4-[(2-methylpropan-2-yl)oxycarbonyl]morpholine-3-carboxylic acid

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

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

Conditions: temp:23.01; pressure:0.00; stir:

Procedure: Prior to irradiation, the reaction mixture was degassed by bubbling argon for 20 minutes diluted with saturated aqueous NaHCO3 extracted with Et2O (3 x 100 mL) washed with water and brine dried over MgSO4 concentrated in vacuo Fluka, 230-400 mesh, solvent system: 17% ethyl acetate/hexane

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 N-boc-morpholine-3-carboxylic acid (2 g, 9.379 mmol) in 60 mL of dichloromethane and was added TBTU (3.313 g, 10.32 mmol) and diisopropylethyl amine (1.96 mL, 11.25 mmol). The reaction was stirred for 30 min. In the meantime, a solution of D-alanine methyl ester hydrochloride (1.93 g, 18.76 mmol) and diisopropylethylamine (3.27 mL, 18.76 mmol) in 20 mL of dichloromethane was prepared and finally added to the reaction mixture. The reaction was left stirring at room temperature for 2 h. UPLC-MS analysis showed the expected product (peak at 0.60 min, m/z=317 (M+1), 261 (M−t-Bu+1), 217 (M−Boc+1)). The reaction was diluted with dichloromethane and extracted with sat. NaHCO3, dried (Na2SO4), and the solvent removed. The crude (5.56 g) was taken to the next step without further purification. finally added to the reaction mixture The reaction was left stirring at room temperature for 2 h extracted with sat. NaHCO3 dried (Na2SO4) the solvent removed The crude (5.56 g) was taken to the next step without further purification

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

Procedure: 4-{[(1,1-Dimethylethyl)oxy]carbonyl}morpholine-3-carboxylic acid (0.5 g, 2.162 mmol), ammonium chloride (0.347 g, 6.49 mmol), EDC (0.622 g, 3.24 mmol), HOBt (0.993 g, 6.49 mmol) and DIPEA (1.699 mL, 9.73 mmol) were stirred in DMF (10 mL) at room temperature overnight. Saturated NaHCO3 was then added and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give the title compound as a yellow gum. the mixture was extracted with EtOAc (2×) The combined organic extracts were washed with brine dried over MgSO4 filtered concentrated in vacuo

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

Procedure: To a cold (0° C.) solution of morpholine-3,4-dicarboxylic acid 4-tert-butyl ester (100 mg; 0.432 mmol) and 3-amino-5-t-butylisoxazole (58.9 mg; 0.42 mmol) in anhydrous pyridine (1.2 mL) is added phosphorous oxychloride (0.039 mL; 0.432 mmol). The reaction mixture is left stirring at room temperature for 1 hour. After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution and extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 354 [M+H+]. The reaction mixture is left After this time, the reaction mixture is quenched with saturated NH4Cl aqueous solution extracted with ethyl acetate twice washed with brine dried over Na2SO4 filtered concentrated under reduced pressure Purification by flash chromatography on silica gel

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

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

Procedure: Saturated aqueous NaHCO3 (15 mL) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.09 g, 5.0 mmol) (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580, WO 2006/114606 and US 2010/210640) in acetone (50 mL) at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added for 20 min at 0° C. After addition, the reaction mixture was allowed to room temperature (RT) and further maintained overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at RT for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL), acidified with 6N HCl and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to give title compound as a white solid (760 mg). (M−H)−229.9. After addition was allowed to room temperature (RT) further maintained overnight filtered through a pad of Celite concentrated under vacuum treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL) extracted with EtOAc (5×10 mL) The combined organic layers were dried over Na2SO4 the solvent was concentrated

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

Procedure: Saturated aqueous NaHCO3 (15 mL) was added to a stirred solution of tert-butyl 3-(hydroxymethyl)morpholine-4-carboxylate (1.09 g, 5.0 mmol) (Organic and Bio-Organic Chemistry (1972-1999); (1985); 2577-2580, WO 2006/114606 and US 2010/210640) in acetone (50 mL) at 0° C. Solid NaBr (0.1 g, 1 mmol) and TEMPO (0.015 g, 0.1 mmol) were added. Trichloroisocyanuric acid (2.32 g, 10.0 mmol) was then added for 20 min at 0° C. After addition, the reaction mixture was allowed to room temperature (RT) and further maintained overnight. 2-Propanol (3 mL) was added and the resulting solution was stirred at RT for 30 min, filtered through a pad of Celite, concentrated under vacuum, and treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL), acidified with 6N HCl and extracted with EtOAc (5×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to give title compound as a white solid (760 mg). (M−H)−229.9. After addition was allowed to room temperature (RT) further maintained overnight filtered through a pad of Celite concentrated under vacuum treated with saturated aqueous Na2CO3 solution (15 mL) The aqueous solution was extracted with EtOAc (5 mL) extracted with EtOAc (5×10 mL) The combined organic layers were dried over Na2SO4 the solvent was concentrated

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1.500 g, 6.49 mmol) and 1,1′-carbonyldiimidazole (1.578 g, 9.73 mmol) in N,N-dimethylformamide (2 mL) and dichloromethane (6 mL) was stirred 4.5 h at room temperature under nitrogen. N,N-Diisopropylethylamine (2.260 mL, 12.97 mmol) was added followed by 3,5-dibromopyrazin-2-amine (3.28 g, 12.97 mmol). The resulting mixture was stirred and heated at 50° C. under a reflux condenser under nitrogen for 2 d. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexanes) to give the desired product (2.136 g, 4.58 mmol, 71% yield) as a slightly yellow foam-solid. MS (ESI) m/z 467 [M+1]+. The resulting mixture was concentrated under reduced pressure The residue was diluted with water extracted 3 times with ethyl acetate The combined organics were washed with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 4-(tert-butoxycarbonyl)morpholine-3-carboxylic acid (1.500 g, 6.49 mmol) and 1,1′-carbonyldiimidazole (1.578 g, 9.73 mmol) in N,N-dimethylformamide (2 mL) and dichloromethane (6 mL) was stirred 4.5 h at room temperature under nitrogen. N,N-Diisopropylethylamine (2.260 mL, 12.97 mmol) was added followed by 3,5-dibromopyrazin-2-amine (3.28 g, 12.97 mmol). The resulting mixture was stirred and heated at 50° C. under a reflux condenser under nitrogen for 2 d. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted 3 times with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified using flash chromatography (20-30-50% ethyl acetate in hexanes) to give the desired product (2.136 g, 4.58 mmol, 71% yield) as a slightly yellow foam-solid. MS (ESI) m/z 467 [M+1]+. The resulting mixture was concentrated under reduced pressure The residue was diluted with water extracted 3 times with ethyl acetate The combined organics were washed with water and brine dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified