methyl 2-(phenylmethoxycarbonylamino)acetate

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

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

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

Procedure: Under a nitrogen atmosphere, a mixture of carbobenzyloxyglycine methyl ester (3.0 mmol), t-butanol (3.6 mmol), a zinc cluster Zn4O (OCOCF3)6 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, carbobenzyloxyglycine t-butyl ester was obtained in a yield of 83.8%.

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

Procedure: Under a nitrogen atmosphere, a mixture of carbobenzyloxyglycine methyl ester (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, carbobenzyloxyglycine t-butyl ester was obtained in a yield of 91.8%. was refluxed for 18 hours

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

Procedure: Under a nitrogen atmosphere, a mixture of carbobenzyloxyglycine methyl ester (3.0 mmol), t-butanol (3.6 mmol), the zinc cluster obtained in the above-described Example 5 (0.0375 mmol), and diisopropyl ether (5.0 ml) was refluxed for 18 hours. As a result, carbobenzyloxyglycine t-butyl ester was obtained in a yield of 91.8%. was refluxed for 18 hours

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

Procedure: A solution of Carbobenzyloxyglycine methyl ester (10 g, 44.8 mmol) and Methyl acrylate (4.03 mL, 44.8 mmol) in Toluene (100 mL) at 0° C. was added 60% NaH in mineral oil (1.971 g, 49.3 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 20 minutes. The reaction mixture was heated to 50° C. for 3 hrs. The reaction mixture was quenched with 10% citric acid solution until pH about 3, and then it was extracted with 100 mL×3 of EtOAc. The combined organic phases were washed with 100 mL of brine and dried over Na2SO4. Filtration and concentration to yield the product (12 g, 96% yield). MS (ES+) m/z: 278.2 (M+H); HPLC retention time: 2.44 min (analytical HPLC Method H). stirred for 20 minutes The reaction mixture was heated to 50° C. for 3 hrs The reaction mixture was quenched with 10% citric acid solution until pH about 3 it was extracted with 100 mL×3 of EtOAc The combined organic phases were washed with 100 mL of brine dried over Na2SO4 Filtration and concentration

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene (10 ml) was added to methyl-N-benzyloxycarbonyl-glycinate (1.50 g, 6.73 mmol) and tert-butoxybisdimethylaminomethane (1.83 ml, 8.91 mmol) and the mixture was stirred overnight at 70° C. The mixture was then washed with saturated brine and concentrated under reduced pressure. MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was separated and the organic layer was washed with saturated brine. A solution (1.23 g, 6.39 mmol) of 28% sodium methoxide in methanol was added dropwise and the mixture was concentrated under reduced pressure. Acetonitrile was added and O-methylisourea hydrochloride (0.72 g, 6.50 mmol) was added. The mixture was stirred overnight at 70° C. and concentrated. Water (5 ml) was added and the mixture was stirred for 1 hr. The precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-benzyloxycarbonylamino-1,6-dihydropyrimidine (1.43 g, 5.20 mmol). The property values were the same as in Example 3. The mixture was then washed with saturated brine concentrated under reduced pressure MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath the mixture was stirred at room temperature for 2 hr Thereafter, the mixture was separated the organic layer was washed with saturated brine the mixture was concentrated under reduced pressure Acetonitrile was added The mixture was stirred overnight at 70° C. concentrated Water (5 ml) was added the mixture was stirred for 1 hr The precipitate was collected by filtration and vacuum dried

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Toluene (10 ml) was added to N-benzyloxycarbonyl-glycine methyl ester (1.50 g, 6.73 mmol) and tert-butoxybisdimethylaminomethane (1.83 ml, 8.91 mmol) and the mixture was stirred overnight at 70° C. The mixture was washed with saturated brine and concentrated under reduced pressure. MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath and the mixture was stirred at room temperature for 2 hr. Thereafter, the mixture was separated and the organic layer was washed with saturated brine. A solution (1.23 g, 6.39 mmol) of 28% sodium methoxide in methanol was added drop-wise and the mixture was concentrated under reduced pressure. The solvent was substituted by acetonitrile and O-methylisourea hydrochloride (0.72 g, 6.50 mmol) was added. The mixture was stirred overnight at 70° C. and concentrated. Water (5 ml) was added and the mixture was stirred for 1 hr. The precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-benzyloxycarbonylamino-1,6-dihydropyrimidine (1.43 g, 5.20 mmol). The mixture was washed with saturated brine concentrated under reduced pressure MTBE (20 ml) and 1N hydrochloric acid (15 ml) were added to the residue in an ice bath the mixture was stirred at room temperature for 2 hr Thereafter, the mixture was separated the organic layer was washed with saturated brine the mixture was concentrated under reduced pressure was added The mixture was stirred overnight at 70° C. concentrated Water (5 ml) was added the mixture was stirred for 1 hr The precipitate was collected by filtration and vacuum dried

