benzyl N-[(2S)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl]carbamate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg, 3.75 mmol) in THF (4 mL) at −78° C. under N2, was added n-Butyllithium (2.3 mL of a 1.6 M solution in hexanes). The mixture was stirred at −78° C. for 30 min. To a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200 mg, 0.75 mmol) in THF (2 mL) under N2 at −15° C., was added isopropylmagnesium chloride (375 μL of a 2.0 M solution in THF). The resulting mixture was stirred at −15° C. for 15 min. This mixture was then added, by cannula to the solution above at −78° C. The mixture stirred at −78° C. for about 3 h, then warmed up gradually to room temperature and stirred overnight. The mixture was quenched with saturated NH4Cl. The aqueous layer was extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamate contaminated with about 30% of the unreacted starting material benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. The mixture was carried forward to the next step without further purification. LCMS calc.=394.18; found=394.2 (M+1)+. The resulting mixture was stirred at −15° C. for 15 min This mixture was then added, by cannula to the solution above at −78° C The mixture stirred at −78° C. for about 3 h warmed up gradually to room temperature stirred overnight The mixture was quenched with saturated NH4Cl The aqueous layer was extracted with CH2Cl2 (3×25 mL) dried (Na2SO4) concentrated in vacuo The residue was purified by flash chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-[(benzyloxy)methyl]-1H-imidazole (706 mg, 3.75 mmol) in THF (4 mL) at −78° C. under N2, was added n-Butyllithium (2.3 mL of a 1.6 M solution in hexanes). The mixture was stirred at −78° C. for 30 min. To a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (200 mg, 0.75 mmol) in THF (2 mL) under N2 at −15° C., was added isopropylmagnesium chloride (375 μL of a 2.0 M solution in THF). The resulting mixture was stirred at −15° C. for 15 min. This mixture was then added, by cannula to the solution above at −78° C. The mixture stirred at −78° C. for about 3 h, then warmed up gradually to room temperature and stirred overnight. The mixture was quenched with saturated NH4Cl. The aqueous layer was extracted with CH2Cl2 (3×25 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford benzyl ((1S)-2-{1-[(benzyloxy)methyl]-1H-imidazol-2-yl}-1-methyl-2-oxoethyl)carbamate contaminated with about 30% of the unreacted starting material benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate. The mixture was carried forward to the next step without further purification. LCMS calc.=394.18; found=394.2 (M+1)+. The resulting mixture was stirred at −15° C. for 15 min This mixture was then added, by cannula to the solution above at −78° C The mixture stirred at −78° C. for about 3 h warmed up gradually to room temperature stirred overnight The mixture was quenched with saturated NH4Cl The aqueous layer was extracted with CH2Cl2 (3×25 mL) dried (Na2SO4) concentrated in vacuo The residue was purified by flash chromatography

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (64 mg, 0.24 mmol) in CH2Cl2 (1 mL) was cooled to −20° C. under N2, and isopropylmagnesium chloride (120 μL of a 2.0 M solution in THF) was added dropwise. The mixture was stirred at −20° C. for 20 min. In a separate flask ethylmagnesium bromide (480 μL of a 2.0 M solution in Et2O) was added to a solution of 4-iodo-1-methyl-1-H-imidazole (109 mg, 0.48 mmol) in dry CH2Cl2 (1.5 mL) at room temperature. The resulting mixture was stirred for 20 min and then added by cannula to the solution above slowly. The resulting solution was left to stir overnight. Saturated NH4Cl was added to the reaction solution. The mixture was diluted with water and the aqueous phase was extracted with CH2Cl2 (2×25 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Flash chromatography of the residue yielded benzyl [(1S)-1-methyl-2-(1-methyl-1H-imidazol-4-yl)-2-oxoethyl]carbamate. LCMS calc.=288.14; found=288.3 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.65 (s, 1 H); 7.47 (s, 1 H); 7.35-7.28 (m, 5 H); 5.93 (d, J=6.9 Hz, 1 H); 5.29-5.25 (m, 1 H); 5.13 (s, 2 H); 3.73 (s, 3 H); 1.26 (d, J=7.1 Hz, 3H). The resulting mixture was stirred for 20 min added by cannula to the solution above slowly The resulting solution was left to stir overnight the aqueous phase was extracted with CH2Cl2 (2×25 mL) The combined organic extracts were dried (Na2SO4) concentrated in vacuo

