methyl (2S)-3-(4-iodophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate

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

Procedure: To a suspension of zinc dust (800 mmol, 52.29 g) in THF (26.0 mL) was added 1,2-dibromoethane (53.2 mmol, 4.58 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased (observed). The suspension was cooled to room temperature, trimethylchlorosilane (26.6 mmol, 3.38 mL) was added and the mixture was stirred for 15 min. A suspension of 5-iodo-1,3,6-trimethyl uracil (266 mmol, 74.6 g) in DMA (225 mL) was warmed to obtain a clear solution and was added in one portion to the reaction mixture. After addition, the mixture was heated to 70° C. The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction. The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride indicated the absence of starting material. The reaction mixture was diluted with THF (140 mL), was cooled to room temperature and the excess zinc dust was allowed to settle over 2-3 h. This solution containing the zinc compound (266 mmol) was added to a solution of Pd(dba)2 (8 mmol, 4.6 g), tri-o-tolylphosphine [P(Tol)3] (29.6 mmol, 9.0 g) and N-[(1,1-dimethylethoxy)carbonyl]-4-iodo-L-phenylalanine methyl ester (186 mmol, 75.56 g) in THF (280 mL) at room temperature and the light yellow mixture was stirred for 48 h at 50-55° C. The reaction mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×750 mL). The combined extracts were washed with brine solution (1.5 L) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel column chromatography using a Biotage (75m) column to obtain 57.88 g (72% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. EI-HRMS m/e calcd for C22H29N3O6 (M+) 431.2056, found 431.2054. was warmed to obtain a clear solution was added in one portion to the reaction mixture After addition the mixture was heated to 70° C The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride The reaction mixture was diluted with THF (140 mL) was cooled to room temperature to settle over 2-3 h the light yellow mixture was stirred for 48 h at 50-55° C was extracted with ethyl acetate (3×750 mL) The combined extracts were washed with brine solution (1.5 L) dried over anhydrous magnesium sulfate Filtration of the drying agent and concentration gave the crude product which 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 zinc dust (800 mmol, 52.29 g) in THF (26.0 mL) was added 1,2-dibromoethane (53.2 mmol, 4.58 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased (observed). The suspension was cooled to room temperature, trimethylchlorosilane (26.6 mmol, 3.38 mL) was added and the mixture was stirred for 15 min. A suspension of 5-iodo-1,3,6-trimethyl uracil (266 mmol, 74.6 g) in DMA (225 mL) was warmed to obtain a clear solution and was added in one portion to the reaction mixture. After addition, the mixture was heated to 70° C. The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction. The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride indicated the absence of starting material. The reaction mixture was diluted with THF (140 mL), was cooled to room temperature and the excess zinc dust was allowed to settle over 2-3 h. This solution containing the zinc compound (266 mmol) was added to a solution of Pd(dba)2 (8 mmol, 4.6 g), tri-o-tolylphosphine [P(Tol)3] (29.6 mmol, 9.0 g) and N-[(1,1-dimethylethoxy)carbonyl]-4-iodo-L-phenylalanine methyl ester (186 mmol, 75.56 g) in THF (280 mL) at room temperature and the light yellow mixture was stirred for 48 h at 50-55° C. The reaction mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×750 mL). The combined extracts were washed with brine solution (1.5 L) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel column chromatography using a Biotage (75m) column to obtain 57.88 g (72% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. EI-HRMS m/e calcd for C22H29N3O6 (M+) 431.2056, found 431.2054. was warmed to obtain a clear solution was added in one portion to the reaction mixture After addition the mixture was heated to 70° C The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride The reaction mixture was diluted with THF (140 mL) was cooled to room temperature to settle over 2-3 h the light yellow mixture was stirred for 48 h at 50-55° C was extracted with ethyl acetate (3×750 mL) The combined extracts were washed with brine solution (1.5 L) dried over anhydrous magnesium sulfate Filtration of the drying agent and concentration gave the crude product which was purified by silica gel column chromatography