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

Procedure: 3-Bromotoluene (0.8 mL, 6.6 mmol) was added to Mg turnings (0.312 g, 13 mmol) in diethyl ether (5 mL) and an iodine crystal was also added. The reaction was stirred for 30 minutes. The solution was then transferred to another flask (via a pipet) to separate from the excess Mg. A solution of carbobenzyloxyglycine methyl ester (0.294 g, 1.32 mmol) in diethyl ether (3 mL) was then added to the solution of the Grignard reagent and the reaction was stirred for 1 hour. The reaction was then quenched with sat. aq ammonium chloride and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on Biotage chromatography (10% to 10% ethyl acetate/hexane) to give the title material (0.309 g, 62%) as an oil. 1H NMR (400 MHz, DMSO-d6) δ: 2.26 (6H, s), 3.82 (2H, d, J=5.81 Hz), 4.99 (2H, s), 5.76 (1H, s), 6.79 (1H, t, J=5.56 Hz), 7.01 (2H, d, J=7.07 Hz), 7.09-7.40 (11H, m). LC/MS (M−H)−: 374. HPLC ret. time (Condition B): 2.133 min. The solution was then transferred to another flask (via a pipet) to separate from the excess Mg the reaction was stirred for 1 hour The reaction was then quenched with sat. aq ammonium chloride the aqueous phase was extracted with ethyl acetate (3×) The combined organic layers were dried over anhydrous magnesium sulfate filtered concentrated The residue was purified on Biotage chromatography (10% to 10% ethyl acetate/hexane)

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

Procedure: A solution of 5.58 g (25 mmol) of N-benzyloxycarbonyl glycine methyl ester in dry THF (70 ml) is added dropwise to a solution at -78° C. of lithium diisopropylamine (8.76 ml, 62.5 mmol) and tetramethylethylene diamine (9.43 ml, 62.5 mmol) in dry THF (100 ml), under nitrogen. After the addition is complete, the solution is stirred for 2 hours at -78° C., then 15 minutes at -30° C. and cooled to -78° C. A solution of 5.36 g (25 mmol) of iodomethyl-trimethylsilane in dry hexamethylphosphoramide (39 ml) is added dropwise to the resultant syrupy mixture. After the addition is complete, the reaction mixture is warmed up to -50° C., kept at this temperature for 1 hour and cooled to -78° C., just before hydrolysis. The reaction mixture is quenched by addition of water and ammonium chloride and diluted with ether. The organic layer is washed with 1N potassium hydrogen sulfate, twice with water and dried over sodium sulfate. The solvent is evaporated and the residue obtained (8.03 g) is purified by flash chromatography (silica gel,ethyl acetate/petroleum ether: 2/8). 4.30 g of the title compound are obtained (yield: 56%) (colorless oil). Rf : 0.51 (ethyl acetate/petroleum ether: 2/8). After the addition 15 minutes at -30° C. and cooled to -78° C After the addition the reaction mixture is warmed up to -50° C. kept at this temperature for 1 hour cooled to -78° C., just before hydrolysis The reaction mixture is quenched by addition of water and ammonium chloride diluted with ether The organic layer is washed with 1N potassium hydrogen sulfate, twice with water dried over sodium sulfate The solvent is evaporated the residue obtained (8.03 g) is purified by flash chromatography (silica gel,ethyl acetate/petroleum ether: 2/8)

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

Procedure: A solution of carbobenzyloxyglycine methyl ester (10 g, 44.8 mmol) and methyl acrylate (4.03 mL, 44.8 mmol) in toluene (100 mL) at 0° C. was added 60% NaH in mineral oil (1.971 g, 49.3 mmol) which was stirred for 10 minutes, and then it was warmed up to RT and stirred for 20 minutes. The reaction mixture was heated to 50° C. for 3 hrs. The reaction mixture was quenched with 10% citric acid solution until pH about 3, and then it was extracted with 100 mL×3 of EtOAc. The combined organic phases were washed with 100 mL of brine and dried over Na2SO4. Filtration and concentration to yield the product (12 g, 96% yield). MS(ES+) m/z: 278.2 (M+H); HPLC retention time: 2.44 min (analytical HPLC Method B). stirred for 20 minutes The reaction mixture was heated to 50° C. for 3 hrs The reaction mixture was quenched with 10% citric acid solution until pH about 3 it was extracted with 100 mL×3 of EtOAc The combined organic phases were washed with 100 mL of brine dried over Na2SO4 Filtration and concentration

Conditions: temp:-70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of lithium bis(trimethylsilyl)amide (44.8 ml, 1M solution) in anhydrous THF (50 ml) was cooled to −70° C. under argon in a dry flask with stirring. To the solution was added Cbz glycine methyl ester (10.0 g) in THF (20 mL) dropwise while maintaining the reaction temperature at −70° C. After 30 min stirring at −70° C., a solution of the (E)-tetradec-2-enoyl chloride (12.1 g) in THF (10 mL) was added slowly at −70° C. The reaction mixture was stirred at −70° C. for 1 hr and then allowed to warm up to 0° C. The reaction was quenched with aqueous citric acid solution (5%, 300 ml) and warmed up to room temperature. The crude product was extracted with ethyl acetate (500 ml). The ethyl acetate phase was washed with DI water twice and dried with sodium sulfate. The solvent was removed under vacuum to yield oily residue, which was purified by silica gel column chromatography. Pure product was obtained after column purification as a clear oil (12.8 g, 66.2% yield). Proton NMR(CDCl3) δ 0.88 (t, 3H), 1.26 (m, 16H), 1.43 (m, 2H), 2.22 (m, 2H), 3.67 (s, 3H), 4.53 (s, 2H), 5.24 (s, 2H), 6.94 (d, 1H), 7.05 (td, 1H). 7.36 (m, 5H). After 30 min stirring at −70° C. The reaction mixture was stirred at −70° C. for 1 hr to warm up to 0° C The reaction was quenched with aqueous citric acid solution (5%, 300 ml) warmed up to room temperature The crude product was extracted with ethyl acetate (500 ml) The ethyl acetate phase was washed with DI water twice dried with sodium sulfate The solvent was removed under vacuum to yield oily residue, which was purified by silica gel column chromatography Pure product was obtained