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6M in hexanes, 1.76 mL, 2.83 mmol) was added dropwise to a stirred solution of 2-bromothiazole (462 mg, 251 μL, 2.82 mmol) in dry THF (13 mL) at −78° C. under N2 and the reaction was stirred at −78° C. for 45 min. Separately, isopropylmagnesium chloride (2M in THF, 0.94 mL, 1.99 mmol) was added to a stirred solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (500 mg, 1.88 mmol) in dry THF (4 mL) at −15° C. under N2. This solution was stirred for 15 min at −15° C. and was added dropwise to the above 2-lithiothiazole solution at −78° C. The reaction was allowed to warm to room temperature overnight and saturated NH4Cl (20 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to afford benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate. Rf=0.28 (20% EtOAc in hexanes). LCMS calc.=291.1; found=291.3 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.70 (d, J=3.1 Hz, 1H), 7.34-7.29 (m, 5H), 5.79 (d, J=6.6 Hz, 1H), 5.53-5.49 (m, 1H), 5.14-5.08 (m, 2H), 1.55 (d, J=6.4 Hz, 3H). This solution was stirred for 15 min at −15° C. to warm to room temperature overnight the mixture was extracted with EtOAc (3×30 mL) The combined extracts were washed with brine dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: n-Butyllithium (1.6M in hexanes, 1.76 mL, 2.83 mmol) was added dropwise to a stirred solution of 2-bromothiazole (462 mg, 251 μL, 2.82 mmol) in dry THF (13 mL) at −78° C. under N2 and the reaction was stirred at −78° C. for 45 min. Separately, isopropylmagnesium chloride (2M in THF, 0.94 mL, 1.99 mmol) was added to a stirred solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (500 mg, 1.88 mmol) in dry THF (4 mL) at −15° C. under N2. This solution was stirred for 15 min at −15° C. and was added dropwise to the above 2-lithiothiazole solution at −78° C. The reaction was allowed to warm to room temperature overnight and saturated NH4Cl (20 mL) and water (10 mL) were added and the mixture was extracted with EtOAc (3×30 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient) to afford benzyl [(1S)-1-methyl-2-oxo-2-(1,3-thiazol-2-yl)ethyl]carbamate. Rf=0.28 (20% EtOAc in hexanes). LCMS calc.=291.1; found=291.3 (M+1)+. 1H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.70 (d, J=3.1 Hz, 1H), 7.34-7.29 (m, 5H), 5.79 (d, J=6.6 Hz, 1H), 5.53-5.49 (m, 1H), 5.14-5.08 (m, 2H), 1.55 (d, J=6.4 Hz, 3H). This solution was stirred for 15 min at −15° C. to warm to room temperature overnight the mixture was extracted with EtOAc (3×30 mL) The combined extracts were washed with brine dried (Na2SO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 25×160 mm, 0-50% EtOAc in hexanes gradient)

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

Procedure: A solution of 2-(dimethylamino)ethanol (471 mg, 531 mL, 5.28 mmol) in dry hexanes (3.3 mL) was cooled to −5° C. and n-butyllithium (1.6 M in hexanes, 6.60 mL, 10.6 mmol) was added dropwise under N2. After 30 min at 0° C., the solution was cooled to −78° C. and a solution of 4-chloropyridine (obtained by washing a solution of the corresponding HCl salt (264 mg, 1.76 mmol) in CH2Cl2 (20 mL) with saturated K2CO3 (10 mL), then back extracting with CH2Cl2 (2×20 mL), combining the organic layers, drying (Na2SO4) and concentrating in vacuo) in hexanes (3.3 mL) was added dropwise by cannula. The solution became dark red in color and after 1 h at −78° C., a solution of the electrophile (prepared by adding isopropylmagnesium chloride (2M in THF, 1.29 mL, 2.59 mmol) to a solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (702 mg, 2.64 mmol) in dry THF (3.5 mL) at −15° C. under N2 and stirring for 15 min) was added by cannula. The reaction was allowed to warm slowly to room temperature overnight. Water (25 mL) and saturated NH4Cl (50 mL) were added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 40×160 mm, 0-30% EtOAc in hexanes gradient) to afford benzyl [(1S)-2-(4-chloropyridin-2-yl)-1-methyl-2-oxoethyl]carbamate. Rf=0.46 (20% EtOAc in hexanes). LCMS calc.=319.1; found=319.3 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 8.58 (d, J=5.0 Hz, 1H), 8.04 (s, 1H), 7.47 (dd, J=5.2, 2.0 Hz, 1H), 7.35-7.30 (m, 5H), 5.78 (s, 1H), 5.72 (m, 1H), 5.11 (m, 2H), 1.47 (d, J=7.0 Hz, 3H). back extracting with CH2Cl2 (2×20 mL) drying (Na2SO4) concentrating in vacuo) in hexanes (3.3 mL) was added dropwise by cannula a solution of the electrophile (prepared was added by cannula the mixture was extracted with EtOAc (3×50 mL) The combined extracts were dried (MgSO4) concentrated in vacuo to give the crude product This was purified by flash chromatography (Si, 40×160 mm, 0-30% EtOAc in hexanes gradient)