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

Procedure: To a suspension of zinc dust (30 mmol, 2.0 g) in THF (3.0 mL) was added 1,2-dibromoethane (2.0 mmol, 0.174 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased (observed). This process was repeated three times. Then, the suspension was cooled to r.t. and trimethylchlorosilane (1.0 mmol, 0.15 mL) was added and the mixture was stirred for 10 min. A hot (the iodo compound was not very soluble in either solvent and it precipitated upon cooling to room temperature) solution of 5-iodo-1,3-dimethyluracil (11.0 mmol, 2.92 g) in THF (3.0 mL) and DMA (10 mL) was added to the zinc suspension. After addition, the mixture was heated to 73° C. The internal temperature of the reaction mixture rose to 77-78° C., due to the exothermic reaction. The reaction mixture was stirred at a bath temperature of 73° C. for 1.5 h and then was cooled to room temperature and stirred another 1.5 h. 1H-NMR of a hydrolysate of a 0.25 mL aliquot of the mixture indicated the presence of traces of starting material and iodolysis of a 0.25 mL aliquot of the mixture gave the iodide back. The reaction mixture was heated to 70° C. and stirred for another 30 min. The reaction mixture was diluted with THF (5 mL) after cooling to room temperature and the excess zinc was allowed to settle for 30-60 min. The above prepared zinc compound (5.5 mmol) was added to a suspension of Pd(dba)2 (0.07 mmol, 40 mg), trifurylphosphine (TFP) (0.26 mmol, 66.6 mg) and Boc-4-iodo-L-phenylalanine methyl ester (4.5 mmol, 1.823 g) in THF (10 mL) at room temperature and the light yellow mixture was stirred for 15 h. The mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solution gave the crude product which was purified by column chromatography to obtain 0.80 g (43%) of N-[(1,1-dimethylethoxy)carbonyl]-4-[1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)]-L-phenylalanine methyl ester as a white solid: mp 65-69° C. EI-HRMS m/e calcd for C21H27N3O6 (M+) 418.1978, found 418.1965. after cooling to room temperature to settle for 30-60 min the light yellow mixture was stirred for 15 h was extracted with ethyl acetate (3×50 mL) The combined extracts were washed with brine solution dried over anhydrous magnesium sulfate Filtration of the drying agent and concentration of the solution gave the crude product which was purified by column chromatography

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

Procedure: To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate:hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.04 (2dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3H), 4.58 (m, 1H), 4.97 (brs, NH, 1H), 6.88 (d, J=7.8 Hz, 2H), 7.62 (d, J=7.8 Hz, 2H); HRMS (ESI, M+1) calcd for C15H21INO4 406.0510, found 406.0515. the mixture was washed with 3×100 mL of deionized water The organic layer was separated dried over Na2SO4 concentrated under vacuum

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

Procedure: To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate: hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.04 (2dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3H), 4.58 (m, 1H), 4.97 (brs, NH, 1H), 6.88 (d, J=7.8 Hz, 2H), 7.62 (d, J=7.8 Hz, 2H); HRMS (ESI, M+1) calcd for C15H21INO4 406.0510. Found 406.0515. the mixture was washed with 3×100 mL of deionized water The organic layer was separated dried over Na2SO4 concentrated under vacuum

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

Procedure: To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate:hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 3.04 (2 dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3 H), 4.58 (m, 1 H), 4.97 (brs, NH, 1 H), 6.88 (d, J=7.8 Hz, 2 H), 7.62 (d, J=7.8 Hz, 2 H); HRMS (ESI, M+1) calcd for C15H21INO4406.0510, found 406.0515. the mixture was washed with 3×100 mL of deionized water The organic layer was separated dried over Na2SO4 concentrated under vacuum

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

Procedure: To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate:hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 3.04 (2 dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3 H), 4.58 (m, 1 H), 4.97 (brs, NH, 1 H), 6.88 (d, J=7.8 Hz, 2 H), 7.62 (d, J=7.8 Hz, 2 H); HRMS (ESI, M+1) calcd for C15H21INO4406.0510, found 406.0515. the mixture was washed with 3×100 mL of deionized water The organic layer was separated dried over Na2SO4 concentrated under vacuum

