5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid

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

Procedure: A solution of (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (432 mg, 70% pure, 0.70 mmol), AcOH (0.10 mL) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (470 mg, 2.0 mmol) in DCE (20 mL) was stirred at 75° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (0.633 g, 3.0 mmol). The reaction was allowed to proceed overnight with stirring at room temperature. The reaction mixture was quenched with water and concentrated under reduced pressure to afford a residue which was purified by on a Biotage SP4 utilizing a gradient of 5-50% MeOH in DCM to afford (S)-4-(34(S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (300 mg, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.84 (s, 2H), 4.57 (s, 4H), 4.29-4.19 (m, 2H), 3.66-3.56 (m, 4H), 2.98-2.90 (m, 2H), 2.49-2.37 (m, 4H), 1.95-1.41 (m, 42H); ESMS m/z: 410.8 (M/2+H)+. The reaction mixture was quenched with water concentrated under reduced pressure to afford a residue which was purified by on a Biotage

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

Procedure: A suspension of (9S,13S)-15-benzyl 13,9-di-tert-butyl 3,11-dioxo-1-phenyl-2-oxa-4,10,12-triazapentadecane-9,13,15-tricarboxylate (4.30 g, 6.64 mmol), 10% Pd/C (1.0 g) and ammonium formate (4.0 g) in EtOH (70 mL) under a empty balloon was stirred at room temperature overnight. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The solvent was evaporated to give (S)-4-(3-(S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (4.07 g, 70%) which was used without further purification. ESMS m/z: 432.3 (M/2+H)+. The reaction mixture was filtered through a pad of celite washed with EtOAc The solvent was evaporated

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

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

Procedure: A suspension of oxycodone free base (100 mg, 0.317 mmol) in 1.5 mL of anhydrous acetonitrile was stirred for 20 min with DIEA (0.2 mL 1.15 mmol). DMAP (63 mg, 0.516 mmol) and DCC (112 mg, 0.545 mmol) were then added to the stirred suspension. After 5 min 1-2 (150 mg, 0.8 mmol) was added, the mixture stirred for 16 h at rt, and the resulting orange suspension concentrated to an oil under reduced pressure. The concentrated mixture was stirred with 6 mL of acetone for 10 min, and the precipitated DCU removed by filtration. The filtrate was concentrated to give a brown oil. HPLC analysis of the oil indicated that the primary reaction product was 1-3. The concentrated oil was subjected to reverse phase C-18 silica gel chromatography using a gradient of 25–40% acetonitrile in 0.07% aqueous TFA as eluent. Evaporation of the eluent from the fraction containing 1-3 gave 82 mg (53% yield) of a colorless oil which was greater than >99% pure 1-3 (HPLC). the resulting orange suspension concentrated to an oil under reduced pressure The concentrated mixture was stirred with 6 mL of acetone for 10 min the precipitated DCU removed by filtration The filtrate was concentrated to give a brown oil Evaporation of the eluent from the fraction containing 1-3

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

Procedure: Potassium tert-butoxide (2.7 g, 24 mmol) was dissolved in 17 mL of anhydrous THF at rt. After 5 min glutaric anhydride (2.4 g, 21 mmol) was added and the resulting suspension stirred for 2 h at rt. The reaction mixture was then quenched with 20 mL of 1 M KHSO4, extracted with 50 mL of EtOAc, adjusted to pH 2–3 with 1 M KHSO4 and extracted twice with 50 mL EtOAc. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil which was purified by silica gel flash chromatography (eluent: EtOAc:Hexanes- 1:1) to give 1.65 g (35% yield) pure (TLC) 1-2. The reaction mixture was then quenched with 20 mL of 1 M KHSO4 extracted with 50 mL of EtOAc extracted twice with 50 mL EtOAc The combined extracts were dried over anhydrous magnesium sulfate filtered concentrated to give a yellow oil which was purified by silica gel flash chromatography (eluent: EtOAc:Hexanes- 1:1) to give 1.65 g (35% yield) pure (TLC) 1-2

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diphenylphosphoryl azide (12.25 g.) was added dropwise to a solution of glutaric acid mono-tert-butyl ester (8.38 g.) in dry pyridine (37 ml.) and stirred at 90° C. for 40 minutes to give 3-tert-butoxycarbonylpropyl isocyanate (I.R.: 2270 cm-1).

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Glutaric anhydride (11.41 g.) was added portion-wise to a solution of potassium tert-butoxide (14.02 g.) in tetrahydrofuran (100 ml.) at ambient temperature. After the exothermic reaction was ceased, the reaction mixture was stirred at 40° C. for 15 minutes. Tetrahydrofuran was distilled off under reduced pressure. The residue was dissolved in water. After ethyl acetate was added, the solution was adjusted to pH 9 with aqueous potassium carbonate solution under ice-cooling. The separated water layer was washed with ethyl acetate, treated with activated charcoal, overlapped with ethyl acetate, and then adjusted to pH 4.0 with 10% hydrochloric acid under ice-cooling. The ethyl acetate layer was dried over magnesium sulfate, treated with activated charcoal, filtered and concentrated under reduced pressure to give glutaric acid mono-tert-butyl ester (10 g.). After the exothermic reaction Tetrahydrofuran was distilled off under reduced pressure The residue was dissolved in water After ethyl acetate was added cooling The separated water layer was washed with ethyl acetate treated with activated charcoal cooling The ethyl acetate layer was dried over magnesium sulfate treated with activated charcoal filtered concentrated under reduced pressure

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

Procedure: A solution of (S)-4-(3-((S)-6-amino-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (432 mg, 70% pure, 0.70 mmol), AcOH (0.10 mL) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (470 mg, 2.0 mmol) in DCE (20 mL) was stirred at 75° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated with NaBH(OAc)3 (0.633 g, 3.0 mmol). The reaction was allowed to proceed overnight with stirring at room temperature. The reaction mixture was quenched with water and concentrated under reduced pressure to afford a residue which was purified by on a Biotage SP4 utilizing a gradient of 5-50% MeOH in DCM to afford (S)-4-(34(S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (300 mg, 52%) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 6.99 (s, 2H), 6.84 (s, 2H), 4.57 (s, 4H), 4.29-4.19 (m, 2H), 3.66-3.56 (m, 4H), 2.98-2.90 (m, 2H), 2.49-2.37 (m, 4H), 1.95-1.41 (m, 42H); ESMS m/z: 410.8 (M/2+H)+. The reaction mixture was quenched with water concentrated under reduced pressure to afford a residue which was purified by on a Biotage