solution was concentrated in vacuo The resulting syrup was washed with 1.0 M HCl (2×30 mL) and saturated NaHCO3 (1×30 mL) dried over Na2SO4 Purification of the crude compound by silica gel chromatography yielded a white foam

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 88.8 mg (0.68 mmol) of 4-oxohexanoic acid,* 100 mg (0.62 mmol) of (4-fluorophenyl)hydrazine hydrochloride, 3 mL of methanol and 80 μL of concentrated sulfuric acid in a 5 mL microwave process vial was heated for 10 min at 120° C. under argon in a microwave synthesizer. The alcoholic solution was concentrated to about one-third of its original volume and then transferred to a phase separator syringe filled with cold water (4 mL). The organic compound was repeatedly extracted with dichloromethane (3×5 mL) and the combined organic phases were washed with brine (4 mL), dried over Na2SO4 and filtered. Removal of the organic solvent and treatment of the residue with a little hexane afford the title compound in 46% yield (67 mg) as viscous mass. C13H14FNO2, Mr=235.25; 1H NMR (400 MHz, DMSO-d6) d: 2.12 (s, 3H), 2.66 (t, J=8.0 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.58 (s, 3H), 6.80 (td, J=2.8/9.2 Hz, 1H), 7.10 (dd, J=2.4/10.2 Hz, 1H), 7.20 (dd, J=4.6/8.6 Hz, 1H), 10.74 (bs, 1H); 19F NMR (282 MHz, DMSO-d6) d: −124.03 (d, 5′-F); LCMS (ESI) tR: 2.58 min (>99%, UV220), m/z: 236.2 [M+1]+. [* instead of the acid one could also use the methyl ester with the same outcome.] The alcoholic solution was concentrated to about one-third of its original volume transferred to a phase separator syringe filled with cold water (4 mL) The organic compound was repeatedly extracted with dichloromethane (3×5 mL) the combined organic phases were washed with brine (4 mL) dried over Na2SO4 filtered Removal of the organic solvent and treatment of the residue with a little hexane

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred mixture of 88.8 mg (0.68 mmol) of 4-oxohexanoic acid,* 100 mg (0.62 mmol) of (4-fluorophenyl)hydrazine hydrochloride, 3 mL of methanol and 80 μL of concentrated sulfuric acid in a 5 mL microwave process vial was heated for 10 min at 120° C. under argon in a microwave synthesizer. The alcoholic solution was concentrated to about one-third of its original volume and then transferred to a phase separator syringe filled with cold water (4 mL). The organic compound was repeatedly extracted with dichloromethane (3×5 mL) and the combined organic phases were washed with brine (4 mL), dried over Na2SO4 and filtered. Removal of the organic solvent and treatment of the residue with a little hexane afford the title compound in 46% yield (67 mg) as viscous mass. C13H14FNO2, Mr=235.25; 1H NMR (400 MHz, DMSO-d6) d: 2.12 (s, 3H), 2.66 (t, J=8.0 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 3.58 (s, 3H), 6.80 (td, J=2.8/9.2 Hz, 1H), 7.10 (dd, J=2.4/10.2 Hz, 1H), 7.20 (dd, J=4.6/8.6 Hz, 1H), 10.74 (bs, 1H); 19F NMR (282 MHz, DMSO-d6) d: −124.03 (d, 5′-F); LCMS (ESI) tR: 2.58 min (>99%, UV220), m/z: 236.2 [M+1]+. [* instead of the acid one could also use the methyl ester with the same outcome.] The alcoholic solution was concentrated to about one-third of its original volume transferred to a phase separator syringe filled with cold water (4 mL) The organic compound was repeatedly extracted with dichloromethane (3×5 mL) the combined organic phases were washed with brine (4 mL) dried over Na2SO4 filtered Removal of the organic solvent and treatment of the residue with a little hexane

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

Procedure: To a stirring suspension of 8.15 g (25 mmol) of Cs2CO3 in DMF was added 5.79 g (44 mmol) of 4-oxohexanoic acid. After 5 minutes, 6.81 g (48 mmol) of iodomethane was added. The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction was then added 250 mL of EtOAc and 250 mL of H2O. The layers were separated, and the organic layer was washed with 3×250 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated under vacuum. The yield of methyl 4-oxohexanoate (16) was 4.15 g (65%), which was employed in Example 17 below. The layers were separated the organic layer was washed with 3×250 mL of H2O The organic layer was then dried over Na2SO4 anhydrous filtered concentrated under vacuum

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

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

Procedure: Reaction was conducted in the same manner as Reference Example 86, except that phenylhydrazine hydrochloride was used instead of 3-tolylhydrazine hydrochloride and 4-oxohexanoic acid was used instead of levulinic acid, to obtain the title compound (10% yield). Reaction

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

Procedure: To a stirring suspension of 8.15 g (25 mmol) of Cs2CO3 in DMF was added 5.79 g (44 mmol) of 4-oxohexanoic acid. After 5 minutes, 6.81 g (48 mmol) of iodomethane was added. The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction was then added 250 mL of EtOAc and 250 mL of H2O. The layers were separated, and the organic layer was washed with 3×250 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated under vacuum. The yield of methyl 4-oxohexanoate (16) was 4.15 g (65%), which was employed in Example 17 below. The layers were separated the organic layer was washed with 3×250 mL of H2O The organic layer was then dried over Na2SO4 anhydrous filtered concentrated under vacuum

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

Procedure: To a stirring suspension of 8.15 g (25 mmol) of Cs2CO3 in DMF was added 5.79 g (44 mmol) of 4-oxohexanoic acid. After 5 minutes, 6.81 g (48 mmol) of iodomethane was added. The reaction mixture was stirred at ambient temperature for 16 hours. To the reaction was then added 250 mL of EtOAc and 250 mL of H2O. The layers were separated, and the organic layer was washed with 3×250 mL of H2O. The organic layer was then dried over Na2SO4 anhydrous, filtered, and concentrated under vacuum. The yield of methyl 4-oxohexanoate (16) was 4.15 g (65%), which was employed in Example 17 below. The layers were separated the organic layer was washed with 3×250 mL of H2O The organic layer was then dried over Na2SO4 anhydrous filtered concentrated under vacuum

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

Procedure: 4-Oxohexanoic acid (56.2 μl) was dissolved in methylene chloride (1.4 ml), and the solution was added with triethylamine (98.5 so 1) and pivalic chloride (58.0 μl) and stirred under an argon atmosphere at room temperature for 15 minutes. The resulting mixture was added to a methylene chloride (1.4 ml) solution of the crude benzyl (S)-2-((1-amino-2-methylpropyl)(benzyloxyphosphinoyl)oxy)-6-benzyloxycarbonylaminohexanate (140.5 mg) obtained in the step (e) of Example 24, and the mixture was further stirred at room temperature for 4 hours. Saturated aqueous ammonium chloride was added to the mixture, and then the organic substances were extracted with ethyl acetate and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15 g, hexane:acetone=3:1) to obtain benzyl (S)-6-benzyloxycarbonylamino-2-((2-methyl-1-(5-oxohexanoylamino)propyl)(benzyloxyphosphinoyl)oxy)hexanoate (105.4 mg, 63.1%). This compound was subjected to the measurement of molecular weight and then used in the following reaction without further purification. obtained in the step (e) of Example 24 the mixture was further stirred at room temperature for 4 hours the organic substances were extracted with ethyl acetate the organic layer was concentrated under reduced pressure The residue was purified by silica gel column chromatography (15 g, hexane:acetone=3:1)