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −15° C. solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mL of a 2M solution in Et2O, 7.2 mmol). The reaction was stirred at −15° C. for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was then poured into saturated NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. Rf=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na)+. The reaction was warmed to room temperature stirred for 24 hours extracted with EtOAc (3×100 mL) The organic extracts were washed with water and brine (100 mL each) dried over Na2SO4 filtered concentrated Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes)

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a −15° C. solution of benzyl {(1S)-2-[methoxy(methyl)amino]-1-methyl-2-oxoethyl}carbamate (1.96 g, 7.36 mmol) in THF (9.4 mL) was added i-propyl magnesium chloride (3.6 mL of a 2M solution in Et2O, 7.2 mmol). The reaction was stirred at −15° C. for 15 minutes and then 3,5-difluorophenylmagnesium bromide (29.44 mL of a 0.5 M solution in THF, 14.72 mmol) was added. The reaction was warmed to room temperature and stirred for 24 hours. The reaction was then poured into saturated NH4Cl (100 mL) and extracted with EtOAc (3×100 mL). The organic extracts were washed with water and brine (100 mL each), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes) afforded benzyl [(1S)-2-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate. Rf=0.34 (15% EtOAc/hexanes). LCMS=342.3 (M+Na)+. The reaction was warmed to room temperature stirred for 24 hours extracted with EtOAc (3×100 mL) The organic extracts were washed with water and brine (100 mL each) dried over Na2SO4 filtered concentrated Purification of the residue by flash chromatography on silica gel (15% EtOAc/hexanes)

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

Procedure: Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: [(S)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester and 3,5-bis(trifluoromethyl)bromobenzene. Prepared

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

Procedure: Prepared according to the procedure described in Example 16, Step 2, using the following starting materials: [(S)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester and 1-bromo-3,5-difluorobenzene. Prepared

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

Procedure: [(S)-1-(Methoxy-methyl-carbamoyl)-ethyl]-carbamic acid benzyl ester (1 g, 3.8 mmol) and 4-bromochlorobenzene (0.9 g, 4.7 mmol) were dissolved in THF (10 mL). The solution was degassed with N2 for 5 minutes, and then cooled to 0° C. Isopropylmagnesium chloride (2M in THF; 4.7 mL, 9.4 mmol) was added slowly, and the reaction was stirred at room temperature for 2 hours. Once no starting material was seen by analytical tlc, the mixture was cooled to 0° C. 1N Aqueous HCl was added, and the organic layer was separated and washed with brine. After concentrating, the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (1 g). The solution was degassed with N2 for 5 minutes the mixture was cooled to 0° C the organic layer was separated washed with brine After concentrating the crude material was purified by silica gel chromatography

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

Procedure: N-Benzyloxycarbonyl-L-alanine (6.5 g, 28.5 mmol), N,O-dimethylhydroxylamine hydrochloride (3.4 g, 36.2 mmol), and N-hydroxybenzotriazole (4.8 g, 34.8 mmol) were dissolved in THF (32 mL) and cooled to 0° C. under N2. Diisopropylethylamine (12.3 mL, 71.3 mmol) was slowly added, maintaining the temperature below 25° C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.0 g, 36.2 mmol) was then added slowly, maintaining the temperature at 15-25° C. The slurry was stirred overnight at room temperature, and then cooled to 0° C. 1N Aqueous HCl (36 mL) was added slowly, and the mixture was warmed to room temperature and extracted with EtOAc. The combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and brine, and then concentrated and purified by silica gel chromatography to give the desired product as a white solid (6 g). maintaining the temperature below 25° C maintaining the temperature at 15-25° C cooled to 0° C the mixture was warmed to room temperature extracted with EtOAc The combined organic layers were washed with 10% aqueous HCl, saturated aqueous NaHCO3, and brine concentrated purified by silica gel chromatography