Ethylene → N-[(1,1-dimethylethoxyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester

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

1. temperaturewas warmed
2. dissolutiondissolution
3. additionwas added in one portion to the reaction mixture
4. additionAfter addition
5. temperaturethe mixture was heated to 70° C.
6. stirringwas stirred for 15 h, at which time the TLC analysis of an aliquot, which
7. customhad been quenched with saturated ammonium chloride solution
8. additionThe reaction mixture was diluted with THF (4 mL)
9. temperaturewas cooled to room temperature
10. customformed (˜3 h)
11. customThe above prepared solution
12. stirringthe light yellow mixture was stirred for 15 h at 50° C
13. extractionwas extracted with ethyl acetate (3×50 mL)
14. washThe combined extracts were washed with brine solution (150 mL)
15. dry with materialwere dried over anhydrous magnesium sulfate
16. filtrationFiltration of the drying agent and concentration
17. customgave the crude product which
18. customwas purified by silica gel chromatography on a Biotage (40 m) column

ORD record

ord-42a074ace21444e5a68e8f0b51b7f7a0

Source dataset

uspto-grants-2002_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06388084B1