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

Procedure: To a solution of 5.02 g (12.8 mmol) of N-Boc-4-iodophenylalanine in 60 mL of DMF was added NaHCO3 (1.42 g, 16.9 mmol) followed by methyl iodide (3.0 mL, 48.2 mmol). The mixture was stirred under argon for 40 h at room temperature. After this time, 150 mL of ethyl acetate was added, and the mixture was washed with 3×100 mL of deionized water. The organic layer was separated, dried over Na2SO4, and concentrated under vacuum to yield 5.80 g of a yellow oily solid. The crude product was purified by flash chromatography (1:5 ethyl acetate:hexanes) to afford a white solid (4.72 g, 91%). mp 79-80° C.; 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9 H), 3.04 (2 dd, J=4.8 Hz, 12.8 Hz), 3.72 (s, 3 H), 4.58 (m, 1 H), 4.97 (brs, NH, 1 H), 6.88 (d, J=7.8 Hz, 2 H), 7.62 (d, J=7.8 Hz, 2 H); HRMS (ESI, M+1) calcd for C15H21INO4406.0510, found 406.0515. the mixture was washed with 3×100 mL of deionized water The organic layer was separated dried over Na2SO4 concentrated under vacuum

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

Procedure: To a suspension of zinc dust (0.66 g, 10 mmol) in THF (1.0 mL) was added 1,2-dibromoethane (86 μL, 1 mmol)) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased. Then, the suspension was cooled to room temperature and trimethylchlorosilane (0.126 mL, 1 mmol)) was added and the mixture was stirred for 15 min. A mixture of 1,4-dimethyl-3-iodo-2(1H)-pyridone and 1,4-dimethyl-5-iodo-2(1H)-pyridone (0.92 g, 3.69 mmol) in DMA (3 mL) was warmed to effect dissolution and was added in one portion to the reaction mixture. After addition, the mixture was heated to 70° C. and was stirred for 15 h, at which time the TLC analysis of an aliquot, which had been quenched with saturated ammonium chloride solution, indicated the absence of starting material. The reaction mixture was diluted with THF (4 mL) and was cooled to room temperature. The excess zinc dust was allowed to settle until a clear supernatant liquid formed (˜3 h). The above prepared solution containing the zinc compound (3.69 mmol) was added to a solution of Pd(dba)2 (54 mg, 0.1 mmol), trifurylphosphine (102 mg, 0.4 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-iodo-L-phenylalanine methyl ester (1.01 g, 2.5 mmol) in THF (4 mL) at room temperature and the light yellow mixture was stirred for 15 h at 50° C. Then, the mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×50 mL). The combined extracts were washed with brine solution (150 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column to obtain 0.141 g (14% yield) of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C22H28N2O5 (M+Na) 423.1890, found 423.1894 and 0.350 g (35% yield) of N-[(1,1-dimethylethoxyl)carbonyl]-4-(1,4-dimethyl-2-oxo-5-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C22H28N2O5 (M+Na) 423.1890, found 423.1897 was warmed dissolution was added in one portion to the reaction mixture After addition the mixture was heated to 70° C. was stirred for 15 h, at which time the TLC analysis of an aliquot, which had been quenched with saturated ammonium chloride solution The reaction mixture was diluted with THF (4 mL) was cooled to room temperature formed (˜3 h) The above prepared solution the light yellow mixture was stirred for 15 h at 50° C was extracted with ethyl acetate (3×50 mL) The combined extracts were washed with brine solution (150 mL) were dried over anhydrous magnesium sulfate Filtration of the drying agent and concentration gave the crude product which was purified by silica gel chromatography on a Biotage (40 m) column

