1-aminopropan-2-one

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:0.00; pressure:0.00; stir:

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

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (201 mg, 0.43 mmol), 1-aminopropan-2-one (47 mg, 0.43 mmol) and T3P (641 μL of 50% w/w, 1.08 mmol) was added 2-methyltetrahydrofuran (1 mL) and the reaction mixture was then heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 20-70% EtOAC in DCM as eluent to afford N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (92 mg, 41%) as a yellow solid. ESI-MS m/z calc. 521.6. found 522.5 (M+1)+; Retention time: 1.48 minutes (3 min run). The reaction mixture was cooled to room temperature partitioned between EtOAc/saturated aq. NaHCO3 The layers were separated the aqueous layer was extracted with EtOAc (2×) The combined organics were dried over Na2SO4 filtered concentrated in vacuo to a dark foam The crude product was purified by silica gel column chromatography

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (201 mg, 0.43 mmol), 1-aminopropan-2-one (47 mg, 0.43 mmol) and T3P (641 μL of 50% w/w, 1.08 mmol) was added 2-methyltetrahydrofuran (1 mL) and the reaction mixture was then heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 20-70% EtOAC in DCM as eluent to afford N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (92 mg, 41%) as a yellow solid. ESI-MS m/z calc. 521.6. found 522.5 (M+1)+; Retention time: 1.48 minutes (3 min run). The reaction mixture was cooled to room temperature partitioned between EtOAc/saturated aq. NaHCO3 The layers were separated the aqueous layer was extracted with EtOAc (2×) The combined organics were dried over Na2SO4 filtered concentrated in vacuo to a dark foam The crude product was purified by silica gel column chromatography

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

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

Procedure: To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)acetic acid (200 mg, 0.5 mmol) in anhydrous CH2Cl2 (10 mL) was added 1-aminopropan-2-one (119 mg, 0.7 mmol), HOBt (195 mg, 1.44 mmol), EDCl (283 mg, 1.44 mmol) and DIEA (620 mg, 4.8 mol) at 0° C. The formed mixture was stirred overnight at ambient temperature under nitrogen. Then the reaction mixture was washed with 1N aq HCl and water. The organic phase was dried over Na2SO4, filtered and concentrated to afford the residue, which was purified by prep TLC to give 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-N-(2-oxopropyl)acetamide (118 mg, 50%). 1H NMR (400 MHz, CDCl3): δ=1.43 (d, 3H), 2.06 (s, 3H), 2.20 (m, 1H), 2.43 (m, 2H), 2.68 (m, 1H), 2.86 (m, 2H), 3.90 (m, 1H), 4.12 (m, 1H), 5.51 (m, 1H), 6.53 (m, 1H), 6.78 (m, 2H), 7.14 (m, 2H), 7.30 (m, 5H). Then the reaction mixture was washed with 1N aq HCl and water The organic phase was dried over Na2SO4 filtered concentrated to afford the residue, which was purified by prep TLC

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxylic acid (201 mg, 0.43 mmol), 1-aminopropan-2-one (47 mg, 0.43 mmol) and T3P (641 μL of 50% w/w, 1.08 mmol) was added 2-methyltetrahydrofuran (1 mL) and the reaction mixture was then heated at 75° C. for 2 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc/saturated aq. NaHCO3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to a dark foam. The crude product was purified by silica gel column chromatography using 20-70% EtOAC in DCM as eluent to afford N-acetonyl-8-benzyl-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3,8-diazaspiro[5.5]undecane-10-carboxamide (92 mg, 41%) as a yellow solid. ESI-MS m/z calc. 521.6. Found 522.5 (M+1)+; Retention time: 1.48 minutes (3 min run). The reaction mixture was cooled to room temperature partitioned between EtOAc/saturated aq. NaHCO3 The layers were separated the aqueous layer was extracted with EtOAc (2×) The combined organics were dried over Na2SO4 filtered concentrated in vacuo to a dark foam The crude product was purified by silica gel column chromatography

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

Procedure: To a suspension of 40 g (0.370 mol) of aminoacetone in 500 ml of dry dichloromethane, 50 g (0.350 mol) of nicotinoyl chloride was added dropwise at room temperature under a nitrogen atmosphere. The mixture was refluxed 5 h followed by stirring overnight at room temperature. The colorless precipitate was collected by filtration and dissolved in 400 ml of water. After basification with ammonia the aqueous solution was extracted with 3×400 ml of dichloromethane. The combined organic phases were treated with charcoal and dried over magnesium sulphate. Removal of the solvent in vacuo gave a colorless solid, 73. Yield: 30.0 g (0.170 mol, 48%). was added dropwise at room temperature under a nitrogen atmosphere The mixture was refluxed 5 h The colorless precipitate was collected by filtration dissolved in 400 ml of water After basification with ammonia the aqueous solution was extracted with 3×400 ml of dichloromethane The combined organic phases were treated with charcoal dried over magnesium sulphate Removal of the solvent in vacuo gave a colorless solid, 73