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

Procedure: A mixture of N-Boc-4-iodo-L-phenylalanine methyl ester (810 mg, 2 mmol, Lei, H et al, ibid) tetrakis(triphenylphosphine)palladium (0) (231 mg, 0.2 mmol), aqueous sodium carbonate (4 mmol, 2 ml of a 2M solution) and diethyl(3-pyridyl)borane (294 mg, 2 mmol) in dimethoxyethane (30 ml) was refluxed for 6 hr. The solvent was removed in vacuo, the residue dissolved in EtOAc (100 ml) and washed with water (30 ml) aqueous sodium thiosulphate (20 ml) and brine (30 ml) dried (Na2SO4)and evaporated in vacuo. Purification by column chromatography (SiO2, EtOAc/hexane 30:70) gave the title compound (335 mg,47%) as a yellow oil. δH (CDCl3) 8.81 (1 H, d, J 1.7 Hz, PyrH), 8.56 (1 H, dd, J 4.8, 1.6 Hz, PyrH), 7.84 (1 H, dt, J 7.9, 2.0 Hz, PyrH), 7.49 (2 H, d, J 8.2 Hz, ArH), 7.34 (1 H, ddd, J 7.9, 4.8, 0.6 Hz, PyrH), 7.23 (2 H, d, J 8.2 Hz, ArH), 5.09 (1 H, br d, J 7.8 Hz, CONH), 4.62 (1 H, br q, J 6.8 Hz, CHα), 3.73 (3 H, s, CO2Me), 3.18 (1 H, dd, J 13.8, 5.6 Hz, CHAHBAr), 3.07 (1 H, dd, J 13.8, 5.8 Hz, CHAHBAr) and 1.40 (9 H, s, tBu); m/z (ESI, 15 V) 357 (MH+). was refluxed for 6 hr The solvent was removed in vacuo the residue dissolved in EtOAc (100 ml) washed with water (30 ml) aqueous sodium thiosulphate (20 ml) and brine (30 ml) dried (Na2SO4)and evaporated in vacuo Purification by column chromatography (SiO2, EtOAc/hexane 30:70)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: PdCl2(dppf) (127 mg), triethylamine (2.14 ml), 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (1.13 ml) and 1,4-dioxane (21 ml) were added to methyl (2S)-2-[(t-butoxycarbonyl)amino]-3-(4-iodophenyl)propionate (1.8 g) and stirred at 100° C. for 14 hours. The reaction solution was diluted with ethyl acetate, washed with water and dried over magnesium sulfate to remove the solvent. The residue was purified with a silica gel chromatography (hexane-ethyl acetate) to obtain the title compound (1.05 g). washed with water dried over magnesium sulfate to remove the solvent The residue was purified with a silica gel chromatography (hexane-ethyl acetate)

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

Procedure: To a suspension of zinc dust (800 mmol, 52.29 g) in THF (26.0 mL) was added 1,2-dibromoethane (53.2 mmol, 4.58 mL) at room temperature. This suspension was heated to 60-65° C. with a heat gun until evolution of ethylene gas ceased (observed). The suspension was cooled to room temperature, trimethylchlorosilane (26.6 mmol, 3.38 mL) was added and the mixture was stirred for 15 min. A suspension of 5-iodo-1,3,6-trimethyl uracil (266 mmol, 74.6 g) in DMA (225 mL) was warmed to obtain a clear solution and was added in one portion to the reaction mixture. After addition, the mixture was heated to 70° C. The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction. The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride indicated the absence of starting material. The reaction mixture was diluted with THF (140 mL), was cooled to room temperature and the excess zinc dust was allowed to settle over 2-3 h. This solution containing the zinc compound (266 mmol) was added to a solution of Pd(dba)2 (8 mmol, 4.6 g), tri-o-tolylphosphine [P(Tol)3] (29.6 mmol, 9.0 g) and N-[(1,1-dimethylethoxy)carbonyl]-4-iodo-L-phenylalanine methyl ester (186 mmol, 75.56 g) in THF (280 mL) at room temperature and the light yellow mixture was stirred for 48 h at 50-55° C. The reaction mixture was poured into a saturated ammonium chloride solution and was extracted with ethyl acetate (3×750 mL). The combined extracts were washed with brine solution (1.5 L) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave the crude product which was purified by silica gel column chromatography using a Biotage (75m) column to obtain 57.88 g (72% yield) of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. EI-HRMS m/e calcd for C22H29N3O6 (M+) 431.2056, found 431.2054. was warmed to obtain a clear solution was added in one portion to the reaction mixture After addition the mixture was heated to 70° C The internal temperature of the reaction mixture rose to 80-85° C. due to the exothermic reaction The reaction mixture was stirred at 70° C. for 3-4 h at which time TLC of an aliquot which had been quenched with saturated ammonium chloride The reaction mixture was diluted with THF (140 mL) was cooled to room temperature to settle over 2-3 h the light yellow mixture was stirred for 48 h at 50-55° C was extracted with ethyl acetate (3×750 mL) The combined extracts were washed with brine solution (1.5 L) dried over anhydrous magnesium sulfate Filtration of the drying agent and concentration gave the crude product which was purified by silica gel column chromatography